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Alveologenesis, the final stage in lung development, substantially remodels the distal lung, expanding the alveolar surface area for efficient gas exchange. Secondary crest myofibroblasts (SCMF) exist transiently in the neonatal distal lung and are crucial for alveologenesis. However, the pathways that regulate SCMF function, proliferation and temporal identity remain poorly understood. To address this, we purified SCMFs from reporter mice, performed bulk RNA-seq and found dynamic changes in Hippo-signaling components during alveologenesis. We deleted the Hippo effectors Yap/Taz from Acta2-expressing cells at the onset of alveologenesis, causing a significant arrest in alveolar development. Using single cell RNA-seq, we identified a distinct cluster of cells in mutant lungs with altered expression of marker genes associated with proximal mesenchymal cell types, airway smooth muscle and alveolar duct myofibroblasts. In vitro studies confirmed that Yap/Taz regulates myofibroblast-associated gene signature and contractility. Together, our findings show that Yap/Taz is essential for maintaining functional myofibroblast identity during postnatal alveologenesis.
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Diferenciación Celular , Vía de Señalización Hippo , Morfogénesis , Miofibroblastos , Proteínas Serina-Treonina Quinasas , Alveolos Pulmonares , Transducción de Señal , Proteínas Señalizadoras YAP , Animales , Ratones , Miofibroblastos/metabolismo , Miofibroblastos/citología , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/citología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Morfogénesis/genética , Mesodermo/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Pulmón/metabolismo , Organogénesis/genética , Regulación del Desarrollo de la Expresión GénicaRESUMEN
OBJECTIVE: To establish consensus practices among a panel of national experts for the discharge of premature infants with bronchopulmonary dysplasia (BPD) from the hospital to home. STUDY DESIGN: We conducted a Delphi study that included US neonatologists and pediatric pulmonologists from the Bronchopulmonary Dysplasia Collaborative to establish consensus practices-defined as recommendations with at least 80% agreement-for infants with BPD being discharged from the hospital. Specifically, we evaluated recommendations for diagnostic tests to be completed around discharge, follow-up respiratory care, and family education. RESULTS: Thirty-one expert participants completed 3 rounds of surveys, with a 99% response rate (92 of 93). Consensus was established that infants with moderate-severe BPD (ie, those who remain on respiratory support at 36 weeks) and those discharged on oxygen should be targeted for in-person pulmonary follow-up within 1 month of hospital discharge. Specialized neonatal follow-up is an alternative for infants with mild BPD. Infants with moderate or severe BPD should have an echocardiogram performed after 36 weeks to screen for pulmonary hypertension. Infants with BPD warrant additional evaluations if they have growth restriction or poor growth, pulmonary hypertension, or tachypnea and if they are discharged to home on oxygen, diuretics, or nonoral feeds. CONCLUSIONS: This Delphi survey establishes expert consensus around best practices for follow-up respiratory management and routine evaluation for infants with BPD surrounding neonatal discharge. Areas of disagreement for which consensus was not established are discussed.
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Displasia Broncopulmonar , Hipertensión Pulmonar , Recién Nacido , Lactante , Humanos , Niño , Displasia Broncopulmonar/diagnóstico , Displasia Broncopulmonar/terapia , Alta del Paciente , Recien Nacido Prematuro , Consenso , Edad GestacionalRESUMEN
OBJECTIVE: The study aimed to identify factors that impact timing of gastrostomy placement/removal and Nissen fundoplication (NF) in infants with bronchopulmonary dysplasia (BPD). STUDY DESIGN: Clinical data were reviewed retrospectively from patients recruited from the Johns Hopkins Bronchopulmonary Dysplasia Clinic (January 1, 2014-December 31, 2018). RESULTS: Patients with gastrostomy tubes (GTs) placed in the neonatal intensive care unit (NICU) were older at discharge (p < 0.001) and less likely to have abnormal upper gastrointestinal series findings (p = 0.005) than those with GTs placed after NICU discharge. Patients with NF had lower mean gestational ages (p = 0.011), longer NICU stays (p = 0.019), more frequent home ventilation requirements (p = 0.005), and greater likelihood of pulmonary hypertension (p = 0.032) compared with those without. Median age of GT removal was 61.6 months. Patients with GTs were weaned from supplemental oxygen and/or home ventilation before GT removal (p < 0.001). CONCLUSION: Patients with GT/NF were more medically complex than those with GT alone. Patients were more likely to be weaned from home respiratory support before GT removal. KEY POINTS: · Patients with GT/NF were more medically complex than those with GT alone.. · Patients were more likely to be weaned from home respiratory support before GT removal.. · Patients with GTs placed in NICU were older at discharge and less likely to have abnormal upper gastrointestinal series result..
