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A common factor in landslide activation (or reactivation) is subsurface moisture and associated pore pressure variations linked to rainfall. Monitoring of these subsurface hydrogeological processes is necessary to improve our understanding of water-induced landslide activation. Geophysical approaches, electrical methods in particular, are increasingly being applied to landslide monitoring because they provide non-invasive spatial information in heterogeneous subsurface environments that can be difficult to characterise using surface observations or intrusive sampling alone. Electrical techniques are sensitive to changing subsurface moisture conditions, and have proven to be a useful tool for investigating the hydrogeology of natural and engineered slopes. The objectives of this investigation were to further develop electrical resistance monitoring for slope stability assessment, and to validate the approach at an intermittently-active UK landslide system to advance the understanding of complex landslide activation mechanisms. A long-term transfer resistance dataset was collected from a grid of electrodes to allow spatial monitoring of the landslide. These data were interpreted using a synthesis of rainfall, temperature, GPS and piezometric records. The resistance data were corrected for seasonal temperature variations and electrode movements were monitored, as these processes were shown to mask moisture related changes. Results reveal that resistance monitoring is sensitive to soil moisture accumulation, including changes in piezometric levels, and can be used to study the principal activation mechanism of slow-moving shallow earthflows. Spatial monitoring using resistance maps was shown to be particularly valuable as it revealed the evolution of subsurface moisture distribution, in the lead up to landslide activation. Key benefits of this approach are that it provides a simple, rapid and non-invasive means of spatially monitoring subsurface moisture dynamics linked to landslide activation at high-temporal resolution. Crucially, it provides a means of monitoring subsurface hydraulic changes in the build-up to slope failure, thereby contributing to early warning of landslide events. Copyright © 2018 John Wiley & Sons, Ltd.

A methodology for developing resistivity-moisture content relationships of materials associated with a clayey landslide is presented. Key elements of the methodology include sample selection and preparation, laboratory measurement of resistivity with changing moisture content, and the derivation of models describing the relationship between resistivity and moisture content. Laboratory resistivity measurements show that the techniques utilised (samples and square array) have considerable potential as a means of electropetrophysical calibration of engineering soils and weak rock. Experimental electrical resistivity results show a hierarchy of values dependent on sample lithology, with silty clay exhibiting the lowest resistivities, followed by siltstones and sands, which return the highest resistivities. In addition, finer grained samples show a greater degree of anisotropy between measurement orientations than coarser grained samples.However, suitability of results in light of issues such as sample cracking and electrical conduction must be identified and accounted for if the results are to be accurately up-scaled to inverted model resistivity results. The existence of directional anisotropy makes model calibration curve selection more difficult due to variability in the range of measured laboratory resistances. The use of larger measurement array size means that experimental data will be more representative of bulk lithological properties. In addition, use of electrodes with a relatively high surface area (wide diameter) help maintain low contact resistances and repeat measurement error, relative to narrow electrodes.Variation exists between the fit of experimental data and petrophysical models. Model fit is best for clay-dominated samples but fits less well for sand-dominated samples. Waxman-Smits equation is appropriately applied in this investigation as all samples have considerable clay mineral content, as is shown in non-negligible CEC results. The incorporation of pressure plate suction measurements on samples, allows suction dissipation to be quantified and evaluated alongside moisture content and electrical resistivity.

Flow-cytometric immune phenotyping is influenced by cryopreservation and inter-laboratory variability limiting comparability in multicenter studies. We assessed a system of optimized, pre-mixed dry-antibody panel tubes requiring small amounts of whole blood for validity, reliability and challenges in a Canadian multicenter study (POSITIVE) with long-distance sample shipping, using standardized protocols. Thirty-seven children awaiting solid-organ transplant were enrolled for parallel immune-phenotyping with both validated, optimized in-house panels and the dry-antibody system. Samples were collected before, 3 and 12 months post-transplant. Quality-assurance measures and congruence of phenotypes were compared using Bland-Altman comparisons, linear regression and group comparisons. Samples showed excellent lymphocyte viability (mean 94.8 %) and recovery when processed within 30 h. Comparing staining methods, significant correlations (Spearman correlation coefficient >0.6, p < 0.05), mean difference <5 % and variation 2SD <25 % were found for natural-killer, T and B cells, including many immunologically important cell subsets (CD8+, naïve, memory CD4+ T; switched-memory, transitional B). Some subgroups (plasmablasts, CD1d+CD5hi B cells) showed weak correlations, limiting interpretation reliability. The dry-antibody system provides a reliable method for standardized analysis of many immune phenotypes after long-distance shipping when processed within 30 h, rendering the system attractive for pediatric studies due to small blood amounts required and highly standardized processing and analysis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Seema Mital reports a relationship with Bristol Myers Squibb that includes: consulting or advisory. Seema Mital reports a relationship with Tenaya Therapeutics that includes: consulting or advisory. Lavinia Ionescu reports a relationship with Beckman Coulter Canada that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

