Regulation of mast cells by overlapping but distinct protein interactions of Siglec-6 and Siglec-8.

BACKGROUND: Sialic acid-binding immunoglobulin-like lectin (Siglec)-6 and Siglec-8 are closely related mast cell (MC) receptors with broad inhibitory activity, but whose functional differences are incompletely understood. METHODS: Proteomic profiling using quantitative mass spectrometry was performed on primary mouse MCs to identify proteins associated with Siglec-6 and Siglec-8. For functional characterization, each receptor was evaluated biochemically and in ex vivo and in vivo inhibition models of IgE and non-IgE-mediated MC activation in Siglec-6- or Siglec-8-expressing transgenic mice. RESULTS: Siglec-6 and Siglec-8 were found in MCs within large complexes, interacting with 66 and 86 proteins, respectively. Strikingly, Siglec-6 and Siglec-8 interacted with a large cluster of proteins involved in IgE and non-IgE-mediated MC activation, including the high affinity IgE receptor, stem cell factor (SCF) receptor KIT/CD117, IL-4 and IL-33 receptors, and intracellular kinases LYN and JAK1. Protein interaction networks revealed Siglec-6 and Siglec-8 had overlapping yet distinct MC functions, with a potentially broader regulatory role for Siglec-6. Indeed, Siglec-6 preferentially interacted with the mature form of KIT at the cell surface, and treatment with an anti-Siglec-6 antibody significantly inhibited SCF-mediated MC activation more in comparison to targeting Siglec-8. CONCLUSION: These data demonstrate a central role for Siglec-6 and Siglec-8 in controlling MC activation through interactions with multiple activating receptors and key signaling molecules. Our findings suggest that Siglec-6 has a role distinct from that of Siglec-8 in regulating MC function and represents a distinct potential therapeutic target in mast cell-driven diseases.

Evaluation of the association between patent ductus arteriosus approach and neurodevelopment in extremely preterm infants.

OBJECTIVE: Assess if unit-level PDA management correlates with neurodevelopmental impairment (NDI) at 18-24 months corrected postnatal age (CPA) in extremely preterm infants. STUDY DESIGN: Retrospective analysis of infants born at <29 weeks (2014-2017) across two units having distinct PDA strategies. Site 1 utilized an echocardiography-based treatment strategy aiming for accelerated closure (control). Site 2 followed a conservative approach. PRIMARY ENDPOINT: NDI, characterized by cerebral palsy, any Bayley-III composite score <85, sensorineural/mixed hearing loss, or at least unilateral visual impairment. RESULTS: 377 infants were evaluated. PDA treatment rates remained unchanged in Site 1 but eventually reached 0% in Site 2. Comparable rates of any/significant NDI were seen across both sites (any NDI: 38% vs 36%; significant NDI: 13% vs 10% for Site 1 and 2, respectively). After adjustments, NDI rates remained similar. CONCLUSION: PDA management strategies in extremely preterm newborns showed no significant impact on neurodevelopment outcomes at 18-24 months CPA.

Multisystem inflammatory syndrome in 1.2 million children: longitudinal cohort study of risk factors.

BACKGROUND: We identified patient characteristics associated with an increased risk of developing MIS-C. METHODS: We conducted a longitudinal cohort study of 1,195,327 patients aged 0-19 years between 2006 and 2021, including the first two waves of the pandemic (February 25-August 22, 2020 and August 23, 2020-March 31, 2021). Exposures included prepandemic morbidity, birth outcomes, and family history of maternal disorders. Outcomes included MIS-C, Kawasaki disease, and other Covid-19 complications during the pandemic. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) for the association between patient exposures and these outcomes using log-binomial regression models adjusted for potential confounders. RESULTS: Among 1,195,327 children, 84 developed MIS-C, 107 Kawasaki disease, and 330 other Covid-19 complications during the first year of the pandemic. Prepandemic hospitalizations for metabolic disorders (RR 11.3, 95% CI 5.61-22.6), atopic conditions (RR 3.34, 95% CI 1.60-6.97), and cancer (RR 8.11, 95% CI 1.13-58.3) were strongly associated with the risk of MIS-C, compared with no exposure. These same exposures were also associated with Kawasaki disease and other Covid-19 complications. However, birth characteristics and history of maternal morbidity were not associated with MIS-C development. CONCLUSIONS: Children with pre-existing morbidity have a considerably elevated risk of MIS-C. IMPACT: Morbidities that predispose children to multisystem inflammatory syndrome (MIS-C) are unclear. In this study, prepandemic hospitalizations for metabolic disorders, atopic conditions, and cancer were associated with an elevated risk of MIS-C. Birth characteristics and family history of maternal morbidity were not, however, associated with MIS-C. Pediatric morbidities may play a greater role in MIS-C onset than maternal or perinatal characteristics, and may help clinicians better recognize children at risk for this complication.

