Single-Nucleus and In Situ RNA-Sequencing Reveal Cell Topographies in the Human Pancreas.

BACKGROUND & AIMS: Molecular evidence of cellular heterogeneity in the human exocrine pancreas has not been yet established because of the local concentration and cascade of hydrolytic enzymes that can rapidly degrade cells and RNA upon pancreatic resection. We sought to better understand the heterogeneity and cellular composition of the pancreas in neonates and adults in healthy and diseased conditions using single-cell sequencing approaches. METHODS: We innovated single-nucleus RNA-sequencing protocols and profiled more than 120,000 cells from pancreata of adult and neonatal human donors. We validated the single-nucleus findings using RNA fluorescence in situ hybridization, in situ sequencing, and computational approaches. RESULTS: We created the first comprehensive atlas of human pancreas cells including epithelial and nonepithelial constituents, and uncovered 3 distinct acinar cell types, with possible implications for homeostatic and inflammatory processes of the pancreas. The comparison with neonatal single-nucleus sequencing data showed a different cellular composition of the endocrine tissue, highlighting the tissue dynamics occurring during development. By applying spatial cartography, involving cell proximity mapping through in situ sequencing, we found evidence of specific cell type neighborhoods, dynamic topographies in the endocrine and exocrine pancreas, and principles of morphologic organization of the organ. Furthermore, similar analyses in chronic pancreatitis biopsy samples showed the presence of acinar-REG+ cells, a reciprocal association between macrophages and activated stellate cells, and a new potential role of tuft cells in this disease. CONCLUSIONS: Our human pancreas cell atlas can be interrogated to understand pancreatic cell biology and provides a crucial reference set for comparisons with diseased tissue samples to map the cellular foundations of pancreatic diseases.

Long-term COVID symptoms, work ability and fitness to work in healthcare workers hospitalized for Sars-CoV-2 infection.

BACKGROUND: COVID-19 can affect the persistence of symptoms and work ability (WA), hence the fitness to work of healthcare workers (HCW). We describe the effects of COVID-19 in hospitalized HCWs of a large Hospital in Lombardy and their implications on WA and fitness to work. METHODS: Fifty-six HCWs of Fatebenefratelli-Sacco Hospital have been hospitalized for COVID-19 since March 2020. Clinical and fitness-to-work data were acquired from Occupational Health Surveillance Program. A structured questionnaire was administered to 53/56 HCWs 18 months after infection to investigate Long-COVID symptoms and WA. RESULTS: Symptoms most reported at recovery (rhino-pharyngeal swab-NPS-negative) were exertional dyspnea (86.8%), asthenia (86.8%), arthro-myalgia (71.7%), sleep disorders (64.2%), resting dyspnea (62.3%), cough (56.6%). 69.6% underwent evaluation at out-patient clinics experienced in Long-COVID. Ten months after recovery, symptoms related to physical well-being decreased while memory and anxiety/depression were more persistent. At recovery, the WA score decreased from 10 to 8, and then an improvement from 8 to 9 was noted during the survey. At the return-to-work examination, fit-to-work judgements with restrictions increased from 31.4% to 58.7%; then, a slight decrease in the rate of judgements with restrictions was observed at the survey's time. CONCLUSION: Post-COVID-19 symptoms can persist for a long time and could impact WA and fitness-to-work of HCW. Adequate health surveillance protocols should guarantee the health protection of HCW with persistent disorders after COVID-19.

Mapping transcription factor occupancy using minimal numbers of cells in vitro and in vivo.