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Displasia Broncopulmonar , Gastrostomía , Recién Nacido , Lactante , Humanos , Niño , Preescolar , Fundoplicación , Displasia Broncopulmonar/cirugía , Estudios Retrospectivos , Alta del PacienteRESUMEN
Advancements in methods, technology, and our understanding of the pathobiology of lung injury have created the need to update the definition of experimental acute lung injury (ALI). We queried 50 participants with expertise in ALI and acute respiratory distress syndrome using a Delphi method composed of a series of electronic surveys and a virtual workshop. We propose that ALI presents as a "multidimensional entity" characterized by four "domains" that reflect the key pathophysiologic features and underlying biology of human acute respiratory distress syndrome. These domains are 1) histological evidence of tissue injury, 2) alteration of the alveolar-capillary barrier, 3) presence of an inflammatory response, and 4) physiologic dysfunction. For each domain, we present "relevant measurements," defined as those proposed by at least 30% of respondents. We propose that experimental ALI encompasses a continuum of models ranging from those focusing on gaining specific mechanistic insights to those primarily concerned with preclinical testing of novel therapeutics or interventions. We suggest that mechanistic studies may justifiably focus on a single domain of lung injury, but models must document alterations of at least three of the four domains to qualify as "experimental ALI." Finally, we propose that a time criterion defining "acute" in ALI remains relevant, but the actual time may vary based on the specific model and the aspect of injury being modeled. The continuum concept of ALI increases the flexibility and applicability of the definition to multiple models while increasing the likelihood of translating preclinical findings to critically ill patients.
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Lesión Pulmonar Aguda/patología , Inflamación/fisiopatología , Informe de Investigación/tendencias , Lesión Pulmonar Aguda/inmunología , AnimalesRESUMEN
OBJECTIVES: To study the demographic and clinical characteristics of preterm infants with bronchopulmonary dysplasia (BPD) to identify the factors most strongly predictive of outpatient mortality, with the goal of identifying those individuals at greatest risk. STUDY DESIGN: Demographic and clinical characteristics were retrospectively reviewed for 862 subjects recruited from an outpatient BPD clinic. Characteristics of the deceased and living participants were compared using nonparametric analysis. Regression analysis was performed to identify factors associated with mortality. RESULTS: Of the 862 subjects, 13 (1.5%) died during follow-up, for an overall mortality rate of approximately 15.1 deaths per 1000 subjects. Two patients died in the postneonatal period (annual mortality incidence, 369.9 per 100 000), 9 died between age 1 and 4 years (annual mortality incidence, 310.2 per 100 000), and 2 died between age of 5 and 14 years (annual mortality incidence, 71.4 per 100 000). After adjusting for gestational age and BPD severity, mortality was found to be associated with the amount of supplemental oxygen required at discharge from the neonatal intensive care unit (adjusted hazard ratio [aHR], 4.10; P = .001), presence of a gastrostomy tube (aHR, 8.13; P = .012), and presence of a cerebrospinal fluid (CSF) shunt (aHR, 4.31; P = .021). CONCLUSIONS: The incidence of mortality among preterm infants with BPD is substantially higher than that seen in the general population. The need for greater amounts of home supplemental oxygen and the presence of a gastrostomy tube or CSF shunt were associated with an increased risk of postdischarge mortality. Future studies should focus on clarifying risk factors for the development of severe disease to allow for early identification and treatment of those at highest risk.
