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Trisomy 21 (TS21), also known as Down syndrome (DS), increases pediatric mortality risk from respiratory syncytial virus (RSV) by nine-fold, yet its underlying immunological basis remains unclear. Here, we investigated RSV-induced immunological responses in TS21 airway epithelial cells (AECs), the primary site of respiratory virus entry and host defense. TS21 AECs exhibit hyperactive interferon (IFN) signaling and reduced RSV infectivity, but they also show impaired type-III IFN responses during viral infection. Furthermore, TS21 AECs demonstrate heightened production of proinflammatory mediators CXCL5 and CXCL10 both before and after RSV exposure. Infants with DS suffering from severe viral bronchiolitis demonstrate dysregulated airway immune responses in vivo, characterized by diminished type-III IFN levels and increased CXCL5/CXCL10 secretion. Our results indicate that RSV severity in DS is not due to impaired viral control but to dysregulated airway proinflammatory responses, offering new therapeutic opportunities to mitigate the severity of RSV infection in children with DS.

Ring chromosome 17 and 17p13.3 deletion syndrome are phenotypically heterogeneous diseases with similar clinical features. The ring chromosome 17 phenotypic features range from the Miller-Dieker syndrome characterized by deletion of the PAFAH1B1 gene, lissencephaly, hypotonia, dysphagia, café au lait spots, and severe intellectual disability, to a milder phenotype characterized by microcephaly, seizures, delayed development, minor facial dysmorphic features, clinodactyly, short stature, café au lait spots, retinal flecking, and deletion of the YWHAE and CRK genes. Similarly, the phenotypic features of the 17p13.3 deletion syndrome range from the Miller-Dieker syndrome caused by loss of function of the PAFAH1B1 gene and characterized by lissencephaly, microcephaly, seizures, hypotonia, and severe intellectual disability to a milder phenotype characterized by nonspecific white matter changes, microcephaly, seizures, delayed development, short stature, and deletion of the YWHAE and CRK genes. Café au lait spots and retinal or axillary freckling have been noted in the ring chromosome 17 syndrome but not in 17p13.3 deletion syndrome. We report a 5-year-old girl with a history of intrauterine growth retardation, short stature, intractable epilepsy, expressive language disorder, clinodactyly, multiple café au lait spots, and retinal freckling who was initially diagnosed with 17p13.3 deletion syndrome involving YWHAE and CRK but not PAFAH1B1 on CGH array. However, cytogenetic analysis of G-banded chromosomes revealed mosaic ring chromosome 17. Optical genome mapping simultaneously identified the 17p13.3 deletion and the mosaic ring chromosome 17. This case report highlights the limitations of the arrays and sequencing methods for identifying structural variants, the need to investigate further deletions and duplications identified by arrays, mainly considering atypical phenotypic features, and suggests that OGM could be used as a first-tier test with exome sequencing for the diagnosis of patients with dysmorphic features, intellectual disability, and seizure disorder., (© 2024 Wiley Periodicals LLC.)

Obstructive sleep apnea (OSA) and viral respiratory infections are highly prevalent conditions in children and a major cause of respiratory morbidity in this age group. Severe viral respiratory infections are a known risk factor for pediatric OSA, which is primarily caused by hypertrophy of upper airway lymphoid tissues (adenoids and tonsils). This review examines recent progress in understanding early-life development of lymphoid tissues in the human upper airway, with a particular focus on how respiratory viruses may influence this process and contribute to OSA pathogenesis. It also explores the bidirectional relationship between OSA and severe viral infections, highlighting the need for ongoing monitoring and novel primary prevention strategies to address these interconnected conditions., (© 2024 Wiley Periodicals LLC.)

The lungs are integral to immune defense, and inborn errors of immunity (IEI) often manifest as lung disease. Lung complications of IEI can involve the airways, alveolar spaces, interstitium, vasculature, and pleura. Accurate identification of these lung disease patterns requires a thorough clinical history, physical examination, and high-resolution computed tomography (HRCT), as lung imaging patterns guide further respiratory and immunological evaluations. Respiratory assessment may also include pulmonary function tests, bronchoscopy with bronchoalveolar lavage, and, in some cases, lung biopsy. Additionally, molecular diagnosis of underlying immune defects, typically through comprehensive clinical phenotyping, functional immune studies, and genetic testing, is crucial for informing patient management and guiding targeted therapies. Importantly, given the complexity of IEI, a multidisciplinary approach is necessary. Furthermore, ongoing research is required to refine therapies and improve outcomes for lung complications., (© 2024 Wiley Periodicals LLC.)

Lower respiratory tract infections (LRTIs) remain the leading cause of infant morbidity and mortality worldwide and affect long-term respiratory health. Identifying immunological determinants of LRTI susceptibility may help stratify disease risk and identify therapies. This study aimed to identify neonatal immunological factors predicting LRTI risk in infancy. Cord blood plasma from 191 neonates from the Boston Birth Cohort was analyzed for 28 soluble immune factors. LRTI was defined as bronchiolitis, bronchitis, or pneumonia during the first year of life. Welch's t -test demonstrated significantly higher log 10 transformed concentrations of IL-17 and IFNγ in the LRTI group compared to neonates without LRTI in the first year of life ( p < 0.05). Risk associations were determined using multivariate survival models. There were 29 infants with LRTIs. High cord blood levels of IFNγ (aHR = 2.35, 95% CI 1.07-5.17), TNF-β (aHR = 2.86, 95% CI 1.27-6.47), MIP-1α (aHR = 2.82, 95% CI 1.22-6.51), and MIP-1β (aHR = 2.34, 95% CI 1.05-5.20) were associated with a higher risk of LRTIs. RANTES was associated with a lower risk (aHR = 0.43, 95% CI 0.19-0.97). Soluble immune factors linked to antiviral immunity (IFNγ) and cytokines mediating inflammatory responses (TNF-β), and cell homing (MIP-1α/b), at birth were associated with an increased risk of LRTIs during infancy.

Background: The opinion on whether a patient with an anterior open bite should be treated surgically or not is controversial. These patients generally suffer from associated discomfort due to their occlusal instability and musculoskeletal pain., Clinical Presentation: A 60-year-old woman visited the clinic with dental mobility of her upper central incisors as her chief complaint. She had a severe anterior open bite, with a history of continuous grinding and multiple dental restorations in poor condition. Additionally, she suffered neck pain with movement restrictions., Conclusion: Dentists can evaluate and treat patients with an anterior open bite using this integrative model (physical therapy/dentistry) as a possible alternative as part of the treatment for anterior open bite patients.

