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This European Academy of Allergy and Clinical Immunology (EAACI) guideline provides recommendations for the management of IgE-mediated food allergy and was developed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Following the confirmation of IgE-mediated food allergy diagnosis, allergen avoidance and dietary advice (with support of a specialised dietitian, if possible) together with the provision of a written treatment plan, education on the recognition of allergic symptoms and prescription of medication including adrenaline using an auto-injector are essential. Patients with significant anxiety and requirement for coping strategies may benefit from support from a clinical psychologist. As immunomodulatory interventions, omalizumab is suggested for treatment of IgE-mediated food allergy in children from the age of 1 and adults; and oral allergen-specific immunotherapy is recommended for children and adolescents with peanut allergy and suggested for milk and egg allergies (generally after 4 years of age for milk and egg). Sublingual and epicutaneous immunotherapy are suggested for peanut allergy but are not yet available at the point of care. Future research into disease modifying treatments for IgE-mediated food allergy are highly needed, with standardised and patient-focused protocols and outcomes., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The prevalence of asthma, rhinitis, and food allergies has increased dramatically over the last few decades. This increase originally started in western countries, but is now also evident in many other regions of the world. Given the fact that the increase is so quick, the noted increase cannot be linked to a genetic effect, and many environmental factors have been identified that are associated with increased or reduced prevalence of allergies, like changing dietary habits, increased urbanization, pollution, exposure to microorganisms and LPS, and the farming environment and raw milk consumption. Although the key role of allergen-specific IgE in allergies is well known, the role of allergen-specific IgG and IgA antibodies is less well defined. This review will provide an overview of the functions of allergen-specific IgE in allergy, the role of allergen-specific antibodies (IgG (4) and IgA) in allergen immunotherapy (AIT), the possibility to use allergen-specific antibodies for treatment of ongoing allergies, and the potential role of allergen-specific antibodies in tolerance induction to allergens in a preventive setting. In the last, more speculative, section we will present novel hypotheses on the potential role of allergen-specific non-IgE antibodies in allergies by directing antigen presentation, Th2 development, and innate immune training., (© 2024 The Author(s). Immunological Reviews published by John Wiley & Sons Ltd.)

Background: Immune system activation in the neonatal period is associated with white matter injury in preterm infants. In animal studies, neonatal priming of the immune system leads to chronic activation of i.e. microglia cells and altered neuroinflammatory responses potentially years after preterm birth. This may contribute further to brain injury and neurodevelopmental impairment. It is unknown to what extend this also occurs in human., Aim: To identify neuro-inflammatory markers at school age that relate to motor, cognitive and behavioral impairments in preterm born children in a pilot case-control study., Methods: We included n  = 20 preterm born children (GA < 28 weeks) in this study, of which n = 10 with motor, cognitive and behavorial impairments and n  = 10 preterm born controls next to n = 30 healthy adult controls. In the preterm children, at 8-9 years, 39 inflammatory markers were assessed by Luminex assay in blood serum samples. Firstly, the preterm concentrations of these markers were compared to n  = 30 adult controls. Then a univariate analysis was performed to determine differences in values between preterm children with and without impairment at school age. Finally, a principal component analysis and hierarchical clustering was performed to identify protein profiles in preterm born children that relate to impairment at school age., Results: Inflammatory proteins in preterm children at school age differed from values of adult controls. Within the group of preterm children, we found significantly higher levels of GM-CSF in preterms with impairment ( p  < 0.01) and a trend towards significance for Gal1 and TRAIL ( p  = 0.06 and p  = 0.06 respectively) when compared to preterms without impairment. In addition, differences in clustering of proteins between preterm children was observed, however this variance was not explained by presence of neurodevelopmental impairments., Conclusion: The inflammatory profile at school age in preterm children is different from that of adult controls. The immune modulating cytokines GM-CSF, Gal1 and TRAIL were higher in preterm children with impairment than control preterm children, suggesting that immune responses are altered in these children. No specific cluster of inflammatory markers could be identified. Results indicate that even at school age, neuroinflammatory pathways are activated in preterm born children with neurodevelopmental impairments., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Inc.)

