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This report evaluates the training courses delivered under the contract OC/EFSA/SCER/2017/01 ‐ Lot 1. Within the period of January 2018 to February 2022 a total of 21 training courses were provided, eight on‐site training courses in Parma at EFSA, six virtual training courses during the Covid‐19 pandemic and seven eLearning courses comprising various numbers of modules. The courses covered different aspects of chemical and biological risk assessment and related tools, namely i) harmonisation of risk assessment methodologies for human health and ecological risk assessment of combined exposure to multiple chemicals (mixture assessment), ii) risk assessment of the application of nanoscience and nanotechnologies in agro/food/feed (nanotoxicity); iii) science‐based criteria for identifying endocrine disruptors in the context of EU legislation on pesticides and biocides (endocrine disruption); iv) principles on genotoxicity on scientific assessment (genotoxicity) and v) computational toxicology approaches and tools (in silico). All tutors were experts in their field and had previously performed training courses on these topics. The target participants of the training courses were members of EFSA’s Scientific Committee/Panels and their working groups as well as employees from national and international regulatory agencies associated with risk assessment of feed and food compounds. Members of the EFSA Networks as well as EFSA scientific staff also participated in the training courses. Courses were evaluated based on the feedback of participants and continuously improved also by integrating updated or new EFSA guidance documents.

Microbial transglutaminase from Streptomyces mobaraensis (mTG) has emerged as a useful biotechnological tool due to its ability to crosslink a side chain of glutamine and primary amines. To date, the substrate specificity of mTG is not fully understood, which poses an obvious challenge when mTG is used to address novel targets. To that end, a viable strategy providing an access to tailor-made transglutaminases is required. This work reports an ultrahigh-throughput screening approach based on yeast surface display and fluorescence-activated cell sorting (FACS) that enabled the evolution of microbial transglutaminase towards enhanced activity. Five rounds of FACS screening followed by recombinant expression of the most potent variants in E. coli yielded variants that possessed, compared to the wild type enzyme, improved enzymatic performance and labeling behavior upon conjugation with an engineered therapeutic anti-HER2 antibody. This robust and generally applicable platform enables tailoring of the catalytic efficiency of mTG.

Identifying someone else's noncooperative intentions can prevent exploitation in social interactions. Hence, the inference of another person's mental state might be most pronounced in order to improve social decision‐making. Here, we tested the hypothesis that brain regions associated with Theory of Mind (ToM), particularly the right temporo–parietal junction (rTPJ), show higher neural responses when interacting with a selfish person and that the rTPJ‐activity as well as cooperative tendencies will change over time. We used functional magnetic resonance imaging (fMRI) and a modified prisoner's dilemma game in which 20 participants interacted with three fictive playing partners who behaved according to stable strategies either competitively, cooperatively or randomly during seven interaction blocks. The rTPJ and the posterior–medial prefrontal cortex showed higher activity during the interaction with a competitive compared with a cooperative playing partner. Only the rTPJ showed a high response during an early interaction phase, which preceded participants increase in defective decisions. Enhanced functional connectivity between the rTPJ and the left hippocampus suggests that social cognition and learning processes co‐occur when behavioral adaptation seems beneficial.

A novel reaction based on synergistic catalysis, combining palladium- and organocatalysis has been developed. The palladium catalyst activates vinyl benzoxazinanones via a decarboxylation to undergo a [4+2] cycloaddition with iminium-ion activated α,β-unsaturated aldehydes. The reaction is demonstrated to proceed for a number of combinations of vinyl benzoxazinanones reacting with α,β-unsaturated aldehydes, providing highly substituted vinyl tetrahydroquinolines in good to high yields, and excellent enantio- and diastereoselectivities (>98 % ee and >20:1 d.r.). The palladium catalyst used in the synergistic catalysis can be re-used in a one-pot sequential coupling reaction with an aromatic boronic acid forming the coupling product in 95 % yield, >20:1 d.r. and 99 % ee.