Macro- and micro-scale culture environment differentially regulate the effects of crowding on macrophage function.

Macrophages hold vital roles in immune defense, wound healing, and tissue homeostasis, and have the exquisite ability to sense and respond to dynamically changing cues in their microenvironment. Much of our understanding of their behavior has been derived from studies performed using in vitro culture systems, in which the cell environment can be precisely controlled. Recent advances in miniaturized culture platforms also offer the ability to recapitulate some features of the in vivo environment and analyze cellular responses at the single-cell level. Since macrophages are sensitive to their surrounding environments, the specific conditions in both macro- and micro-scale cultures likely contribute to observed responses. In this study, we investigate how the presence of neighboring cells influence macrophage activation following proinflammatory stimulation in both bulk and micro-scale culture. We found that in bulk cultures, higher seeding density negatively regulated the average TNF-α secretion from individual macrophages in response to inflammatory agonists, and this effect was partially caused by the reduced cell-to-media volume ratio. In contrast, studies conducted using microwells to isolate single cells and groups of cells revealed that increasing numbers of cells positively influences their inflammatory activation, suggesting that the absolute cell numbers in the system may be important. In addition, a single inflammatory cell enhanced the inflammatory state of a small group of cells. Overall, this work helps to better understand how variations of macroscopic and microscopic culture environments influence studies in macrophage biology and provides insight into how the presence of neighboring cells and the soluble environment influences macrophage activation.

Cardiopulmonary response to exercise in adults born very preterm.

This study aims to compare cardiopulmonary response to aerobic exercise between young adults born very preterm, including a subgroup with bronchopulmonary dysplasia (BPD), and term controls.Seventy-one adults (18-29 years) born <30 weeks' gestational age (24 with BPD) and 73 term controls were recruited. Assessment included cardiopulmonary exercise testing with impedance cardiography. We compared group differences in peak O2 consumption (peak VO2) and in ventilatory and cardiovascular responses to exercise using linear regression analyses.Preterm participants had reduced peak VO2 (mean difference -2.7; 95% CI -5.3, -0.1 mL·kg-1 lean body mass·min-1) versus controls. Those with BPD achieved lower peak work-rate compared to term controls (-21; 95% CI -38, -5 watts). There was no difference across groups in breathing reserve, ventilatory efficiency, peak heart rate and cardiac output. VO2 to work-rate relationship (ΔVO2/ΔWR) was reduced in preterm versus term. Peak systolic blood pressure and circulatory power (systolic blood pressure*VO2) were also lower in BPD versus term controls. In the preterm group, longer NICU stay and lower peak cardiac output were associated with lower peak VO2Results suggest limitations with peripheral O2 uptake in the muscle with reduced ΔVO2/ΔWR and peak circulatory power, but normal cardiac output. Investigations into skeletal muscle perfusion and O2 use during exercise are warranted to better understand mechanisms of exercise limitation.

SHP-1 localization to the activating immune synapse promotes NK cell tolerance in MHC class I deficiency.

Natural killer (NK) cells recognize virally infected cells and tumors. NK cell function depends on balanced signaling from activating receptors, recognizing products from tumors or viruses, and inhibitory receptors (such as KIR/Ly49), which recognize major histocompatibility complex class I (MHC-I) molecules. KIR/Ly49 signaling preserves tolerance to self but also conveys reactivity toward MHC-I-low target cells in a process known as NK cell education. Here, we found that NK cell tolerance and education were determined by the subcellular localization of the tyrosine phosphatase SHP-1. In mice lacking MHC-I molecules, uneducated, self-tolerant Ly49A+ NK cells showed accumulation of SHP-1 in the activating immune synapse, where it colocalized with F-actin and the signaling adaptor protein SLP-76. Education of Ly49A+ NK cells by the MHC-I molecule H2Dd led to reduced synaptic accumulation of SHP-1, accompanied by augmented signaling from activating receptors. Education was also linked to reduced transcription of Ptpn6, which encodes SHP-1. Moreover, synaptic SHP-1 accumulation was reduced in NK cells carrying the H2Dd-educated receptor Ly49G2 but not in those carrying the noneducating receptor Ly49I. Colocalization of Ly49A and SHP-1 outside of the synapse was more frequent in educated compared with uneducated NK cells, suggesting a role for Ly49A in preventing synaptic SHP-1 accumulation in NK cell education. Thus, distinct patterning of SHP-1 in the activating NK cell synapse may determine NK cell tolerance.