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Most deleterious variants are recessive and segregate at relatively low frequency. Therefore, high sample sizes are required to identify these variants. In this study we report a large-scale sequence based genome-wide association study (GWAS) in pigs, with a total of 120,000 Large White and 80,000 Synthetic breed animals imputed to sequence using a reference population of approximately 1,100 whole genome sequenced pigs. We imputed over 20 million variants with high accuracies (R2>0.9) even for low frequency variants (1-5% minor allele frequency). This sequence-based analysis revealed a total of 14 additive and 9 non-additive significant quantitative trait loci (QTLs) for growth rate and backfat thickness. With the non-additive (recessive) model, we identified a deleterious missense SNP in the CDHR2 gene reducing growth rate and backfat in homozygous Large White animals. For the Synthetic breed, we revealed a QTL on chromosome 15 with a frameshift variant in the OBSL1 gene. This QTL has a major impact on both growth rate and backfat, resembling human 3M-syndrome 2 which is related to the same gene. With the additive model, we confirmed known QTLs on chromosomes 1 and 5 for both breeds, including variants in the MC4R and CCND2 genes. On chromosome 1, we disentangled a complex QTL region with multiple variants affecting both traits, harboring 4 independent QTLs in the span of 5 Mb. Together we present a large scale sequence-based association study that provides a key resource to scan for novel variants at high resolution for breeding and to further reduce the frequency of deleterious alleles at an early stage in the breeding program., Competing Interests: All authors declare that the results are presented in full and present no conflict of interest., (Copyright: © 2024 Boshove et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Antibody- and complement-mediated peripheral nerve inflammation are central in the pathogenesis of MMN. Here, we studied innate immune responses to endotoxin in patients with MMN and controls to further our understanding of MMN risk factors and disease modifiers., Methods: We stimulated whole blood of 52 patients with MMN and 24 controls with endotoxin and collected plasma. With a multiplex assay, we determined levels of the immunoregulating proteins IL-1RA, IL-1β, IL-6, IL-10, IL-21, TNF-α, IL-8 and CD40L in unstimulated and LPS-stimulated plasma. We compared baseline and stimulated protein levels between patients and controls and correlated concentrations to clinical parameters., Results: Protein level changes after stimulation were comparable between groups (p > 0.05). IL-1RA, IL-1β, IL-6 and IL-21 baseline concentrations showed a positive correlation with monthly IVIg dosage (all corrected p-values < 0.016). Patients with anti-GM1 IgM antibodies showed a more pronounced IL-21 increase after stimulation (p 0.048)., Conclusions: Altered endotoxin-induced innate immune responses are unlikely to be a susceptibility factor for MMN., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The genetic background of variability remains of interest especially in traits of high economic importance, e.g. litter size in pigs. It has been indicated that the data transformation can affect the variability phenotype. This study aims to evaluate the phenotypic and genomic background of variability of litter size obtained from data before and after the Box-Cox transformation. In total, 67 500 records on the total number born (TNB) in Landrace pig population were used. Since the data presented skewness, the decision was made to perform Box-Cox transformation on TNB and obtain bcTNB. Next, the phenotypic variability was estimated as log-transformed variance of residuals (LnVar) for both TNB (LnVar&#95;TNB) and bcTNB (LnVar&#95;bcTNB). The variability traits were further used in the genome-wide association study (GWAS) performed on 10 688 sows genotyped with Axiom porcine 660 K or imputed to 660 K SNP-chip. The substantial difference in skewness was observed after data transformation, represented as a change from -0.46 to -0.02. Heritability for TNB was 0.118 vs 0.125 for bcTNB. The heritability for LnVar&#95;TNB was 0.0025 vs 0.0037 for LnVar&#95;bcTNB. The change in the genetic variance was confirmed when genetic coefficients on SD level were compared: 2% for LnVar&#95;TNB vs 4% for LnVar&#95;bcTNB. In bivariate analysis, the genetic correlation between the additive genetic effects of the mean TNB and its variability changed from 0.38 to 0.63. The observed positive genetic correlations indicated that selection focused on increasing the litter size will simultaneously cause an increase in litter size variability. Based on GWAS, 14 SNPs were detected for LnVar&#95;TNB and eight for LnVar&#95;bcTNB, with two of them indicating the most promising candidate