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Objectives: People living with HIV (PLWH) are at increased risk of asymptomatic neurosyphilis; thus, it has been common practice to perform a lumbar puncture (LP) in all PLWH presenting with syphilis regardless of stage, signs or symptoms. However, this practice varies widely among clinicians. Our objective was to elucidate the number of LPs required to diagnose a single case of asymptomatic neurosyphilis. Methods: We performed an electronic health record (EHR) review of PLWH who were diagnosed with syphilis of any stage over a 10‐year period. EHRs were reviewed to determine the number of subjects who had an LP performed, what proportion had neurological signs or symptoms, and whether a diagnosis of neurosyphilis was made at presentation or follow‐up. Results: In 261 separate episodes of syphilis in 230 subjects, we found the major risk factors for asymptomatic neurosyphilis to be low CD4 T‐cell count (P = 0.0007), high rapid plasma reagin (RPR) titre (P = 0.019) and lack of HIV virological suppression (P = 0.003). The majority of our subjects (78%) with neurosyphilis presented with central nervous system (CNS) symptoms. We estimate, if standard practice is to perform LP in all patients, that the number needed to test (NNTT) = 38. Conclusions: This large number of potentially unnecessary LPs, along with heterogeneity of presentation, and the never‐nil risk of asymptomatic neurosyphilis should be incorporated into clinical decision‐making. The majority of PLWH presenting with a serological diagnosis of syphilis, but no neurological signs or symptoms, do not necessarily require an LP for an evaluation of asymptomatic neurosyphilis. [ABSTRACT FROM AUTHOR]

Rationale: We identified a 6-year-old girl with pulmonary alveolar proteinosis (PAP), impaired granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor function, and increased GM-CSF.Objectives: Increased serum GM-CSF may be useful to identify individuals with PAP caused by GM-CSF receptor dysfunction.Methods: We screened 187 patients referred to us for measurement of GM-CSF autoantibodies to diagnose autoimmune PAP. Five were children with PAP and increased serum GM-CSF but without GM-CSF autoantibodies or any disease causing secondary PAP; all were studied with family members, subsequently identified patients, and controls.Measurement and Main Results: Eight children (seven female, one male) were identified with PAP caused by recessive CSF2RA mutations. Six presented with progressive dyspnea of insidious onset at 4.8 ± 1.6 years and two were asymptomatic at ages 5 and 8 years. Radiologic and histopathologic manifestations were similar to those of autoimmune PAP. Molecular analysis demonstrated that GM-CSF signaling was absent in six and severely reduced in two patients. The GM-CSF receptor β chain was detected in all patients, whereas the α chain was absent in six and abnormal in two, paralleling the GM-CSF signaling defects. Genetic analysis revealed multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing. All symptomatic patients responded well to whole-lung lavage therapy.Conclusions: CSF2RA mutations cause a genetic form of PAP presenting as insidious, progressive dyspnea in children that can be diagnosed by a combination of characteristic radiologic findings and blood tests and treated successfully by whole-lung lavage. [ABSTRACT FROM AUTHOR]