In the 1990s, neonates born with severe congenital heart disease faced more than 50% mortality awaiting an ABO-compatible (ABOc) transplant donor. This desperate situation, together with knowledge of gaps in the adaptive immune system in early childhood, led to the clinical exploration of intentional ABO-incompatible (ABOi) heart transplantation. In 2001, West et al. reported the first series of 10 infants in Canada. Since then, consideration of ABOi heart donors has become the standard of care for children awaiting transplantation in the first few years of life, resulting in reduced wait times and better organ utilization with noninferior post-transplant outcomes compared to ABOc recipients. This state-of-the-art review discusses the clinical development and evolution, underlying and resulting immunological aspects, current challenges, and future directions of ABOi heart transplantation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Strontium-90 ( 90 Sr) is a major contaminant at nuclear legacy sites. The mobility of 90 Sr is primarily governed by sorption reactions with sediments controlled by high surface area phases such as clay and iron oxides. Sr 2+ adsorption was investigated in heterogeneous unconsolidated aquifer sediments, analogous to those underlying the UK Sellafield nuclear site, with grainsizes ranging from gravels to clays. Batch sorption tests showed that a linear K d adsorption model was applicable to all grainsize fractions up to equilibrium [Sr] of 0.28 mmol L -1 . Sr 2+ sorption values (K d ; Langmuir q max ) correlated well with bulk sediment properties such as cation exchange capacity and surface area. Electron microscopy showed that heterogeneous sediments contained porous sandstone clasts with clay minerals (i.e. chlorite) providing an additional adsorption capacity. Therefore, gravel corrections that assumed that the > 2 mm fractions are inert were not appropriate and underestimated K d (bulk) adsorption coefficients. However, K d (<2 mm) values measured from sieved sediment fractions, were effectively adjusted to within error of K d (bulk) using a surface area dependant gravel correction based on particle size distribution data. Amphoteric pH dependent Sr 2+ sorption behaviour observed in batch experiments was consistent with cation exchange modelling between pH 2-7 derived from the measured cation exchange capacities. Above pH 7 model fits were improved by invoking a coupled cation exchange/surface complexation which allowed for addition sorption to iron oxide phases. The overall trends in Sr 2+ sorption (at pH 6.5-7) produced by increasing solution ionic strength was also reproduced in cation exchange models. Overall, the results showed that Sr 2+ sorption to heterogeneous sediment units could be estimated from K d (<2 mm) data using appropriate gravel corrections, and effectively modelled using coupled cation exchange and surface complexation processes., 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., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Pediatric heart (HTx) and kidney transplant (KTx) recipients may have lower physical fitness than healthy children. This study sought to quantify fitness levels in transplant recipients, investigate associations to clinical factors and quality of life, and identify whether a quick, simple wall-sit test is feasible as a surrogate for overall fitness for longitudinal assessment., Methods: Aerobic capacity (6-min walk test, 6MWT), normalized muscle strength, muscle endurance, physical activity questionnaire (PAQ), and quality of life (PedsQL™) were prospectively assessed in transplanted children and matched healthy controls., Results: Twenty-two HTx were compared to 20 controls and 6 KTx. 6MWT %predicted was shorter in HTx (87.2 [69.9-118.6] %) than controls (99.9 [80.4-120] %), but similar to KTx (90.3 [78.6-115] %). Muscle strength was lower in HTx deltoids (6.15 [4.35-11.3] kg/m 2 ) and KTx quadriceps (9.27 [8.65-19.1] kg/m 2 ) versus controls. Similarly, muscle endurance was lower in HTx push-ups (28.6 [0-250] %predicted), KTx push-ups (8.35 [0-150] %predicted), HTx curl-ups (115 [0-450] %predicted), and KTx wall-sit time (18.5 [10.0-54.0] s) than controls. In contrast to HTx with only 9%, all KTx were receiving steroid therapy. The wall-sit test significantly correlated with other fitness parameters (normalized quadriceps strength R = .31, #push-ups R = .39, and #curl-ups R = .43) and PedsQL™ (R = .36)., Conclusions: Compared to controls, pediatric HTx and KTx have similarly lower aerobic capacity, but different deficits in muscle strength, likely related to steroid therapy in KTx. The convenient wall-sit test correlates with fitness and reported quality of life, and thus could be a useful easy routine for longitudinal assessment., (© 2024 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Groundwater flow and contaminant migration tracing is a vital method of identifying and characterising pollutant source-pathway-receptor linkages in karst aquifers. Bacteriophages are an attractive alternative tracer to non-reactive fluorescent dye tracers, as high titres (>10 12 pfu mL -1 ) can be safely released into the aquifer, offering improved tracer detectability. However, the interpretation of bacteriophage tracer breakthrough curves is complicated as their fate and transport are impacted by aquifer physicochemical conditions. A comparative tracer migration experiment was conducted in a peri-urban catchment in southeast England to characterise the behaviour of MS2 bacteriophage relative to sodium fluorescein dye in a karstic chalk aquifer. Tracers were released into a stream sink and detected at two abstraction boreholes located 3 km and 10 km away. At both sites, the loss of MS2 phage greatly exceeded that of the solute tracer. In contrast, the qualitative shape of the dye and phage breakthrough curves were visually very similar, suggesting that the bacteriophage arriving at each site was governed by comparable transport parameters to the non-reactive dye tracer. The colloid filtration theory was applied to explain the apparent contradiction of comparable tracer breakthrough patterns despite massive phage losses in the subsurface. One-dimensional transport models were also fitted to each breakthrough curve to facilitate a quantitative comparison of the transport parameter values. The model results suggest that the bacteriophage migrates through the conduit system slightly faster than the fluorescent dye, but that the former is significantly less dispersed. These results suggest that whilst the bacteriophage tracer cannot be used to predict receptor concentrations from transport via karstic flow paths, it can provide estimates for groundwater flow and solute contaminant transit times. This study also provides insight into the attenuation and transport of pathogenic viruses in karstic chalk aquifers.

