Robust and prototypical immune responses toward COVID-19 vaccine in First Nations peoples are impacted by comorbidities.

High-risk groups, including Indigenous people, are at risk of severe COVID-19. Here we found that Australian First Nations peoples elicit effective immune responses to COVID-19 BNT162b2 vaccination, including neutralizing antibodies, receptor-binding domain (RBD) antibodies, SARS-CoV-2 spike-specific B cells, and CD4+ and CD8+ T cells. In First Nations participants, RBD IgG antibody titers were correlated with body mass index and negatively correlated with age. Reduced RBD antibodies, spike-specific B cells and follicular helper T cells were found in vaccinated participants with chronic conditions (diabetes, renal disease) and were strongly associated with altered glycosylation of IgG and increased interleukin-18 levels in the plasma. These immune perturbations were also found in non-Indigenous people with comorbidities, indicating that they were related to comorbidities rather than ethnicity. However, our study is of a great importance to First Nations peoples who have disproportionate rates of chronic comorbidities and provides evidence of robust immune responses after COVID-19 vaccination in Indigenous people.

PEGylated liposomes for diagnosis of polyethylene glycol allergy.

BACKGROUND: Polyethylene glycol (PEG) is a nonprotein polymer that is present in its native (unbound) form as an excipient in a range of products. It is increasingly being utilized clinically in the form of PEGylated liposomal medications and vaccines. PEG is the cause of anaphylaxis in a small percentage of drug reactions; however, diagnosis of PEG allergy is complicated by the variable and poor diagnostic performance of current skin testing protocols. OBJECTIVE: We assessed the diagnostic performance of PEGylated lipid medications as an alternative to currently described tests that use medications containing PEG excipients. METHODS: Nine patients with a strong history of PEG allergy were evaluated by skin testing with a panel of PEG-containing medications and with a PEGylated lipid nanoparticle vaccine (BNT162b2). Reactivity of basophils to unbound and liposomal PEG was assessed ex vivo, and specificity of basophil responses to PEGylated liposomes was investigated with a competitive inhibition assay. More detailed information is provided in this article's Methods section in the Online Repository available at www.jacionline.org. RESULTS: Despite compelling histories of anaphylaxis to PEG-containing medications, only 2 (22%) of 9 patients were skin test positive for purified PEG or their index reaction-indicated PEG-containing compound. Conversely, all 9 patients were skin test positive or basophil activation test positive to PEGylated liposomal BNT162b2 vaccine. Concordantly, PEGylated liposomal drugs (BNT162b2 vaccine and PEGylated liposomal doxorubicin), but not purified PEG2000, consistently induced basophil activation ex vivo in patients with PEG allergy but not in nonallergic controls. Basophil reactivity to PEGylated nanoparticles competitively inhibited by preincubation of basophils with native PEG2000. CONCLUSION: Presentation of PEG on the surface of a lipid nanoparticle increases its in vivo and ex vivo allergenicity, and improves diagnosis of PEG allergy.

Outcomes of Serum Food-Specific Immunoglobulin G 4 to Guide Elimination Diet in Patients With Eosinophilic Esophagitis.