The identification of transcription factor (TF) binding sites in the genome is critical to understanding gene regulatory networks (GRNs). While ChIP-seq is commonly used to identify TF targets, it requires specific ChIP-grade antibodies and high cell numbers, often limiting its applicability. DNA adenine methyltransferase identification (DamID), developed and widely used in Drosophila, is a distinct technology to investigate protein-DNA interactions. Unlike ChIP-seq, it does not require antibodies, precipitation steps, or chemical protein-DNA crosslinking, but to date it has been seldom used in mammalian cells due to technical limitations. Here we describe an optimized DamID method coupled with next-generation sequencing (DamID-seq) in mouse cells and demonstrate the identification of the binding sites of two TFs, POU5F1 (also known as OCT4) and SOX2, in as few as 1000 embryonic stem cells (ESCs) and neural stem cells (NSCs), respectively. Furthermore, we have applied this technique in vivo for the first time in mammals. POU5F1 DamID-seq in the gastrulating mouse embryo at 7.5 d post coitum (dpc) successfully identified multiple POU5F1 binding sites proximal to genes involved in embryo development, neural tube formation, and mesoderm-cardiac tissue development, consistent with the pivotal role of this TF in post-implantation embryo. This technology paves the way to unprecedented investigation of TF-DNA interactions and GRNs in specific cell types of limited availability in mammals, including in vivo samples.

Exposure to PFOA and PFOS and fetal growth: a critical merging of toxicological and epidemiological data.

Toxicological and epidemiological evidence on the association between perfluorooctanoic acid (PFOA) or perfluorooctane sulfonic acid (PFOS) and birth/fetal weight was assessed. An extensive search for toxicological information in rats and mice, and a systematic search for epidemiological evidence were conducted. The linear regression coefficient (LRC) of birth weight (BrthW) on PFOA/PFOS was considered, and separate random effects meta-analyses for untransformed (i.e. not mathematically transformed) and log-transformed values were performed. Toxicological evidence: PFOA: 12 studies (21 datasets) in mice showed statistically significant lower birth/fetal weights from 5 mg/kg body weight per day. PFOS: most of the 13 studies (19 datasets) showed lower birth/fetal weights following in utero exposure. Epidemiological evidence: Sixteen articles were considered. The pooled LRC for a 1 ng/mL increase in untransformed PFOA (12 studies) in maternal plasma/serum was -12.8 g (95% CI -23.2; 2.4), and -27.1 g (95% CI -50.6; -3.6) for an increase of 1 loge ng/mL PFOA (nine studies). The pooled LRC for untransformed PFOS (eight studies) was -0.92 g (95%CI -3.4; 1.6), and for an increase of 1 loge ng/mL was -46.1(95% CI -80.3; -11.9). No consistent pattern emerged for study location or timing of blood sampling. CONCLUSIONS: Epidemiological and toxicological evidence suggests that PFOA and PFOS elicit a decrease in BrthW both in humans and rodents. However, the effective animal extrapolated serum concentrations are 102-103 times higher than those in humans. Thus, there is no quantitative toxicological evidence to support the epidemiological association, thus reducing the biological plausibility of a causal relationship.

Assessment of the feed additive consisting of endo-1,4-beta-xylanase (produced with Trichoderma reesei MUCL 49755), endo-1,3(4)-beta-glucanase (produced with T. reesei MUCL 49754) and polygalacturonase (produced with Aspergillus fijiensis CBS 589.94) (AveMix® 02 CS) for weaned piglets for the renewal of its authorisation and for its extension of use to suckling piglets (AVEVE BV).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of the feed additive consisting of endo-1,4-beta-xylanase (produced with Trichoderma reesei MUCL 49755), endo-1,3(4)-beta-glucanase (produced with T. reesei MUCL 49754) and polygalacturonase (produced with Aspergillus fijiensis CBS 589.94) (AveMix® 02 CS/ AveMix® 02 CS L) as a zootechnical feed additive for weaned and suckling piglets. The additive is already authorised for use with weaned piglets. This scientific opinion concerns the request for the renewal of the authorisation of the additive for weaned piglets and the extension of use to suckling piglets. The applicant provided evidence that the additive currently in the market complies with the conditions of the authorisation. There was no new evidence that would lead the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) to reconsider its previous conclusions that the additive is safe for weaned piglets, the consumer and the environment under the authorised conditions of use. This conclusion applied also to the new target species (suckling piglets) for which a request for an extension of use was made. The additive in both formulations (powder and liquid) is not irritant to skin or eyes but should be considered a dermal and respiratory sensitiser. There was no need for assessing the efficacy of the additive in the context of the renewal of the authorisation for weaned piglets. The Panel concluded that the additive is efficacious in suckling piglets at 2140 XU, 1230 BGU and 46 PGLU/kg complete feed.