Rationale: Considerable confusion exists regarding nomenclature, classification, and management of pediatric diffuse lung diseases due to the relative rarity and differences in the spectrum of disease between adults and young children.Objectives: A multidisciplinary working group was formed to: (1) apply consensus terminology and diagnostic criteria for disorders presenting with diffuse lung disease in infancy; and (2) describe the distribution of disease entities, clinical features, and outcome in young children who currently undergo lung biopsy in North America.Methods: Eleven centers provided pathologic material, clinical data, and imaging from all children less than 2 years of age who underwent lung biopsy for diffuse lung disease from 1999 to 2004.Measurements and Main Results: Multidisciplinary review categorized 88% of 187 cases. Disorders more prevalent in infancy, including primary developmental and lung growth abnormalities, neuroendocrine cell hyperplasia of infancy, and surfactant-dysfunction disorders, constituted the majority of cases (60%). Lung growth disorders were often unsuspected clinically and under-recognized histologically. Cases with known surfactant mutations had characteristic pathologic features. Age at biopsy and clinical presentation varied among categories. Pulmonary hypertension, presence of a primary developmental abnormality, or ABCA3 mutation was associated with high mortality, while no deaths occurred in cases of pulmonary interstitial glycogenosis, or neuroendocrine cell hyperplasia of infancy.Conclusions: This retrospective cohort study identifies a diverse spectrum of lung disorders, largely unique to young children. Application of a classification scheme grouped clinically distinct patients with variable age of biopsy and mortality. Standardized terminology and classification will enhance accurate description and diagnosis of these disorders. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVES: Pneumothorax is a common complication of lymphangioleiomyomatosis (LAM), and the optimal approach to its treatment and prevention is unknown. Chemical or surgical pleurodesis are often required to prevent recurrence. However, their efficacy in LAM is unclear, and whether they contribute to perioperative complications during lung transplantation is uncertain. SETTING: The LAM Foundation database of registered patients. DESIGN: A questionnaire was sent to all registered patients who had at least one pneumothorax to determine rates and patterns of recurrence and efficacy of interventions. A second questionnaire was sent to registered LAM patients who received a lung transplant.Patients or participants: Of 395 registered patients, 260 patients (66%) reported at least one pneumothorax during their lifetime, 193 of whom (74%) completed the questionnaire. Of the 85 lung transplant patients who were sent a separate questionnaire, 80 patients (94%) responded. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Of the 193 respondents to the pneumothorax questionnaire, data on 676 episodes of pneumothorax were collected. Eighty-two percent (158 of 193 patients) had their first pneumothorax prior to a diagnosis of LAM. One hundred forty patients (73%) had at least one additional pneumothorax, either an ipsilateral recurrence (99 of 140 patients, 71%) or a contralateral pneumothorax (104 of 140 patients, 74%). Recurrence rates were 66% after conservative therapy, 27% after chemical pleurodesis, and 32% after surgery. In patients who had undergone lung transplantation, prior chemical or surgical pleurodesis was performed in 45 of 80 patients (56%). Fourteen of 80 patients (18%) reported pleural-related postoperative bleeding, 13 of whom (93%) had prior pleurodesis. CONCLUSIONS: Chemical pleurodesis or surgery are equally effective and better than conservative therapy in preventing recurrence of pneumothorax in LAM. Due to the high recurrence rate, either procedure should be considered for the initial pneumothorax in these patients. However, both contribute to increased perioperative bleeding following lung transplantation, with no effect on length of hospital stay. [ABSTRACT FROM AUTHOR]

Childhood interstitial lung disease (chILD) encompasses a diverse group of genetic, infectious, and inflammatory conditions affecting infants and children. The recognition and understanding of these entities have highlighted the necessity for more accurate classification. This group of rare heterogeneous diseases comprises more than 200 different conditions and has a combined estimated prevalence of less than one patient per 100 000 children. Hence, a systematic diagnostic approach is crucial. This article describes a diagnostic approach for pediatric diffuse lung diseases in infancy, including an analysis of clinical presentations and imaging and histologic features to effectively distinguish among various chILD entities. Although they often have overlapping and nonspecific radiologic features, some chILD entities may exhibit typical imaging findings, resulting in a CT diagnosis or aiding in narrowing the differential diagnosis, thus guiding the clinician to the appropriate genetic tests, potentially limiting unnecessary biopsies. This approach aims to enhance the understanding and diagnosis of chILD in infants, thereby facilitating improved patient care., (© RSNA, 2024.)

Rationale: In the outpatient setting, inhaled corticosteroids (ICS) are frequently given to children with bronchopulmonary dysplasia (BPD) for treatment of respiratory and asthma-associated symptoms. In this study we sought to determine if correlations existed between ICS use and ICS initiation and patient characteristics and outpatient respiratory outcomes., Methods: This study included children with the diagnosis of BPD (n = 661) who were seen in outpatient pulmonary clinics at the Children's Hospital of Philadelphia between 2016 and 2021. Chart review was used to determine patient demographics, use and timing of ICS initiation, asthma diagnosis, and acute care usage following initial hospital discharge., Results: At the first pulmonary visit, 9.2% of children had been prescribed an ICS at NICU discharge, 13.9% had been prescribed an ICS after NICU discharge but before their first pulmonary appointment, and 6.9% were prescribed an ICS at the completion of initial pulmonary visit. Children started on an ICS as outpatients had a higher likelihood of ER visits (adjusted odds ratio: 2.68 ± 0.7), hospitalizations (4.81 ± 1.16), and a diagnosis of asthma (3.58 ± 0.84), compared to children never on an ICS. Of those diagnosed with asthma, children prescribed an ICS in the outpatient setting received the diagnosis at an earlier age. No associations between NICU BPD severity scores and ICS use were found., Conclusions: This study identifies an outpatient BPD phenotype associated with ICS use and ICS initiation independent of NICU severity score. Additionally, outpatient ICS initiation correlates with a subsequent diagnosis of asthma and acute care usage in children with BPD., (© 2024 Wiley Periodicals LLC.)