INTRODUCTION: Eosinophilic esophagitis (EoE) is associated with atopy; however, recent studies have identified an association with food-specific immunoglobulin G 4 (FS-IgG 4 ) rather than immunoglobulin E antibodies. This study aimed to evaluate the role of serum FS-IgG 4 in guiding an elimination diet and its outcomes. METHODS: Patients with and without EoE were enrolled in a prospective, controlled, single tertiary center trial. Serum FS-IgG 4 titers, esophageal eosinophil counts, and dysphagia symptom questionnaire scores were assessed, and participants with elevated FS-IgG 4 (ImmunoCAP, cutoff of 10 mgA/L) commenced 6-week targeted elimination diet. Repeat serum FS-IgG 4 and endoscopic and histologic examination were performed at 6-week follow-up. RESULTS: Twenty-two patients with active EoE and 13 controls were recruited. Serum FS-IgG 4 to milk, wheat, soy, eggs, and nuts was significantly higher in EoE ( P = 0.0002, P = 0.002, P = 0.003, P = 0.012, and P < 0.001, respectively). Elevated serum FS-IgG 4 to 1 or more food groups (median 2) was identified in 21/22 (95.4%) patients with EoE; 20/21 underwent 6-week dietary elimination. Median reductions in dysphagia symptom questionnaire score and EoE endoscopic reference score after elimination were 8 ( P = 0.0007) and 1 ( P = 0.002), respectively. Nine (45%) patients had histological remission (<15 eosinophils per high-power field). Fall in median esophageal eosinophil count was not statistically significant (50 vs 23; P = 0.068). Serum FS-IgG 4 did not decline by 6-week follow-up. DISCUSSION: Serum FS-IgG 4 to milk, wheat, soy, egg, and nuts was present at higher levels in EoE, with targeted elimination resulting in 45% histologic remission rate. Serum FS-IgG 4 has potential as a noninvasive biomarker in EoE. When successful, FS-IgG 4 -led elimination diet can negate need for medications and be viewed more favorably by patients because of its smaller endoscopic burden compared with empirical elimination diets.

Linking donor-specific antibody generation with natural killer cells in antibody-mediated kidney graft rejection.

Natural killer (NK) cell infiltration of kidney allografts is a distinguishing feature of antibody-mediated rejection. Bailly et al. identify a distinct population of cytotoxic CD160+ interleukin-21 receptor+ CD56dimCD16bright NK cells that are uniquely found in the peripheral blood of donor-specific antibody-positive kidney transplant recipients and are present in kidney allografts with active antibody-mediated rejection. This population is implicated in a T follicular helper/interleukin-21/NK cell axis that links donor-specific antibody generation with graft-infiltrating NK cells in antibody-mediated rejection.

Protracted COVID-19 pneumonitis early post-ABO incompatible kidney transplantation: Management considerations and the role of whole genome sequencing.

We present the case of a recent ABO incompatible kidney transplant recipient with persistent SARS-CoV-2 infection and pneumonitis. Serial whole genome sequencing confirmed intra-host viral evolution, which was used as a surrogate to confirm active viral replication and support re-treatment with antivirals, late in the course of infection. A prolonged course of remdesivir combined with immunosuppression modulation resulted in successful clearance of virus and clinical improvement. The diagnostic process undertaken in this case provides a useful guide for other clinicians when approaching similar patients.

Osteoporosis identification among previously undiagnosed individuals with vertebral fractures.

Because osteoporosis is under-recognized in patients with vertebral fractures, we evaluated characteristics associated with osteoporosis identification. Most patients with vertebral fractures did not receive evaluation or treatment for osteoporosis. Black, younger, and male participants were particularly unlikely to have had recognized osteoporosis, which could increase their risk of negative outcomes. INTRODUCTION: Vertebral fractures may be identified on imaging but fail to prompt evaluation for osteoporosis. Our objective was to evaluate characteristics associated with clinical osteoporosis recognition in patients who had vertebral fractures detected on their thoracolumbar spine imaging reports. METHODS: We prospectively identified individuals who received imaging of the lower spine at primary care clinics in 4 large healthcare systems who were eligible for osteoporosis screening and lacked indications of osteoporosis diagnoses or treatments in the prior year. We evaluated characteristics of participants with identified vertebral fractures that were associated with recognition of osteoporosis (diagnosis code in the health record; receipt of bone mineral density scans; and/or prescriptions for anti-osteoporotic medications). We used mixed models to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: A total of 114,005 participants (47% female; mean age 65 (interquartile range: 57-72) years) were evaluated. Of the 8579 (7%) participants with vertebral fractures identified, 3784 (44%) had recognition of osteoporosis within the subsequent year. In adjusted regressions, Black participants (OR (95% CI): 0.74 (0.57, 0.97)), younger participants (age 50-60: 0.48 (0.42, 0.54); age 61-64: 0.70 (0.60, 0.81)), and males (0.39 (0.35, 0.43)) were less likely to have recognized osteoporosis compared to white participants, adults aged 65 + years, or females. CONCLUSION: Individuals with identified vertebral fractures commonly did not have recognition of osteoporosis within a year, particularly those who were younger, Black, or male. Providers and healthcare systems should consider efforts to improve evaluation of osteoporosis in patients with vertebral fractures.