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Displasia Broncopulmonar/mortalidad , Recien Nacido Prematuro , Adolescente , Derivaciones del Líquido Cefalorraquídeo , Niño , Preescolar , Femenino , Estudios de Seguimiento , Gastrostomía , Humanos , Lactante , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Masculino , Maryland/epidemiología , Terapia por Inhalación de Oxígeno , Estudios RetrospectivosRESUMEN
OBJECTIVE: To measure plasma levels of vascular endothelial growth factor (VEGF) and several cytokines (Interleukin [IL]-6 IL-8, IL-10) during the first week of life to examine the relationship between protein expression and likelihood of developing respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD). STUDY DESIGN: Levels of IL-6, IL-8, IL-10, and VEGF were measured from plasma obtained from preterm patients during the first week of life. Newborns were recruited from a single center between April 2009 and April 2019. Criteria for the study included being inborn, birth weight of less than 1500 grams, and a gestational age of less than 32 weeks at birth. RESULTS: The development of RDS in preterm newborns was associated with lower levels of VEGF during the first week of life. Higher plasma levels of IL-6 and IL-8 plasma were associated with an increased likelihood and increased severity of BPD at 36 weeks postmenstrual age. In contrast, plasma levels of VEGF, IL-6, IL-8, and IL-10 obtained during the first week of life were not associated with respiratory symptoms and acute care use in young children with BPD in the outpatient setting. CONCLUSIONS: During the first week of life, lower plasma levels of VEGF was associated with the diagnosis of RDS in preterm infants. Preterm infants with higher levels of IL-6 and IL-8 during the first week of life were also more likely to be diagnosed with BPD. These biomarkers may help to predict respiratory morbidities in preterm newborns during their initial hospitalization.
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Displasia Broncopulmonar , Síndrome de Dificultad Respiratoria del Recién Nacido , Biomarcadores/sangre , Displasia Broncopulmonar/diagnóstico , Citocinas/sangre , Femenino , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Interleucina-10 , Interleucina-6 , Interleucina-8 , Embarazo , Síndrome de Dificultad Respiratoria del Recién Nacido/diagnóstico , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
OBJECTIVES: To test the hypothesis that daycare attendance among children with bronchopulmonary dysplasia (BPD) is associated with increased chronic respiratory symptoms and/or greater health care use for respiratory illnesses during the first 3 years of life. STUDY DESIGN: Daycare attendance and clinical outcomes were obtained via standardized instruments for 341 subjects recruited from 9 BPD specialty clinics in the US. All subjects were former infants born preterm (<34 weeks) with BPD (71% severe) requiring outpatient follow-up between 0 and 3 years of age. Mixed logistic regression models were used to test for associations. RESULTS: Children with BPD attending daycare were more likely to have emergency department visits and systemic steroid usage. Children in daycare up to 3 years of age also were more likely to report trouble breathing, having activity limitations, and using rescue medications when compared with children not in daycare. More severe manifestations were found in children attending daycare between 6 and 12 months of chronological age. CONCLUSIONS: In this study, children born preterm with BPD who attend daycare were more likely to visit the emergency department, use systemic steroids, and have chronic respiratory symptoms compared with children not in daycare, indicating that daycare may be a potential modifiable risk factor to minimize respiratory morbidities in children with BPD during the preschool years.
