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Type 2 immunity is a stereotyped host response to allergens and parasitic helminths that is sustained in large part by the cytokines IL-4 and IL-13. Recent advances have called attention to the contributions by innate cells in initiating adaptive immunity, including a novel lineage-negative population of cells that secretes IL-13 and IL-5 in response to the epithelial cytokines IL-25 and IL-33. Here, we use IL-4 and IL-13 reporter mice to track lineage-negative innate cells that arise during type 2 immunity or in response to IL-25 and IL-33 in vivo. Unexpectedly, lineage-negative IL-25 (and IL-33) responsive cells are widely distributed in tissues of the mouse and are particularly prevalent in mesenteric lymph nodes, spleen, and liver. These cells expand robustly in response to exogenous IL-25 or IL-33 and after infection with the helminth Nippostrongylus brasiliensis, and they are the major innate IL-13—expressing cells under these conditions. Activation of these cells using IL-25 is sufficient for worm clearance, even in the absence of adaptive immunity. Widely dispersed innate type 2 helper cells, which we designate Ih2 cells, play an integral role in type 2 immune responses.

Interleukin (IL)-17A plays an important role in host defense against a variety of pathogens and may also contribute to the pathogenesis of autoimmune diseases. However, precise identification and quantification of the cells that produce this cytokine in vivo have not been performed. We generated novel IL-17A reporter mice to investigate expression of IL-17A during Klebsiella pneumoniae infection and during experimental autoimmune encephalomyelitis, conditions previously demonstrated to potently induce IL-17A production. In both settings, the majority of IL-17A was produced by non-CD4(+) T cells, particularly γδ T cells, but also invariant NKT cells and other CD4(-)CD3ε(+) cells. As measured in dual-reporter mice, IFN-γ-producing Th1 cells greatly outnumbered IL-17A-producing Th17 cells throughout both challenges. Production of IL-17A by cells from unchallenged mice or by non-T cells under any condition was not evident. Administration of IL-1β and/or IL-23 elicited rapid production of IL-17A by γδ T cells, invariant NKT cells and other CD4(-)CD3ε(+) cells in vivo, demonstrating that these cells are poised for rapid cytokine production and likely comprise the major sources of this cytokine during acute immunologic challenges.

The role of class IA phosphoinositide 3 kinases (PI3Ks) in immune function and regulation continues to expand with the identification of greater numbers of genetic variants. This case report is the second reported case of a homozygous premature stop codon within the PIK3R1 gene leading to autosomal recessive agammaglobulinemia. The proband, born to consanguineous parents, presented at 10 months of age with a history of oropharyngeal petechiae and bleeding from the mouth, gums, and tear ducts. Initial investigations revealed thrombocytopenia, neutropenia and the absence of B cells. Further genetic testing via a custom next-generation sequencing panel confirmed the presence of a homozygous mutation in PIK3R1, c.901 C>T, a premature stop codon at amino acid position 301. Given their many roles in immune regulation, recessive mutations in the PlK3R1 gene should be considered in infants presenting with hypogammaglobulinemia or agammaglobulinemia, particularly in the setting of parental consanguinity.