Smart capillary suspensions are used to fabricate macroporous solids with unique features regarding porosity and mechanical strength from a wide range of materials, including carbon layers and polyethylene membranes, even if sintering or high-temperature treatment is not feasible. High-strength porous ceramics are obtained, tailoring neck and pore shape via controlled deposition of fine particles at the sintering necks.

BACKGROUND: To evaluate health benefits attributed to Hibiscus sabdariffa L. a randomized, open-label, two-way crossover study was undertaken to compare the impact of an aqueous H. sabdariffa L. extract (HSE) on the systemic antioxidant potential (AOP; assayed by ferric reducing antioxidant power (FRAP)) with a reference treatment (water) in eight healthy volunteers. The biokinetic variables were the areas under the curve (AUC) of plasma FRAP, ascorbic acid and urate that are above the pre-dose concentration, and the amounts excreted into urine within 24 h (Ae0–24) of antioxidants as assayed by FRAP, ascorbic acid, uric acid, malondialdehyde (biomarker for oxidative stress), and hippuric acid (metabolite and potential biomarker for total polyphenol intake). RESULTS: HSE caused significantly higher plasma AUC of FRAP, an increase in Ae0–24 of FRAP, ascorbic acid and hippuric acid, whereas malondialdehyde excretion was reduced. Furthermore, the main hibiscus anthocyanins as well as one glucuronide conjugate could be quantified in the volunteers' urine (0.02% of the administered dose). CONCLUSION: The aqueous HSE investigated in this study enhanced the systemic AOP and reduced the oxidative stress in humans. Furthermore, the increased urinary hippuric acid excretion after HSE consumption indicates a high biotransformation of the ingested HSE polyphenols, most likely caused by the colonic microbiota. Copyright © 2012 Society of Chemical Industry

Various foods of plant and animal origin contain riboflavin or vitamin B2. Major sources are protein-rich foods, such as milk and dairy products, and also meat products. Riboflavin occurs in foods in free form or bound in the flavins FMN (fla- vin mononucleotide) and FAD (flavin adenine dinucleotide). A complete analysis of riboflavin needs combined extraction with dilute mineral acids and enzymatic hydrolysis. In milk and dairy products, free riboflavin is the main component. For the simultaneous determination of flavins plus free riboflavin, extraction with methanol and dichloromethane followed by partitioning with citrate buffer, pH 5.5, or by using dilute formic acid containing 2 mol l−1 urea is practicable. The high- performance liquid chromatographic separation of riboflavin and flavins is mainly carried out by using reversed-phase (RP) C18 columns and in most cases by isocrat- ic elution with mobile phases based on acidified methanol–water or acetonitrile followed by fluorimetric detection (λex = 444 nm; λem = 530–565 nm). Quantifica- tion of the extracted riboflavin after irradiation to lumiflavin and fluorescence de- tection is rarely practiced. riboflavin, vitamin B2, flavins, high-performance liquid chromatography, fluorimetric detection

Bitsch, J. and Bitsch, C. 2010. The tritocerebrum and the clypeolabrum in mandibulate arthropods: segmental interpretations. —Acta Zoologica (Stockholm) 91: 249–266 Different interpretations of the segmental composition of the head in mandibulate arthropods are critically reviewed, with particular focus on three closely associated structures: the tritocerebrum, the stomatogastric nervous system and the clypeolabrum. The main conclusions arising from the different discussions are the following. (1) Each tritocerebral ganglion has a dual composition, clearly discernable in some crustacean and hexapod species, including a dorsal portion connected with the second antennae and a ventral portion connected with the stomatogastric nervous system via the frontal ganglion. (2) The suboesophageal commissure linking the tritocerebral lobes of the two sides, can be wholly ascribed to the tritocerebral segment. (3) The stomatogastric nervous system is a morphologically autonomous system that is not fundamentally affected by head metamerization. (4) The clypeolabrum, the epistome–labrum and the hypostome are regarded as homologous formations. The clypeolabrum represents a fundamental structure of the head probably present in the arthropod ground plan. Its close spatial and developmental association with the stomodeum and its derivative, the stomatogastric nervous system, suggests that it is an anterior outgrowth of the forehead arising from a preoral territory (presegmental acron or protocerebral–ocular region?) and secondarily connected with the tritocerebrum, rather than derived from a pair of reduced appendages.