Severe fetal hypoxia poses a significant risk to lung development resulting in severe postnatal complications. Existing chronic hypoxia animal models lack the ability to achieve pathologically reduced fetal oxygen without compromising animal development, placental blood flow, or maternal health. Using an established model of isolated chronic hypoxia involving the Extrauterine Environment for Neonatal Development (EXTEND), we are able to investigate the direct impact of fetal hypoxia on lung development. Oxygen delivery to preterm fetal lambs (105-110 days GA) delivered by cesarean section was reduced, and animals were supported on EXTEND through the canalicular or saccular stage of lung development. Fetal lambs in hypoxic conditions showed significant growth restriction compared to their normoxic counterparts. We also observed modest aberrant vascular remodeling in the saccular group after hypoxic conditions with decreased macrovessel numbers, microvascular endothelial cell numbers, and increased peripheral vessel muscularization. In addition, fetal hypoxia resulted in enlarged distal airspaces and decreased septal wall volume. Moreover, there was a reduction in mature SFTPB and processed SFTPC protein expression concomitant with a decrease in AT2 cell number. These findings demonstrate that maternally-independent fetal hypoxia predominantly impacts distal airway development, AT2 cell number, and surfactant production with mild effects on the vasculature.

Background: Childhood interstitial lung disease (chILD) encompasses a group of rare heterogeneous respiratory conditions associated with significant morbidity and mortality. Reports suggest that many patients diagnosed with chILD continue to have potentially progressive or fibrosing disease into adulthood. Over the last decade, the spectrum of conditions within chILD has widened substantially, with the discovery of novel entities through advanced genetic testing. However, most evidence is often limited to small case series, with reports disseminated across an array of subspecialty, clinical and molecular journals. In particular, the frequency, management and outcome of paediatric pulmonary fibrosis is not well characterised, unlike in adults, where clear diagnosis and treatment guidelines are available., Methods and Results: This review assesses the current understanding of pulmonary fibrosis in chILD. Based on registry data, we have provisionally estimated the occurrence of fibrosis in various manifestations of chILD, with 47 different potentially fibrotic chILD entities identified. Published evidence for fibrosis in the spectrum of chILD entities is assessed, and current and future issues in management of pulmonary fibrosis in childhood, continuing into adulthood, are considered., Conclusions: There is a need for improved knowledge of chILD among pulmonologists to optimise the transition of care from paediatric to adult facilities. Updated evidence-based guidelines are needed that incorporate recommendations for the diagnosis and management of immune-mediated disorders, as well as chILD in older children approaching adulthood., Competing Interests: Competing interests: MG reports grants from Boehringer Ingelheim for a register analysis regarding fibrosis, paid to his institution; consulting fees from Boehringer Ingelheim and Roche; speaker fees from Boehringer Ingelheim; payment for participation on an adjudication and on an advisory board from Boehringer Ingelheim; and payment for a leadership role in a board society from Vertex. GK has been a faculty member of a paediatric bronchoscopy course, unrelated to the submitted work. MC, RE and DW have nothing to disclose. GD reports grants from NIH and CZI Atlas, paid to their institution; consulting fees from Boehringer Ingelheim as a consulting pathologist on the InPedILD trial, paid to their institution; and support for attending meetings and/or travel from NIH, paid to their institution. NN reports consulting fees from AstraZeneca, unrelated to the submitted work; support for attending meetings and/or travel for COST action CA16125 and CIG16125; and serving as head of a clinical research collaboration for chILD (unpaid). NS reports grants for participation on an advisory board, an expense allowance, payment for lectures and support for attending meetings and/or travel from Boehringer Ingelheim; serving as president elect of the German Society for Pediatric Pneumology and serving as vice chair of Kinderlungenregister. JW reports personal fees and non-financial support from Boehringer Ingelheim and personal fees from Parexel/Calyx. LRY reports grants from the NIH and University of Pennsylvania, consultancy fees from Roche, Sanofi and Boehringer Ingelheim, and honoraria from NYU Langone Health. RD reports two grants from Boehringer Ingelheim; consulting fees from Boehringer Ingelheim and Roche; licensed patents and stocks for Now Vitals, of which she is a founder, EvoEndoscopy, of which she is a founder and Earable, of which she is a founder; personal fees and non-financial support from Boehringer Ingelheim; and personal fees and other from Earable Inc, Now Vitals and EvoEndoscopy., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Children's interstitial and diffuse lung disease (chILD) comprises a large number of diverse entities ranging from disorders of lung development, maturation and function unique in infancy to immune-mediated, environmental, vascular and other conditions overlapping with adult disease. Pathologic evaluation of the lung has played a central role in characterizing many of these disorders, resulting in revised nomenclature and classifications to help guide clinical management(1-4). Technological advancements are rapidly uncovering genetic and molecular underpinnings of these conditions, as well as widening the phenotypes which bridge adult disease, often reducing the perceived need for diagnostic lung biopsy. As such the decision to get a lung biopsy in chILD is frequently for rapid ascertainment of disease in a critically ill child or when clinical presentation, imaging and laboratory studies fail to provide a cohesive diagnosis needed for treatment. While there have been modifications in surgical procedures for lung biopsy that minimize postoperative morbidity, it remains a high-risk invasive procedure, especially in a medically complex patient(5). Thus, it is essential that the lung biopsy be handled properly to maximize diagnostic yield, including close communication between the clinician, radiologist, surgeon, and pathologist before biopsy to determine best sampling site(s) and prioritization of tissue utilization. This review provides an overview of optimal handling and evaluation of a surgical lung biopsy for suspected chILD, with emphasis on specific conditions in which pathologic features play a critical role in providing an integrated diagnosis and guiding management., (© 2023 Wiley Periodicals LLC.)