genes. First candidate gene located on Sus scrofa chromosome (SSC) 3 is STAG3, which plays an essential role in gametogenesis. Second gene located on SSC 10 is ESRRG, which affects placenta development. The additional post-GWAS analysis indicated even more candidate genes for LnVar&#95;TNB and LnVar&#95;bcTNB. The most promising candidate gene was located on SSC 13 - MFN1, which is involved in embryonic development. The results of this study indicated a substantial change in variance components for variability when the Box-Cox transformation was applied to data presenting skewness. Moreover, the data transformation changed the phenotype substantially enough that only part of SNP overlapped between two variability traits. Our investigation shows that it is essential to perform Box-Cox transformation for skewed data in order to properly describe phenotypic and genomic properties of litter size variability in Landrace pigs., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Pelvic organ prolapse (POP) is one contributor to recent increases in sow mortality that have been observed in some populations and environments, leading to financial losses and welfare concerns. Methods: With inconsistent previous reports, the objective here was to investigate the role of genetics on susceptibility to POP, using data on 30,429 purebred sows, of which 14,186 were genotyped (25K), collected from 2012 to 2022 in two US multiplier farms with a high POP incidence of 7.1% among culled and dead sows and ranging from 2% to 4% of all sows present by parity. Given the low incidence of POP for parities 1 and >6, only data from parities 2 to 6 were retained for analyses. Genetic analyses were conducted both across parities, using cull data (culled for POP versus another reason), and by parity, using farrowing data. (culled for POP versus culled for another reason or not culled). Results and Discussion: Estimates of heritability from univariate logit models on the underlying scale were 0.35 ± 0.02 for the across-parity analysis and ranged from 0.41 ± 0.03 in parity 2 to 0.15 ± 0.07 in parity 6 for the by-parity analyses. Estimates of genetic correlations of POP between parities based on bivariate linear models indicated a similar genetic basis of POP across parities but less similar with increasing distance between parities. Genome wide association analyses revealed six 1 Mb windows that explained more than 1% of the genetic variance in the across-parity data. Most regions were confirmed in several by-parity analyses. Functional analyses of the identified genomic regions showed a potential role of several genes on chromosomes 1, 3, 7, 10, 12, and 14 in susceptibility to POP, including the Estrogen Receptor gene. Gene set enrichment analyses showed that genomic regions that explained more variation for POP were enriched for several terms from custom transcriptome and gene ontology libraries. Conclusion: The influence of genetics on susceptibility to POP in this population and environment was confirmed and several candidate genes and biological processes were identified that can be targeted to better understand and mitigate the incidence of POP., Competing Interests: Co-authors TS, MFLD, JD, and EFK are employed by the company that provided the data (TopigsNorsvin). JCMD is involved in other research that is partially funded by TopigsNorsvin. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bhatia, Stevens, Derks, Dunkelberger, Knol, Ross and Dekkers.)

Preimplantation genetic testing for aneuploidy (PGT-A) is widespread, but controversial, in humans and improves pregnancy and live birth rates in cattle. In pigs, it presents a possible solution to improve in vitro embryo production (IVP), however, the incidence and origin of chromosomal errors remains under-explored. To address this, we used single nucleotide polymorphism (SNP)-based PGT-A algorithms in 101 in vivo-derived (IVD) and 64 IVP porcine embryos. More errors were observed in IVP vs. IVD blastocysts (79.7% vs. 13.6% p < 0.001). In IVD embryos, fewer errors were found at blastocyst stage compared to cleavage (4-cell) stage (13.6% vs. 40%, p = 0.056). One androgenetic and two parthenogenetic embryos were also identified. Triploidy was the most common error in IVD embryos (15.8%), but only observed at cleavage, not blastocyst stage, followed by whole chromosome aneuploidy (9.9%). In IVP blastocysts, 32.8% were parthenogenetic, 25.0% (hypo-)triploid, 12.5% aneuploid, and 9.4% haploid. Parthenogenetic blastocysts arose from just three out of ten sows, suggesting a possible donor effect. The high incidence of chromosomal abnormalities in general, but in IVP embryos in particular, suggests an explanation for the low success of porcine IVP. The approaches described provide a means of monitoring technical improvements and suggest future application of PGT-A might improve embryo transfer success.