Pulmonary important outcomes after extremely preterm birth: Parental perspectives.

AIM: To describe pulmonary important outcomes (PIO) reported by parents of children born extremely preterm. METHODS: Over 1-year, all parents of children aged 18 months-7-years born <29 weeks' GA were asked regarding their perspectives. The proportion of parents who described PIO and the themes they invoked were examined. Results were analysed using mixed methods. RESULTS: Among parental responses (n = 285, 98% participation rate), 44% spoke about PIO, invoking 24 themes pertaining to NICU hospitalisation and/or long-term respiratory health. Some themes had an impact primarily on the child (e.g. exercise limitation), while the majority had an impact on the whole family (e.g. hospital readmissions). None mentioned oxygen at 36 weeks nor bronchopulmonary dysplasia (BPD). The proportion of responses invoking PIO were statistically similar between parents of children with and without BPD, born before or after 25 weeks or with birthweight < or ≥750 g. PIO were more likely to be mentioned in males and among those readmitted for respiratory problems. CONCLUSION: Parents describe many PIO, most related to the functional impact of lung disease on their child (and family), rather than the diagnosis of BPD itself. Most of these PIO are not primary outcomes in large neonatal trials nor collected in neonatal databases.

Physical activity levels, pulmonary function, and MRI in children born extremely preterm: A comparison between children with and without bronchopulmonary dysplasia.

INTRODUCTION: Children with a history of bronchopulmonary dysplasia (BPD) may have lower physical activity levels, but evidence to date is mixed. This study compared physical activity levels between children born extremely preterm with and without history of BPD, and examined their associations with pulmonary magnetic resonance imaging (MRI) and pulmonary function test (PFT) indices. METHODS: This multicentre cross-sectional study included children aged 7-9 years born extremely preterm, with and without BPD. Children wore a pedometer for 1 week, then completed the Physical Activity Questionnaire (PAQ), pulmonary MRI, and PFT. Spearman correlations and multivariable linear regression modeling were performed. RESULTS: Of 45 children, 28 had a history of moderate-severe BPD. There were no differences in any physical activity outcomes by BPD status. Higher average daily step count and higher average daily moderate-to-vigorous physical activity (MVPA) were each correlated with greater forced vital capacity (r = 0.41 and 0.58), greater MRI lung proton density at full expiration (r = 0.42 and 0.49), and lower lung clearance index (r = -0.50 and -0.41). After adjusting for MRI total proton density and BPD status, a 5% increase in forced expiratory volume at 1 s was associated with 738 (95% CI: 208, 1268) more steps per day and 0.1 (0.0, 0.2) more hours of MVPA, respectively. CONCLUSION: School-aged children born extremely preterm have similar physical activity levels to their peers, regardless of history of BPD. MRI and PFT measures suggestive of gas trapping and/or airflow obstruction are associated with lower physical activity levels.

Sleep-disordered breathing symptoms and their association with structural and functional pulmonary changes in children born extremely preterm.