Safety and efficacy of a feed additive consisting of 6-phytase produced by Aspergillus oryzae DSM 33737 (HiPhorius™) for all poultry, all Suidae and all fin fish (DSM Nutritional Products Ltd).

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of 6-phytase produced by the genetically modified strain Aspergillus oryzae DSM 33737 (HiPhorius™ 10, 40, 20L and 50L) as a zootechnical feed additive for all poultry, all Suidae and all fin fish. The FEEDAP Panel concluded that the genetic modification of the production strain does not give rise to safety concerns. Based on the no observed adverse effect level identified in a subchronic oral toxicity study in rats, the additive was considered safe for all poultry, all Suidae and all fin fish at the proposed conditions of use. The Panel also concluded that the use of the product as a feed additive is of no concern for the consumers and the environment. The liquid formulations of the additive are not skin or eye irritants. The two solid ones are not skin irritants but are eye irritants. Owing to the lack of data, the Panel cannot conclude on the skin sensitisation of the final formulations of the additive. Due to the proteinaceous nature of the active substance (6-phytase), the additive is considered a respiratory sensitiser. The Panel concludes that the additive is efficacious when included in the diet of poultry for fattening or reared for laying/breeding, reproductive Suidae, and all fin fish. Due to the lack of sufficient data, the Panel could not conclude on the efficacy for laying and reproductive poultry and growing Suidae.

Characterization of a flexible a-Si:H detector for in vivo dosimetry in therapeutic x-ray beams.

BACKGROUND: The increasing use of complex and high dose-rate treatments in radiation therapy necessitates advanced detectors to provide accurate dosimetry. Rather than relying on pre-treatment quality assurance (QA) measurements alone, many countries are now mandating the use of in vivo dosimetry, whereby a dosimeter is placed on the surface of the patient during treatment. Ideally, in vivo detectors should be flexible to conform to a patient's irregular surfaces. PURPOSE: This study aims to characterize a novel hydrogenated amorphous silicon (a-Si:H) radiation detector for the dosimetry of therapeutic x-ray beams. The detectors are flexible as they are fabricated directly on a flexible polyimide (Kapton) substrate. METHODS: The potential of this technology for application as a real-time flexible detector is investigated through a combined dosimetric and flexibility study. Measurements of fundamental dosimetric quantities were obtained including output factor (OF), dose rate dependence (DPP), energy dependence, percentage depth dose (PDD), and angular dependence. The response of the a-Si:H detectors investigated in this study are benchmarked directly against commercially available ionization chambers and solid-state diodes currently employed for QA practices. RESULTS: The a-Si:H detectors exhibit remarkable dose linearities in the direct detection of kV and MV therapeutic x-rays, with calibrated sensitivities ranging from (0.580 ± 0.002) pC/cGy to (19.36 ± 0.10) pC/cGy as a function of detector thickness, area, and applied bias. Regarding dosimetry, the a-Si:H detectors accurately obtained OF measurements that parallel commercially available detector solutions. The PDD response closely matched the expected profile as predicted via Geant4 simulations, a PTW Farmer ionization chamber and a PTW ROOS chamber. The most significant variation in the PDD performance was 5.67%, observed at a depth of 3 mm for detectors operated unbiased. With an external bias, the discrepancy in PDD response from reference data was confined to ± 2.92% for all depths (surface to 250 mm) in water-equivalent plastic. Very little angular dependence is displayed between irradiations at angles of 0° and 180°, with the most significant variation being a 7.71% decrease in collected charge at a 110° relative angle of incidence. Energy dependence and dose per pulse dependence are also reported, with results in agreement with the literature. Most notably, the flexibility of a-Si:H detectors was quantified for sample bending up to a radius of curvature of 7.98 mm, where the recorded photosensitivity degraded by (-4.9 ± 0.6)% of the initial device response when flat. It is essential to mention that this small bending radius is unlikely during in vivo patient dosimetry. In a more realistic scenario, with a bending radius of 15-20 mm, the variation in detector response remained within ± 4%. After substantial bending, the detector's photosensitivity when returned to a flat condition was (99.1 ± 0.5)% of the original response. CONCLUSIONS: This work successfully characterizes a flexible detector based on thin-film a-Si:H deposited on a Kapton substrate for applications in therapeutic x-ray dosimetry. The detectors exhibit dosimetric performances that parallel commercially available dosimeters, while also demonstrating excellent flexibility results.