The swine inflammation and necrosis syndrome (SINS) is a syndrome visually characterized by the presence of inflamed and necrotic skin at extreme body parts, such as the teats, tail, ears, and claw coronary bands. This syndrome is associated with several environmental causes, but knowledge of the role of genetics is still limited. Moreover, piglets affected by SINS are believed to be phenotypically more susceptible to chewing and biting behaviors from pen mates, which could cause a chronic reduction in their welfare throughout the production process. Our objectives were to 1) investigate the genetic basis of SINS expressed on piglets' different body parts and 2) estimate SINS genetic relationship with post-weaning skin damage and pre and post-weaning production traits. A total of 5,960 two to three-day-old piglets were scored for SINS on the teats, claws, tails, and ears as a binary phenotype. Later, those binary records were combined into a trait defined as TOTAL&#95;SINS. For TOTAL&#95;SINS, animals presenting no signs of SINS were scored as 1, whereas animals showing at least one affected part were scored as 2. Apart from SINS traits, piglets had their birth weight (BW) and weaning weight (WW) recorded, and up to 4,132 piglets were later evaluated for combined skin damage (CSD), carcass backfat (BF), and loin depth (LOD). In the first set of analyses, the heritability of SINS on different body parts was estimated with single-trait animal-maternal models, and pairwise genetic correlations between body parts were obtained from two-trait models. Later, we used four three-trait animal models with TOTAL&#95;SINS, CSD, and an alternative production trait (i.e., BW, WW, LOD, BF) to access trait heritabilities and genetic correlations between SINS and production traits. The maternal effect was included in the BW, WW, and TOTAL&#95;SINS models. The direct heritability of SINS on different body parts ranged from 0.08 to 0.34, indicating that reducing SINS incidence through genetic selection is feasible. The direct genetic correlation between TOTAL&#95;SINS and pre-weaning growth traits (BW and WW) was favorable and negative (from -0.40 to -0.30), indicating that selection for animals genetically less prone to present signs of SINS will positively affect the piglet's genetics for heavier weight at birth and weaning. The genetic correlations between TOTAL&#95;SINS and BF and between TOTAL&#95;SINS and LOD were weak or not significant (-0.16 to 0.05). However, the selection against SINS was shown to be genetically correlated with CSD, with estimates ranging from 0.19 to 0.50. That means that piglets genetically less likely to present SINS signs are also more unlikely to suffer CSD after weaning, having a long-term increase in their welfare throughout the production system., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Spinal muscular atrophy (SMA) is a progressive motor neuron disease with onset during infancy or early childhood. Recent therapeutic advances targeting the genetic defect that underlies SMA improved survival in patients with infantile onset SMA (type 1) and improved motor function in SMA type 1-3. The most commonly used therapy for SMA, the antisense oligonucleotide nusinersen, is delivered by repeated intrathecal injections. The long-term safety effects of this procedure, however, have not yet been investigated in detail. We here present case reports of three children with SMA in which routine laboratory investigation revealed increased leukocyte counts in cerebrospinal fluid (CSF) collected during the course of nusinersen treatment. To further characterize this observation, we used a multiplex method to analyse a broad spectrum of inflammatory markers in the CSF of these patients. We found that interleukin-10 (IL10) was consistently elevated in CSF with increased leukocyte counts, but other inflammatory markers were not. Based on this analysis we selected 7 markers for further analysis in a cohort of 38 children with SMA and determined their expression during the course of nusinersen therapy. No consistent association was found between levels of inflammatory markers and the duration of nusinersen therapy in individual patients. However, monocyte chemoactive protein 1 (MCP1/CCL2) -a neuroprotective protein secreted by astrocytes and previously associated with SMA- levels increased over the course of nusinersen treatment, indicating a possible neuroprotective mechanism associated with nusinersen therapy. In summary, our findings confirm that repeated intrathecal injections are safe and do not trigger unwanted immune responses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

In livestock, mortality in general, and mortality of the young, is societal worries and is economically relevant for farm efficiency. Genetic change is cumulative; if it exists for survival of the young and genetic merit can be estimated with sufficient accuracy, it can help alleviate the pressure of mortality. Lack of survival is a moving target; livestock production is in continuous change and labor shortage is a given. There is now ample evidence of clear genetic variance and of models able to provide genomic predictions with enough accuracy for selection response. Underlying traits such as birth weight, uniformity in birth weight, gestation length, number of teats, and farrowing duration all show genetic variation and support selection for survival or, alternatively, be selected for on their own merit., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Background: Component-resolved diagnostics (CRD) help predict hazelnut allergy (HA) in children, but are of unknown diagnostic value in adults. This study aimed to evaluate the diagnostic accuracy of IgE to hazelnut extract and components in adults., Methods: A Dutch population of consecutively presenting adults suspected of HA, who underwent a double-blind placebo-controlled food challenge, were included. Serum IgE to hazelnut extract and Cor a 1, 8, 9, and 14 was measured on ImmunoCAP. Diagnostic accuracy was assessed by area under the curve (AUC) analysis., Results: Of 89 patients undergoing challenge, 46 had challenge-confirmed HA: 17 based on objective and 29 based on subjective symptoms. At commonly applied cutoffs 0.1 and 0.35 kU A /L, high sensitivity was observed for IgE to hazelnut extract and Cor a 1 (range 85-91%), and high specificity for IgE to Cor a 8, 9 and 14 (range 77-95%). However, the AUCs for hazelnut extract and components were too low for accurate prediction of HA (range 0.50-0.56). Combining hazelnut extract and component IgE measurements did not significantly