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Displasia Broncopulmonar , Displasia Broncopulmonar/complicaciones , Displasia Broncopulmonar/epidemiología , Niño , Guarderías Infantiles , Preescolar , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Morbilidad , Esteroides/uso terapéuticoRESUMEN
We performed a point prevalence study on infants with severe bronchopulmonary dysplasia (BPD), collecting data on type and settings of ventilatory support; 187 infants, 51% of whom were on invasive positive-pressure ventilation (IPPV), from 15 centers were included. We found a significant center-specific variation in ventilator modes.
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Displasia Broncopulmonar , Displasia Broncopulmonar/epidemiología , Displasia Broncopulmonar/terapia , Humanos , Lactante , Recién Nacido , Prevalencia , Ventiladores MecánicosRESUMEN
Background: Premature birth affects millions of neonates each year, placing them at risk for respiratory disease due to prematurity. Bronchopulmonary dysplasia is the most common chronic lung disease of infancy, but recent data suggest that even premature infants who do not meet the strict definition of bronchopulmonary dysplasia can develop adverse pulmonary outcomes later in life. This post-prematurity respiratory disease (PPRD) manifests as chronic respiratory symptoms, including cough, recurrent wheezing, exercise limitation, and reduced pulmonary function. This document provides an evidence-based clinical practice guideline on the outpatient management of infants, children, and adolescents with PPRD. Methods: A multidisciplinary panel of experts posed questions regarding the outpatient management of PPRD. We conducted a systematic review of the relevant literature. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of the clinical recommendations. Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations were developed for or against three common medical therapies and four diagnostic evaluations in the context of the outpatient management of PPRD. Conclusions: The panel developed recommendations for the outpatient management of patients with PPRD on the basis of limited evidence and expert opinion. Important areas for future research were identified.
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Enfermedades del Prematuro/terapia , Enfermedades Respiratorias/terapia , Adolescente , Cuidados Posteriores , Niño , Enfermedad Crónica , Humanos , Lactante , Recién Nacido , Recien Nacido PrematuroRESUMEN
OBJECTIVE: Bronchopulmonary dysplasia (BPD) remains the most common late morbidity for extremely premature infants. Care of infants with BPD requires a longitudinal approach from the neonatal intensive care unit to ambulatory care though interdisciplinary programs. Current approaches for the development of optimal programs vary among centers. STUDY DESIGN: We conducted a survey of 18 academic centers that are members of the BPD Collaborative, a consortium of institutions with an established interdisciplinary BPD program. We aimed to characterize the approach, composition, and current practices of the interdisciplinary teams in inpatient and outpatient domains. RESULTS: Variations exist among centers, including composition of the interdisciplinary team, whether the team is the primary or consult service, timing of the first team assessment of the patient, frequency and nature of rounds during the hospitalization, and the timing of ambulatory visits postdischarge. CONCLUSION: Further studies to assess long-term outcomes are needed to optimize interdisciplinary care of infants with severe BPD. KEY POINTS: · Care of infants with BPD requires a longitudinal approach from the NICU to ambulatory care.. · Benefits of interdisciplinary care for children have been observed in other chronic conditions.. · Current approaches for the development of optimal interdisciplinary BPD programs vary among centers..
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OBJECTIVE: The objective of this study was to identify factors associated with the cessation of human milk prior to neonatal intensive care unit (NICU) discharge for infants diagnosed with bronchopulmonary dysplasia (BPD). STUDY DESIGN: Participants were recruited from the Johns Hopkins BPD Clinic between January 2016 and October 2018. Clinical and demographic characteristics were analyzed based on whether participants stopped human milk before or after NICU discharge. RESULTS: Of the 224 infants included, 109 (48.7%) infants stopped human milk prior to discharge. The median duration of human milk intake was less for infants who stopped human milk prior to discharge compared with those who continued after discharge (2 vs. 8 months, p < 0.001). In multivariate regression analysis, pulmonary hypertension (odds ratio [OR]: 2.90; p = 0.016), public insurance (OR: 2.86; p < 0.001), and length of NICU admission (OR: 1.26 per additional month; p = 0.002) were associated with human milk cessation prior to NICU discharge. CONCLUSION: Infants with BPD who have severe medical comorbidities and markers of lower socioeconomic status may be at higher risk for earlier human milk discontinuation. KEY POINTS: · Half of infants in our study with BPD who received human milk stopped human milk prior to NICU discharge.. · For infants on human milk after discharge, the duration of human milk intake was 8.6 months.. · Infants with pulmonary hypertension, tracheostomies, and ventilation stopped human milk earlier.. · Non-White race, lower income, and public insurance were predictors of early human milk cessation..