Competing Interests: The authors declare no funding or conflicts of interest.

Due to their suppressive capacity, regulatory T cells (Tregs) have attracted growing interest as an adoptive cellular therapy for the prevention of allograft rejection, but limited Treg recovery and lower quality of adult-derived Tregs could represent an obstacle to success. To address this challenge, we developed a new approach that provides large quantities of Tregs with high purity and excellent features, sourced from thymic tissue routinely removed during pediatric cardiac surgeries (thyTregs). We report on a 2-year follow-up of the first patient treated worldwide with thyTregs, included in a phase I/II clinical trial evaluating the administration of autologous thyTreg in infants undergoing heart transplantation. In addition to observing no adverse effects that could be attributed to thyTreg administration, we report that the Treg frequency in the periphery was preserved during the 2-year follow-up period. These initial results are consistent with the trial objective, which is to confirm safety of the autologous thyTreg administration and its capacity to restore the Treg pool., (© 2023 Bernaldo-de-Quirós et al.)

Many healthcare facilities in the United States currently utilize electronic health record triggers to promote and facilitate palliative care referral. The purpose of this study was to explore perceived needs regarding electronic health record trigger criteria for palliative care referral among healthcare providers caring for seriously ill adult hospitalized patients in a teaching hospital in New York State. A qualitative descriptive approach was utilized with use of individual semistructured interviews. Braun and Clarke's Reflexive Thematic Analysis method was used to analyze data. Data analysis generated one overarching theme, I'm in Favor of an Electronic Health Record Automatic Trigger for Palliative Care , and three key themes, Build a Checklist Screening Tool Into Epic With Predefined Conditions and a Palliative Consult in the Admission Order Set , If Providers Call a Palliative Care Consult Sooner, We Give Patients a Better Quality of Life , and Providers Need to Be Aware of the Different Facets of What Palliative Care Actually Does. Findings revealed that all participants supported incorporating electronic health record palliative care triggers. Future research is needed exploring provider palliative care education approaches to promote understanding of palliative care services and to address personal and/or professional bias., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: "Natural" ABO antibodies (Abs) are produced without known exposure to A/B carbohydrate antigens, posing significant risks for hyperacute rejection during ABO-incompatible transplantation. We investigated anti-A "natural" ABO antibodies versus intentionally induced Abs with regard to the need for T-cell help, the impact of sex, and stimulation by the microbiome., Methods: Anti-A was measured by hemagglutination assay of sera from untreated C57BL/6 wild-type (WT) or T cell-deficient mice of both sexes. Human ABO-A reagent blood cell membranes were injected intraperitoneally to induce anti-A Abs. The gut microbiome was eliminated by maintenance of mice in germ-free housing., Results: Compared with WT mice, CD4 + T-cell knockout (KO), major histocompability complex-II KO, and αβ/γδ T-cell receptor KO mice produced much higher levels of anti-A nAbs; females produced dramatically more anti-A nAbs than males, rising substantially with puberty. Sensitization with human ABO-A reagent blood cell membranes did not induce additional anti-A in KO mice, unlike WT. Sex-matched CD4 + T-cell transfer significantly suppressed anti-A nAbs in KO mice and rendered mice responsive to A-sensitization. Even under germ-free conditions, WT mice of several strains produced anti-A nAbs, with significantly higher anti-A nAbs levels in females than males., Conclusions: Anti-A nAbs were produced without T-cell help, without microbiome stimulation, in a sex- and age-dependent manner, suggestive of a role for sex hormones in regulating anti-A nAbs. Although CD4 + T cells were not required for anti-A nAbs, our findings indicate that T cells regulate anti-A nAb production. In contrast to anti-A nAbs, induced anti-A production was T-cell dependent without a sex bias., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Ventricular assist devices (VADs) have improved survival to heart transplantation (HTx). However, VADs have been associated with development of antibodies against human leukocyte antigen (HLA-Ab) which may limit the donor pool and decrease survival post-HTx. Since HLA-Ab development after VAD insertion is poorly understood, the purpose of this prospective single-center study was to quantify the incidence of and evaluate risk factors for HLA-Ab development across the age spectrum following VAD implantation., Methods: Adult and pediatric patients undergoing VAD placement as bridge to transplant or transplant candidacy between 5/2016 and 7/2020 were enrolled. HLA-Ab were assessed pre-VAD and at 1-, 3-, and 12-months post-implant. Factors associated with HLA-Ab development post-VAD implant were explored using univariate and multivariate logistic regression., Results: 15/41 (37%) adults and 7/17 (41%) children developed new HLA-Ab post-VAD. The majority of patients (19/22) developed HLA-Ab within two months of implant. New class I HLA-Ab were more common (87% adult, 86% pediatric). Prior pregnancy was strongly associated with HLA-Ab development in adults post-VAD (HR 16.7, 95% CI 1.8-158, p = 0.01). Of the patients who developed new HLA-Ab post-VAD, in 45% (10/22) the HLA-Ab resolved while in 55% (12/22) the HLA-Ab persisted., Conclusion: More than one-third of adult and pediatric VAD patients developed new HLA-Ab early after VAD implant with the majority having class I antibodies. Prior pregnancy was strongly associated with post-VAD HLA-Ab development. Further studies are needed to predict regression or persistence of HLA-Ab developed post-VAD, to understand modulation of individuals' immune responses to sensitizing events, and to determine whether transiently detected HLA-Ab post-VAD recur and have long-term clinical impact post-heart transplantation., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Immunomodulatory Siglecs are controlled by their glycoprotein and glycolipid ligands. Siglec-glycolipid interactions are often studied outside the context of a lipid bilayer, missing the complex behaviors of glycolipids in a membrane. Through optimizing a liposomal formulation to dissect Siglec-glycolipid interactions, it is shown that Siglec-6 can recognize glycolipids independent of its canonical binding pocket, suggesting that Siglec-6 possesses a secondary binding pocket tailored for recognizing glycolipids in a bilayer. A panel of synthetic neoglycolipids is used to probe the specificity of this glycolipid binding pocket on Siglec-6, leading to the development of a neoglycolipid with higher avidity for Siglec-6 compared to natural glycolipids. This neoglycolipid facilitates the delivery of liposomes to Siglec-6 on human mast cells, memory B-cells and placental syncytiotrophoblasts. A physiological relevance for glycolipid recognition by Siglec-6 is revealed for the binding and internalization of extracellular vesicles. These results demonstrate a unique and physiologically relevant ability of Siglec-6 to recognize glycolipids in a membrane., (© 2023. The Author(s).)