improve accuracy. Higher IgE levels to Cor a 9 and 14 were tentatively associated with HA with objective symptoms, but the corresponding AUCs still only reached 0.68 and 0.63, respectively., Conclusions: Although hazelnut allergic adults are generally sensitized to hazelnut extract and Cor a 1, and hazelnut tolerant adults are usually not sensitized to Cor a 8, 9, or 14, challenge testing is still needed to accurately discriminate between presence and absence of HA in adults from a birch-endemic country., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Little is known about the impact of social and environmental enrichment on improving livestock resilience, i.e. the ability to quickly recover from perturbations. We evaluated the effect of an alternative housing system (AHS) on resilience of pigs, as compared to conventional housing (CONV). The AHS consisted of multi-litter housing during lactation, delayed weaning, extra space allowance and environmental enrichment at all times. We assessed recovery to a 2 h-transport challenge, an LPS injection, 2 h-heat stress and a biopsy wound in 96 pigs. Additionally, indicators of long-term "wear and tear" on the body were determined. AHS pigs had better physiological recoveries with quicker returns to baseline in the transport and LPS challenges, showed lower cortisol accumulation in hairs and lower variance in weight gain over the experimental period compared to conventionally-housed (CONV) pigs. They also had higher levels of natural antibodies binding KLH than CONV pigs. Their response to heat stress revealed a different strategy compared to CONV pigs. Taken together, AHS pigs appear to be more resilient and experience less chronic stress. Enhancing welfare by provision of social and environmental enrichment that better meets the behavioural needs of pigs seems to be a promising approach to improve their resilience., (© 2022. The Author(s).)

Improving welfare is still a critical issue in pig husbandry. Upgrades of the housing environment seem to be a promising solution to optimise resilience as a whole, and therefore improve animal welfare. The objective of this study was to evaluate the effect of an alternative housing system to enhance cognitive resilience and also to promote the pigs' welfare. A total of 96 piglets from two contrasted housing systems [alternative housing system (AHS) vs. conventional system (CONV)] was used. The major upgrades of the alternative system were multi-litter housing during lactation, delayed weaning, extra space allowance, and environmental enrichment from birth onwards. To estimate welfare, weight, and feed intake (as a general indicator of performances), the tear staining area (as a chronic stress indicator), behavioural postures, heart rate traits, and saliva cortisol concentration were measured over a 21 h-isolation. To assess cognitive resilience, the pigs were subjected to a maze with a social reward both before and after the isolation challenge and indicators of cognitive abilities were followed. The AHS pigs showed lower cortisol levels and tear staining area before the challenge, demonstrating overall better welfare due to the alternative housing conditions. During the challenge, AHS pigs had a lower heart rate, higher heart rate variability, and higher vagal activity than the CONV pigs, which might indicate a reduced sensitivity to the stressor. AHS pigs appeared to have a better long-term memory tested in a maze. Providing social and environmental enrichments, that fit the satisfaction of the essential needs of the pigs better, appears to be beneficial for pig welfare as a whole. Its effects on cognitive resilience still need to be proven., Competing Interests: EK was employed by Topigs Norsvin Research Center. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Parois, Van Der Zande, Knol, Kemp, Rodenburg and Bolhuis.)

Resilience, the capacity of animals to be minimally affected by a disturbance or to rapidly bounce back to the state before the challenge, may be improved by enrichment, but negatively impacted by a high allostatic load from stressful management procedures in pigs. We investigated the combined effects of diverging environmental conditions from weaning and repeated mixing to create high allostatic load on resilience of pigs. Pigs were either exposed to barren housing conditions (B) from weaning onwards or provided with sawdust, extra toys, regular access to a "play arena" and daily positive human contact (E). Half of the pigs were exposed to repeated mixing (RM) and the other half to one mixing only at weaning (minimal mixing, MM). To assess their resilience, the response to and recovery from a lipopolysaccharide (LPS) sickness challenge and a Frustration challenge were studied. In addition, potential long-term resilience indicators, i.e. natural antibodies, hair cortisol and growth were measured. Some indications of more favorable responses to the challenges in E pigs were found, such as lower serum reactive oxygen metabolite (dROM) concentrations and a smaller area under the curve of dROM after LPS injection. In the Frustration challenge, E pigs showed less standing alert, escape behaviors and other negative behaviors, a tendency for a smaller area under the curve of salivary cortisol and a lower plasma cortisol level at 1 h after the challenge. Aggression did not decrease over mixings in RM pigs and was higher in B pigs than in E pigs. Repeated mixing did not seem to reduce resilience. Contrary to expectations, RM pigs showed a higher relative growth than MM pigs during the experiment, especially in the week of the challenges. Barren RM pigs showed a lower plasma cortisol concentration than barren MM pigs after the LPS challenge, which may suggest that those RM pigs responded less detrimentally than MM pigs. Enriched RM pigs showed a higher level of IgM antibodies binding keyhole limpet hemocyanin (KLH) than enriched MM and barren RM pigs, and RM pigs showed a sharper decline in IgG antibodies binding Bovine Serum Albumin (PC-BSA) over time than MM pigs. Hair cortisol concentrations were not affected by enrichment or mixing. To conclude, enrichment did not enhance the speed of recovery from challenges in pigs, although there were indications of reduced stress. Repeated as opposed to single mixing did not seem to aggravate the negative effects of barren housing on resilience and for some parameters even seemed to reduce the negative effects of barren housing., Competing Interests: EK was employed by Topigs Norsvin. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Luo, Zande, Marwijk, Knol, Rodenburg, Bolhuis and Parois.)