This study aimed to evaluate symptoms of sleep-disordered breathing (SDB) among children born extremely preterm, with and without a history of bronchopulmonary dysplasia (BPD), including associations between sleep and respiratory symptoms, physical activity, pulmonary function, and pulmonary magnetic resonance imaging (MRI). This multi-center cross-sectional study enrolled children aged 7-9 years born extremely preterm with and without BPD. Participants completed the Pediatric Sleep Questionnaire (PSQ), the modified Epworth sleepiness scale, a respiratory symptom questionnaire, pedometer measurements, pulmonary function testing, and pulmonary MRI. Spearman's correlations and univariate and multivariable linear regression modelling were performed. Twenty-eight of 45 children included had a history of moderate-to-severe BPD. The prevalence of sleep-related symptoms was low, with the exception of hyperactivity and inattention. There were no differences in mean (SD) scores on sleep questionnaires in children with and without BPD (PSQ: 0.21 (0.13) vs 0.16 (0.14), p = 0.3; modified Epworth: 2.4 (2.4) vs 1.8 (2.8), p = 0.4). Multiple regression analyses examining difference in sleep scores between groups, adjusting for gestational age and intraventricular hemorrhage, found no statistical difference (p > 0.05). Greater daytime sleepiness was moderately correlated with FEV1%-predicted (r = - 0.52); no other moderate-strong associations were identified.  Conclusions: There was no evidence of clinically important differences in sleep symptoms between children with and without BPD, suggesting that sleep symptoms may be related to prematurity-related factors other than a BPD diagnosis, including airflow limitation. Further research is necessary to explore the relationship between sleep symptoms, airway obstruction, and neurobehavioral symptoms among premature-born children.  Trial registration: NCT02921308. Date of registration: October 3, 2016. What is Known: • Presence of bronchopulmonary dysplasia (BPD) may further contribute to the development of SDB, though its impact is not well-studied. • Premature-born children have a greater risk of lung structural and functional differences, including sleep-disordered breathing (SDB). What is New: • There was no difference in sleep symptoms between children with and without BPD, suggesting that sleep symptoms are related to other prematurity-related factors, such as airflow limitation. • Greater daytime sleepiness was correlated with lower FEV1 in our population, which reflects greater airflow limitation.

Timing of Systemic Steroids and Neurodevelopmental Outcomes in Infants < 29 Weeks Gestation

Objective: To determine the association between postnatal age (PNA) at first administration of systemic postnatal steroids (sPNS) for bronchopulmonary dysplasia (BPD) and mortality or significant neurodevelopmental impairment (sNDI) at 18−24 months corrected age (CA) in infants < 29 weeks' gestation. Methods: Data from the Canadian Neonatal Network and Canadian Neonatal Follow-up Network databases were used to conduct this retrospective cohort study. Infants exposed to sPNS for BPD after the 1st week of age were included and categorized into 8 groups based on the postnatal week of the exposure. The primary outcome was a composite of mortality or sNDI. A multivariable logistic regression model adjusting for potential confounders was used to determine the association between the sPNS and ND outcomes. Results: Of the 10,448 eligible infants, follow-up data were available for 6200 (59.3%) infants. The proportion of infants at first sPNS administration was: 8%, 17.5%, 23.1%, 18.7%, 12.6%, 8.3%, 5.8%, and 6% in the 2nd, 3rd, 4th, 5th, 6th, 7th, 8−9th, and ≥10th week of PNA respectively. No significant association between the timing of sPNS administration and the composite outcome of mortality or sNDI was observed. The odds of sNDI and Bayley-III motor composite < 70 increased by 1.5% (95% CI 0.4, 2.9%) and 2.6% (95% CI 0.9, 4.4%), respectively, with each one-week delay in the age of initiation of sPNS. Conclusions: No significant association was observed between the composite outcome of mortality or sNDI and PNA of sPNS. Among survivors, each week's delay in initiation of sPNS may increase the odds of sNDI and motor delay.

Assisted reproductive technology and childhood morbidity: a longitudinal cohort study.

OBJECTIVE: To evaluate the association between assisted reproductive technology (ART) and offspring morbidity in the first decade of life. DESIGN: Longitudinal cohort study. SETTING: Provincial health registry in Quebec, Canada. PATIENT(S): A total of 797,654 singleton children born between 2008 and 2019, followed up to 2020. INTERVENTION(S): Retrospective, noninterventional study of any ART procedure vs. no ART. MAIN OUTCOME MEASURE(S): Childhood morbidity, including hospitalization for infectious, allergic, malignant, and other diseases, assessed using adjusted Cox proportional hazards regression to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association with ART. We controlled for unmeasured family-level confounders that were shared among siblings through stratified Cox regression. To do so, we restricted the analysis to 10,097 siblings with discordant exposure to ART and compared the risk of outcomes in exposed vs. unexposed siblings. RESULT(S): Compared with no ART, ART was associated with 1.23 times the risk of any hospitalization (95% CI 1.19-1.27), 1.25 times the risk of infectious disease hospitalization (95% CI 1.21-1.29), and 1.25 times the risk of allergy hospitalization (95% CI 1.14-1.38). When we used a sibling design to control for shared genetic and environmental confounders, ART was not associated with a greater risk of childhood hospitalization (HR 0.92, 95% CI 0.78-1.08). CONCLUSION(S): ART is associated with an elevated risk of hospitalization up to 11 years of age, but discordant sibling analysis suggests that the association may be due to genetic, environmental, or other shared familial confounders.

FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development.

Natural killer (NK) cells play roles in viral clearance and early surveillance against malignant transformation, yet our knowledge of the underlying mechanisms controlling their development and functions remain incomplete. To reveal cell fate-determining pathways in NK cell progenitors (NKP), we utilized an unbiased approach and generated comprehensive gene expression profiles of NK cell progenitors. We found that the NK cell program was gradually established in the CLP to preNKP and preNKP to rNKP transitions. In line with FOXO1 and FOXO3 being co-expressed through the NK developmental trajectory, the loss of both perturbed the establishment of the NK cell program and caused stalling in both NK cell development and maturation. In addition, we found that the combined loss of FOXO1 and FOXO3 caused specific changes to the composition of the non-cytotoxic innate lymphoid cell (ILC) subsets in bone marrow, spleen, and thymus. By combining transcriptome and chromatin profiling, we revealed that FOXO TFs ensure proper NK cell development at various lineage-commitment stages through orchestrating distinct molecular mechanisms. Combined FOXO1 and FOXO3 deficiency in common and innate lymphoid cell progenitors resulted in reduced expression of genes associated with NK cell development including ETS-1 and their downstream target genes. Lastly, we found that FOXO1 and FOXO3 controlled the survival of committed NK cells via gene regulation of IL-15Rß (CD122) on rNKPs and bone marrow NK cells. Overall, we revealed that FOXO1 and FOXO3 function in a coordinated manner to regulate essential developmental genes at multiple stages during murine NK cell and ILC lineage commitment.

Plasma copeptin is increased and associated with smaller kidney volume in young adults born very preterm.

Background: Plasma copeptin, a surrogate marker for vasopressin levels, is increased in neonates born preterm, particularly in those with a more severe neonatal course, as reflected by bronchopulmonary dysplasia. Copeptin levels in adulthood are unknown. Methods: In this case-control study of 101 adults born very preterm (<30 weeks of gestation) and 105 control adults born full-term, a comprehensive clinical and biological assessment was performed, including blood pressure measurements, kidney ultrasound and determination of plasma copeptin, renin activity, angiotensin II, aldosterone, apelin, sodium and potassium, serum and morning urine osmolality. Results: The median age in the study was 23.1 years [interquartile range (IQR) 21.2-24.8] and 57% were females. In males, the median copeptin levels were 8.2 pmol/L (IQR 6.3-12.4) and 6.1 pmol/L (IQR 4.3-9.0) in the preterm and term groups, respectively (P = 0.022). In females, the median copeptin levels were 5.2 pmol/L (IQR 3.9-7.6) and 4.0 pmol/L (IQR 2.8-5.7) in the preterm and term groups, respectively (P = 0.005). Adults born preterm with a history of bronchopulmonary dysplasia had further increased copeptin levels. The kidney volume, adjusted for height, was smaller and albuminuria was higher in the preterm group, and both were associated with higher plasma copeptin levels. Conclusions: Plasma copeptin is higher in young adults born preterm and is related to a more severe neonatal course and smaller kidney volume.

Functional and Phenotypic Characterization of Siglec-6 on Human Mast Cells.

Mast cells are tissue-resident cells that contribute to allergic diseases, among others, due to excessive or inappropriate cellular activation and degranulation. Therapeutic approaches to modulate mast cell activation are urgently needed. Siglec-6 is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptor selectively expressed by mast cells, making it a promising target for therapeutic intervention. However, the effects of its engagement on mast cells are poorly defined. Siglec-6 expression and endocytosis on primary human mast cells and mast cell lines were assessed by flow cytometry. SIGLEC6 mRNA expression was examined by single-cell RNAseq in esophageal tissue biopsy samples. The ability of Siglec-6 engagement or co-engagement to prevent primary mast cell activation was determined based on assessments of mediator and cytokine secretion and degranulation markers. Siglec-6 was highly expressed by all mast cells examined, and the SIGLEC6 transcript was restricted to mast cells in esophageal biopsy samples. Siglec-6 endocytosis occurred with delayed kinetics relative to the related receptor Siglec-8. Co-crosslinking of Siglec-6 with FcεRIα enhanced the inhibition of mast cell activation and diminished downstream ERK1/2 and p38 phosphorylation. The selective, stable expression and potent inhibitory capacity of Siglec-6 on human mast cells are favorable for its use as a therapeutic target in mast cell-driven diseases.