Urine stem cells are equipped to provide B cell survival signals.

The interplay between mesenchymal stem cells (MSCs) and immune cells has been studied for MSCs isolated from different tissues. However, the immunomodulatory capacity of urine stem cells (USCs) has not been adequately researched. The present study reports on the effect of USCs on peripheral blood lymphocytes. USCs were isolated and characterized before coculture with resting and with anti-CD3/CD28 bead stimulated lymphocytes. Similarly to bone marrow mesenchymal stem cells (BM-MSCs), USCs inhibited the proliferation of activated T lymphocytes and induced their apoptosis. However, they also induced strong activation, proliferation, and cytokine and antibody production by B lymphocytes. Molecular phenotype and supernatant analysis revealed that USCs secrete a range of cytokines and effector molecules, known to play a central role in B cell biology. These included B cell-activating factor (BAFF), interleukin 6 (IL-6) and CD40L. These findings raise the possibility of an unrecognized active role for kidney stem cells in modulating local immune cells.

Characterization of Urine Stem Cell-Derived Extracellular Vesicles Reveals B Cell Stimulating Cargo.

Elucidation of the biological functions of extracellular vesicles (EVs) and their potential roles in physiological and pathological processes is an expanding field of research. In this study, we characterized USC-derived EVs and studied their capacity to modulate the human immune response in vitro. We found that the USC-derived EVs are a heterogeneous population, ranging in size from that of micro-vesicles (150 nm-1 µm) down to that of exosomes (60-150 nm). Regarding their immunomodulatory functions, we found that upon isolation, the EVs (60-150 nm) induced B cell proliferation and IgM antibody secretion. Analysis of the EV contents unexpectedly revealed the presence of BAFF, APRIL, IL-6, and CD40L, all known to play a central role in B cell stimulation, differentiation, and humoral immunity. In regard to their effect on T cell functions, they resembled the function of mesenchymal stem cell (MSC)-derived EVs previously described, suppressing T cell response to activation. The finding that USC-derived EVs transport a potent bioactive cargo opens the door to a novel therapeutic avenue for boosting B cell responses in immunodeficiency or cancer.

Current advisory interventions for grazing ruminant farming cannot close exceedance of modern background sediment loss - Assessment using an instrumented farm platform and modelled scaling out.

Water quality impairment by elevated sediment loss is a pervasive problem for global water resources. Sediment management targets identify exceedance or the sediment loss 'gap' requiring mitigation. In the UK, palaeo-limnological reconstruction of sediment loss during the 100-150 years pre-dating the post-World War II intensification of agriculture, has identified management targets (0.20-0.35 t ha-1 yr-1) representing 'modern background sediment delivery to rivers'. To assess exceedance on land for grazing ruminant farming, an integrated approach combined new mechanistic evidence from a heavily-instrumented experimental farm platform and a scaling out framework of modelled commercial grazing ruminant farms in similar environmental settings. Monitoring (2012-2016) on the instrumented farm platform returned sediment loss ranges of 0.11-0.14 t ha-1 yr-1 and 0.21-0.25 t ha-1 yr-1 on permanent pasture, compared with between 0.19-0.23 t ha-1 yr-1 and 0.43-0.50 t ha-1 yr-1and 0.10-0.13 t ha-1 yr-1and 0.25-0.30 t ha-1 yr-1 on pasture with scheduled plough and reseeds. Excess sediment loss existed on all three farm platform treatments but was more extensive on the two treatments with scheduled plough and reseeds. Excessive sediment loss from land used by grazing ruminant farming more strategically across England, was estimated to be up to >0.2 t ha-1 yr-1. Modelled scenarios of alternative farming futures, based on either increased uptake of interventions typically recommended by visual farm audits, or interventions selected using new mechanistic understanding for sediment loss from the instrumented farm platform, returned minimum sediment loss reductions. On the farm platform these were 2.1 % (up to 0.007 t ha-1 yr-1) and 5.1 % (up to 0.018 t ha-1 yr-1). More strategically, these were up to 2.8 % (0.014 t ha-1 yr-1) and 4.1 % (0.023 t ha-1 yr-1). Conventional on-farm measures will therefore not fully mitigate the sediment loss gap, meaning that more severe land cover change is required.

