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Atmospheric carbon‐dioxide concentration ([CO2]) is increasing rapidly, but its interactions with nitrogen (N) and phosphorus (P) fertiliser on wheat grain quality are not well understood. We investigated the effects of ambient CO2 (aCO2; ∼410 ppm) and elevated CO2 (eCO2; 760 ppm) on crop harvest index (CHI), nutrient harvest index (NuHI), shoot macro‐nutrient content and grain macro‐nutrient concentration of wheat grown under two contrasting amounts of N (0.5 and 6 mol m−3 NO3− N) and P (10 and 250 mmol P m−3) fertiliser supply (low and optimum, respectively). Our results highlighted interactions between [CO2] and N and P fertiliser supply for the shoot biomass at anthesis and straw biomass at harvest maturity. This was because biomass yield did not respond to CO2 level when fertiliser was deficient. However, shoot and straw yield increased (10.0–‐34.0%) with increasing [CO2] at optimum fertiliser rates. Across experiments, grain yield increased (15.6%) with increasing [CO2], which resulted in grain nutrient concentration decreasing (3.0–‐13.0%) with increasing [CO2]. This was attributed to nutrient 'dilution' due to increased carbohydrate content in the grain. Overall, fertiliser supply impacted crop responses more than CO2 treatments, and the impact was greater under N than P deficiency. This was reflected through conservative values for CHI, thousand grain weight and NuHIs suggesting plants allocated biomass and nutrients at similar rates for vegetative and reproductive organs independent of [CO2]. [ABSTRACT FROM AUTHOR]

Summary This article describes the clinical features of anaphylaxis in children and young people. The acute management of anaphylaxis in hospital and community is described and various prevention strategies are [...]

Nut allergy, in particular peanut allergy, is becoming more common in children. Immune sensitisation to nuts appears to be occurring earlier in life. High incidence of other allergic diseases in children with nut allergy. Onset of anaphylactic symptoms is quick but symptoms last for a short time. Necessity for hospital admission due to severity of allergic reaction is low. [ABSTRACT FROM AUTHOR]

Two sibs, diagnosed prenatally, had holoprosencephaly, midface hypoplasia, and normal chromosomes. The first fetus also had polydactyly. This sibship may represent an example of autosomal recessive pseudotrisomy 13. [ABSTRACT FROM PUBLISHER]

Clinical trials investigating the potential of mesenchymal stromal cells (MSCs) for the treatment of inflammatory diseases, such as acute respiratory distress syndrome (ARDS), have been disappointing, with less than 50% of patients responding to treatment. Licensed MSCs show enhanced therapeutic efficacy in response to cytokine-mediated activation signals. There are two distinct sub-phenotypes of ARDS: hypo- and hyper-inflammatory. We hypothesized that pre-licensing MSCs in a hyper-inflammatory ARDS environment would enhance their therapeutic efficacy in acute lung inflammation (ALI). Serum samples from patients with ARDS were segregated into hypo- and hyper-inflammatory categories based on interleukin (IL)-6 levels. MSCs were licensed with pooled serum from patients with hypo- or hyper-inflammatory ARDS or healthy serum controls. Our findings show that hyper-inflammatory ARDS pre-licensed MSC conditioned medium (MSC-CM Hyper ) led to a significant enrichment in tight junction expression and enhanced barrier integrity in lung epithelial cells in vitro and in vivo in a vascular endothelial growth factor (VEGF)-dependent manner. Importantly, while both MSC-CM Hypo and MSC-CM Hyper significantly reduced IL-6 and tumor necrosis factor alpha (TNF-α) levels in the bronchoalveolar lavage fluid (BALF) of lipopolysaccharide (LPS)-induced ALI mice, only MSC-CM Hyper significantly reduced lung permeability and overall clinical outcomes including weight loss and clinical score. Thus, the hypo- and hyper-inflammatory ARDS environments may differentially influence MSC cytoprotective and immunomodulatory functions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of interests The authors declare no competing interests.