Die Elektromobilitat und die Speicherung regenerativ erzeugter elektrischer Energie stellen hohe Anforderungen an die Leistung und Kosten von Li-Ionen-Zellen. Sie erfordern ein tiefgreifendes Verstandnis uber die Materialeigenschaften der Rohstoffe und die verfahrenstechnischen Prozesse zur Herstellung der Elektroden. Zahlreiche Parameter mussen in der Produktentwicklung und spateren Produktion gemessen und gesteuert werden, um gezielt spezifische Zelleigenschaften einzustellen und gleichzeitig das Verstandnis fur einen stabilen Fertigungsprozess zu etablieren. Electromobility and storage of renewable electrical energy set high demands on the performance and the costs of lithium-ion cells. For the production of electrodes a thorough understanding of raw materials and their processing is required. Numerous process parameters need to be monitored and controlled in the development and series production stages. This is essential for adjusting specific cell properties as well as for establishing a stable electrode production process.

The present paper is a critical review of data and hypotheses on the head segmental composition in chelicerates and in extinct non-mandibulate arthropods. It successively takes into account data from morphology and embryology, from the structure of the nervous system, from palaeontology and from developmental genetics. Discussion focuses on possible homologies between the head segments and appendages in arachnomorphs and those in mandibulates. The comparative anatomical and ontogenetic data, especially those concerning the central nervous system, its connections with the stomatogastric system, and head innervation, show many similarities between the head organization of chelicerates and that of mandibulates, and lead to conclusions that contradict some of the hypotheses deduced from recent studies on developmental biology, but favour more traditional views. In particular they support the presence of a deutocerebral segment in the head region of the ground pattern of arthropods and its loss in all extant chelicerates. They also support the homology of the cheliceral ganglia with the tritocerebral ganglia of mandibulates. The possible existence of a precheliceral segment and of a presegmental acron remains open to question.

In this paper we propose a reappraisal of the relationships between the basal hexapod lineages (the former ‘apterygote’ insects) and the other major groups of mandibulate arthropods. It results from a cladistic analysis including 72 characters based on external morphology, internal anatomy and development. Detailed comments are provided on the various characters used and the scoring of their states. The 35 terminal taxa include 12 hexapods (9 of which are basal ‘apterygote’ representatives), 7 myriapods, 13 crustaceans, and 3 chelicerates taken as outgroups. The results of our analyses are discussed in detail for each of the taxonomic groupings, and compared with those recently obtained by other authors using different approaches based on morphological, palaeontological, developmental or molecular sequence data. Our results support the monophyly of the Mandibulata, Crustacea, Atelocerata (Tracheata) and Hexapoda, but the assemblage of Myriapoda appears poorly supported. A close relationship between Crustacea and Hexapoda, as hypothesized by several authors, is not found in any of our analyses. Within Hexapoda, the Protura and the Collembola appear as independent clades, whereas the two unresolved dipluran taxa are grouped with the monophyletic Ectognatha (Archaeognatha, Zygentoma and Pterygota).