Background: The genetic background of trait variability has captured the interest of ecologists and animal breeders because the genes that control it could be involved in buffering various environmental effects. Phenotypic variability of a given trait can be assessed by studying the heterogeneity of the residual variance, and the quantitative trait loci (QTL) that are involved in the control of this variability are described as variance QTL (vQTL). This study focuses on litter size (total number born, TNB) and its variability in a Large White pig population. The variability of TNB was evaluated either using a simple method, i.e. analysis of the log-transformed variance of residuals (LnVar), or the more complex double hierarchical generalized linear model (DHGLM). We also performed a single-SNP (single nucleotide polymorphism) genome-wide association study (GWAS). To our knowledge, this is only the second study that reports vQTL for litter size in pigs and the first one that shows GWAS results when using two methods to evaluate variability of TNB: LnVar and DHGLM., Results: Based on LnVar, three candidate vQTL regions were detected, on Sus scrofa chromosomes (SSC) 1, 7, and 18, which comprised 18 SNPs. Based on the DHGLM, three candidate vQTL regions were detected, i.e. two on SSC7 and one on SSC11, which comprised 32 SNPs. Only one candidate vQTL region overlapped between the two methods, on SSC7, which also contained the most significant SNP. Within this vQTL region, two candidate genes were identified, ADGRF1, which is involved in neurodevelopment of the brain, and ADGRF5, which is involved in the function of the respiratory system and in vascularization. The correlation between estimated breeding values based on the two methods was 0.86. Three-fold cross-validation indicated that DHGLM yielded EBV that were much more accurate and had better prediction of missing observations than LnVar., Conclusions: The results indicated that the LnVar and DHGLM methods resulted in genetically different traits. Based on their validation, we recommend the use of DHGLM over the simpler method of log-transformed variance of residuals. These conclusions can be useful for future studies on the evaluation of the variability of any trait in any species., (© 2021. The Author(s).)

Hypersensitivity reactions are overreactions of the immune system clinically seen as allergic and autoimmune diseases. Gell and Coombs originally described four different types of hypersensitivity reactions almost 60 years ago, and their description still applies in large parts. However, some modifications and extensions have been included in original definition. Especially in allergic diseases, it became clear that often, multiple types of hypersensitivity reaction can occur simultaneously. This improved insight is not only important for a better understanding of hypersensitivity disorders, but is especially of importance for improved diagnostics and directing therapeutic interventions., (© 2021. Springer Nature Switzerland AG.)

Including Indirect Genetic Effects (IGE) in breeding programs to reduce aggression in group housed animals has been proposed. However, the effect of selection for IGE for growth on animal metabolism and physiology is unknown. The purpose of this study was twofold: (1) To investigate the effects of this new breeding method along with two housing (barren and straw), coping style (high and low resisters) and sex (female and castrated males) options on the metabolome profile of pigs. (2) To identify and map biological processes associated with a regrouping test at 9 weeks of age. We used Nuclear Magnetic Resonance to quantify 49 serum metabolites at week 8, 9 and 22. Also, we quantified 3 catecholamines (tyramine, epinephrine, phenylethylamine) and serotonin and three water soluble vitamins (B2, B5 and B7). Overall, no significant differences were observed between negative and positive IGE animals. The magnitude of change (delta) of many metabolites as a response to the regrouping test was significantly affected by IGE, especially that of the amino acids (P < 0.05), being greater in positive IGE pigs. The regrouping test was associated with alteration in glycine, serine and threonine metabolism. In conclusion positive and negative IGE animals respond differently to the regrouping test., (© 2021. The Author(s).)