Background: Trained immunity results in long-term immunological memory, provoking a faster and greater immune response when innate immune cells encounter a secondary, often heterologous, stimulus. We have previously shown that house dust mite (HDM)-induced innate training is amplified in mice expressing the human macrophage migration inhibitory factor (MIF) CATT 7 functional polymorphism., Aim: This study investigated the ability of mesenchymal stromal cells (MSCs) to modulate MIF-driven trained immunity both in vitro and in vivo., Methods: Compared with wild-type mice, in vivo HDM-primed bone marrow-derived macrophages (BMDMs) from CATT 7 mice expressed significantly higher levels of M1-associated genes following lipopolysaccharide stimulation ex vivo. Co-cultures of CATT 7 BMDMs with MSCs suppressed this HDM-primed effect, with tumor necrosis factor alpha (TNF-α) being significantly decreased in a cyclooxygenase 2 (COX-2)-dependent manner. Interestingly, interleukin 6 (IL-6) was suppressed by MSCs independently of COX-2. In an in vitro training assay, MSCs significantly abrogated the enhanced production of pro-inflammatory cytokines by HDM-trained CATT 7 BMDMs when co-cultured at the time of HDM stimulus on day 0, displaying their therapeutic efficacy in modulating an overzealous human MIF-dependent immune response. Utilizing an in vivo model of HDM-induced trained immunity, MSCs administered systemically on day 10 and day 11 suppressed this trained phenomenon by significantly reducing TNF-α and reducing IL-6 and C-C motif chemokine ligand 17 (CCL17) production., Conclusions: This novel study elucidates how MSCs can attenuate an MIF-driven, HDM-trained response in CATT 7 mice in a model of allergic airway inflammation., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. All rights reserved.)

High level expression of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has been associated with severe asthma. The role of MIF and its functional promotor polymorphism in innate immune training is currently unknown. Using novel humanized CATT 7 MIF mice, this study is the first to investigate the effect of MIF on bone marrow-derived macrophage (BMDM) memory after house dust mite (HDM) challenge. CATT 7 BMDMs demonstrated a significant primed increase in M1 markers following HDM and LPS stimulation, compared to naive mice. This M1 signature was found to be MIF-dependent, as administration of a small molecule MIF inhibitor, SCD-19, blocked the induction of this pro-inflammatory M1-like phenotype in BMDMs from CATT 7 mice challenged with HDM. Training naive BMDMs in vitro with HDM for 24 h followed by a rest period and subsequent stimulation with LPS led to significantly increased production of the pro-inflammatory cytokine TNFα in BMDMs from CATT 7 mice but not WT mice. Addition of the pan methyltransferase inhibitor MTA before HDM training significantly abrogated this effect in BMDMs from CATT 7 mice, suggesting that HDM-induced training is associated with epigenetic remodelling. These findings suggest that trained immunity induced by HDM is under genetic control, playing an important role in asthma patients with the high MIF genotypes (CATT 6/7/8 )., (© 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodeling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. A polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility to and severity of asthma. We investigated the efficacy of human MSCs in high- vs. low-hMIF environments and the impact of MIF pre-licensing of MSCs using humanized MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodeling in high-MIF-expressing CATT 7 mice but not in CATT 5 or wild-type littermates. Differences in efficacy were correlated with increased MSC retention in the lungs of CATT 7 mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of cyclooxygenase 2 (COX-2) expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT 6/7/8 )., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Macrophage migration inhibitory factor (MIF) expression is controlled by a functional promoter polymorphism, where the number of tetranucleotide repeats (CATT n ) corresponds to the level of MIF expression. To examine the role of this polymorphism in a pre-clinical model of allergic asthma, novel humanized MIF mice with increasing CATT repeats (CATT 5 and CATT 7 ) were used to generate a physiologically relevant scale of airway inflammation following house dust mite (HDM) challenge. CATT 7 mice expressing high levels of human MIF developed an aggressive asthma phenotype following HDM challenge with significantly elevated levels of immune cell infiltration, production of inflammatory mediators, goblet cell hyperplasia, subepithelial collagen deposition, and airway resistance compared to wild-type controls. Importantly the potent MIF inhibitor SCD-19 significantly mitigated the pathophysiology observed in CATT 7 mice after HDM challenge, demonstrating the fundamental role of endogenous human MIF expression in the severity of airway inflammation in vivo. Up to now, there are limited reproducible in vivo models of asthma airway remodeling. Current asthma medications are focused on reducing the acute inflammatory response but have limited effects on airway remodeling. Here, we present a reproducible pre-clinical model that capitulates asthma airway remodeling and suggests that in addition to having pro-inflammatory effects MIF may play a role in driving airway remodeling., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

The objectives of this review were to identify strategies initiated by parents of children with life-limiting conditions to support their own well-being at home and to describe the impact of these strategies on parental well-being. A systematic scoping review was performed using PRISMA-ScR guidelines, identifying 15 relevant studies that fit the inclusion and exclusion criteria. There were no studies that specifically assessed how parents support their own well-being; however, the 15 identified studies did provide pertinent data secondary to the primary aims of each study. This resulted in the identification of 14 parent-initiated strategies which were grouped thematically into 4 categories: (i) social experience and peer support, (ii) information and management techniques, (iii) reframed perspectives and (iv) prioritising own needs. Overall, there was some evidence of parents initiating specific, individualised and useful strategies to supporting their well-being. Notably lacking was any empirical evaluation as to the effectiveness of these strategies and the wider factors associated with them. Further research is required to assess how parents support their personal well-being in daily life and how these strategies can be implemented alongside service-initiated support to ensure full parental well-being.