This article concerns the transformative potential of medical genomics for common disease research. We analysed 13 review articles in asthma research in the period 1999 to 2008. Our aim was to understand how genomics has emerged in this research field, and the attendant changes. Motivated by Lippman’s geneticisation thesis, we use the concept of an ‘innovation journey’ to trace how expectations of improved understanding, prevention, diagnosis and treatment structure a dynamic co-evolutionary process through which a genome-based discourse emerges. We show how the asthma researchers involved continuously struggle to define their contribution to asthma research, as well as to clinical practice. Along the way, the researchers propose changes to both the definition and the aetiological model of asthma, thus highlighting gene–gene and gene–environment interactions. It is, however, difficult to characterise this discourse as one of geneticisation. With increasing attention being given to epigenetics, metabolomics, proteomics and systems biology, the emerging picture suggests an important, but much less deterministic, role for genes

The phylogeny of the basal hexapods, the so-called apterygote insects, was studied using parsimony analysis procedures. Most analyses took into account 47 characters mainly based on external morphology, and 19 taxa including 14 apterygote representatives, 3 pterygotes and also 2 distantly related myriapods were used as outgroups. The binary and multistate characters are discussed in detail and treated as unordered and equally weighted. Other analyses were performed using a second data set in which 28 characters, based on internal anatomy and already used in a previous work (Bitsch & Bitsch 1998), were added to the first data set. This second matrix was restricted to 12 terminal taxa, the same as those of our previous work. The results of the different analyses are generally congruent. They strongly support the monophyly of several orders (Protura, Collembola, Archaeognatha) and of two groupings (Ectognatha, Dicondylia). Three other assemblages (Ellipura, Diplura, Entognatha) appear as parsimonious phylogenetic hypotheses, but they are never supported by the cladistical analyses and are based on a very small number of autapomorphies; so, the monophyly of each of them is not firmly established. Archaeognatha appears as the sister group of the Dicondylia. The three unresolved representatives of the Zygentoma are found as the sister group of the Pterygota. The results are discussed in the light of current concepts in hexapod phylogeny.

The response of individual HeLa cells to extracellularly produced singlet oxygen was examined. The spatial domain of singlet oxygen production was controlled using the combination of a membrane-impermeable Pd porphyrin-dendrimer, which served as a photosensitizer, and a focused laser, which served to localize the sensitized production of singlet oxygen. Cells in close proximity to the domain of singlet oxygen production showed morphological changes commonly associated with necrotic cell death. The elapsed postirradiation "waiting period" before necrosis became apparent depended on: (1) the distance between the cell membrane and the domain irradiated, (2) the incident laser fluence and, as such, the initial concentration of singlet oxygen produced and (3) the lifetime of singlet oxygen. The data imply that singlet oxygen plays a key role in this process of light-induced cell death. The approach of using extracellularly generated singlet oxygen to induce cell death can provide a solution to a problem that often limits mechanistic studies of intracellularly photosensitized cell death: it can be difficult to quantify the effective light dose, and hence singlet oxygen concentration, when using an intracellular photosensitizer.

The objectives were to determine the apparent energy digestibility of six pasture species frequently grazed by European wild boar (Sus scrofa L.) and to estimate the digestible energy (DE) consumption from pasture by grazing wild boar. Seven diets were prepared; a base diet (BD) which did not contain any pasture species, diets D1 to D5 which included 75% of the BD and 25% of the dried pasture species Lolium perenne (D1), Festuca arundinacea (D2), Agrostis capillaris (D3), Bromus staminius (D4) or Trifolium repens (D5) and D6 which contained 85% BD and 15% dried Plantago lanceolata. Seven purebred European wild boar (initial liveweight 24.4 ± 0.8 kg, average ± SEM) were given access to the diets following a Latin Square design. The animals received each diet for eight days, with faecal sampling on days 6, 7 and 8. The total apparent DE consumption from pasture by grazing wild boar was estimated using previously collected pasture consumption data from wild boar. The digestibility coefficients and DE contents of the pasture species ranged from 0.29 to 0.65, and 5.8 to 12.6 MJ/kg DM respectively, with L. perenne and P. lanceolata having the greatest digestibility coefficients and DE contents. The wild boar were estimated to satisfy between 52% and 142% of their maintenance energy requirements through pasture consumption. Grazing wild boar are able to utilise an important proportion of the energy present in pasture species.