The precise evaluation of splenic lesions using cross-sectional imaging presents a complex challenge due to the overlapping imaging characteristics of most splenic diseases and the absence of specific symptoms, complicating the diagnosis process. This pictorial review highlights the essential elements that should be included in a radiology report to interpret cross-sectional imaging studies of splenic lesions. To augment the diagnostic accuracy, we propose the implementation of a stepwise algorithmic approach. This approach offers a comprehensive analysis of splenic anomalies and lesions, providing an invaluable tool for radiologists and clinicians., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Gestational DNA methylation age (GAmAge) has been developed and validated in European ancestry samples. Its applicability to other ethnicities and associations with fetal stress and newborn phenotypes such as inflammation markers are still to be determined. This study aims to examine the applicability of GAmAge developed from cord blood samples of European decedents to a racially diverse birth cohort, and associations with newborn phenotypes., Methods: GAmAge based on 176 CpGs (Haftorn GAmAge) was calculated for 940 children from a US predominantly urban, low-income, multiethnic birth cohort. Cord blood DNA methylation was profiled by Illumina EPIC array. Newborn phenotypes included anthropometric measurements and, for a subset of newborns (N = 194), twenty-seven cord blood inflammatory markers (sandwich immunoassays)., Results: GAmAge had a stronger correlation with GEAA in boys (r = 0.89, 95% confidence interval (CI) [0.87,0.91]) compared with girls (r = 0.83, 95% CI [0.80,0.86]), and was stronger among extremely preterm to very preterm babies (r = 0.91, 95% CI [0.81,0.96]), compared with moderate (r = 0.48, 95% CI [0.34,0.60]) and term babies (r = 0.58, 95% CI [0.53,0.63]). Among White newborns (N = 51), the correlation between GAmAge vs. GEAA was slightly stronger (r = 0.89, 95% CI [0.82,0.94]) compared with Black/African American newborns (N = 668; r = 0.87, 95% CI [0.85,0.89]) or Hispanic (N = 221; r = 0.79, 95% CI [0.74,0.84]). Adjusting for GEAA and sex, GAmAge was associated with anthropometric measurements, cord blood brain-derived neurotrophic factor (BDNF), and monocyte chemoattractant protein-1 (MCP-1) (p < 0.05 for all)., Conclusions: GAmAge estimation is robust across different populations and racial/ethnic subgroups. GAmAge may be utilized as a proxy for GEAA and for assessing fetus development, indicated by inflammatory state and birth outcomes., (© 2024. The Author(s).)

Rationale: Lower respiratory tract infections (LRTI) during the first 2 years of life increase the risk of pediatric obstructive sleep apnea (OSA), but whether this risk varies by LRTI severity is unknown., Methods: We analyzed data from 2962 children, aged 0-5 years, with early-life LRTI requiring hospitalization (severe LRTI, n = 235), treated as outpatients (mild LRTI, n = 394) and without LRTI (reference group, n = 2333) enrolled in the Boston Birth Cohort. Kaplan-Meier survival estimates and Cox proportional hazards models adjusted by pertinent covariables were used to evaluate the risk of pediatric OSA., Results: Compared to children without LRTI, those with mild LRTI were at a higher risk of having OSA (hazard ratio [HR] 1.44, 95% confidence interval [CI]: 1.01-2.05), and those with severe LRTI were at the highest risk (HR 2.06, 95% CI: 1.41-3.02), independently of relevant covariables (including maternal age, race, gestational age, and type of delivery). Additional risk factors linked to a higher risk of OSA included prematurity (HR 1.34, 95% CI 1.01-1.77) and maternal obesity (HR 1.82, 95% CI 1.32-2.52). The time elapsed between LRTI and OSA diagnosis was similar in mild and severe LRTI cases, with medians of 23 and 25.5 months, respectively (p = .803)., Conclusion: Infants with severe early-life LRTI have a higher risk of developing OSA, and surveillance strategies to identify OSA need to be particularly focused on this group. OSA monitoring should continue throughout the preschool years as it may develop months or years after the initial LRTI hospitalization., (© 2023 Wiley Periodicals LLC.)

Background: Lower respiratory tract infections (LRTIs) are the leading cause of infant morbidity and mortality worldwide, and altered metabolite production is recognised as a critical factor in LRTI pathogenesis., Methods: This study aimed to identify prenatal metabolic changes associated with LRTI risk in infancy, using liquid chromatography-mass spectrometry unbiased metabolomics analysis on cord blood from 810 full-term newborns., Results: We identified 22 compounds linked to LRTIs in infancy, enriched for purine degradation pathway (PDP) metabolites. High cord blood PDP metabolites, including xanthine, hypoxanthine, xanthosine and inosine, were linked to reduced LRTI risk during infancy. Notably, a low xanthine to uric acid ratio at birth predicted a four-fold increased LRTI risk., Conclusion: This study is the first to reveal that high cord blood PDP metabolites identify newborns at lower LRTI risk, stratifying disease risk at birth. Moreover, our results prompt further study on PDP enzymes as pharmacological targets to decrease LRTI morbidity and mortality for at-risk newborns., Competing Interests: Conflict of interest: The authors declare no competing interests., (Copyright ©The authors 2024.)

Thymic stromal lymphopoietin (TSLP) is a primarily epithelial-derived cytokine that drives type 2 allergic immune responses. Early life viral respiratory infections elicit high TSLP production, which leads to the development of type 2 inflammation and airway hyperreactivity. The goal of this study was to examine in vivo and in vitro the human airway epithelial responses leading to high TSLP production during viral respiratory infections in early infancy. A total of 129 infants (<1-24 m, median age 10 m) with severe viral respiratory infections were enrolled for in vivo (n = 113), and in vitro studies (n = 16). Infants were classified as 'high TSLP' or 'low TSLP' for values above or below the 50th percentile. High versus low TSLP groups were compared in terms of type I-III IFN responses and production of chemokines promoting antiviral (CXCL10), neutrophilic (CXCL1, CXCL5, CXCL8), and type 2 responses (CCL11, CCL17, CCL22). Human infant airway epithelial cell (AEC) cultures were used to define the transcriptomic (RNAseq) profile leading to high versus low TSLP responses in vitro in the absence (baseline) or presence (stimulated) of a viral mimic (poly I:C). Infants in the high TSLP group had greater in vivo type III IFN airway production (median type III IFN in high TSLP 183.2 pg/mL vs. 63.4 pg/mL in low TSLP group, p = 0.007) and increased in vitro type I-III IFN AEC responses after stimulation with a viral mimic (poly I:C). At baseline, our RNAseq data showed that infants in the high TSLP group had significant upregulation of IFN signature genes (e.g., IFIT2, IFI6, MX1) and pro-inflammatory chemokine genes before stimulation. Infants in the high TSLP group also showed a baseline AEC pro-inflammatory state characterized by increased production of all the chemokines assayed (e.g., CXCL10, CXCL8). High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity and increased baseline AEC production of pro-inflammatory chemokines. These findings present a new paradigm underlying the production of TSLP in the human infant airway epithelium following early life viral exposure and shed light on the long-term impact of viral respiratory illnesses during early infancy and beyond childhood., (© 2023 John Wiley & Sons Ltd.)