Dosimetry of microbeam radiotherapy by flexible hydrogenated amorphous silicon detectors.

Objective.Detectors that can provide accurate dosimetry for microbeam radiation therapy (MRT) must possess intrinsic radiation hardness, a high dynamic range, and a micron-scale spatial resolution. In this work we characterize hydrogenated amorphous silicon detectors for MRT dosimetry, presenting a novel combination of flexible, ultra-thin and radiation-hard features.Approach.Two detectors are explored: an n-type/intrinsic/p-type planar diode (NIP) and an NIP with an additional charge selective layer (NIP + CSC).Results.The sensitivity of the NIP + CSC detector was greater than the NIP detector for all measurement conditions. At 1 V and 0 kGy under the 3T Cu-Cu synchrotron broadbeam, the NIP + CSC detector sensitivity of (7.76 ± 0.01) pC cGy-1outperformed the NIP detector sensitivity of (3.55 ± 0.23) pC cGy-1by 219%. The energy dependence of both detectors matches closely to the attenuation coefficient ratio of silicon against water. Radiation damage measurements of both detectors out to 40 kGy revealed a higher radiation tolerance in the NIP detector compared to the NIP + CSC (17.2% and 33.5% degradations, respectively). Percentage depth dose profiles matched the PTW microDiamond detector's performance to within ±6% for all beam filtrations except in 3T Al-Al due to energy dependence. The 3T Cu-Cu microbeam field profile was reconstructed and returned microbeam width and peak-to-peak values of (51 ± 1)µm and (405 ± 5)µm, respectively. The peak-to-valley dose ratio was measured as a function of depth and agrees within error to the values obtained with the PTW microDiamond. X-ray beam induced charge mapping of the detector revealed minimal dose perturbations from extra-cameral materials.Significance.The detectors are comparable to commercially available dosimeters for quality assurance in MRT. With added benefits of being micron-sized and possessing a flexible water-equivalent substrate, these detectors are attractive candidates for quality assurance,in-vivodosimetry and in-line beam monitoring for MRT and FLASH therapy.

Fluorescent recovery after photobleaching (FRAP) analysis of nuclear export rates identifies intrinsic features of nucleocytoplasmic transport.

A quantitative description of carrier-mediated nuclear export in live cells is presented. To this end, we fused a prototypical leucine-rich nuclear export signal (NES) to GFP as a cargo model and expressed the fluorescent chimera in live CHO-K1 cells. By modeling FRAP data, we calculate the NES affinity for the export machinery and the maximum rate of nuclear export achievable at saturation of endogenous carriers. The measured active-export time through the Nuclear Pore Complex (NPC) is 18 ms, remarkably similar to the previously determined active-import rate. Also, our results reveal that active export/import and active export/passive diffusion fluxes are uncoupled, thus complementing previous reports on active import/passive diffusion uncoupling. These findings suggest differential gating at the NPC level.

Exposure to environmental pollutants and attention-deficit/hyperactivity disorder: an overview of systematic reviews and meta-analyses.

Although heritability estimates suggest a role for genetic components, environmental risk factors have been described as relevant in the etiology of attention deficit/hyperactivity disorder (ADHD). Several studies have investigated the role of toxicological pollution, i.e., air pollution, heavy metals, POPs, and phthalates. Clear evidence for association of ADHD and environmental factors has not been provided yet. To answer this, we have assessed all available systematic reviews and meta-analyses that focused on the association between pollutant exposure and either ADHD diagnosis or symptoms. More than 1800 studies were screened of which 14 found eligible. We found evidence of a significant role for some pollutants, in particular heavy metals and phthalates, in the increased risk of developing ADHD symptoms. However, at the current stage, data from existing literature also do not allow to weight the role of the different environmental pollutants. We also offer a critical examination of the reviews/meta-analyses and provide indications for future studies in this field. PROSPERO registration: CRD42022341496.