The effects of reactor backmixing on the outcome of RAFT polymerizations are examined. The kinetic model for the RAFT reaction is based on the first principle of mass balances and the method of moments. Two reactor models were applied for the simulation of backmixing, i.e., a PFTR with loop and multiple CSTRs in series. The models predict the behavior of monomer conversion, molecular weights, their distributions as well as the polydispersities for various chain types at different levels of backmixing. Both models demonstrated that a significant impact of reactor backmixing on RAFT kinetics and polymer molecular weight development exists. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

In clinical outcome studies, small component sizes, female gender, femoral shape, focal bone defects, bad bone quality, and biomechanics have been associated with failures of resurfacing arthroplasties. We used a well-established experimental setup and human bone specimens to analyze the effects of bone density on cement fixation of femoral hip resurfacing components. Thirty-one fresh frozen femora were prepared for resurfacing using the original instruments. ASR™ resurfacing prostheses were implanted after dual-energy X-ray densitometer scans. Real-time measurements of pressure and temperature during implantation, analyses of cement penetration, and measurements of micro motions under torque application were performed. The associations of bone density and measurement data were examined calculating regression lines and multiple correlation coefficients; acceptability was tested with ANOVA. We found significant relations between bone density and micro motion, cement penetration, cement mantle thickness, cement pressure, and interface temperature. Mean bone density of the femora was 0.82 ± 0.13 g/cm2, t-score was −0.7 ± 1.0, and mean micro motion between bone and femoral resurfacing component was 17.5 ± 9.1 µm/Nm. The regression line between bone density and micro motion was equal to −56.7 × bone density + 63.8, R = 0.815 (p

Arterial blood lactate, pyruvate, plasma β-hydroxybutyrate and acetone have been followed in 12 patients with diabetic ketoacidosis during the initial 24-hour treatment period. In all cases the acidosis was fully explained by the accumulation of ketone bodies, and blood lactate and pyruvate never exceeded normal values. A slight rise was, however, observed in blood lactate in some patients during the treatment. Some possible explanations of this phenomenon are discussed. β-hydroxybutyrate was cleared from the plasma much faster than acetone, and the ratio between the ketone bodies was constantly changing during treatment of the acidosis.

Background: Aldosterone plays a detrimental role in the pathology of chronic heart failure. An important mechanism resides in its ability to evoke extensive fibrosis in the heart. However, the locations of the aldosterone interaction sites responsible for triggering cardiac fibrosis are puzzling. Extra-cardiac aldosterone actions are known to contribute to cardiac fibrosis but whether local cardiac aldosterone actions are involved is unclear. Aims: This study aimed to investigate whether local aldosterone actions contribute to cardiac fibrosis in vivo. Methods: Saline treated male Wistar rats were intravenously (systemically) or intrapericardially (locally) infused for 8 weeks with 75 or 750 ng/h aldosterone to monitor end point left ventricular epicardial collagen levels (histology). Results: Perivascular fibrosis was observed only at high dose aldosterone infusions and was not different for the administration routes. Regarding interstitial fibrosis however, clear differences between the administration routes were seen. Intrapericardial aldosterone infusions increased interstitial collagen levels 1.72× (P

Background and purpose: Interferon beta (IFNβ) preparations have some effect on the progressive phase of multiple sclerosis (MS). This limited effect might be partially because of a certain number of IFNβ non-responders. Myxovirus resistance protein A (MxA) – a marker of IFNβ bioactivity – was correlated with the clinical response during an uncontrolled trial, investigating the safety of IFNβ-1b in primary progressive (PPMS) patients. Methods: Twenty PPMS were treated with IFNβ-1b (s.c.) for 1 year. Blood samples were taken before and 1, 2, 3, 6, 9, 12, and 15 months after treatment initiation and MxA protein levels were measured. Patients were clinically evaluated by EDSS and the more sensitive Incapacity Status Scale (ISS) and stratified in a stable and a progressing group. Results: Using ISS criteria, 11 patients remained stable and nine patients progressed during treatment. The mean area under the curve of log MxA levels during treatment were significantly higher in stable than in progressing patients (10.87 vs. 5.99; P = 0.002). Conclusion: A good biological response to IFNβ might be associated with a better clinical effect of this drug and could be helpful in future clinical studies for early identification of treatment responders.