Matched cohort study of hospitalization in children who have siblings with cancer.

BACKGROUND: Health outcomes of children in families affected by cancer are poorly understood. The authors assessed the risk of hospitalization in children who have a sibling with cancer. METHODS: This was a longitudinal cohort study in which 1600 children who had a sibling with cancer were matched to 32,000 children who had unaffected siblings in Quebec, Canada, from 2006 to 2020. The exposure of interest was having a sibling with cancer. Outcomes included hospitalization for pneumonia, asthma, fracture, and other morbidities any time after the sibling was diagnosed with cancer. The children were followed over time, and Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the impact of having a sibling with cancer on the risk of hospitalization before age 14 years, adjusted for patient characteristics. RESULTS: Children who had a sibling with cancer had an increased risk of hospitalization compared with unaffected children (HR, 1.15; 95% CI, 1.02-1.29). Conditions associated with a greater risk of hospitalization included pneumonia, hemangioma, other skin conditions, sleep apnea, and inflammatory bowel disease. The risk of hospitalization was greatest for children whose older sibling had cancer (HR, 1.16; 95% CI, 1.01-1.32) and for children whose sibling had hematopoietic cancer (HR, 1.22; 95% CI, 1.01-1.48). CONCLUSIONS: Children who have a sibling with cancer are at risk of hospitalization for conditions such as pneumonia, inflammatory bowel disease, and other morbidities. Families affected by childhood cancer may benefit from additional support to facilitate care for all children in the family. LAY SUMMARY: Little is known about the health of children who have a brother or sister with cancer. The authors studied the types of hospitalization experienced by children who have siblings with cancer. The results indicated that having a sibling with cancer increased the chance of being hospitalized for pneumonia and other conditions that could have been preventable. The results also indicated that children who had an older sibling with cancer or a sibling with blood cancer had a greater chance of being hospitalized. The findings highlight the importance of providing timely care for children in families affected by childhood cancer.

Pulmonary Magnetic Resonance Imaging of Ex-Preterm Children with and without Bronchopulmonary Dysplasia.

Rationale: Children born prematurely, particularly those with bronchopulmonary dysplasia, have persisting lung abnormalities requiring longitudinal monitoring. Pulmonary ultrashort echo time magnetic resonance imaging (MRI) measurements may provide sensitive markers of persisting lung abnormalities and have not been evaluated in school-aged children born prematurely. Objectives: To compare pulmonary MRI and pulmonary function test measurements in preterm-born school-aged children with and without bronchopulmonary dysplasia. Methods: Children aged 7-9 years, born extremely preterm, with and without bronchopulmonary dysplasia, were recruited from three centers. Participants underwent pulmonary ultrashort echo time MRI and pulmonary function tests. Primary outcomes included total proton density and proton density at full expiration, measured using MRI. Multiple linear regression analysis was performed, adjusting for gestational age and bronchopulmonary dysplasia. Associations between MRI and pulmonary function were tested. Results: Thirty-five children were included in the primary analysis (24 with bronchopulmonary dysplasia, 11 without); 29 completed pulmonary function tests, of whom 11 (38%) had airflow limitation. Children with bronchopulmonary dysplasia had 44% (95% confidence interval [CI], 10-66%) lower mean total proton density (mean ± standard deviation, 3.6 ± 2.6) than those without (6.1 ± 4.0). Those with bronchopulmonary dysplasia had 25% (95% CI, 3-42%) lower proton density at full expiration than those without. Lower total proton density and proton density at full expiration were moderately correlated with greater residual volume, residual volume/total lung capacity, and lung clearance index (Spearman correlations for total proton density: -0.42, -0.57, and -0.53, respectively. Spearman correlations for proton density at full expiration: -0.28, -0.57, and -0.45, respectively). Conclusions: School-aged preterm-born children with bronchopulmonary dysplasia have parenchymal tissue abnormalities measured using ultrashort MRI proton density, compared with those without. MRI proton density correlated with pulmonary function measures indicative of gas trapping. Clinical trial registered with www.clinicaltrials.gov (NCT02921308).