Background Newborn screening (NBS) for cystic fibrosis (CF) not only identifies infants with a diagnosis of CF, but also those with an uncertain diagnosis of cystic fibrosis (CF), i.e. CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive inconclusive diagnosis (CFSPID). These infants have an uncertain long-term outcome and it is currently unclear around time of diagnosis, which infants are at higher risk of later fulfilling a CF diagnosis. In this study, we hypothesised that immunoreactive trypsinogen (IRT) levels, used in NBS as a marker of pancreatic disease and function, may reflect the degree of CFTR dysfunction in each individual and therefore would help to identify those with CRMS/CSPID who are later at risk for meeting the criteria of CF. Methods In this longitudinal, prospective study, infants with CRMS/CFSPID and CF were recruited and followed in 9 CF clinics (Canada and Italy). We compared NBS IRT levels between CF and CRMS/CFSPID, and between children with CRMS/CFSPID→CF and CRMS/CFSPID→CRMS/CFSPID during the period of June 2007 to April 2016. Results Ninety eight CRMS/CFSPID and 120 CF subjects were enrolled. During the study period, 14 (14.3%) CRMS/CFSPID subjects fulfilled the diagnostic criteria for CF (CRMS/CFSPID→CF), while the diagnosis remained uncertain (CRMS/CFSPID→ CRMS/CFSPID) in 84 (85.7%) subjects. Significantly higher NBS IRT concentrations (ng/ml) were present in CF than CRMS/CFPSID (median (interquartile range): 143.8 (99.8–206.2) vs. 75.0 (61.0–105.9); P  < 0.0001). Infants with CRMS/CFSPID→CF ( n  = 14) had significantly higher NBS IRT concentrations (ng/ml) than CRMS/CFSPID→ CRMS/CFSPID ( n  = 83) (median (interquartile range): 108.9 (72.3–126.8) vs. 73.7(60.0–96.0); P  = 0.02). Conclusions Amongst infants who tested positive on NBS for CF, there is a gradation of elevated NBS IRT concentrations. Infants with CF have higher NBS IRT levels than CRMS/CFPSID, and higher NBS IRT concentrations were present in infants with CRMS/CFSPID→CF than CRMS/CFSPID→ CRMS/CFSPID. NBS IRT concentrations, in concert with other factors, may have the potential to predict the likelihood of CF amongst infants with CRMS/CFSPID.

Objective Health care is a significant contributor to the climate crisis. Multidisciplinary clinics (MDC) may reduce carbon emissions by combining multiple appointments into one. This is the first program evaluation study to quantify the carbon footprint associated with multidisciplinary pediatric airway clinics. Study Design Retrospective. Setting Children's Hospital at London Health Sciences Center, London, Canada. Methods Pediatric airway MDC allows patients to see otolaryngology and respirology in one appointment. The carbon and financial savings (Canadian Dollars) of all patients attending the MDC from January 1, 2018 to December 31, 2022 were calculated. Patient postal codes and institutional parking rates were inputted into the CASCADES carbon accounting tool. Total distance was divided into unsustainable (vehicles) and sustainable (transit, walking, cycling) transportation to calculate carbon emissions. Travel costs included cost/kilometer for vehicles (maintenance, license/registration, insurance, fuel) and costs/ride for transit. Results A total of 560 MDC appointments for 300 patients saved 77,785 km. Total carbon emissions saved from travel averted was 16.21 tonnes. The total carbon emissions saved, minus public transit, was 15.60 tonnes. Using the Natural Resources Canada Greenhouse Gas Equivalencies Calculator, 16.21 tonnes are approximately equivalent to 5 passenger vehicles, 6906 L of gasoline, 3.8 homes' energy, and 10.8 homes' electricity use for one year, 36.6 barrels of oil consumed, and 675 propane cylinders. Travel costs of$28,891.83 (no parking), $ 30,519.40 ( $4 minimum parking fee), or $ 33,774.55 ($12 maximum parking fee) were saved. Conclusion MDC effectively reduced carbon emissions and offered patients financial savings. Similar models can be adapted across institutions to help mitigate climate change.

Background: Patients with cystic fibrosis (CF) have frequent infectious complications requiring nephrotoxic medications, necessitating monitoring of renal function. Although adult studies have suggested that cystatin C (CysC)-based estimated glomerular filtration rate (eGFR) may be preferable due to reduced muscle mass of patients with CF, pediatric patients remain understudied. Objective: Our objective was to determine which eGFR formula is best for estimating glomerular filtration rate (GFR) in pediatric patients with CF. Methods: A total of 17 patients with CF treated with nephrotoxic antibiotics were recruited from the Children’s Hospital at London Health Sciences Centre, London, Ontario, Canada. 99Tc DTPA GFR (measured GFR [mGFR]) was measured with 4-point measurements starting at 120 minutes using a 2-compartmental model with Brøchner-Mortensen correction, with simultaneous measurement of creatinine, urea, and CysC. The eGFR was calculated using 16 known equations based on creatinine, urea, CysC, or combinations of these. Primary outcome measures were correlation with mGFR, and agreement within 10% for various eGFR equations. Results: Mean mGFR was 136 ± 21 mL/min/1.73 m2. Mean creatinine, CysC, and urea were 38 ± 10 μmol/L, 0.72 ± 0.08 mg/L, and 3.9 ± 1.4 mmol/L, respectively. The 2014 Grubb CysC eGFR had the best correlation coefficient (r = 0.75, P = .0004); however, only 35% were within 10%. The new Schwartz formula with creatinine and urea had the best agreement within 10%, but a relatively low correlation coefficient (r = 0.63, P = .0065, 64% within 10%). Conclusions: Our study suggests that none of the eGFR formulae work well in this small cohort of pediatric patients with CF with preserved body composition, possibly due to inflammation causing false elevations of CysC. Based on the small numbers, we cannot conclude which eGFR formula is best.

Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10−44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

Background. Placental malaria (PM) and maternal infection with human immunodeficiency virus (HIV) type 1 have been shown to affect infant morbidity and immune responses to Plasmodium falciparum. We studied the effects of PM and HIV infection on the antimalarial antibody responses and morbidity outcomes of infants throughout the first year of life. Methods. A total of 411 Kenyan infants who were born to mothers who were singly or dually infected with PM and/or HIV had their levels of immunoglobulin G antibody to 6 P. falciparum antigens/epitopes (apical membrane antigen-1, erythrocyte-binding antigen-175; liver-stage antigen-1 [LSA-1], circumsporozoite protein [CSP], merozoite surface protein-2, and rhoptry-associated protein-1 [RAP-1]) and to tetanus toxoid (TT) tested using enzyme-linked immunosorbent assay. Results. PM had little effect on the antibody responses of infants, whereas maternal HIV infection resulted in decreased levels of antibody to LSA-1, CSP, and RAP-1 epitopes at birth, compared with the absence of PM and maternal HIV infection (P < .0063). Levels of antibodies to TT were significantly reduced in infants born to mothers coinfected with HIV and PM, compared with the levels noted in infants born to HIV-negative mothers (P < .0003). In HIV-infected infants, levels of antibody to TT were reduced, but levels of antibody to malarial antigens were not. Antimalarial antibody levels were positively associated with malaria-related morbidity outcomes. Conclusion. Infant HIV infection and maternal coinfection with HIV and PM negatively influence antibody responses to TT, but not those to malarial antigens, in infants. Antimalarial antibodies rarely showed protective associations with morbidity in infants and were more often a marker for malaria exposure and risk of infection.

Abstract Background Cystic fibrosis (CF) is an autosomal recessive disease that can present with multisystem manifestations based on mutations in the CF transmembrane regulator (CFTR) gene. Screening for CF was added to the Newborn Screening Ontario (NSO) program in 2008 using immunoreactive trypsinogen and genetic testing with a panel of 39 + 3 polymorphisms. From 2008-2020, our centre had all referred screen positive individuals undergo confirmatory genetic testing with an expanded panel of 70 + 4 polymorphisms, occasionally identifying a second mutation of varying clinical consequence. If an individual had a second mutation identified on our panel, prospective follow-up was offered. Objectives The aim of the study is to evaluate the utility of our expanded panel and subsequent identification of individuals with possible CFTR dysfunction. Design/Methods We conducted a retrospective descriptive analysis of our database of screen positive individuals, focusing on the subset who had a second mutation identified through expanded panel and whom we have offered clinical follow-up for 12 years. Results From 2008 to 2020, 718 screen positive individuals were referred to our CF Canada-accredited centre. 566 had one mutation identified by NSO. 94 of these had a second mutation identified on expanded panel. Of these, 13 had a sweat chloride between 30-60 mmol/L and 7 had a positive sweat test. Of those with borderline or negative sweats, 9 individuals continued to be followed. Two have converted to positive sweats, with 1 of these individuals requiring antibiotics for pulmonary exacerbations and the other remaining asymptomatic. Another 2 individuals are trending toward positive sweats (> 50 mmol/L). All spirometry values (FEV1, FVC) have been normal to date, and none have grown Pseudomonas aeruginosa. Conclusion Use of a confirmatory expanded panel identified a second mutation in 94 newborns referred with a positive screen. Offering follow-up has allowed us to monitor clinical progression, including conversion to positive sweats in 2 individuals. While spirometry and cultures have been unremarkable, more sensitive measures such as lung clearance index could be considered for future study. As of 2020, NSO moved to the use of extended sequencing and analysis of this change is ongoing.

Purpose Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator ( CFTR ), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis–related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. Methods Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n  = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n  = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. Results The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1 , which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. Conclusion We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.