Introduction: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders., Methods: This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform., Results: We report the study design and selected elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy, with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%)., Conclusion: This Registry is the largest longitudinal chILD cohort in the United States to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders., (© 2023 Wiley Periodicals LLC.)

Childhood interstitial lung disease (chILD) is a heterogeneous group of diffuse lung diseases that can be challenging to diagnose. With relative rarity of individual entities, data are limited on disease prevalence, care patterns, and healthcare utilization. The objective of this study was to evaluate chILD prevalence and review diagnostic and clinical care patterns at our center. A single-center, retrospective cohort study was conducted of patients receiving care at the Children's Hospital of Philadelphia (CHOP) between 1 January 2019 and 31 December 2021. Through query of selected ICD-10 billing codes relevant for chILD and medical chart review, a total of 306 patients were identified receiving pulmonary care during this period. Respiratory symptom onset was documented to have developed before 2 years of age for 40% of cases. The most common diagnostic categories included those with oncologic disease (21.2%), bronchiolitis obliterans (10.1%), and connective tissue disease (9.5%). Genetic testing was performed in 49% of cases, while 36% underwent lung biopsy. Hospitalization at CHOP had occurred for 80.4% of patients, with 45.1% ever hospitalized in an intensive care unit. One-third of children had required chronic supplemental oxygen. Seven (2.3%) patients died during this 3-year period. Collectively, these data demonstrate the scope of chILD and extent of health care utilization at a large volume tertiary care center. This approach to cohort identification and EMR-driven data collection in chILD provides new opportunities for cohort analysis and will inform the feasibility of future studies., (© 2023 Wiley Periodicals LLC.)