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OBJECTIVE: To evaluate the impact of exposure to indoor air pollution on respiratory health outcomes (healthcare utilization, symptoms, medication use) in infants and children with bronchopulmonary dysplasia (BPD). STUDY DESIGN: A total of 244 subjects were included from the Johns Hopkins Bronchopulmonary Dysplasia registry. Parents completed an environmental exposure questionnaire including secondhand smoke and indoor combustion (gas/propane heat, gas or wood stove, gas/wood burning fireplace) exposures in the home. Respiratory symptoms, both acute (healthcare utilization, steroid/antibiotic use) and chronic (cough/wheeze, nocturnal cough, use of beta-agonists, tolerance of physical activity), were also collected. RESULTS: Three-quarters of the infants were exposed to at least 1 combustible source of air pollution in the home, and this exposure was associated with an increased risk of hospitalization in infants and children on home respiratory support. Only 14% of the study population reported secondhand smoke exposure, but we found that this was associated with chronic respiratory symptoms, including activity limitation and nocturnal cough. Infants on respiratory support also had increased daytime cough and wheezing. Approximately one-third reported having an air purifier in the home, and its presence attenuated the effect of secondhand smoke exposure on reported activity limitation. CONCLUSIONS: Exposure to combustible sources of indoor air pollution was associated with increased respiratory morbidity in a group of high risk of infants with BPD. Our results support that indoor air pollution is a modifiable risk factor for respiratory health in infants with BPD.
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Contaminación del Aire Interior/efectos adversos , Displasia Broncopulmonar/complicaciones , Tos/etiología , Trastornos Respiratorios/etiología , Ruidos Respiratorios/etiología , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Obesity increases susceptibility to chronic pain, increases metabolism, and is associated with obstructive sleep apnea syndrome (OSAS), all which can complicate perioperative pain management of patients. In addition, obesity and OSAS can cause elevation of the adipose-derived hormone leptin, which increases metabolism. We hypothesized that obesity along with sleep apnea and leptin independently enhance morphine pharmacokinetics. METHODS: Children 5-12 years of age who were presenting for surgery were administered a morphine dose of 0.05 mg/kg. Blood was collected at baseline and at subsequent preset times for pharmacokinetic analysis of morphine and its metabolites. Three groups were studied: a nonobese group with severe OSAS, an obese group with severe OSAS, and a control group. RESULTS: Thirty-four patients consisting of controls (n = 16), nonobese/OSAS (n = 8), and obese/OSAS (n = 10) underwent analysis. The obese/OSAS group had a higher dose-adjusted mean maximum morphine concentration (CMAX) over 540 minutes compared to the controls (P < .001) and those with only OSAS (P = .014). The obese/OSAS group also had lower volume of distribution (Vd) when compared to OSAS-only patients (P = .007). In addition, those in the obese/OSAS group had a higher morphine 3-glucuronide (M3G) maximum concentration (P = .012) and a higher ratio of M3G to morphine than did the control group (P = .011). Time to maximum morphine 6-glucuronide (M6G) concentration was significantly lower in both nonobese/OSAS and obese/OSAS groups than in the control group (P < .005). C-reactive protein (CRP), interleukin (IL)-10, and leptin were all higher in the obese/OSAS group than in controls (P = .004, 0.026, and <0.001, respectively), and compared to OSAS-only patients, CRP (P = .013) and leptin (P = .002) levels were higher in the obese/OSAS group. CONCLUSIONS: The combination of obesity and OSAS was associated with an increase in morphine metabolism compared with that in normal-weight controls. Our previous study in mice demonstrated that obesity from leptin deficiency decreased morphine metabolism, but that metabolism normalized after leptin replacement. Leptin may be a cause of the increased morphine metabolism observed in obese patients.