Sustainable grassland systems: a modelling perspective based on the North Wyke Farm Platform.

The North Wyke Farm Platform (NWFP) provides data from the field- to the farm-scale, enabling the research community to address key issues in sustainable agriculture better and to test models that are capable of simulating soil, plant and animal processes involved in the systems. The tested models can then be used to simulate how agro-ecosystems will respond to changes in the environment and management. In this study, we used baseline datasets generated from the NWFP to validate the Soil-Plant-Atmosphere Continuum System (SPACSYS) model in relation to the dynamics of soil water content, water loss from runoff and forage biomass removal. The validated model, together with future climate scenarios for the 2020s, 2050s and 2080s (from the International Panel on Climate Change (IPCC) Special Report on Emissions Scenarios (SRES): medium (A1B) and large (A1F1) emission scenarios), were used to simulate the long-term responses of the system with three contrasting treatments on the NWFP. Simulation results demonstrated that the SPACSYS model could estimate reliably the dynamics of soil water content, water loss from runoff and drainage, and cut biomass for a permanent sward. The treatments responded in different ways under the climate change scenarios. More carbon (C) is fixed and respired by the swards treated with an increased use of legumes, whereas less C was lost through soil respiration with the planned reseeding. The deep-rooting grass in the reseeding treatment reduced N losses through leaching, runoff and gaseous emissions, and water loss from runoff compared with the other two treatments.

Spatial variation in soil properties and diffuse losses between and within grassland fields with similar short-term management.

One of the major challenges for agriculture is to understand the effects of agricultural practices on soil properties and diffuse pollution, to support practical farm-scale land management. Three conventionally managed grassland fields with similar short-term management, but different ploughing histories, were studied on a long-term research platform: the North Wyke Farm Platform. The aims were to (i) quantify the between-field and within-field spatial variation in soil properties by geostatistical analysis, (ii) understand the effects of soil condition (in terms of nitrogen, phosphorus and carbon contents) on the quality of discharge water and (iii) establish robust baseline data before the implementation of various grassland management scenarios. Although the fields sampled had experienced the same land use and similar management for at least 6 years, there were differences in their mean soil properties. They showed different patterns of soil spatial variation and different rates of diffuse nutrient losses to water. The oldest permanent pasture field had the largest soil macronutrient concentrations and the greatest diffuse nutrient losses. We show that management histories affect soil properties and diffuse losses. Potential gains in herbage yield or benefits in water quality might be achieved by characterizing every field or by area-specific management within fields (a form of precision agriculture for grasslands). Permanent pasture per se cannot be considered a mitigation measure for diffuse pollution. The between- and within-field soil spatial variation emphasizes the importance of baseline characterization and will enable the reliable identification of any effects of future management change on the Farm Platform. HIGHLIGHTS: Quantification of soil and water quality in grassland fields with contrasting management histories.Considerable spatial variation in soil properties and diffuse losses between and within fields.Contrasting management histories within and between fields strongly affected soil and water quality.Careful pasture management needed: the oldest pasture transferred the most nutrients from soil to water.

The North Wyke Farm Platform: effect of temperate grassland farming systems on soil moisture contents, runoff and associated water quality dynamics.