Background: ABO-incompatible transplantation has improved accessibility of kidney, heart, and liver transplantation. Pancreatic islet transplantation continues to be ABO-matched, yet ABH antigen expression within isolated human islets or novel human embryonic stem cell (hESC)-derived islets remain uncharacterized., Methods: We evaluated ABH glycans within human pancreata, isolated islets, hESC-derived pancreatic progenitors, and the ensuing in vivo mature islets following kidney subcapsular transplantation in rats. Analyses include fluorescence immunohistochemistry and single-cell analysis using flow cytometry., Results: Within the pancreas, endocrine and ductal cells do not express ABH antigens. Conversely, pancreatic acinar tissues strongly express these antigens. Acinar tissues are present in a substantial portion of cells within islet preparations obtained for clinical transplantation. The hESC-derived pancreatic progenitors and their ensuing in vivo-matured islet-like clusters do not express ABH antigens., Conclusions: Clinical pancreatic islet transplantation should remain ABO-matched because of contaminant acinar tissue within islet preparations that express ABH glycans. Alternatively, hESC-derived pancreatic progenitors and the resulting in vivo-matured hESC-derived islets do not express ABH antigens. These findings introduce the potential for ABO-incompatible cell replacement treatment and offer evidence to support scalability of hESC-derived cell therapies in type 1 diabetes., Competing Interests: A.M.J.S. is supported through a Canada Research Chair (Tier 1) in Regenerative Medicine and Transplant Surgery, and through grant support from the Juvenile Diabetes Research Foundation, Diabetes Canada, the Canadian Donation and Transplant Research Program, the Diabetes Research Institute Foundation of Canada, the Alberta Diabetes Foundation, and the Canadian Stem Cell Network. B.A.M.-G. is supported by the Patronato del Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ), the Fundacion para la Salud y la Educacion Dr. Salvador Zubirán (FunSaEd), and the CHRISTUS Excellence and Innovation Center. A.M.J.S. serves as a consultant to ViaCyte Inc. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite heart and lung transplantation being life-saving therapies for children and adolescents, little research has focused on recipients' lived experience post-transplant. This study captures the subjective experiences of adolescent thoracic transplant recipients, providing insight into the impact of life changes following transplantation in this population., Methods: A grounded theory approach guided an iterative process of data collection and data analysis. Adolescent heart and lung transplant recipients were recruited from a large Canadian pediatric teaching hospital to participate in one-on-one semi-structured interviews. Analysis using line-by-line coding and constant comparison methods facilitated reflection and agreement on categories and emergent themes., Results: A total of 27 heart and 5 lung transplant recipients (66% female) participated at a median age of 15.9 years and a median time post-transplant of 2.7 years. Participant narratives illuminated three themes describing (1) personal growth - an awareness of personal strengths and coping abilities, (2) relationship growth - a greater appreciation for family and friends, and (3) introspective growth - a developing life philosophy. Findings suggest that adolescents experience an emergent 'transplanted self', positioning thoracic transplantation as a potential catalyst for positive growth and personal change., Conclusions: The study findings describe pediatric thoracic transplantation as potentially transformative in nature and sheds light on the application of post-traumatic growth theory. Practitioners and researchers are encouraged to acknowledge the possibility of growth, transformation, and positive change that may be possible within the adolescent thoracic transplant experience and leverage such strengths in clinical care., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The COVID-19 pandemic has had deleterious impacts on pediatric patients and families, as well as the healthcare providers who have attended to their care needs., Methods: In this qualitative study, children with a cardiac transplant, as well as their families and healthcare providers were interviewed to explore the impact of the COVID-19 pandemic on pediatric care, as well as on patients' and their families' daily lives. Participants were recruited from a children's hospital in western Canada. Fifteen caregiving parents of transplanted children, 2 young patients, and 8 healthcare providers participated in interviews., Results: Findings highlighted how families and their healthcare providers experienced pandemic-related shifts. Themes highlighted experiences, which entailed (1) initially hearing about the COVID-19 pandemic; (2) learning about their new reality; (3) adjusting to the pandemic; (4) adjusting to shifts in pediatric services; (5) evolving a view on the future, and (6) offering recommendations for cardiac care in a pandemic., Conclusions: Study implications emphasize the need to critically reflect on, and advance, methods of helping young patients and their families in pandemic circumstances, and supporting healthcare providers., (© 2022 Wiley Periodicals LLC.)