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Analgésicos Opioides/farmacocinética , Morfina/farmacocinética , Obesidad Infantil/complicaciones , Apnea Obstructiva del Sueño/complicaciones , Procedimientos Quirúrgicos Operativos , Factores de Edad , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/sangre , Biomarcadores/sangre , Biotransformación , Niño , Preescolar , Cálculo de Dosificación de Drogas , Femenino , Humanos , Leptina/sangre , Masculino , Modelos Biológicos , Morfina/administración & dosificación , Morfina/sangre , Obesidad Infantil/sangre , Obesidad Infantil/diagnóstico , Apnea Obstructiva del Sueño/sangre , Apnea Obstructiva del Sueño/diagnósticoRESUMEN
Pediatric acute lung injury, usually because of pneumonia, has a mortality rate of more than 20% and an incidence that rivals that of all childhood cancers combined. CD4+ T-cells coordinate the immune response to pneumonia but fail to function robustly among the very young, who have poor outcomes from lung infection. We hypothesized that DNA methylation represses a mature CD4+ T-cell transcriptional program in neonates with pneumonia. Here, we found that neonatal mice (3-4 days old) aspirated with Escherichia coli bacteria had a higher mortality rate than juvenile mice (11-14 days old). Transcriptional profiling with an unsupervised RNA-Seq approach revealed that neonates displayed an attenuated lung CD4+ T-cell transcriptional response to pneumonia compared with juveniles. Unlike neonates, juveniles up-regulated a robust set of canonical T-cell immune response genes. DNA methylation profiling with modified reduced representation bisulfite sequencing revealed 44,119 differentially methylated CpGs, which preferentially clustered around transcriptional start sites and CpG islands. A methylation difference-filtering algorithm detected genes with a high likelihood of differential promoter methylation regulating their expression; these 731 loci encoded important immune response and tissue-protective T-cell pathway components. Disruption of DNA methylation with the hypomethylating agent decitabine induced plasticity in the lung CD4+ T-cell marker phenotype. Altogether, multidimensional profiling suggested that DNA methylation within the promoters of a core set of CD4+ T-cell pathway genes contributes to the hyporesponsive neonatal immune response to pneumonia. These findings also suggest that DNA methylation could serve as a mechanistic target for disease-modifying therapies in pediatric lung infection and injury.
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Linfocitos T CD4-Positivos/inmunología , Metilación de ADN , Infecciones por Escherichia coli/inmunología , Escherichia coli/inmunología , Neumonía/inmunología , Animales , Animales Recién Nacidos , Linfocitos T CD4-Positivos/metabolismo , Islas de CpG , Epigénesis Genética , Infecciones por Escherichia coli/genética , Ratones , Ratones Endogámicos C57BL , Neumonía/genética , Activación TranscripcionalRESUMEN
RATIONALE: The tobacco harm reduction literature is replete with vague language, far-reaching claims, and unwarranted certainty. The American Thoracic Society has increasingly recognized the need for a framework for reliably making such claims. Evidence-based standards improving the scientific value and transparency of harm reduction claims are expected to improve their trustworthiness, clarity, and consistency. METHODS: Experts from relevant American Thoracic Society committees identified key topic areas for discussion. Literature search strategy included English language articles across Medline, Google Scholar, and the Cochrane Collaborative databases, with expanded search terms including tobacco, addiction, smoking, cigarettes, nicotine, and harm reduction. Workgroup members synthesized their evidentiary summaries into a list of candidate topics suitable for inclusion in the final report. Breakout groups developed detailed content maps of each topic area, including points to be considered for suggested recommendations. Successive draft recommendations were modified using an iterative consensus process until unanimous approval was achieved. Patient representatives ensured the document's relevance to the lay public. RESULTS: Fifteen recommendations were identified, organized into four framework elements dealing with: estimating harm reduction among individuals, making claims on the basis of population impact, appropriately careful use of language, and ethical considerations in harm reduction. DISCUSSION: This statement clarifies important principles guiding valid direct and inferential harm reduction claims. Ideals for effective communication with the lay public and attention to unique ethical concerns are also delineated. The authors call for formal systems of grading harm reduction evidence and regulatory assurances of longitudinal surveillance systems to document the impact of harm reduction policies.