Background: As in many fields of medical care, the coronavirus disease 2019 (COVID-19) resulted in an increased uncertainty regarding the safety of allergen immunotherapy (AIT). Therefore, the European Academy of Allergy and Clinical Immunology (EAACI) aimed to analyze the situation in different countries and to systematically collect all information available regarding tolerability and possible amendments in daily practice of sublingual AIT (SLIT), subcutaneous AIT (SCIT) for inhalant allergies and venom AIT., Methods: Under the framework of the EAACI, a panel of experts in the field of AIT coordinated by the Immunotherapy Interest Group set-up a web-based retrospective survey (SurveyMonkey ® ) including 27 standardized questions on practical and safety aspects on AIT in worldwide clinical routine., Results: 417 respondents providing AIT to their patients in daily routine answered the survey. For patients (without any current symptoms to suspect COVID-19), 60% of the respondents informed of not having initiated SCIT (40% venom AIT, 35% SLIT) whereas for the maintenance phase of AIT, SCIT was performed by 75% of the respondents (74% venom AIT, 89% SLIT). No tolerability concern arises from this preliminary analysis. 16 physicians reported having performed AIT despite (early) symptoms of COVID-19 and/or a positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Conclusions: This first international retrospective survey in atopic diseases investigated practical aspects and tolerability of AIT during the COVID-19 pandemic and gave no concerns regarding reduced tolerability under real-life circumstances. However, the data indicate an undertreatment of AIT, which may be temporary, but could have a long-lasting negative impact on the clinical care of allergic patients., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Introduction: Clinically diagnosed pneumonia in children is a leading cause of paediatric hospitalisation and mortality. The aetiology is usually bacterial or viral, but malaria can cause a syndrome indistinguishable from clinical pneumonia. There is no method with high sensitivity to detect a bacterial infection in these patients and, as result, antibiotics are frequently overprescribed. Conversely, unrecognised concomitant bacterial infection in patients with malarial infections occur with omission of antibiotic therapy from patients with bacterial infections. Previously, we identified two combinations of blood proteins with 96% sensitivity and 86% specificity for detecting bacterial disease. The current project aimed to validate and improve these combinations by evaluating additional biomarkers in paediatric patients with clinical pneumonia. Our goal was to describe combinations of a limited number of proteins with high sensitivity and specificity for bacterial infection to be incorporated in future point-of-care tests. Furthermore, we seek to explore signatures to prognosticate clinical pneumonia., Methods and Analysis: Patients (n=900) aged 2-59 months presenting with clinical pneumonia at two Gambian hospitals will be enrolled and classified according to criteria for definitive bacterial aetiology (based on microbiological tests and chest radiographs). We will measure proteins at admission using Luminex-based immunoassays in 90 children with definitive and 160 with probable bacterial aetiology, and 160 children classified according to the prognosis of their disease. Previously identified diagnostic signatures will be assessed through accuracy measures. Moreover, we will seek new diagnostic and prognostic signatures through machine learning methods, including support vector machine, penalised regression and classification trees., Ethics and Dissemination: Ethics approval has been obtained from the Gambia Government/Medical Research Council Unit The Gambia Joint Ethics Committee (protocol 1616) and the institutional review board of Boston University Medical Centre (STUDY00000958). Study results will be disseminated to the staff of the study hospitals, in scientific seminars and meetings, and in publications., Trial Registration Number: H-38462., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Pig survival is an economically important trait with relevant social welfare implications, thus standing out as an important selection criterion for the current pig farming system. We aimed to estimate (co)variance components for survival in different production phases in a crossbred pig population as well as to investigate the benefit of including genomic information through single-step genomic best linear unbiased prediction (ssGBLUP) on the prediction accuracy of survival traits compared with results from traditional BLUP. Individual survival records on, at most, 64,894 crossbred piglets were evaluated under two multi-trait threshold models. The first model included farrowing, lactation, and combined postweaning survival, whereas the second model included nursery and finishing survival. Direct and maternal breeding values were estimated using BLUP and ssGBLUP methods. Furthermore, prediction accuracy, bias, and dispersion were accessed using the linear regression validation method. Direct heritability estimates for survival in all studied phases were low (from 0.02 to 0.08). Survival in preweaning phases (farrowing and lactation) was controlled by the dam and piglet additive genetic effects, although the maternal side was more important. Postweaning phases (nursery, finishing, and the combination of both) showed the same or higher direct heritabilities compared with preweaning phases. The genetic correlations between survival traits within preweaning and