The advancement of women's careers in transplantation continues to be challenging. Academic careers in both basic and clinical disciplines in transplantation, such as surgery and management of end organ failure in medical specialties, have been underrepresented by diverse genders and ethnicities. Over the last decade, the Women in Transplantation Initiative (WIT) has solidified to becoming an internationally recognized organization with activities focused on diversity and inclusion in terms of the sexes. The WIT organization is divided into 3 pillars that address career advancement and networking (Pillar 1), scientific investigation and presentations on sex and gender in transplantation (Pillar 2) and investigating and facilitating equitable access to transplantation for women throughout the world (Pillar 3). By taking this multipronged approach of collaborating across continents, leveraging virtual platforms for information dissemination and discussion, and providing financial support for research, WIT has become a highly visible grass roots organization that aims to improve the experience of women as transplant professionals as well as transplant donors and recipients., Competing Interests: The authors are members of the WIT leadership and wish to thank their industry partners: Novartis, Sanofi, ThermoFisher-One Lambda, and Veloxis for their continued unrestricted support of activities in Women in Transplantation., (Copyright © 2022 Mannon, Reed, Melk, Vinson, Wong, Ahn, Davidson, Foster, West, Tait and Chong.)

Synthetic glycoconjugates are used in the development of vaccines and the design of inhibitors for glycan-protein interactions. The in vivo persistence of synthetic glycoconjugates is an important factor in their efficacy, especially when prolonged interactions with specific cell types may be required. In this study, we applied a strategy for non-covalent association of an active compound with serum proteins for extension of glycoconjugate half-life in serum. The small molecule, AG10, has previously been used to extend the half-life of small molecules through its high affinity for transthyretin (TTR), a serum protein. Using a tetravalent polyethylene glycol (PEG)-based scaffold we developed a synthetic strategy for glycoconjugates that allowed for controlled addition of multiple tags, such as a TTR affinity tag or fluorophore. We designed a version of AG10 modified at the pyrazole core, named GD10, amenable to our conjugation strategy and introduced to glycoconjugates using a tri-functional linker. This approach allowed for attachment of GD10 and fluorophore tags, as well as carbohydrate antigens. We then tested the influence of the GD10 tag on glycoconjugate half-life in vivo using a mouse model. Our results suggest that the combination of the GD10 tag and the PEG scaffold extended the half-life of glycoconjugates by as much as 10-fold when compared to proteins of similar molecular weight. The GD10 tag was able to extend the half-life of similar glycoconjugates by as much as 2-fold. We observed a role for the terminal saccharide residue of the carbohydrate antigen and confirmed that conjugates were able to penetrate multiple compartments in vivo including bone marrow, lymph nodes, and other organs. The introduction of the GD10 tag did not obstruct the ability of conjugates to interact with lectin receptors. We conclude that serum protein binders can be used to extend the persistence of glycoconjugates in vivo ., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Atopic disorders are more common in children after heart transplant (HTx). We hypothesized that HTx at an early age and thymus excision (TE) affect development of T and B cells, especially regulatory T cells (Tregs), which help maintain tolerance., Methods: In this single-center study including 24 patients transplanted between 2013 and 2018, we investigated lymphocyte patterns in relation to these factors using flow cytometry. Clinical data were collected from standardized questionnaires and medical charts. Patients were stratified into TE and non-TE groups as well as patients with and without post-transplant atopy development/worsening., Results: 64% of TE patients experienced new or worsening asthma/eczema post-transplant compared to 20% of non-TE patients. TE patients had higher total Treg proportions (CD4+CD25+CD127lo) than non-TE patients (p = .043), but borderline significantly lower naïve Tregs (CD45RA+CD27-) (p = .057). Memory CD4+ T cells were higher in TE patients in trend (p = .084). Total Tregs did not differ between atopic/nonatopic groups, although naïve Tregs were significantly lower in atopic patients (p = .028). Memory CD4+ T cells were higher in atopic patients in trend (p = .082). IgM+IgD+ B cells were higher in nonatopic patients in trend (p = .064)., Conclusions: New/worsening atopy is more common in thymectomized HTx children and is associated with alterations in T-cell profiles. Avoiding TE may prevent these alterations and reduce incidence of atopy post-HTx., (© 2022 Wiley Periodicals LLC.)