Background: Bronchiectasis is a major respiratory complication in patients with common variable immunodeficiency (CVID) and is associated with recurrent pulmonary infections. However, it is unclear whether other infections or non-infectious respiratory conditions are related to its development., Objective: To identify respiratory comorbidities associated with bronchiectasis in patients with CVID., Methods: A total of 1470 CVID patients enrolled in the USIDNET registry were included in a cross-sectional analysis. The primary outcome of our study was to determine the clinical characteristics and other respiratory conditions associated with respiratory comorbidities and physician-reported bronchiectasis., Results: One hundred ninety-seven CVID patients were noted to have bronchiectasis (13.4%). Affected patients were significantly older than patients without bronchiectasis (median age 54 years vs. 49 years, p = 0.0004). These patients also had lower serum IgA (13 mg/dL IQR 60 mg/dL vs. 28.4 mg/dL IQR 66 mg/dL, p = 0.000). Notably, chronic rhinosinusitis (OR = 1.69 95%CI 1.05-2.75), sinusitis (OR = 2.06 95%CI 1.38-3.09), pneumonia (OR = 2.70 95%CI 1.88-3.88), COPD (OR = 2.66 95%CI 1.51-4.67), and interstitial lung disease (OR = 2.34 95%CI 1.41-3.91) were independently associated with the development of bronchiectasis in this population., Conclusion: These data suggest that lower and upper respiratory infections, chronic lower airway disease, and interstitial lung diseases are independently associated with bronchiectasis in CVID patients. Further study into predisposing conditions related to the development of bronchiectasis in CVID patients may allow prediction and early intervention strategies to prevent the development of this complication., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The impact of the COVID-19 pandemic on new diagnoses of recurrent fevers and autoinflammatory diseases is largely unknown. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) PFAPA/AID Working Group aimed to investigate the impact of the COVID-19 pandemic on the number of pediatric patients evaluated for recurrent fevers and autoinflammatory diseases in North America. The absolute number of new outpatient visits and the proportion of these visits attributed to recurrent fever diagnoses during the pre-pandemic period (1 March 2019-29 February 2020) and the first year of the COVID-19 pandemic (1 March 2020-28 February 2021) were examined. Data were collected from 27 sites in the United States and Canada. Our results showed an increase in the absolute number of new visits for recurrent fever evaluations in 21 of 27 sites during the COVID-19 pandemic compared to the pre-pandemic period. The increase was observed across different geographic regions in North America. Additionally, the proportion of new visits to these centers for recurrent fever in relation to all new patient evaluations was significantly higher during the first year of the pandemic, increasing from 7.8% before the pandemic to 10.9% during the pandemic year ( p  < 0.001). Our findings showed that the first year of the COVID-19 pandemic was associated with a higher number of evaluations by pediatric subspecialists for recurrent fevers. Further research is needed to understand the reasons behind these findings and to explore non-infectious triggers for recurrent fevers in children., Competing Interests: Authors (including those in consortium) and their disclosures (vast majority nonrelevant to this brief report) include Maryam Piram with Patent Valor, L’Oreal, Novartis, Pierre Fabre Dermatology, Lakshmi N Moorthy with Bristol-Myers Squibb, Brian E Nolan with Sobi, Eveline Wu with AstraZeneca, Bristol-Myers Squibb, Janssen, Pharming Healthcare Inc, Felice C Adler-Shohet with BioNTech, Moderna, Seqirus, Tiphanie Vogel with Moderna, Novartis, Pfizer, Sobi, Smriti Mohan with CARRA, Fatma Dedeoglu with Novartis, Kathryn Edwards with NIH and CDC funding, Bionet, IBM, Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, Roche, Novavax, Brighton Collaboration, and Grant Schulert with Novartis, SOBI. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Mansfield, Lapidus, Romero, Moorthy, Adler-Shohet, Hollander, Cherian, Twilt, Lionetti, Mohan, DeLaMora, Durrant, Muskardin, Correia Marques, Onel, Dedeoglu, Gutierrez, Schulert and the CARRA Autoinflammatory Network Consortium for the CARRA PFAPA/Autoinflamamtory Working Group.)

In addition to being a vital organ for gas exchange, the lung is a crucial immune organ continuously exposed to the external environment. Genetic defects that impair immune function, called inborn errors of immunity (IEI), often have lung disease as the initial and/or primary manifestation. Common types of lung disease seen in IEI include infectious complications and a diverse group of diffuse interstitial lung diseases. Although lung damage in IEI has been historically ascribed to recurrent infections, contributions from potentially targetable autoimmune and inflammatory pathways are now increasingly recognized. This article provides a practical guide to identifying the diverse pulmonary disease patterns in IEI based on lung imaging and respiratory manifestations, and integrates this clinical information with molecular mechanisms of disease and diagnostic assessments in IEI. We cover the entire IEI spectrum, including immunodeficiencies and immune dysregulation with monogenic autoimmunity and autoinflammation, as well as recently described IEI with pulmonary manifestations. Although the pulmonary manifestations of IEI are highly relevant for all age groups, special emphasis is placed on the pediatric population, because initial presentations often occur during childhood. We also highlight the pivotal role of genetic testing in the diagnosis of IEI involving the lungs and the critical need to develop multidisciplinary teams for the challenging evaluation of these rare but potentially life-threatening disorders., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Rationale: Thymic stromal lymphopoietin (TSLP) is increasingly recognized as a key molecule in asthma pathogenesis and as a promising therapeutic target in adults. In contrast, in asthmatic children the clinical relevance of TSLP secretion in the lower airways has been remarkably understudied. We tested the hypothesis that pulmonary TSLP levels in asthmatic children correlate with clinical severity, airway inflammation and lower airway obstruction., Methods: Bronchoalveolar lavage (BAL) samples and relevant clinical data were collected from asthmatic children undergoing clinically indicated bronchoscopy at Children's National Hospital in Washington D.C. Protein levels of TSLP, IL-5, IL-1β, and IL-33 were quantified in BAL at baseline and correlated with individual severity and clinical features including spirometry, serum IgE and eosinophils, BAL neutrophil and eosinophil counts., Results: We enrolled a total of 35 asthmatic children (median age: 9 years). Pediatric subjects with severe asthma had greater TSLP BAL levels at baseline relative to mild or moderate asthmatic subjects ( p = 0.016). Asthmatic children with the highest TSLP levels (>75th percentile) had higher IL-5 and IL-1β BAL levels and greater lower airway obstruction (lower FEV1/FVC ratios)., Conclusion: Our study demonstrates for the first time that higher pulmonary TSLP levels obtained at baseline are linked to asthma disease severity in a subset of children. These data indicate that TSLP may play a key role in the pathogenesis of pediatric asthma and thus provide initial support to investigate the potential use of anti-TSLP biologics to treat severe uncontrolled asthmatic children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chorvinsky, Nino, Salka, Gaviria, Gutierrez and Pillai.)