postweaning phases were favorable and strong, but correlations between preweaning and postweaning phases were moderate. The prediction accuracy of survival traits was low, although it increased by including genomic information through ssGBLUP compared with the prediction accuracy from BLUP. Direct and maternal breeding values were similarly accurate with BLUP, but direct breeding values benefited more from genomic information. Overall, a slight increase in bias was observed when genomic information was included, whereas dispersion of breeding values was greatly reduced. Combined postweaning survival presented higher direct heritability than in the preweaning phases and the highest prediction accuracy among all evaluated production phases, therefore standing out as a candidate trait for improving survival. Survival is a complex trait with low heritability; however, important genetic gains can still be obtained, especially under a genomic prediction framework., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Background: The pathogenesis of chronic spontaneous urticaria (CSU), including the mechanism of action of omalizumab, remain unclear. We hypothesized complement system involvement given the often fast clinical response induced by treatment, including omalizumab. Therefore, we assessed the role of various complement factors surrounding omalizumab treatment., Methods: Thirty CSU patients (median age 42 [range 21-70]; 73 % female) with a median once daily Urticaria Activity Score over 7 days (UAS7) score at baseline of 31.5 points were enrolled. Treatment consisted of six administrations of 300 mg omalizumab every 4 weeks succeeded by a follow-up period of 12 weeks. Four punch skin biopsies were taken per patient; at baseline from lesional skin, at baseline from nonlesional skin, and after 1 and 7 days from formerly lesional skin. Complement activity, including C1q, C3, C3bc/C3, C4, C4bc/C4, C5a, and Membrane Attack Complex in peripheral blood were analyzed and complement activation in the skin was determined by the analysis of C4d deposition. Results were related to the clinical response to omalizumab., Results: Fifteen patients showed a UAS7 score of 6 or lower (median 0) at Week 24, 15 patients did not (median 16). Lesional skin biopsies at baseline revealed complement deposition (C4d) in blood vessels in the papillary dermis of 53% (16/30) of the patients, which suggests involvement of immune complexes in the pathogenesis of urticaria. Moreover, indication of increased complement activation in CSU was substantiated by increased C5a levels in peripheral blood compared to healthy controls ( p  = 0.010). The clinical effect of omalizumab could not be linked to the variation of complement components., Conclusions: Both C4d deposition in lesional skin and elevated C5a levels in peripheral blood indicate the involvement of complement activation in the pathogenesis of CSU. No correlation was found between omalizumab and activation of complement indicative of independent processes in the immunopathogenesis of CSU., Competing Interests: Mignon van den Elzen received reimbursements to attend symposia and speaker's fees from Novartis Pharma B.V. to the institution. André C. Knulst received funds for research and healthcare innovation from Novartis Pharma B.V. to the institution and was involved in the advisory board of Novartis Pharma B.V. Heike Röckmann received speaker's fees, and funds for research from Novartis Pharma B.V. to the institution. Henny G. Otten received funds for this research from Novartis Pharma B.V. to the institution. The other authors declare that there are no conflict of interests., (© 2021 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Biological information regarding markers and gene association may be used to attribute different weights for single nucleotide polymorphism (SNP) in genome-wide selection. Therefore, we aimed to evaluate the predictive ability and the bias of genomic prediction using models that allow SNP weighting in the genomic relationship matrix (G) building, with and without incorporating biological information to obtain the weights. Firstly, we performed a genome-wide association studies (GWAS) in data set containing single- (SL) or a multi-line (ML) pig population for androstenone, skatole and indole levels. Secondly, 1%, 2%, 5%, 10%, 30% and 50% of the markers explaining the highest proportions of the genetic variance for each trait were selected to build gene networks through the association weight matrix (AWM) approach. The number of edges in the network was computed and used to derive weights for G (AWM-WssGBLUP). The single-step GBLUP (ssGBLUP) and weighted ssGBLUP (WssGBLUP) were used as standard scenarios. All scenarios presented predictive abilities different from zero; however, the great overlap in their confidences interval suggests no differences among scenarios. Most of scenarios of based on AWM provide overestimations for skatole in both SL and ML populations. On the other hand, the skatole and indole prediction were no biased in the ssGBLUP (S1) in both SL and ML populations. Most of scenarios based on AWM provide no biased predictions for indole in both SL and ML populations. In summary, using biological information through AWM matrix and gene networks to derive weights for genomic prediction resulted in no increase in predictive ability for boar taint compounds. In addition, this approach increased the number of analyses steps. Thus, we can conclude that ssGBLUP is most appropriate for the analysis of boar taint compounds in comparison with the weighted strategies used in the present work., (© 2020 Wiley-VCH GmbH.)