Objectives: The COVID-19 pandemic has impacted mental health at a population level. Families of children with health vulnerabilities have been disproportionately affected by pandemic-related policies and service disruptions as they substantially rely on the health and social care system. We elicited the impact of the COVID-19 pandemic on children with health and disability-related vulnerabilities, their families, and their health care providers (HCPs)., Methods: Children with diverse health vulnerabilities (cardiac transplantation, respiratory conditions, sickle cell disease, autism spectrum disorder, mental health issues, and nearing the end of life due to a range of underlying causes), as well as their parents and HCPs, participated in semi-structured interviews. Data were analyzed using qualitative content analysis in determining themes related to impact and recommendations for practice improvement., Results: A total of 262 participants (30 children, 76 parents, 156 HCPs) were interviewed. Children described loneliness and isolation; parents described feeling burnt out; and HCPs described strain and a sense of moral distress. Themes reflected mental health impacts on children, families, and HCPs, with insufficient resources to support mental health; organizational and policy influences that shaped service delivery; and recommendations to enhance service delivery., Conclusion: Children with health vulnerabilities, their families and HCPs incurred profound mental health impacts due to pandemic-imposed public health restrictions and care shifts. Recommendations include the development and application of targeted pandemic information and mental health supports. These findings amplify the need for capacity building, including proactive strategies and mitigative planning in the event of a future pandemic., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Emerging evidence suggests that host glycans influence severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we reveal that the receptor-binding domain (RBD) of the spike (S) protein on SARS-CoV-2 recognizes oligosaccharides containing sialic acid (Sia), with preference for monosialylated gangliosides. Gangliosides embedded within an artificial membrane also bind to the RBD. The monomeric affinities (K d  = 100-200 μM) of gangliosides for the RBD are similar to another negatively charged glycan ligand of the RBD proposed as a viral co-receptor, heparan sulfate (HS) dp2-dp6 oligosaccharides. RBD binding and infection of SARS-CoV-2 pseudotyped lentivirus to angiotensin-converting enzyme 2 (ACE2)-expressing cells is decreased following depletion of cell surface Sia levels using three approaches: sialyltransferase (ST) inhibition, genetic knockout of Sia biosynthesis, or neuraminidase treatment. These effects on RBD binding and both pseudotyped and authentic SARS-CoV-2 viral entry are recapitulated with pharmacological or genetic disruption of glycolipid biosynthesis. Together, these results suggest that sialylated glycans, specifically glycolipids, facilitate viral entry of SARS-CoV-2., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

ABO-incompatible (ABOi) transplantation requires preemptive antibody reduction; however, the relationship between antibody-mediated rejection (AMR) and ABO-antibodies, quantified by hemagglutination (HA), is inconsistent, possibly reflecting variable graft resistance to AMR or HA assay limitations. Using an ABH-glycan microarray, we quantified ABO-A antigen-subtype (A-subtype)-specific IgM and IgG in 53 ABO-O recipients of ABO-A kidneys, before and after antibody removal (therapeutic plasma exchange [TPE] or ABO-A-trisaccharide immunoadsorption [IA]) and 1-year posttransplant. IgM binding to all A-subtypes correlated highly (R 2  ≥ .90) and A-subtype antibody specificities was reduced equally by IA versus TPE. IgG binding to the A-subtypes (II-IV) expressed in kidney correlated poorly (.27 ≤ R 2  ≤ .69). Reduction of IgG specific to A-subtype-II was equivalent for IA and TPE, whereas IgG specific to A-subtypes-III/IV was not as greatly reduced by IA (p < .005). One-year posttransplant, IgG specific to A-II remained the most reduced antibody. Immunostaining revealed only A-II on vascular endothelium but A-subtypes II-III/IV on tubular epithelium. These results show that ABO-A-trisaccharide is sufficient for IgM binding to all A-subtypes; this is true for IgG binding to A-II, but not subtypes-III/IV, which exhibits varying degrees of specificity. We identify A-II as the major, but importantly not the sole, antigen relevant to treatment and immune modulation in adult ABO-A-incompatible kidney transplantation., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Competing Interests: The authors declare no funding or conflicts of interest.

We review scale dependence of hydraulic conductivities and effective porosities for prediction of contaminant transport in four UK karst aquifers. Approaches for obtaining hydraulic parameters include core plug, slug, pumping and pulse tests, calibration of groundwater flow models and spring recession curves. Core plug and slug tests are unsuitable because they do not characterize a large enough volume to include a representative fracture network. Pumping test values match regional-scale hydraulic conductivities from flow modelling for the less intensively karstified aquifers: Magnesian Limestone, Jurassic Limestone and Cretaceous Chalks. Reliable bulk hydraulic conductivities were not available for the intensively karstified Carboniferous Limestone due to dominance of flow through pipe conduits in Mendips. Here, the only hydraulic conductivity value found from spring recession is one order of magnitude higher than that indicated by pumping tests. For all four carbonate aquifers, effective porosities assumed for transport modelling are two orders of magnitude higher than those found from tracer and hydrogeophysical tests. Thus, a combination of low hydraulic conductivities and assumed flowing porosities resulted in underestimated flow velocities. The UK karst aquifers are characterized by a range of hydraulic behaviours that fit those of karst aquifers worldwide. Indeed, underestimation of flow velocity due to inappropriate parameter selection is common to intensively karstified aquifers of southern France, north-western Germany and Italy. Similar issues arise for the Canadian Silurian carbonates where the use of high effective porosities (e.g. 5%) in transport models leads to underestimation of groundwater velocities. We recommend values in the range of 0.01-1% for such aquifers., (© 2021. Crown.)