Cardiopulmonary Function Abnormalities in Cohort of Adults following Bronchopulmonary Dysplasia as Preterm Infants.

OBJECTIVE: This study was aimed to describe the cardiopulmonary profiles of adult patients with bronchopulmonary dysplasia (BPD), comparing them to normative adult values. STUDY DESIGN: This study presents a retrospective chart review of all BPD patients followed in the adult BPD clinic, identified from institutional and archive databases, born preterm at ≤33 weeks of estimated gestational age (EGA) between January 1980 and December 2000. RESULTS: Forty-four patients with BPD (26.4 ± 2.7 weeks of EGA) were included. Average age at follow-up was 19 years. Majority (61.4%) of the patients had a diagnosis of asthma. Mean spirometry values were: first second of forced expiration (FEV1) 74.1%, forced vital capacity (FVC) 80.7%, and FEV1/FVC 82.5%. Echocardiography (ECHO) images were reviewed, left ventricular (LV) structure and performance did not differ between obstructive and nonobstructive pulmonary function test (PFT) groups, but values of LV longitudinal strain were 4.8% lower than expected normal for adults. Patients with obstructive PFT had additional decreased right ventricular (RV) function by ECHO. CONCLUSION: BPD patients in this study were found to have a burden of cardiorespiratory alterations that persisted into adulthood, with RV performance abnormalities found among patients with obstructive PFT. KEY POINTS: · BPD patients born at extremes of prematurity have cardiorespiratory alterations in adulthood.. · Among patients with obstructive lung function, subtle cardiac performance abnormalities were found.. · Future directions should include systematic follow-up of premature newborns with BPD..

A Src-H3 acetylation signaling axis integrates macrophage mechanosensation with inflammatory response.

Macrophages are mechanosensitive cells that can exquisitely fine-tune their function in response to their microenvironment. While macrophage polarization results in concomitant changes in cell morphology and epigenetic reprogramming, how biophysically-induced signaling cascades contribute to gene regulatory programs that drive polarization remains unknown. We reveal a cytoskeleton-dependent Src-H3 acetylation (H3Ac) axis responsible for inflammation-associated histone hyperacetylation. Inflammatory stimuli caused increases in traction forces, Src activity and H3Ac marks in macrophages, accompanied by reduced cell elongation and motility. These effects were curtailed following disruption of H3Ac-signaling through either micropattern-induced cell elongation or inhibition of H3Ac readers (BRD proteins) directly. Src activation relieves the suppression of p300 histone acetyltransferase (HAT) activity by PKCδ. Furthermore, while inhibition of Src reduced p300 HAT activity and H3Ac marks globally, local H3Ac levels within the Src promoter were increased, suggesting H3Ac regulates Src levels through feedback. Together, our study reveals an adhesome-to-epigenome regulatory nexus underlying macrophage mechanosensation, where Src modulates H3Ac-associated epigenetic signaling as a means of tuning inflammatory gene activity and macrophage fate decisions in response to microenvironmental cues.

Prenatal cannabis use disorder and future risk of road traffic injuries in Canadian children.

The extent to which child traffic injuries may be attributed to parents who use cannabis before driving is unknown. We investigated whether prenatal cannabis use disorders may predict future road traffic injuries in children. We conducted a cohort study of 792,082 children in Quebec, Canada with 6,280,663 years of follow-up between 2006 and 2019. The main exposure measure was maternal cannabis use disorder before or during pregnancy. The main outcome measure was future hospitalizations for transport-related injuries in children after birth. Using Cox proportional hazards regression models adjusted for potential confounders, we estimated hazard ratios and 95% confidence intervals (CI) for the association of prenatal cannabis use disorders with transport-related injuries in children. Maternal cannabis use disorders before birth were associated with 5.64 times the risk of hospitalization for future motor vehicle crash injuries in children (95% CI 2.61-12.21). The risk increased with the child's age. Prenatal cocaine, opioid, and other drug use disorders were not associated with pediatric transport-related injuries. Maternal cannabis use disorders before birth may be an early predictor of childhood injuries from motor vehicle crashes.