Assessment of the feed additive consisting of niacinamide for all animal species for the renewal of its authorisation (Arxada Ltd).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the assessment of the application for renewal of niacinamide as a nutritional additive for use in all animal species. The applicant has provided evidence that the additive currently on the market complies with the existing conditions of authorisation. There is no new evidence that would lead the FEEDAP Panel to reconsider its previous conclusions. Thus, the Panel concludes that the additive remains safe for all animal species, consumers and the environment under the authorised conditions of use. Regarding user safety, the additive is not irritant to skin but irritant to eyes. It is not a dermal sensitiser. Exposure through inhalation is likely. There is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.

Assessment of the feed additive consisting of niacin (nicotinic acid) for all animal species for the renewal of its authorisation (Arxada Ltd).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the assessment of the application for renewal of niacin (nicotinic acid) as a nutritional additive for use in all animal species. The applicant has provided evidence that the additive currently on the market complies with the existing conditions of authorisation. There is no new evidence that would lead the FEEDAP Panel to reconsider its previous conclusions. Thus, the Panel concludes that the additive remains safe for all animal species, consumers and the environment under the authorised conditions of use. Regarding user safety, the additive is not irritant to skin but is irritant to eyes. It is not a dermal sensitiser. Exposure through inhalation is likely. There is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.

Safety of a feed additive consisting of sodium saccharin for suckling and weaned piglets, fattening pigs, calves for rearing and for fattening (FEFANA asbl).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety of sodium saccharin as a sensory feed additive (flavouring compound) for suckling and weaned piglets, fattening pigs, calves for rearing and for fattening. In a previous assessment, the Panel on Additives and Products or substances used in Animal Feed (FEEDAP Panel) could not conclude on the safety of the additive for the environment because concentrations of the additive or its degradation product 4-hydroxysaccharin in groundwater above 0.1 µg/L were likely to occur. In addition, regarding user safety, sodium saccharin was considered to be potentially harmful by inhalation or by contact to skin and eyes. In the current opinion, the applicant restricted the use to suckling and weaned piglets and up to a use level of 5 mg/kg complete feed. In relation to the user safety, the additive was neither a skin or eye irritant, nor a dermal sensitiser. In the absence of data, the FEEDAP Panel could not conclude on the potential of the additive to be toxic by inhalation. Regarding the safety of the additive for the environment, the new conditions of use describe a maximum use level of 5 mg sodium saccharin/kg feed. The applicant indicated that a restriction to a lower use level due to environmental safety would be accepted and submitted an environment risk assessment based on a use level of 1.13 mg sodium saccharin/kg feed. This use level cannot be considered safe. The estimated use level that would result in a concentration in groundwater below 0.1 µg/L is of 0.022 mg sodium saccharin/kg feed. The available data do not allow to conclude on the potential effect of the degradation product 4-hydroxysaccharin in ground water.

Safety and efficacy of a feed additive consisting of Streptococcus salivarius DSM 13084/ATCC BAA 1024 for dogs and cats (BLIS Technologies Limited).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of Streptococcus salivarius DSM 13084/ATCC BAA 1024 as a technological additive (functional group: acidity regulators) in feed for dogs and cats. The additive is intended for use at a proposed minimum concentration of 1 × 1011 CFU/l or kg liquid feed for dogs and cats. Due to the lack of adequate data, the FEEDAP Panel could not conclude on the safety of the additive for the target species. The additive was considered a respiratory sensitiser, but not irritant to skin. No conclusions could be drawn on the potential of the additive to be an eye irritant or a skin sensitiser. No environmental risk assessment is necessary for the use of the additive in feeds for pets. The Panel concluded that the additive has the potential to be efficacious in feeds for dogs and cats at the proposed conditions of use.

Safety and efficacy of a feed additive consisting of endo-1,4-ß-xylanase produced by Trichoderma citrinovirideDSM 34663 (Hostazym® X) for use in all poultry species, ornamental birds, all growing Suidae and carp (Huvepharma NV).