Background: In Medawar's murine neonatal tolerance model, injection of adult semiallogeneic lymphohematopoietic cells (spleen cells [SC] and bone marrow cells [BMC]) tolerizes the neonatal immune system. An eventual clinical application would require fully allogeneic (allo) cells, yet little is known about the complex in vivo/in situ interplay between those cells and the nonconditioned neonatal immune system., Methods: To this end, labeled adult SC and BMC were injected into allogeneic neonates; interactions between donor and host cells were analyzed and modulated by systematic depletion/inactivation of specific donor and host immune effector cell types., Results: Consistent with effector cell compositions, allo-SC and allo-SC/BMC each induced lethal acute graft-versus-host disease, whereas allo-BMC alone did so infrequently. CD8 T cells from SC inoculum appeared naïve, while those of BMC were more memory-like. Age-dependent, cell-type dominance defined the interplay between adult donor cells and the neonatal host immune system such that if the dominant adult effector type was removed, then the equivalent neonatal one became dominant. Depletion of donor/host peripheral T cells protected against acute graft-versus-host disease and prolonged heart allograft survival; peripheral CD8 T-cell depletion together with CD4 T cell-costimulation blockade induced more robust tolerance., Conclusions: This comprehensive study provides direct observation of the cellular interplay between allogeneic donor and host immune systems, adds to our previous work with semiallogeneic donor cells, and provides important insights for robust tolerance induction. Induction of transplant tolerance in neonates will likely require "crowd sourcing" of multiple tolerizing cell types and involve depletion of immune effector cells with costimulation blockade., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Patient-reported outcome measures (PROMs) are standardized instruments used to collect data about the subjective assessment of medical care from the patient perspective. Implementing PROMs within pediatric clinical settings has gained increasing importance as health services prioritize patient-centred pediatric care. This study explores the perspectives of pediatric solid organ transplant patients, caregivers, and healthcare practitioners (HCPs) on implementing PROMs into clinical practice., Methods: Qualitative description methods were used to elicit stakeholder perspectives. Semi-structured interviews were conducted across five Canadian transplant centres. Purposive sampling was used to obtain maximum variation across age, gender, and transplant program for all participants, as well as discipline for HCPs., Results: The study included a total of 63 participants [patients (n = 20), caregivers (n = 22) and HCPs (n = 21)]. Nearly all participants endorsed the implementation of PROMs to enhance pediatric transplant clinical care. Three primary roles for PROMs emerged: (1) to bring a transplant patient's overall well-being into the clinical care conversation; (2) to improve patient communication and engagement; and, (3) to inform the practice of clinical pediatric transplant care. Insights for effective implementation included completing electronic PROMs remotely and prior to clinical appointments by patients who are eight to 10 years of age or older., Conclusions: This study contributes to current research that supports the use of PROMs in clinical pediatric care and guides their effective implementation into practice. Future directions include the development, usability testing, and evaluation of a proposed electronic PROM platform that will inform future research initiatives.

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are immunomodulatory receptors that are regulated by their glycan ligands. The connections between Siglecs and human disease motivate improved methods to detect Siglec ligands. Here, we describe a new versatile set of Siglec-Fc proteins for glycan ligand detection. Enhanced sensitivity and selectivity are enabled through multimerization and avoiding Fc receptors, respectively. Using these Siglec-Fc proteins, Siglec ligands are systematically profiled on healthy and cancerous cells and tissues, revealing many unique patterns. Additional features enable the production of small, homogenous Siglec fragments and development of a quantitative ligand-binding mass spectrometry assay. Using this assay, the ligand specificities of several Siglecs are clarified. For CD33 (Siglec-3), we demonstrate that it recognizes both α2-3 and α2-6 sialosides in solution and on cells, which has implications for its link to Alzheimer's disease susceptibility. These soluble Siglecs reveal the abundance of their glycan ligands on host cells as self-associated molecular patterns.

As allergists, we are frequently consulted to evaluate patients with swelling presumed to be angioedema. Patients with presumed angioedema can have multiple possible underlying triggers. We present the case of a hospitalized 72-year-old woman with a history of hypertension and metastatic chordoma who developed marked periorbital swelling that precluded eye opening 2 days after a neurosurgical operation (chordoma resection and T10-11 hardware repair). After a detailed evaluation of her swelling, a broad differential diagnosis was made; she did not respond to high-dose antihistamines, systemic steroids, icatibant and angiotensin-converting enzyme inhibitor cessation. Ultimately, computed tomography imaging confirmed a specific diagnosis. The differential diagnosis for swelling is complex, and this case illustrated the importance of considering alternative causes of swelling when evaluating cases of possible angioedema.

Background: Ventricular assist device (VAD) therapy has become an important tool for end-stage heart failure. VAD therapy has increased survival but is associated with complications including the development of human leukocyte antigen (HLA) antibodies. We sought to determine the incidence of HLA antibody development post-VAD insertion, across the age spectrum, in patients receiving leukocyte-reduced blood products, with standardized HLA antibody detection methods and to investigate factors associated with antibody development., Methods: This was a retrospective analysis of all patients who underwent durable VAD placement between 2005 and 2014. Inclusion criteria included availability of pre- and post-VAD HLA antibody results. Associations between HLA antibody development in the first-year postimplant and patient factors were explored., Results: Thirty-nine adult and 25 pediatric patients made up the study cohort. Following implant, 31% and 8% of patients developed new class I and class II antibodies. The proportion of newly sensitized patients was similar in adult and pediatric patients. The class I HLA panel reactive antibody only significantly increased in adults. Pre-VAD sensitization, age, sex (pediatrics), and transfusion were not associated with the development of HLA antibodies., Conclusions: In a cohort of VAD patients receiving leukocyte-reduced blood products and standardized HLA antibody testing, roughly one-third developed new class I antibodies in the first-year postimplant. Adults showed significantly increased class I panel reactive antibody following VAD support. No patient-related factors were associated with HLA antibody development. Larger prospective studies are required to validate these findings and determine the clinical impact of these antibodies following VAD insertion.