Background: Chronic granulomatous disease (CGD) is an inborn error of immunity caused by defects in the phagocytic nicotinamide adenine dinucleotide phosphate oxidase complex, leading to increased susceptibility to infection and inflammatory autoimmune diseases. Up to 50% of patients have gastrointestinal (GI) involvement and meet diagnostic criteria for inflammatory bowel disease (CGD-IBD)., Objective: We analyzed patients with CGD from the US Immunodeficiency Network (USIDNET) registry to determine whether IBD changes the presentation, treatment, and outcomes of patients with CGD., Methods: A retrospective evaluation of CGD cases from the USIDNET registry was completed. CGD-IBD was defined as the presence of any major physician-reported inflammatory, noninfectious GI disease manifestation. Demographic information, conditions, infections, antimicrobial therapies, immunomodulator use, and hematopoietic stem cell transplantation data were analyzed., Results: Of 194 patients with a diagnosis of CGD, 96 met criteria for IBD and 98 were categorized in the non-IBD group. Patients with CGD-IBD had an increased rate of infection compared with the non-IBD group (0.66 vs 0.36 infections/patient/year). Enteric organism infections were more common in patients with IBD. Immunomodulators were used at a significantly higher percentage in patients with IBD compared with patients without IBD (80% vs 56%, P < .001). Of the entire CGD cohort, 17 patients died (8.8%), with no significant difference between patients with IBD and patients without IBD (P = 1.00)., Conclusion: Infectious events, enteric organism infections, and use of immunomodulatory drugs were higher in patients with IBD than patients without IBD; however, mortality was not increased. Patients with CGD and concurrent IBD are at increased risk for disease complications, supporting the importance of early recognition, diagnosis, and treatment., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background Advances in perinatal and neonatal medicine have led to an increasing number of infants surviving extreme prematurity (≤27 weeks gestational age, GA). The goal of this study was to examine the respiratory outcomes after neonatal intensive care unit (NICU) discharge of this vulnerable population. We hypothesized that the rates of respiratory hospitalizations are disproportionally higher in the subset of infants born ≤27 weeks GA relative to premature infants born 28-32 weeks GA. Methodology A retrospective longitudinal study of severe premature children (≤32 weeks GA, n = 183) was conducted. We subdivided our sample into extremely preterm infants (≤27 weeks GA; n = 101) and those born very preterm (28-32 weeks GA; n = 82). Our main outcome was the presence of respiratory hospitalizations within 24 months of NICU discharge. Results Extremely premature infants had more than three times higher odds of respiratory hospitalization at 24 months relative to infants born 28-32 weeks GA (adjusted odds ratio = 3.4; 95% confidence interval = 1.8, 6.4; p < 0.01). The increased risk of respiratory hospitalization in extremely premature infants was independent of GA. Regression models identified that the duration of supplemental oxygen and Black/African American ethnicity were significant predictors of respiratory hospitalizations in both prematurity groups independent of gender and birth weight. Conclusions The results support that babies born ≤27 weeks GA represent a distinct high-risk group of severely premature infants that needs novel preventive strategies and targeted interventions to improve their respiratory outcomes after NICU discharge., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Weinstock et al.)

Systemic autoinflammatory diseases (SAIDs) are characterized by unprovoked exaggerated inflammation on a continuum from benign recurrent oral ulceration to life-threatening strokes or amyloidosis, with renal failure as a potential sequela. The ability to discriminate these diagnoses rests on the genetic and mechanistic defect of each disorder, considering potential overlapping autoinflammation, autoimmunity, and immune deficiency. A comprehensive and strategic genetic investigation influences management as well as the consequential expected prognoses in these subsets of rare diseases. The ever-expanding therapeutic armamentarium reflects international collaborations, which will hasten genetic discovery and consensus-driven treatment., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Study Objectives: Several birth cohorts have defined the pivotal role of early lower respiratory tract infections (LRTI) in the inception of pediatric respiratory conditions. However, the association between early LRTI and the development of obstructive sleep apnea (OSA) in children has not been established., Methods: To investigate whether early LRTIs increase the risk of pediatric OSA, we analyzed clinical data in children followed during the first 5 years in the Boston Birth Cohort (n = 3114). Kaplan-Meier survival estimates and Cox proportional hazards models adjusted by pertinent covariates were used to evaluate the risk of OSA by the age of 5 years between children with LRTI during the first 2 years of life in comparison to those without LRTI during this period., Results: Early life LRTI increased the risk of pediatric OSA independently of other pertinent covariates and risk factors (hazard ratio, 1.53; 95% CI, 1.15 to 2.05). Importantly, the association between LRTI and pediatric OSA was limited to LRTIs occurring during the first 2 years of life. Complementarily to this finding, we observed that children who had severe respiratory syncytial virus bronchiolitis during infancy had two times higher odds of OSA at 5 years in comparison with children without this exposure (odds ratio, 2.09; 95% CI, 1.12 to 3.88)., Conclusions: Children with severe LRTIs in early life have significantly increased risk of developing OSA during the first 5 years of life. Our results offer a new paradigm for investigating novel mechanisms and interventions targeting the early pathogenesis of OSA in the pediatric population., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT., Study Design: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120)., Results: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242-128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m 2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models., Conclusions: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Over the past decade, "omics" approaches have advanced our understanding of the molecular programming of the airways in humans. Several studies have identified potential molecular mechanisms that contribute to early life epigenetic reprogramming, including DNA methylation, histone modifications, microRNAs, and the homeostasis of the respiratory mucosa (epithelial function and microbiota). Current evidence supports the notion that early infancy is characterized by heightened susceptibility to airway genetic reprogramming in response to the first exposures in life, some of which can have life-long consequences. Here, we summarize and analyze the latest insights from studies that support a novel epigenetic paradigm centered on human maturational and developmental programs including three cardinal elements: genes, environment, and developmental timing. The combination of these factors is likely responsible for the functional trajectory of the respiratory system at the molecular, functional, and clinical levels., (© 2021 Wiley Periodicals LLC.)