Objective: Assessing asthma control is an essential part of the outpatient management of children with asthma and can be performed through validated questionnaires such as the Asthma Control Test (ACT). Systematic approaches to incorporating the ACT in outpatient visits are often lacking, contributing to inconsistent completion rates. We conducted a quality improvement initiative to increase the proportion of visits where the ACT is completed for children with asthma in our multi-site pediatric pulmonary clinic network., Methods: We developed an intervention of sending the ACT questionnaire to patients and caregivers through the electronic patient portal to complete prior to their visits. This strategy was first piloted at one clinic beginning in July 2020 and then expanded to 5 other clinics in the network in October 2020. Our outcome measure was average monthly proportion of visits with a completed ACT, tracked using statistical process control charts. The process measure was method of ACT completion tracked using run charts., Results: At the pilot clinic, average monthly completion rate rose within 3 months of the intervention from 27% to 72% and was sustained more than 22 months. Completion across all clinics increased from 57% pre-intervention to 76% post-intervention. Importantly, the intervention did not rely on clinic staff to administer the questionnaire and did not interfere with existing clinic flow., Conclusion: An intervention of delivering the ACT electronically to patients and caregivers for completion prior to visits led to a rapid and sustained improvement in ACT completion rates across a large, pediatric pulmonary clinic network.

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., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: The rarity of childhood interstitial lung disease (chILD) makes it challenging to conduct powered trials. In the InPedILD trial, among 39 children and adolescents with fibrosing ILD, there was a numerical benefit of nintedanib versus placebo on change in forced vital capacity (FVC) over 24 weeks (difference in mean change in FVC % predicted of 1.21 [95% confidence interval: -3.40, 5.81]). Nintedanib has shown a consistent effect on FVC across populations of adults with different diagnoses of fibrosing ILD., Methods: In a Bayesian dynamic borrowing analysis, prespecified before data unblinding, we incorporated data on the effect of nintedanib in adults and the data from the InPedILD trial to estimate the effect of nintedanib on FVC in children and adolescents with fibrosing ILD. The data from adults were represented as a meta-analytic predictive (MAP) prior distribution with mean 1.69 (95% credible interval: 0.49, 3.08). The adult data were weighted according to expert judgment on their relevance to the efficacy of nintedanib in chILD, obtained in a formal elicitation exercise., Results: Combined data from the MAP prior and InPedILD trial analyzed within the Bayesian framework resulted in a median difference between nintedanib and placebo in change in FVC % predicted at Week 24 of 1.63 (95% credible interval: -0.69, 3.40). The posterior probability for superiority of nintedanib versus placebo was 95.5%, reaching the predefined success criterion of at least 90%., Conclusion: These findings, together with the safety data from the InPedILD trial, support the use of nintedanib in children and adolescents with fibrosing ILDs., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Introduction: Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy., Methods: Participants with classic A-T (n = 77), mild A-T (n = 13), and unaffected controls (n = 15) were recruited from two outpatient clinics. PBMCs were isolated and bulk RNAseq was performed. Plasma was also isolated in a subset of individuals. Affected individuals were designated mild or classic based on ATM mutations and clinical and laboratory features., Results: People with classic A-T were more likely to be younger and IgA deficient and to have higher alpha-fetoprotein levels and lower % forced vital capacity compared to individuals with mild A-T. In classic A-T, the expression of genes required for V(D)J recombination was lower, and the expression of genes required for inflammatory activity was higher. We assigned inflammatory scores to study participants and found that inflammatory scores were highly variable among people with classic A-T and that higher scores were associated with lower ATM mRNA levels. Using a cell type deconvolution approach, we inferred that CD4 + T cells and CD8 + T cells were lower in number in people with classic A-T. Finally, we showed that individuals with classic A-T exhibit higher SERPINE1 (PAI-1) mRNA and plasma protein levels, irrespective of age, and higher FLT4 (VEGFR3) and IL6ST (GP130) plasma protein levels compared with mild A-T and controls., Conclusion: Using a transcriptomic approach, we identified novel features and developed an inflammatory score to identify subsets of individuals with different inflammatory phenotypes in A-T. Findings from this study could be used to help direct treatment and to track treatment response to therapy., (© 2024. The Author(s).)