Recent clinical trials of mesenchymal stromal cell (MSC) therapy for various inflammatory conditions have highlighted the significant benefit to patients who respond to MSC administration. Thus, there is strong interest in investigating MSC therapy in acute inflammatory lung conditions, such as acute respiratory distress syndrome (ARDS). Unfortunately, not all patients respond, and evidence now suggests that the differential disease microenvironment present across patients and sub-phenotypes of disease or across disease severities influences MSC licensing, function and therapeutic efficacy. Here, we discuss the importance of licensing MSCs and the need to better understand how the disease microenvironment influences MSC activation and therapeutic actions, in addition to the need for a patient-stratification approach.

Cell-based therapy for the treatment of inflammatory disorders has focused on the application of mesenchymal stromal cells (MSCs) and multipotent adult progenitor cells (MAPCs). Despite the recent positive findings in industry-sponsored clinical trials of MSCs and MAPCs for graft vs host disease (GvHD), cell therapy is efficacious in some but not all patients, highlighting the need to identify strategies to enhance cell-based therapeutic efficacy. Here, we demonstrate the capacity for interferon (IFN)-γ licensing to enhance human MAPC efficacy and retention following early administration in a humanized mouse model of acute GvHD (aGvHD). Activation of the nuclear receptor peroxisome proliferator-activated receptor delta (PPARδ) negatively influenced the retention and efficacy of human MAPCs as well as IFN-γ-licensed MAPCs in the aGvHD model. PPARδ antagonism significantly enhanced the efficacy of human MAPCs when administered early in the humanized aGvHD model. COX-2 expression in human MAPC was significantly decreased in IFN-γ licensed MAPCs exposed to a PPARδ agonist. Importantly, MAPC exposure to the PPARδ antagonist in the presence of a COX-2 inhibitor indomethacin before administration significantly reduced the efficacy of PPARδ antagonized MAPCs in the aGvHD humanized mouse model. This is the first study to demonstrate the importance of PPARδ in human MAPC efficacy in vivo and highlights the importance of understanding the disease microenvironment in which cell-based therapies are to be administered. In particular, the presence of PPARδ ligands may negatively influence MAPC or MSC therapeutic efficacy., (© 2021 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Immunosuppressive ability in human MSC donors has been shown to be variable and may be a limiting factor in MSC therapeutic efficacy in vivo. The importance of cytokine activation of mesenchymal stromal cells (MSCs) to facilitate their immunosuppressive function is well established. This study sought to further understand the interactions between MSCs and the commonly used calcineurin inhibitor cyclosporine A (CsA). The existing literature regarding approaches that use MSCs and cyclosporine are conflicting regarding the effect of CsA on MSC potency and function. Here, we clearly demonstrate that when added at the same time as MSCs, CsA negatively affects MSC suppression of T cell proliferation. However, licencing MSCs with IFNγ before addition of CsA protects MSCs from this negative effect. Notably, adding CsA to MSCs after IFNγ pre-stimulation enhances MSC production of IDO. Mechanistically, we identified that CsA reduces SOCS1 expression to facilitate enhanced IDO production in IFNγ pre-stimulated MSCs. Importantly, CsA exposure to IFNγ pre-stimulated MSC before administration, significantly enhanced the potency of MSCs in a human relevant humanised mouse model of acute Graft versus Host Disease. In summary, this study identified a novel licencing strategy to enhance MSC potency in vitro and in vivo.

Purpose: Non-urgent face-to-face outpatient ophthalmology appointments were suspended in the United Kingdom in March 2020, due to the COVID-19 outbreak. In common with other centres, Moorfields Eye Hospital NHS Foundation Trust (London) offered modified telephone consultations to new and follow-up patients in the low vision clinic. Here we assess the success of this telephone service., Methods: Data were collected for 500 consecutive telephone low vision appointments. Successful completion of the assessment and clinical outcomes (low vision aids prescribed, onward referral) were recorded., Results: Telephone assessments were completed for 364 people (72.8%). The most common reasons for non-completion were either no answer to the telephone call (75 people, 15%), or the patient declining assessment (20 people, 4%). There was no association between age and the likelihood of an assessment being completed. 131 new low vision aids were dispensed, 77 internal referrals were made and 15 people were referred to outside services. More than 80% of the low vision aids prescribed were useful., Conclusions: Telephone low vision assessments were completed in about three-quarters of cases. About one-quarter of consultations resulted in new low vision aids being dispensed, which were generally found useful. Telephone low vision assessments can be used successfully in a large low vision clinic, but have many limitations when compared to face-to-face assessments., (© 2021 The Authors Ophthalmic and Physiological Optics © 2021 The College of Optometrists.)