Over the past two decades, several studies have positioned early-life microbial exposure as a key factor for protection or susceptibility to respiratory diseases. Birth cohorts have identified a strong link between neonatal bacterial colonization of the nasal airway and gut with the risk for respiratory infections and childhood asthma. Translational studies have provided companion mechanistic insights on how viral and bacterial exposures in early life affect immune development at the respiratory mucosal barrier. In this review, we summarize and discuss our current understanding of how early microbial-immune interactions occur during infancy, with a particular focus on the emergent paradigm of "innate immune training". Future human-based studies including newborns and infants are needed to inform the timing and key pathways implicated in the development, maturation, and innate training of the airway immune response, and how early microbiota and virus exposures modulate these processes in the respiratory system during health and disease.

The prevalence of maternal obesity has increased dramatically with adverse consequences on infant health. Prior studies have reported associations between maternal obesity and childhood wheeze, asthma as well as lower respiratory tract infections (LRTI). However, studies examining the association of obesity with early-life LRTIs in low-income urban minority populations are still lacking. This is a critical gap because both obesity and infant respiratory morbidity are more prevalent and severe in these communities. We examined mother-child dyads from the Boston Birth Cohort (BBC) to define the longitudinal association of maternal pre-pregnancy BMI and LRTI in infancy, defined as the presence of bronchiolitis, bronchitis, or pneumonia during the first year of life (< 12 months of age). A total of 2,790 mother-child dyads were included in our analyses. Infants born to pre-pregnancy obese mothers (n = 688, 25%) had 1.43 increased odds (adjOR = 1.43, 95% CI 1.08-1.88, p = 0.012) of developing LRTI during the first year of life when compared with newborns born to normal-weight mothers after adjusting by relevant LRTI risk factors. Notably, infants born to overweight mothers (n = 808, 29%) followed a similar trend (adjOR = 1.31, 95% CI 1.00-1.72, p = 0.048). Our study demonstrated that maternal pre-pregnancy obesity is an independent risk factor for the development of LRTI during infancy in a low-income urban minority birth cohort.

Background: Early rhinovirus (RV) infection is a strong risk factor for asthma development. Airway remodeling factors play a key role in the progression of the asthmatic condition. We hypothesized that RV infection in young children elicits the secretion of growth factors implicated in airway remodeling and asthma progression. Methods: We examined the nasal airway production of remodeling factors in children ( ≤ 2 years old) hospitalized due to PCR-confirmed RV infection. Airway remodeling proteins included: MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, TIMP-2, EGF, Angiopoietin-2, G-CSF, BMP-9, Endoglin, Endothelin-1, Leptin, FGF-1, Follistatin, HGF, HB-EGF, PLGF, VEGF-A, VEGF-C, VEGF-D, FGF-2, TGF-β1, TGF-β2, TGF-β3, PDGF AA, PDGF BB, SPARC, Periostin, OPN, and TGF-α. Results: A total of 43 young children comprising RV cases ( n = 26) and uninfected controls ( n = 17) were included. Early RV infection was linked to (1) enhanced production of several remodeling factors (e.g., HGF, TGFα), (2) lower MMP-9/TIMP-2 and MMP-2/TIMP-2 ratios, and (3) increased MMP-10/TIMP-1 ratios. We also found that relative to term infants, severely premature children had reduced MMP-9/TIMP-2 ratios at baseline. Conclusion: RV infection in young children elicits the airway secretion of growth factors implicated in angiogenesis, fibrosis, and extracellular matrix deposition. Our results highlight the potential of investigating virus-induced airway remodeling growth factors during early infancy to monitor and potentially prevent chronic progression of respiratory disorders in all ages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 XuChen, Weinstock, Arroyo, Salka, Chorvinsky, Abutaleb, Aguilar, Kahanowitch, Rodríguez-Martínez, Perez, Gutierrez and Nino.)

Rationale: Pediatric COVID-19 studies have been mostly restricted to case reports and small case series, which have prevented the identification of specific pediatric lung disease patterns in COVID-19. The overarching goal of this systematic review and meta-analysis is to provide the first comprehensive summary of the findings of published studies thus far describing COVID-19 lung imaging data in the pediatric population., Methods: A systematic literature search of PubMed was performed to identify studies assessing lung-imaging features of COVID-19 pediatric patients (0-18 years). A single-arm meta-analysis was conducted to obtain the pooled prevalence and 95% confidence interval (95% CI)., Results: A total of 29 articles (n = 1026 children) based on chest computerized tomography (CT) images were included. The main results of this comprehensive analysis are as follows: (1) Over a third of pediatric patients with COVID-19 (35.7%, 95% CI: 27.5%-44%) had normal chest CT scans and only 27.7% (95% CI: 19.9%-35.6%) had bilateral lesions. (2) The most typical pediatric chest CT findings of COVID-19 were ground-glass opacities (GGO) (37.2%, 95% CI: 29.3%-45%) and the presence of consolidations or pneumonic infiltrates (22.3%, 95% CI: 17.8%-26.9%). (3) The lung imaging findings in children with COVID-19 were overall less frequent and less severe than in adult patients. (4) Typical lung imaging features of viral respiratory infections in the pediatric population such as increased perihilar markings and hyperinflation were not reported in children with COVID-19., Conclusion: Chest CT manifestations in children with COVID-19 could potentially be used for early identification and prompt intervention in the pediatric population., (© 2020 Wiley Periodicals LLC.)