The resurgence of metal–metal bearings has renewed interest in hip resurfacing, but a paucity of information exists regarding femoral cementing technique. We developed a laboratory model in which 72 open-cell foam specimens were used to simulate bone. Analyses of two cement viscosities, two foam porosities, and six cementing techniques were performed: manual cement application only, manual application and filling of one quarter of the component with cement, filling of half of the component, manual application and half component filling, full component filling, and manual application and full component filling. For manual application, cement was pressurized into the foam by rolling the finger tips. For component filling, a defined quantity of cement was poured into the component before pressing it onto the foam. Specimens were cut into quarters, and cement penetration was quantified in seven areas: top, chamfer, wall, interior area, and proximal, medial, and distal stem. The manual technique showed a 3-mm thick, even cement penetration of the outer fixation surface (top = 26 ± 0 mm2, chamfer = 14.9 ± 0.2 mm2, wall = 55.6 ± 5.2 mm2). None of the other techniques showed a significantly higher penetration in these areas. Large differences were found between all techniques at the medial stem (27.7 ± 17.5 mm2, p

Background: Patients undergoing hip fracture surgery often experience acute post-operative cognitive dysfunction (APOCD). The pathogenesis of APOCD is probably multifactorial, and no single intervention has been successful in its prevention. No studies have investigated the incidence of APOCD after hip fracture surgery in an optimized, multimodal, peri-operative rehabilitation regimen. Methods: One hundred unselected hip fracture patients treated in a well-defined, optimized, multimodal, peri-operative rehabilitation regimen were included. Patients were tested upon admission and on the second, fourth and seventh post-operative days with the Mini Mental State Examination (MMSE) score. Results: Thirty-two per cent of patients developed a significant post-operative cognitive decline, which was associated with several pre-fracture patient characteristics, including age and cognitive function, but also the number of peri-operative transfusions. The development of APOCD was also associated with impaired post-operative rehabilitation and an increased length of stay. APOCD was associated with the development of a major medical complication in 35% of all patients. In 65% of patients developing APOCD without a concomitant medical complication, the only risk factors were cognitive level and regular anti-psychotic treatment. Conclusion: On the basis of current evidence, APOCD is prevalent amongst hip fracture patients despite multimodal intervention; future research should therefore focus on defining subgroups of hip fracture patients amenable to specific prophylactic or interventional measures against APOCD.

Background Recent reports on Achilles tendon lengthening (ATL) have documented rapid healing of chronic plantar neuropathic forefoot ulcers. Methods Sixty-eight patients with 75 ulcerated neuropathic feet (63 patients with diabetes with 69 ulcerated feet) underwent ATL and were retrospectively studied for chronic plantar ulceration in the forefoot and reduced dorsiflexion range of motion at the ankle. Median duration of ulcers was 48 months (range 11-84 months) in 16 forefoot amputation stumps and 11 months (range 3-84 months) for the rest of the patients. Results Healing of the ulcers was obtained in 68/75 feet (91%). At a median follow-up of 12 months (3-26 months), 4 had never healed, 5/10 recurrent ulcers and 6/11 transfer ulcers (localized to the heel) had not healed, that is, a healing rate of 60/75 (80%). Acute transfer ulcers to the heel occurred in 47% of patients with complete anaesthesia of the heel pad. Late heel ulceration occurred in 14% of those with extreme ankle dorsiflexion (>15 degrees). Failure to heal or ulcer recurrence occurred more frequently at dorsiflexion