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of a feed additive containing endo-1,4-ß-xylanase produced by Trichoderma citrinoviride DSM 34663 (Hostazym® X). The product is authorised as a zootechnical additive (digestibility enhancers) for use in all poultry species for fattening, for laying and reared for laying, weaned piglets, pigs for fattening and carp. The current opinion concerns the request for the renewal of the authorisation for the use in those species/categories and the extension of use to all poultry species for breeding and reared for breeding, ornamental birds, suckling piglets and minor porcine species for fattening. The applicant provided evidence that the additive in the market complies with the conditions of the authorisation. There is no new evidence that would lead the Panel to reconsider previous conclusions that the additive is safe for the target species, the consumers and the environment under the authorised conditions of use. This conclusion also applies to the target species for which a request for extension of use is made. The additive is considered not a skin corrosive or skin sensitiser, but it is an eye irritant. The Panel cannot conclude on the potential of the additive to be a skin irritant. Due to the proteinaceous nature of the active substance, the additive is considered a respiratory sensitiser. The Panel considers that the additive has the potential to be efficacious in all poultry species, ornamental birds, all growing Suidae and carp at the proposed conditions of use.

Safety and efficacy of a feed additive consisting of ß-mannanase produced by Aspergillus nigerCBS 120604 (Nutrixtend Optim) for use in all poultry for fattening (Kerry Ingredients & Flavours Ltd).

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of a product containing ß-mannanase produced by a non-genetically modified strain of Aspergillus niger (CBS 120604). The commercial name is Nutrixtend Optim and it is intended to be used as a zootechnical feed additive for all poultry for fattening. Based on a tolerance trial in chickens for fattening and the no observed adverse effect level identified in a subchronic oral toxicity study in rats, the additive was considered safe for all poultry for fattening. The Panel concluded that the use of the product as a feed additive does not give rise to concerns for consumers and the environment. The additive is considered an irritant to skin and eyes and a dermal sensitiser. Due to the proteinaceous nature of the active substance, it is also considered a respiratory sensitiser. The Panel concludes that the additive has the potential to be efficacious as a zootechnical additive at the level of inclusion in feed of chickens for fattening of 30 U ß-mannanase/kg complete feed. This conclusion was extrapolated to all poultry for fattening.

Safety and efficacy of the feed additive Anpro consisting of a mixture of Sepiolite and Kieselguhr (diatomaceous earth) for all terrestrial animal species (Anpario plc).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of the mixture of Sepiolite and Kieselguhr (diatomaceous earth) (Anpro) as a technological feed additive for all terrestrial animal species. According to the conventional risk assessment, due to lack of adequate data, the safety of the additive Anpro for the target species cannot be established. Based on current knowledge, there is no indication of substantial absorption of the components of the additive and therefore no concern for the consumer. The additive poses a risk by inhalation. It is not irritant to the skin or eyes but should be considered as skin sensitiser. As no suitable data in line with the requirements of the Guidance on risk assessment of nanomaterials were provided by the applicant, the potential risks associated with the presence of nanoparticles could not be assessed for the target species, the consumer and the user. The additive is safe for the environment. The FEEDAP Panel is not in the position to conclude on the efficacy of the additive for all terrestrial animal species.

Hydrogenated amorphous silicon high flux x-ray detectors for synchrotron microbeam radiation therapy.

Objective. Microbeam radiation therapy (MRT) is an alternative emerging radiotherapy treatment modality which has demonstrated effective radioresistant tumour control while sparing surrounding healthy tissue in preclinical trials. This apparent selectivity is achieved through MRT combining ultra-high dose rates with micron-scale spatial fractionation of the delivered x-ray treatment field. Quality assurance dosimetry for MRT must therefore overcome a significant challenge, as detectors require both a high dynamic range and a high spatial resolution to perform accurately.Approach. In this work, a series of radiation hard a-Si:H diodes, with different thicknesses and carrier selective contact configurations, have been characterised for x-ray dosimetry and real-time beam monitoring applications in extremely high flux beamlines utilised for MRT at the Australian Synchrotron.Results. These devices displayed superior radiation hardness under constant high dose-rate irradiations on the order of 6000 Gy s-1, with a variation in response of 10% over a delivered dose range of approximately 600 kGy. Dose linearity of each detector to x-rays with a peak energy of 117 keV is reported, with sensitivities ranging from (2.74 ± 0.02) nC/Gy to (4.96 ± 0.02) nC/Gy. For detectors with 0.8µm thick active a-Si:H layer, their operation in an edge-on orientation allows for the reconstruction of micron-size beam profiles (microbeams). The microbeams, with a nominal full-width-half-max of 50µm and a peak-to-peak separation of 400µm, were reconstructed with extreme accuracy. The full-width-half-max was observed as 55 ± 1µm. Evaluation of the peak-to-valley dose ratio and dose-rate dependence of the devices, as well as an x-ray induced charge (XBIC) map of a single pixel is also reported.Significance. These devices based on novel a-Si:H technology possess a unique combination of accurate dosimetric performance and radiation resistance, making them an ideal candidate for x-ray dosimetry in high dose-rate environments such as FLASH and MRT.