The molecular machinery controlling immune development has been extensively investigated. Studies in animal models and adult individuals have revealed fundamental mechanisms of disease and have been essential to understanding how humans sense and respond to cellular stress, tissue damage, pathogens and their environment. Nonetheless, our understanding of how immune responses originate during human development is just starting to emerge. In particular, studies to unveil how environmental and other non-heritable factors shape the immune system at the beginning of life offer great promise to yield important knowledge about determinants of normal inter-individual immune variation and to prevent and treat many human diseases. In this review, we summarize our current understanding of some of the mechanisms determining early life antibody production as a model of an immune process with sequential molecular checkpoints susceptible to influence by non-heritable factors. We discuss the potential of epigenomics as a valuable approach that may reveal not only relevant gene-environment interactions but important clues about immune developmental processes and homeostasis in early life. We then highlight the novel paradigm of human immunology as a complex field that nowadays requires a longitudinal systems-biology approach to understand normal variation and developmental changes during the first few years of life., (Copyright © 2020 Gutierrez, Nino, Hong and Wang.)

DNA methylation (DNAm) is an essential mechanism governing normal development in humans. Although most DNAm patterns in blood cells are established in utero , the genes associated with immune function undergo postnatal DNAm modifications, and the characterization of this subset of genes is incomplete. Accordingly, we used available longitudinal DNAm datasets from a large birth cohort in the U.S. to further identify postnatal DNAm variation in peripheral leukocytes from 105 children ( n = 105) between birth and the first two years of life, as determined by postnatal changes in β values (with the percentage of methylation ranging from 0 to 1.0 at individual CpG sites). Our study is an extension of a previous analysis performed by our group and identified that: (1) as previously described, DNAm patterns at most CpG sites were established before birth and only a small group of genes underwent DNAm modifications postnatally, (2) this subset includes multiple immune genes critical for lymphocyte development, and (3) several members of the tumor necrosis factor receptor and cytokine superfamilies with essential roles in immune cell activation, survival, and lymphoid tissue development were among those with a larger postnatal variation. This study describes the precise epigenetic DNA methylation marks in important immune genes that change postnatally and raises relevant questions about the role of DNAm during postnatal immune development in early childhood., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Introduction: IFN lambda (type III-IFN-λ1) is a molecule primarily produced by epithelial cells that provides an important first-line defence against viral respiratory infections and has been linked to the pathogenesis of viral-induced wheezing in early life. The goal of this study was to better understand the regulation of innate IFN-lambda responses in vitro in primary human infant airway epithelial cells (AECs) and in vivo using nasal aspirates during viral respiratory infections., Methods: IFN-lambda protein levels were quantified: (a) in human infant AECs exposed to (poly(I:C) dsRNA) under different experimental conditions (n = 8 donors); and (b) in nasal aspirates of young children (≤3 years) hospitalized with viral respiratory infection (n = 138) and in uninfected controls (n = 74). In vivo IFN-lambda airway levels during viral infections were correlated with individual characteristics and respiratory disease parameters., Results: Our in vitro experiments showed that the poly(I:C)-induced innate production of IFN lambda in human infant AECs is regulated by (a) p38-MAPK/NF-kB dependent mechanism; and (b) exposure to pro-inflammatory signals such as IL1β. Our in vivo studies demonstrated that (a) infants (<18 months) had higher virus-induced IFN-lambda airway secretion; (b) subjects with RSV infection showed the highest IFN-lambda airway levels; and (c) individuals with the highest virus-induced IFN-lambda levels (>90th percentile) had higher viral loads and were more likely to have respiratory sick visits within 12 months of discharge (OR = 5.8)., Conclusion: IFN-lambda responses to dsRNA in the human infant airway epithelium are regulated by p38-MAPK and NF-kB signalling. High in vivo IFN-lambda production is influenced by virus type and associated with recurrent respiratory sick visits in young children., (© 2020 John Wiley & Sons Ltd.)

Background: MicroRNAs (miRs) control gene expression and the development of the immune system and antiviral responses. MiR-155 is an evolutionarily-conserved molecule consistently induced during viral infections in different cell systems. Notably, there is still an unresolved paradox for the role of miR-155 during viral respiratory infections. Despite being essential for host antiviral TH1 immunity, miR-155 may also contribute to respiratory disease by enhancing allergic TH2 responses and NFkB-mediated inflammation. The central goal of this study was to define how airway miR-155 production is related to TH1, TH2, and pro-inflammatory cytokine responses during naturally occurring viral respiratory infections in young children., Methods: Normalized nasal airway levels of miR-155 and nasal protein levels of IFN-γ, TNF-α, IL-1β, IL-13, IL-4 were quantified in young children (≤2 years) hospitalized with viral respiratory infections and uninfected controls. These data were linked to individual characteristics and respiratory disease parameters., Results: A total of 151 subjects were included. Increased miR-155 levels were observed in nasal samples from patients with rhinovirus, RSV and all respiratory viruses analyzed. High miR-155 levels were strongly associated with high IFN-γ production, increased airway TH1 cytokine polarization (IFN-γ/IL-4 ratios) and increased pro-inflammatory responses. High airway miR-155 levels were linked to decreased respiratory disease severity in individuals with high airway TH1 antiviral responses., Conclusions: The airway secretion of miR-155 during viral respiratory infections in young children is associated with enhanced antiviral immunity (TH1 polarization). Further studies are needed to define additional physiological roles of miR-155 in the respiratory tract of human infants and young children during health and disease., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Viral bronchiolitis is a term often used to group all infants with the first episode of severe viral respiratory infection. However, this term encompasses a collection of different clinical and biological processes. We hypothesized that the first episode of severe viral respiratory infection in infants can be subset into clinical phenotypes with distinct outcomes and underlying airway disease patterns. Methods: We included children (≤2 years old) hospitalized for the first time due to PCR-confirmed viral respiratory infection. All cases were categorized based on primary manifestations (wheezing, sub-costal retractions and hypoxemia) into mild, hypoxemia or wheezing phenotypes. We characterized these phenotypes using lung-X-rays, respiratory outcomes and nasal protein levels of antiviral and type 2 cytokines (IFNγ, IL-10, IL-4, IL-13, IL-1β, and TNFα). Results: A total of 50 young children comprising viral respiratory infection cases ( n = 41) and uninfected controls ( n = 9) were included. We found that 22% of viral respiratory infection cases were classified as mild ( n = 9), 39% as hypoxemia phenotype ( n = 16) and 39% as wheezing phenotype ( n = 16). Individuals in the hypoxemia phenotype had more lung opacities, higher probability of PICU admission and prolonged hospitalizations. Subjects in the wheezing phenotype had higher probability of recurrent sick visits. Nasal cytokine profiles showed that individuals with recurrent sick visits in the wheezing phenotype had increased nasal airway levels of type 2 cytokines (IL-13/IL-4). Conclusion: Clinically-based classification of the first episode of severe viral respiratory infection into mild, hypoxemia or wheezing phenotypes provides critical information about respiratory outcomes, lung disease patterns and underlying airway immunobiology., (Copyright © 2020 Arroyo, Salka, Perez, Rodríguez-Martínez, Castro-Rodriguez, Gutierrez and Nino.)