Children's hospices are key players in the provision of palliative care services for families with children with life-limiting conditions (LLCs). However, evidence suggests that some of the negative terminology/language which surrounds the notions of palliative and hospice care may contribute to the lack of uptake of hospice services by families. This article reports two elements of place bonding: parents' experiences of place identity and place belongingness at a children's hospice in a region in England. Underpinned by a constructivist grounded theory methodology, focus groups were undertaken with 24 parents of children with LLCs accessing a children's hospice. Despite initial reservations associated with the identity of the hospice, parents described how and why their view changed and therefore consequently how they were able to experience the hospice differently. This article demonstrates how parents' views of the identity of the hospice change and how the hospice becomes a place where parents experience a sense of belongingness.

The slow progression of early age-related macular degeneration (AMD) stages to advanced AMD requires the use of surrogate end points in clinical trials. The use of combined end points may allow for shorter and smaller trials due to increased precision. We performed a literature search for the use of composite end points as primary outcome measures in clinical studies of early AMD stages. PubMed was searched for composite end points used in early/intermediate AMD studies published during the last 10 years. A total of 673 articles of interest were identified. After reviewing abstracts and applicable full-text articles, 33 articles were eligible and thus included in the qualitative synthesis. The main composite end point categories were: combined structural and functional end points, combined structural end points, combined functional end points and combined multicategorical end points. The majority of the studies included binary composite end points. There was a lack of sensitivity analyses of different end points against accepted outcomes (i.e., progression) in the literature. Various composite outcome measures have been used but there is a lack of standardization. To date no agreement on the optimal approach to implement combined end points in clinical studies of early stages of AMD exists, and no surrogate end points have been accepted for AMD progression., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Endpoint development trials are underway across the spectrum of retinal disease. New validated endpoints are urgently required for the assessment of emerging gene therapies and in preparation for the arrival of novel therapeutics targeting the early stages of common sight-threatening conditions such as age-related macular degeneration and diabetic macular oedema. Visual function measures are likely to be key candidates in this search. Over the last 2 decades, microperimetry has been used extensively to characterise functional vision in a wide range of retinal conditions, often detecting subtle defects in retinal sensitivity that precede visual acuity loss and tracking disease progression over relatively short periods of time. Given these appealing features, microperimetry has already been adopted as an endpoint in interventional studies, including multicentre trials, on a modest scale. A review of its use to date shows a concurrent lack of consensus in test strategy and a wealth of innovative disease and treatment-specific metrics which may show promise as clinical trial endpoints. There are practical considerations to consider for its use, but these have not held back its popularity and it remains a widely used psychophysical test in research. Endpoint development trials will undoubtedly be key in understanding the validity of microperimetry as a clinical trial endpoint, but existing signs are promising., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Overall, approximately one-quarter of patients with genetic eye diseases will receive a molecular diagnosis. Patients with developmental eye disorders face a number of diagnostic challenges including phenotypic heterogeneity with significant asymmetry, coexisting ocular and systemic disease, limited understanding of human eye development and the associated genetic repertoire, and lack of access to next generation sequencing as regarded not to impact on patient outcomes/management with cost implications. Herein, we report our real world experience from a pediatric ocular genetics service over a 12 month period with 72 consecutive patients from 62 families, and that from a cohort of 322 patients undergoing whole genome sequencing (WGS) through the Genomics England 100,000 Genomes Project; encompassing microphthalmia, anophthalmia, ocular coloboma (MAC), anterior segment dysgenesis anomalies (ASDA), primary congenital glaucoma, congenital cataract, infantile nystagmus, and albinism. Overall molecular diagnostic rates reached 24.9% for those recruited to the 100,000 Genomes Project (73/293 families were solved), but up to 33.9% in the clinic setting (20/59 families). WGS was able to improve genetic diagnosis for MAC patients (15.7%), but not for ASDA (15.0%) and congenital cataracts (44.7%). Increased sample sizes and accurate human phenotype ontology (HPO) terms are required to improve diagnostic accuracy. The significant mixed complex ocular phenotypes distort these rates and lead to missed variants if the correct gene panel is not applied. Increased molecular diagnoses will help to explain the genotype-phenotype relationships of these developmental eye disorders. In turn, this will lead to improved integrated care pathways, understanding of disease, and future therapeutic development., (© 2020 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)