Safety and efficacy of a feed additive consisting of endo-1,4-beta xylanase, endo-1,4-beta-glucanase and xyloglucan-specific-endo-beta-1,4-glucanase produced by Trichoderma citrinovirideDSM 33578 (Huvezym® neXo 100 G/L) for all poultry species, ornamental birds and piglets (weaned and suckling) (Huvepharma EOOD).

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of the product Huvezym® neXo 100 G/L containing an endo-1,4-beta xylanase, an endo-1,4-beta-glucanase and a xyloglucan-specific-endo-beta-1,4-glucanase produced by a non-genetically modified strain of Trichoderma citrinoviride (DSM 33578) as a zootechnical additive for feed in all poultry species, ornamental birds and piglets (weaned and suckling). The information regarding the production strain did not allow to confirm its taxonomic identification. The batches used for the characterisation of the final formulations showed compliance with the minimum specifications of the additive in terms of enzyme activities but showed ratios between the enzymes lower than the ones specified for the additive. The FEEDAP Panel considered that the below-described conclusions would apply to the final formulations of the additive as per specifications with xylanase:glucanase, xylanase:xyloglucanase and glucanase:xyloglucanase ratios of 15, 15 and 1, respectively. Based on the data available, the Panel concluded that the additive is safe for the target species, consumers and the environment. Huvezym® neXo 100 G (granulated form) is neither skin corrosive nor eye irritant but should be considered a potential skin sensitiser. Huvezym® neXo 100 L (liquid) is neither skin corrosive nor sensitising and it is not an eye irritant. Due to lack of data, no conclusions can be drawn on the skin irritation of the final formulations of the additive. Due to the proteinaceous nature of the active substances, the additive is considered a respiratory sensitiser. The FEEDAP Panel concluded that the additive has the potential to be efficacious in chickens for fattening, chickens reared for laying and breeding, and all growing poultry and ornamental birds at the minimum intended level of 1,500 EPU, 100 CU and 100 XGU/kg complete feed. Owing to the lack of sufficient data, the Panel could not conclude on the efficacy of the additive for laying hens and weaned piglets.

Safety and efficacy of a feed additive consisting of 6-phytase produced by Trichoderma reesei CBS 146250 (Axtra® PHY GOLD 30L, Axtra® PHY GOLD 30T, Axtra® PHY GOLD 65G) for all poultry species and all pigs (Danisco (UK) ltd).

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of 6-phytase produced by the genetically modified strain Trichoderma reesei CBS 146250 (Axtra® PHY GOLD 30L, Axtra® PHY GOLD 30 T and Axtra® PHY GOLD 65G) as a zootechnical feed additive for all poultry species and all pigs. The FEEDAP Panel concluded that the genetic modification of the production strain does not give rise to safety concerns. Based on the no observed adverse effect level identified in a subchronic oral toxicity study in rats, the additive was considered safe for all poultry species and all pigs at the proposed conditions of use. The Panel also concluded that the use of the product as a feed additive does not give rise to concerns for consumers and the environment. Owing to the lack of data obtained with the final formulations, the Panel cannot conclude on the potential of the additive to be irritant to eyes or skin. Due to the proteinaceous nature of the active substance, it is considered a respiratory sensitiser. The panel concludes that the additive is efficacious in increasing the phosphorus utilisation when supplemented at 500 FTU/kg for all growing poultry species and all pigs, and at 300 FTU/kg in laying hens and other laying birds.