Introduction: Allogeneic stem cell transplantation is an established procedure for a variety of diseases of the hematopoietic system. Our transplant program started in 1987 and since then advances have been made in the care of patients undergoing transplantation. We conducted a study to evaluate whether the changes implemented over time have improved the outcomes of transplantation., Material and Methods: We analyzed changes in patients, cell source, transplantation and outcome among 682 consecutive patients receiving their first transplant between 1987 and 2016. We compared overall survival, progression-free survival, the incidence of nonrelapse mortality and relapse in 10-year cohorts over the three decades of the study., Results: The median age of transplanted patients, the use of peripheral blood and unrelated donors all increased very significantly. There was an increase in the number of high-risk patients when comparing the first decade with the two subsequent ones. The 3-year non-relapse mortality decreased significantly from 29% to 20% (p = 0.045), while the overall survival, progression free survival and cumulative incidence of relapse remained stable., Discussion: Allogeneic hematopoietic stem cell transplantation has evolved considerably since its introduction in clinical practice. In the present study, we evaluated how these changes affected our practice along 30 years of activity and compared the results with those published in the literature., Conclusion: Despite increasing age, higher risk patients and the increasing use of unrelated donors our results show a continuous significantly reduced non-relapse mortality, with stable overall survival, progression free survival and relapse rate.

Background: Alterations of the hypothalamic-pituitary-adrenal (HPA) axis are common in patients diagnosed with major depressive disorder (MDD). Nevertheless, these alterations are not found in every patient. There is evidence to indicate a possible mediating role of early life stress (ELS) in the relation between dysfunction of the HPA axis and MDD. We conducted a systematic review to understand if the alterations of the HPA axis commonly found in patients with MDD are due to early life stress or are caused by the disorder itself., Methods: The review was conducted by following the PRISMA guidelines. Original articles were found in PubMed and via a manual search. Only studies whose design allowed comparison of the HPA functioning in the 4 groups no-MDD/no-ELS, MDD/no-ELS, no-MDD/ELS, and MDD/ELS were included., Results: Hyperactivity or hypoactivity of the HPA axis was found in 8 articles. A greater number of abnormalities and a higher rate of posttraumatic stress disorder comorbidity were found in the MDD/ELS group. Dysfunction of the HPA axis was also found in the no-MDD/ELS groups., Conclusion: HPA dysfunction found in MDD seems to be more related to the presence of ELS rather than to the MDD itself. Future studies are needed to clarify the exact mechanisms involved., (© 2020 S. Karger AG, Basel.)

Purpose of Review: Pulmonary cytomegalovirus (CMV) infection is a potential lethal disease in children, but it remains a diagnostic challenge. The differentiation between latent CMV infections with viral shedding and active infections is difficult and may lead to false positives in bronchoalvolar lavage (BAL) PCR detection. This review summarizes current diagnostic approaches for CMV lung infection in children including progress in the identification of underlying immune defects linked to this condition., Recent Findings: There is increasing literature supporting that the combined assessment of host risk factors and lung disease pattern is essential for the diagnosis of pulmonary CMV infection in children. The most important host risk factor is an immunecompromised state that has expanded from primary or acquired immunodeficiency (e.g., HIV) to include a myriad of immune-dysregulation syndromes (e.g., CTLA4, PIK3 defects). Newborns, paricularly those born premature, are also a high-risk group. At the pulmonary level, active CMV infection is typically characterized by alveolar compromise leading to hypoxemia, ground-glass opacities, and intra-alveolar infiltrates with CMV inclusions in lung biopsy. The identification of active CMV lung infection should trigger additional evaluation of immune defects (primary or secondary) impairing T and NK cell function or innate antiviral responses as well as other immune dysregulation disorders. Lung CMV infections in children are more prevalent in immunocompromised hosts and premature newborns. Lung CMV infections should prompt further investigation into conditions altering immune mechanisms usually in place to contain CMV infections. Common clinical and radiological patterns such as hypoxemia and ground-glass pulmonary opacities may allow early identification and treatment of CMV lung infection and underlying causes in the pediatric population.

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with immune dysregulation and increased risk of infections. The presence of autoantibodies and immunoglobulin abnormalities indicates B-cell and antibody-secreting cell (ASC) dysfunction. We hypothesize that soluble factors associated with B-cell and ASC activity are decreased in RA patients and that this is linked to higher susceptibility to infections., Methods: Using the Johns Hopkins Arthritis Cohort and Biorepository, we contrasted serum protein levels of soluble factors involved in B-cell activation (CD40, CD40L) and B-cell/ASC homing (CXCL10, CXCL11, and CXCL13) or survival (BAFF, APRIL, TACI, and BCMA) in 10 healthy subjects and 23 adult RA patients (aged 24-65 years). We subdivided RA patients into those with ( n = 17) and those without infections ( n = 6) within a 2-year period. In order to reduce the effect of RA treatment, we only included patients receiving methotrexate monotherapy or no RA treatments at baseline. Soluble serum protein levels of B-cell/ASC factors were quantified by multiplex immunoassays., Results: We identified that (1) serum levels of soluble BCMA, APRIL, CD40, and CD40L were significantly decreased in RA patients relative to healthy individuals; (2) serum soluble BCMA, predominantly released by ASC, correlated with serum concentrations of class-switched immunoglobulins, IgG and IgA; and (3) RA patients with a history of infections had significantly lower soluble BCMA levels compared with healthy donors and with RA patients without infections., Conclusions: Our study using soluble factors linked to B-cell/ASC activation and survival suggests that there is a paucity of ASC in a subset of RA patients and that this may be linked to altered antibody production and increased risk of infections. Further delineating the link between ASC and infection susceptibility in RA may optimize disease management and provide novel insights into disease pathogenesis that are susceptible to intervention.