During July 7-11, 2023, CDC received reports of two patients in different states with a tuberculosis (TB) diagnosis following spinal surgical procedures that used bone allografts containing live cells from the same deceased donor. An outbreak associated with a similar product manufactured by the same tissue establishment (i.e., manufacturer) occurred in 2021. Because of concern that these cases represented a second outbreak, CDC and the Food and Drug Administration worked with the tissue establishment to determine that this product was obtained from a donor different from the one implicated in the 2021 outbreak and learned that the bone allograft product was distributed to 13 health care facilities in seven states. Notifications to all seven states occurred on July 12. As of December 20, 2023, five of 36 surgical bone allograft recipients received laboratory-confirmed TB disease diagnoses; two patients died of TB. Whole-genome sequencing demonstrated close genetic relatedness between positive Mycobacterium tuberculosis cultures from surgical recipients and unused product. Although the bone product had tested negative by nucleic acid amplification testing before distribution, M. tuberculosis culture of unused product was not performed until after the outbreak was recognized. The public health response prevented up to 53 additional surgical procedures using allografts from that donor; additional measures to protect patients from tissue-transmitted M. tuberculosis are urgently needed., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Saroj Rai reports uncompensated service as the Association of Immunization Managers’ (AIM) liaison to CDC’s Advisory Committee on Immunization Practices – Chikungunya Workgroup and on the Legacy Council for AIM; and retirement stocks at Novartis Pharmaceuticals. Jeffrey M. Percak reports travel support from the County of San Diego and from the California Tuberculosis Controller’s Association for attendance at the California Tuberculosis Controller’s Association fall meeting. Lisa Y. Armitige reports support from the Texas Department of State Health Services, consulting fees (paid to institution) from the Kansas Health Department, and honoraria (forwarded to institution) from the American Academy of HIV Medicine. No other potential conflicts of interest were disclosed.

Introduction: Radiation-induced lung injury is a rare complication of radioactive iodine therapy (RAIT) in pediatric thyroid cancer treatment. In this case report, we describe a pediatric patient with an ERC1::RET-positive classic papillary thyroid carcinoma who developed progressive respiratory symptoms and chest imaging abnormalities following RAIT for lymph node and pulmonary disease., Case Presentation: A pediatric patient with ERC1::RET-positive classic papillary thyroid carcinoma was hospitalized for pulmonary decompensation 3 months following one empiric dose of RAIT. Testing revealed no evidence of infection or progression of pulmonary metastases, and there was no improvement with empiric antibiotic therapy for pneumonia. Despite empiric anti-inflammatory therapies, the patient remains symptomatic from a respiratory standpoint with requirement for supplemental oxygen and evidence of fibrotic changes on chest imaging., Conclusions: This patient's pulmonary condition is consistent with radiation-induced pulmonary injury including development of pulmonary fibrosis. With the availability of RET fusion-targeted inhibitors, this case highlights a rare pulmonary side effect of radioactive iodine for clinicians to recognize. Upfront targeted therapy protocols may help avoid radioactive iodine-associated adverse reactions., (© 2023 S. Karger AG, Basel.)