The North Wyke Farm Platform was established as a United Kingdom national capability for collaborative research, training and knowledge exchange in agro-environmental sciences. Its remit is to research agricultural productivity and ecosystem responses to different management practices for beef and sheep production in lowland grasslands. A system based on permanent pasture was implemented on three 21-ha farmlets to obtain baseline data on hydrology, nutrient cycling and productivity for 2 years. Since then two farmlets have been modified by either (i) planned reseeding with grasses that have been bred for enhanced sugar content or deep-rooting traits or (ii) sowing grass and legume mixtures to reduce nitrogen fertilizer inputs. The quantities of nutrients that enter, cycle within and leave the farmlets were evaluated with data recorded from sensor technologies coupled with more traditional field study methods. We demonstrate the potential of the farm platform approach with a case study in which we investigate the effects of the weather, field topography and farm management activity on surface runoff and associated pollutant or nutrient loss from soil. We have the opportunity to do a full nutrient cycling analysis, taking account of nutrient transformations in soil, and flows to water and losses to air. The NWFP monitoring system is unique in both scale and scope for a managed land-based capability that brings together several technologies that allow the effect of temperate grassland farming systems on soil moisture levels, runoff and associated water quality dynamics to be studied in detail. HIGHLIGHTS: Can meat production systems be developed that are productive yet minimize losses to the environment?The data are from an intensively instrumented capability, which is globally unique and topical.We use sensing technologies and surveys to show the effect of pasture renewal on nutrient losses.Platforms provide evidence of the effect of meteorology, topography and farm activity on nutrient loss.

Lift vs. drag based mechanisms for vertical force production in the smallest flying insects.

We used computational fluid dynamics to determine whether lift- or drag-based mechanisms generate the most vertical force in the flight of the smallest insects. These insects fly at Re on the order of 4-60 where viscous effects are significant. Detailed quantitative data on the wing kinematics of the smallest insects is not available, and as a result both drag- and lift-based strategies have been suggested as the mechanisms by which these insects stay aloft. We used the immersed boundary method to solve the fully-coupled fluid-structure interaction problem of a flexible wing immersed in a two-dimensional viscous fluid to compare three idealized hovering kinematics: a drag-based stroke in the vertical plane, a lift-based stroke in the horizontal plane, and a hybrid stroke on a tilted plane. Our results suggest that at higher Re, a lift-based strategy produces more vertical force than a drag-based strategy. At the Re pertinent to small insect hovering, however, there is little difference in performance between the two strategies. A drag-based mechanism of flight could produce more vertical force than a lift-based mechanism for insects at Re<5; however, we are unaware of active fliers at this scale.

Starvation actively inhibits splicing of glucose-6-phosphate dehydrogenase mRNA via a bifunctional ESE/ESS element bound by hnRNP K.

Regulated expression of glucose-6-phosphate dehydrogenase (G6PD) is due to changes in the rate of pre-mRNA splicing and not changes in its transcription. Starvation alters pre-mRNA splicing by decreasing the rate of intron removal, leading to intron retention and a decrease in the accumulation of mature mRNA. A regulatory element within exon 12 of G6PD pre-mRNA controls splicing efficiency. Starvation caused an increase in the expression of heterogeneous nuclear ribonucleoprotein (hnRNP) K protein and this increase coincided with the increase in the binding of hnRNP K to the regulatory element and a decrease in the expression of G6PD mRNA. HnRNP K bound to two C-rich motifs forming an ESS within exon 12. Overexpression of hnRNP K decreased the splicing and expression of G6PD mRNA, while siRNA-mediated depletion of hnRNP K caused an increase in the splicing and expression of G6PD mRNA. Binding of hnRNP K to the regulatory element was enhanced in vivo by starvation coinciding with a decrease in G6PD mRNA. HnRNP K binding to the C-rich motifs blocked binding of serine-arginine rich, splicing factor 3 (SRSF3), a splicing enhancer. Thus hnRNP K is a nutrient regulated splicing factor responsible for the inhibition of the splicing of G6PD during starvation.