Patients with common variable immunodeficiency (CVID) have a higher incidence of rheumatologic disorders. To delineate this clinical association, we investigated the phenotypic features of patients with CVID affected by these conditions., Methods: We conducted a retrospective analysis of 870 pediatric and adult patients with CVID included in the United States Immunodeficiency Network (USIDNET) registry. Outcomes included clinical characteristics (age, gender, ethnicity, rheumatologic diagnosis, and comorbidities), infectious history and basic immunophenotype (serum immunoglobulin levels, CD19+ B cells, and CD4/CD8 ratio) in patients with CVID and rheumatologic disorders compared to those with non-inflammatory CVID. Demographic and clinical data were compared using chi-square, Fisher's exact or Wilcoxon-Mann-Whitney tests. Non-parametric tests, single and multiple logistic regression models were used to evaluate the relationship between CVID-associated rheumatologic disorders and basic immunophenotypic parameters (IgA, IgM, CD19+ B-cell counts, and CD4/CD8 ratios)., Results: Physician-reported rheumatic diseases were present in 5.9% of patients with CVID (n = 51) included in the registry. Although CVID affects both sexes equally, and patients are of predominantly White-Caucasian ethnicity, there were more females (3.3:1 female to male ratio) and increased proportion of non-white patients in the rheumatologic disease group (p < 0.05). Specific disorders included: inflammatory arthritis (n = 18), Sjogren's syndrome (n = 11), SLE (n = 8), Raynaud's syndrome (n = 8), vasculitis (n = 9), MCTD (n = 3), and other (n = 5). In about one-third of patients, a rheumatologic condition was associated with an additional inflammatory complication or malignancy. In regards to the immunophenotype parameters compared (CD19+ B-cell counts, CD4/CD8 ratio, IgA, and IgM), no significant differences were demonstrated between the two groups., Conclusion: Our findings highlight the coexistence of primary antibody immunodeficiencies and systemic rheumatologic disorders, describe the spectrum of rheumatologic manifestations, and contrast differences in relevant demographic, clinical and immunophenotype parameters in the largest registry of CVID patients in the U.S. In spite of its limitations, our study details the intersection of systemic autoimmunity and CVID and provides valuable insights into these two groups of disorders. Further delineating the link between systemic autoimmunity and humoral immunodeficiencies can provide novel insights into the immune abnormalities underlying these related conditions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The current structure of the Spanish State of Autonomies is characterized by institutional pluralism and the autonomy of the different public administrations. In this context, the principle of coordination is fundamental for the cohesion of the system, but experience shows that its implementation is difficult. This paper examines the set of actions carried out by the administrations in relation to an occupational and public health problem raised in March 2016. The Public Health General Direction of Aragon's Government was informed of a possible use of brake linings with asbestos to manufacture axles for agricultural machinery by a Company from Zaragoza; the collaboration from Aragon's Institute of Occupational Safety and Health, the Industry Department and the Labour and Social Security Inspectorate were asked; the joint action of these administrations detected the use of several models of brake linings with a content of 2-5% of Chrysotile. The brake linings came from a Chinese company. The axles nated are sold in several Spanish Autonomous Communities. A national alert was activated by the SIRIPQ (System of Rapid Exchange of Information on Chemical Products) which is coordinated by the Ministry of Health, Social Services and Equality. Several measures were taken including: ceasing the work with the brake linings, the replacement of brake linings with asbestos, the immobilization of brake linings in the company by application of the REACH Reglament, etc. This case shows that the cooperation and co-responsibility of public administrations from different territorial, sectoral and competence areas allows improving the occupational risks prevention and the public health.

Human respiratory conditions are largely influenced by the individual's sex resulting in overall higher risk for males. Sex-based respiratory differences are present at birth suggesting a strong genetic component. Our objective was to characterize early life sex-based genomic signatures determined by variable X-chromosome methylation in the airways. We compared male versus female genome-wide DNA methylation in nasal airway samples from newborns and infants aged 1-6 months (N = 12). We analyzed methylation signals across CpG sites mapped to each X-linked gene using an unsupervised classifier (principal components) followed by an internal evaluation and an exhaustive cross-validation. Results were validated in an independent population of children (N = 72) following the same algorithm. X-linked genes with significant sex-based differential methylation in the nasal airway of infants represented only about 50% of the unique protein coding transcripts. X-linked genes without significant sex-based differential methylation included genes with evidence of escaping X-inactivation and female-biased airway expression. These genes showed similar methylation patterns in males and females suggesting unbalanced X-chromosome dosage. In conclusion, we identified that the human airways have already sex-based DNA methylation signatures at birth. These early airway epigenomic marks may determine sex-based respiratory phenotypes and overall predisposition to develop respiratory disorders later in life.

Objective: Despite cautions by professional associations, benzodiazepines (BZD) and Z hypnotics (BZD/Z) are widely prescribed to older adults who are particularly susceptible to insomnia and anxiety, but who are also more sensitive to drugs adverse events. In this study, we assessed the prescription of BZD/Z drugs in a sample of older adults (≥65) who presented for emergency care after a fall., Methods: We collected the type, number and dose of BZD/Z drugs prescribed and explored gender differences in the prescription., Results: BZD/Z drugs were prescribed to 43.6% of the sample (n=654) and more frequently to women; 78.4% of prescriptions were for BZD/Z drugs with a short half-life. The majority of patients (83.5%) were prescribed only one type of BZD/Z, but 16.5% had been prescribed multiple BZD/Z drugs, with no gender difference. Doses higher than those recommended for older adults were prescribed to 58% of patients, being the doses significantly higher for men compared to women (70.0% vs 53.1%)., Conclusions: Over 40% of older adults presenting for emergency care after a fall had previously been prescribed BZD/Z drugs. Some important gender differences in the prescription of BZD/Z drugs were seen, especially prescription above the recommended dose and of drugs with a long-half life., (Copyright © 2017 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.)

Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) is a rare disorder of immune dysregulation caused by mutations in the autoimmune regulator ( AIRE ) gene. Individuals affected with APECED develop a clinical syndrome characterized by ectodermal abnormalities, autoantibody production, and organ-specific autoimmune manifestations. Inflammatory arthritis is usually not described as a part of the syndrome, and only sporadic cases are reported. We describe the case of a preschool-age girl who presented with hypoparathyroidism, hepatitis, interstitial pneumonitis, and chronic polyarthritis at 4 years of age and was found to have two compound heterozygous disease-associated mutations in the AIRE gene. We also conducted a literature review of the main characteristics of inflammatory arthritis in APECED patients. Our case and review demonstrate that (1) inflammatory arthritis, although rare, can be an early manifestation of APECED; (2) the diagnosis of APECED should be considered if mucocutaneous candidiasis, multiple organ-specific autoimmune manifestations, polyendocrinopathy, especially hypoparathyroidism or adrenal failure, or ectodermal dystrophy accompany joint symptoms; and (3) genotyping interpretation should take into account that mutations are found in the 14 exons of the gene, compound heterozygosity is common, and in some cases, only one or no mutated alleles are found.