Background: Childhood interstitial lung disease (ILD) comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD., Methods: Patients aged 6-17 years with fibrosing ILD on high-resolution computed tomography and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks and then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary end-points were the area under the plasma concentration-time curve at steady state (AUC τ,ss ) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24., Results: 26 patients received nintedanib and 13 patients received placebo. The geometric mean (geometric coefficient of variation) AUC τ,ss for nintedanib was 175 µg·h·L -1 (85.1%) in patients aged 6-11 years and 160 µg·h·L -1 (82.7%) in patients aged 12-17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean±se changes in percentage predicted forced vital capacity at week 24 were 0.3±1.3% in the nintedanib group and -0.9±1.8% in the placebo group., Conclusions: In children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population., Competing Interests: Conflict of interest: R. Deterding reports consultancy fees, fees for participation on the steering committee of the InPedILD trial and support for travel from Boehringer Ingelheim (BI); and consultancy fees from Roche. L.R. Young reports grants paid to her institution from the National Institutes of Health and Orphan Disease Center at the University of Pennsylvania; royalties from UpToDate; consultancy fees and fees for participation on the steering committee of the InPedILD trial from BI; consultancy fees from Roche and Sanofi; and honoraria from NYU Langone Health. E.M. DeBoer reports fees from BI for participation on the steering committee of the InPedILD trial. S. Cunningham reports fees paid to his institution by BI for his participation on the steering committee of the InPedILD trial. D. Warburton reports a grant re: the RECOVER (COVID-19) initiative from the National Heart, Lung, and Blood Institute (NHLBI) and fees from BI for participation on the steering committee of the InPedILD trial. N. Schwerk reports consultancy fees from Novartis; payment for lectures from AbbVie, Allergopharma, Chiesi, Infectopharm, Novartis, Pfizer and Sanofi; fees for participation in data safety monitoring boards or advisory boards for BI and Novartis; and fees from BI for participation on the steering committee of the InPedILD trial; he is a member of the German Society for Pediatric Pneumology, European Respiratory Society, Children's Interstitial Lung Disease Clinical Research Collaboration (chILD-EU), European Cooperation in Science and Technology (COST) network for translational research in children's and adult ILD (ENTeR-chILD), and Secretary of Kinderlungenregister. K.R. Flaherty reports grants paid to his institution from BI; royalties from UpToDate; and consultancy fees from Arrowhead, AstraZeneca, Bellerophon, BI, CSL Behring, Daewoong, DevPro, Dispersol, FibroGen, Horizon, Immunet, Lupin, NeRRe Therapeutics, Pliant, Polarean, Pure Health, PureTech, Respivant, Roche/Genentech, Shionogi, Sun Pharmaceuticals, Trevi and United Therapeutics; he is a steering committee chair for the Pulmonary Fibrosis Foundation and reports fees from BI for participation on the steering committee of the InPedILD trial. K.K. Brown reports grants from NHLBI; consultancy fees, speaker fees, support for travel and/or has served as an advisor or on a data monitoring committee for AbbVie, Biogen, Blade Therapeutics, BI, Bristol Myers Squibb, CSL Behring, DevPro Biopharma, Dispersol, Eleven P15, Galapagos, Galecto, Huitai Biomedcine, Humanetics, the Open Source Imaging Consortium (OSIC), Pliant, Redx Pharma, Sanofi, Third Pole and Translate Bio; and fees from BI for participation on the steering committee of the InPedILD trial; he holds leadership or fiduciary roles with the Fleischner Society and OSIC. M. Dumistracel, E. Erhardt, J. Bertulis, M. Gahlemann and S. Stowasser are employees of BI. M. Griese reports grants from BI for analysis of the chILD-EU register; has received fees from BI for membership of the InPedILD steering committee, an advisory board and an adjudication board, and for a web-based series., (Copyright ©The authors 2023.)

BACKGROUND: Diabetes mellitus (DM) increases the risk of TB disease and poor treatment outcomes such as delayed sputum culture conversion due to inadequate drug exposure. Therapeutic drug monitoring (TDM) has improved these outcomes in some settings. METHODS: To compare treatment outcomes in programs with routine TDM vs. programs that did not use TDM, we conducted a retrospective study among people with DM and TB at health departments in four US states. RESULTS: A total of 170 patients were enrolled (73 patients in the non-TDM group and 97 patients in the TDM group). Days to sputum culture conversion and total treatment duration were significantly shorter in the TDM group vs. the non-TDM group. In adjusted analyses, patients who underwent TDM were significantly more likely to achieve sputum culture conversion at 2 months ( P = 0.007). CONCLUSION: TDM hastened microbiological cure from TB among people with DM and a high risk for poor treatment outcomes in the programmatic setting.