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Reducción del Daño , Comunicación en Salud , Política de Salud , Nicotiana/efectos adversos , Fumar/efectos adversos , Humanos , Sociedades Médicas , Estados UnidosRESUMEN
Neonates have greater morbidity/mortality from lower respiratory tract infections (LRTI) compared to older children. Lack of conditioning of the pulmonary immune system due to limited environmental exposures and/or infectious challenges likely contributes to the increase susceptibility in the neonate. In this study, we sought to gain insights into the nature and dynamics of the neonatal pulmonary immune response to LRTI using a murine model. METHODS: Wildtype (WT) and Ccr2-/- C57BL/6 neonatal and juvenile mice received E. coli or PBS by direct pharyngeal aspiration. Flow cytometry was used to measure immune cell dynamics and identify cytokine-producing cells. Real-time PCR and ELISA were used to measure cytokine/chemokine expression. RESULTS: Innate immune cell recruitment in response to E. coli-induced LRTI was delayed in the neonatal lung compared to juvenile lung. Lung clearance of bacteria was also significantly delayed in the neonate. Ccr2-/- neonates, which lack an intact CCL2-CCR2 axis, had higher mortality after E. coli challenged than Ccr2+/+ neonates. A greater percentage of CD8+ T cells and monocytes from WT neonates challenged with E. coli produced TNF compared to controls. CONCLUSION: The pulmonary immune response to E. coli-induced LRTI differed significantly between neonatal and juvenile mice. Neonates were more susceptible to increasing doses of E. coli and exhibited greater mortality than juveniles. In the absence of an intact CCL2-CCR2 axis, susceptibility to LRTI-induced mortality was further increased in neonatal mice. Taken together these findings underscore the importance of age-related differences in the innate immune response to LRTI during early stages of postnatal life.
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Quimiocina CCL2/inmunología , Infecciones por Escherichia coli/inmunología , Inmunidad Innata , Pulmón/microbiología , Receptores CCR2/metabolismo , Infecciones del Sistema Respiratorio/inmunología , Factores de Edad , Animales , Animales Recién Nacidos , Bronquios/microbiología , Quimiocina CCL2/deficiencia , Quimiocinas/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Escherichia coli , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/mortalidad , Inflamación , Pulmón/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Neumonía Bacteriana/inmunología , Neumonía Bacteriana/microbiología , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores CCR2/deficienciaRESUMEN
OBJECTIVE: To determine the effect of an acute (1 week) and chronic (3 weeks) exposure to E-cigarette (E-cig) emissions on mucociliary clearance (MCC) in murine lungs. METHODS: C57BL/6 male mice (age 10.5 ± 2.4 weeks) were exposed for 20 min/day to E-cigarette aerosol generated by a Joyetech 510-T® E-cig containing either 0% nicotine (N)/propylene glycol (PG) for 1 week (n = 6), or 3 weeks (n = 9), or 2.4% N/PG for one week (n = 6), or 3 weeks (n = 9), followed by measurement of MCC. Control mice (n = 15) were not exposed to PG alone, or N/PG. MCC was assessed by gamma camera following aspiration of 99mtechnetium aerosol and was expressed as the amount of radioactivity removed from both lungs over 6 hours (MCC6hrs). Venous blood was assayed for cotinine levels in control mice and in mice exposed for 3-weeks to PG alone and N/PG. RESULTS: MCC6hrs in control mice and in mice acutely exposed to PG alone and N/PG was similar, averaging (±1 standard deviation) 8.6 ± 5.2%, 7.5 ± 2.8% and 11.2 ± 5.9%, respectively. In contrast, chronic exposure to PG alone stimulated MCC6hrs (17.2 ± 8.0)% and this stimulation was significantly blunted following chronic exposure to N/PG (8.7 ± 4.6)% (p < .05). Serum cotinine levels were <0.5 ng/ml in control mice and in mice exposed to PG alone, whereas, N/PG exposed mice averaged 14.6 ± 12.0 ng/ml. CONCLUSIONS: In this murine model, a chronic, daily, 20 min-exposure to N/PG, but not an acute exposure, slowed MCC, compared to exposure to PG alone and led to systemic absorption of nicotine.