Regulatory T cells (Tregs) are a promising therapy for several immune-mediated conditions but manufacturing a homogeneous and consistent product, especially one that includes cryopreservation, has been challenging. Discarded pediatric thymuses are an excellent source of therapeutic Tregs with advantages including cell quantity, homogeneity and stability. Here we report systematic testing of activation reagents, cell culture media, restimulation timing and cryopreservation to develop a Good Manufacturing Practice (GMP)-compatible method to expand and cryopreserve Tregs. By comparing activation reagents, including soluble antibody tetramers, antibody-conjugated beads and artificial antigen-presenting cells (aAPCs) and different media, we found that the combination of Dynabeads Treg Xpander and ImmunoCult-XF medium preserved FOXP3 expression and suppressive function and resulted in expansion that was comparable with a single stimulation with aAPCs. Cryopreservation tests revealed a critical timing effect: only cells cryopreserved 1-3 days, but not >3 days, after restimulation maintained high viability and FOXP3 expression upon thawing. Restimulation timing was a less critical process parameter than the time between restimulation and cryopreservation. This systematic testing of key variables provides increased certainty regarding methods for in vitro expansion and cryopreservation of Tregs. The ability to cryopreserve expanded Tregs will have broad-ranging applications including enabling centralized manufacturing and long-term storage of cell products., (Copyright © 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Viruses and bacteria which are characterized by finite lives in the subsurface are rapidly transported via fractures and cavities in fractured and karst aquifers. Here, we demonstrate how the coupling of a robust outcrop characterization and hydrogeophysical borehole testing is essential for prediction of contaminant velocities and hence wellhead protection areas. To show this, we use the dolostones of the Permian Magnesian Limestone aquifer in NE England, where we incorporated such information in a groundwater flow and particle tracking model. Within this aquifer, flow in relatively narrow (mechanical aperture of ~ 10 -1 -1 mm) fractures is coupled with that in pipe cavities (~ 0.20-m diameter) following normal faults. Karstic cavities and narrow fractures are hydraulically very different. Thus, the solutional features are represented within the model by a pipe network (which accounts for turbulence) embedded within an equivalent porous medium representing Darcian flowing fractures. Incorporation of fault conduits in a groundwater model shows that they strongly influence particle tracking results. Despite this, away from faulted areas, the effective flow porosity of the equivalent porous medium remains a crucial parameter. Here, we recommend as most appropriate a relatively low value of effective porosity (of 2.8 × 10 -4 ) based on borehole hydrogeophysical testing. This contrasts with earlier studies using particle tracking analyses on analogous carbonate aquifers, which used much higher values of effective porosity, typically ~ 10 2 times higher than our value, resulting in highly non-conservative estimates of aquifer vulnerability. Low values of effective flow porosities yield modelled flow velocities ranging from ~ 100 up to ~ 500 m/day in un-faulted areas. However, the high fracturing density and presence of karstic cavities yield modelled flow velocities up to ~ 9000 m/day in fault zones. The combination of such flow velocities along particle traces results in 400-day particle traces up to 8-km length, implying the need for large well protection areas and high aquifer vulnerability to slowly degrading contaminants.

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed., (© 2019 by The American Society of Hematology.)

Contaminants that are highly soluble in groundwater are rapidly transported via fractures in mechanically resistant sedimentary rock aquifers. Hence, a rigorous methodology is needed to estimate groundwater flow velocities in such fractured aquifers. Here, we propose an approach using borehole hydraulic testing to compute flow velocities in an un-faulted area of a fractured carbonate aquifer by applying the cubic law to a parallel plate model. The Cadeby Formation (Yorkshire, NE England) - a Permian dolostone aquifer present beneath the University of Leeds Farm - is the fractured aquifer selected for this hydraulic experiment. The bedding plane fractures of this dolostone aquifer, which are sub-horizontal, sub-parallel and laterally persistent, largely dominate the flow at shallow (<~40 mBGL) depths. These flowing bedding plane discontinuities are separated by a rock matrix which is relatively impermeable (K well-test /K core-plug ~10 4 ) as is common in fractured carbonate aquifers. In the workflow reported here, the number of flowing fractures - mainly bedding plane fractures - intersecting three open monitoring wells are found from temperature/fluid conductivity and acoustic/optical televiewer logging. Following well installation, average fracture hydraulic apertures for screened intervals are found from analysis of slug tests. For the case study aquifer, this workflow predicts hydraulic apertures ranging from 0.10 up to 0.54 mm. However, groundwater flow velocities range within two order of magnitude from 13 up to 242 m/day. Notably, fracture apertures and flow velocities rapidly reduce with increasing depth below the water table; the upper ~10 m shows relatively high values of hydraulic conductivity (0.30-2.85 m/day) and corresponding flow velocity (33-242 m/day). Permeability development around the water table in carbonate aquifer-types is common, and arises where high pCO 2 recharge water from the soil zone causes calcite/dolomite dissolution. Hence, agricultural contaminants entering the aquifer with recharge water are laterally transported rapidly within this upper part. Computation of groundwater flow velocities allows determination of the Reynolds number. Values of up ~1, indicating the lower limit of the transition from laminar to turbulent flow, are found at the studied site, which is situated away from major fault traces. Hence, turbulent flow is likely to arise in proximity to tectonic structures, such as normal faults, which localize flow and enhance karstification. The occurrence of turbulent flow in correspondence of such tectonic structures should be represented in regional groundwater flow simulations., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)