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Sistemas Electrónicos de Liberación de Nicotina , Depuración Mucociliar/efectos de los fármacos , Nicotina/administración & dosificación , Nicotina/toxicidad , Propilenglicol/administración & dosificación , Propilenglicol/toxicidad , Administración por Inhalación , Animales , Cotinina , Esquema de Medicación , Pulmón , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE: To evaluate the potential link between systemic inflammation and impaired lung function in people with ataxia-telangiectasia (A-T), we hypothesized that serum levels of interleukin (IL)-6, a proinflammatory cytokine, would correlate inversely with lung function in subjects with A-T. STUDY DESIGN: Consecutive subjects with A-T were recruited from the Johns Hopkins Outpatient A-T Clinical Center. Serum levels of IL-6 and 8 were measured by enzyme-linked immunosorbent assay. Spirometry was performed in subjects ≥ 6 years of age on the same day that serum was obtained for measurements of cytokines. RESULTS: Approximately 80% of subjects had elevated serum IL-6 levels (> 1.0 pg/mL). No association was found between elevated IL-6 and age. Elevated IL-8 levels were found in 23.6% of subjects, and all subjects with elevated IL-8 levels had elevated IL-6 levels. Subjects with elevated IL-6 levels (mean: 6.14 ± 7.47 pg/mL) had significantly lower mean percent forced vital capacity (FVC%, 50.5% ± 17.8%) compared with subjects with normal serum IL-6 levels (FVC% of 66.2 ± 16.1, P = .018). Greater IL-6 levels were associated with lower FVC% even after adjustment for receiving gamma globulin therapy (P = .024) and supplemental nutrition (P = .055). CONCLUSIONS: An association was found between elevated serum IL-6 levels and lower lung function in subjects with A-T. In addition, subjects with both elevated IL-6 and IL-8 had the lowest mean lung function. These findings indicate that markers for systemic inflammation may be useful in identifying individuals with A-T at increased risk for lower lung function and may help in assessing response to therapy.
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Ataxia Telangiectasia/sangre , Ataxia Telangiectasia/fisiopatología , Interleucina-6/sangre , Pruebas de Función Respiratoria , Adolescente , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inflamación , Interleucina-8/sangre , Masculino , Fenotipo , Espirometría , Adulto JovenRESUMEN
Despite acute respiratory and chronic respiratory and gastro-intestinal complications, most infants and children with a history of oesophageal atresia / trachea-oesophageal fistula [OA/TOF] can expect to live a fairly normal life. Close multidisciplinary medical and surgical follow-up can identify important co-morbidities whose treatment can improve symptoms and optimize pulmonary and nutritional outcomes. This article will discuss the aetiology, classification, diagnosis and treatment of congenital TOF, with an emphasis on post-surgical respiratory management, recognition of early and late onset complications, and long-term clinical outcomes.