Rationale: Heterogeneous characteristics are observed in familial pulmonary fibrosis (FPF), suggesting that nongenetic factors contribute to disease manifestations. Objectives: To determine the relationship between environmental exposures and disease characteristics of FPF, including the morphological characteristics on chest computed tomography (CT) scan, and timing of FPF symptom onset, lung transplantation, or death. Methods: Subjects with FPF with an exposure questionnaire and chest CT were selected from a prospective cohort at Vanderbilt. Disease characteristics were defined by lung parenchymal findings on chest CT associated with fibrotic hypersensitivity pneumonitis (fHP) or usual interstitial pneumonia (UIP) and by time from birth to symptom onset or a composite of lung transplantation or death. After assessing the potential for confounding by sex or smoking, adjusted logistic or Cox proportional hazards regression models identified exposures associated with fHP or UIP CT findings. Findings were validated in a cohort of patients with sporadic pulmonary fibrosis enrolled in the LTRC (Lung Tissue Research Consortium) study. Results: Among 159 subjects with FPF, 98 (61.6%) were males and 96 (60.4%) were ever-smokers. Males were less likely to have CT features of fHP, including mosaic attenuation (FPF: adjusted [for sex and smoking] odds ratio [aOR], 0.27; 95% confidence interval [CI], 0.09-0.76; P  = 0.01; LTRC: aOR, 0.35; 95% CI, 0.21-0.61; P  = 0.0002). Organic exposures, however, were not consistently associated with fHP features in either cohort. Smoking was a risk factor for honeycombing in both cohorts (FPF: aOR, 2.19; 95% CI, 1.12-4.28; P  = 0.02; LTRC: aOR, 1.69; 95% CI, 1.22-2.33; P  = 0.002). Rock dust exposure may also be associated with honeycombing, although the association was not statistically-significant when accounting for sex and smoking (FPF: aOR, 2.27; 95% CI, 0.997-5.15; P  = 0.051; LTRC: aOR, 1.51; 95% CI, 0.97-2.33; P  = 0.07). In the FPF cohort, ever-smokers experienced a shorter transplant-free survival (adjusted hazard ratio, 1.64; 95% CI, 1.07-2.52; P  = 0.02), whereas sex was not associated with differential survival (male adjusted hazard ratio, 0.75; 95% CI, 0.50-1.14; P  = 0.18). Conclusions: In FPF, smoking contributes to shortened transplant-free survival and development of honeycombing, a finding that is also likely applicable to sporadic pulmonary fibrosis. Females are more likely to manifest CT features of fHP (mosaic attenuation), a finding that was incompletely explained by sex differences in exposures. These findings may have implications for pulmonary fibrosis classification and management.

There is a growing amount of data uncovering the cellular diversity of the pulmonary circulation and mechanisms governing vascular repair after injury. However, the molecular and cellular mechanisms contributing to the morphogenesis and growth of the pulmonary vasculature during embryonic development are less clear. Importantly, deficits in vascular development lead to significant pediatric lung diseases, indicating a need to uncover fetal programs promoting vascular growth. To address this, we used a transgenic mouse reporter for expression of Cxcl12, an arterial endothelial hallmark gene, and performed single-cell RNA sequencing on isolated Cxcl12-DsRed+ endothelium to assess cellular heterogeneity within pulmonary endothelium. Combining cell annotation with gene ontology and histological analysis allowed us to segregate the developing artery endothelium into functionally and spatially distinct subpopulations. Expression of Cxcl12 is highest in the distal arterial endothelial subpopulation, a compartment enriched in genes for vascular development. Accordingly, disruption of CXCL12 signaling led to, not only abnormal branching, but also distal vascular hypoplasia. These data provide evidence for arterial endothelial functional heterogeneity and reveal conserved signaling mechanisms essential for pulmonary vascular development., Competing Interests: Competing interests L.R.Y. declares grants paid to her institution from the National Institutes of Health and the Orphan Disease Center at the University of Pennsylvania; royalties from UpToDate; consultancy fees and fees for participation on the Steering Committee of the InPedILD trial from Boehringer Ingelheim; and consultancy fees from Roche and Sanofi., (© 2022. Published by The Company of Biologists Ltd.)

Rationale: Although persistent fibroblast activation is a hallmark of idiopathic pulmonary fibrosis (IPF), mechanisms regulating persistent fibroblast activation in the lungs have not been fully elucidated. Objectives: On the basis of our observation that lung fibroblasts express TBXA2R (thromboxane-prostanoid receptor) during fibrosis, we investigated the role of TBXA2R signaling in fibrotic remodeling. Methods: We identified TBXA2R expression in lungs of patients with IPF and mice and studied primary mouse and human lung fibroblasts to determine the impact of TBXA2R signaling on fibroblast activation. We used TBXA2R-deficient mice and small-molecule inhibitors to investigate TBXA2R signaling in preclinical lung fibrosis models. Measurements and Main Results: TBXA2R expression was upregulated in fibroblasts in the lungs of patients with IPF and in mouse lungs during experimental lung fibrosis. Genetic deletion of TBXA2R, but not inhibition of thromboxane synthase, protected mice from bleomycin-induced lung fibrosis, thereby suggesting that an alternative ligand activates profibrotic TBXA2R signaling. In contrast to thromboxane, F2-isoprostanes, which are nonenzymatic products of arachidonic acid induced by reactive oxygen species, were persistently elevated during fibrosis. F2-isoprostanes induced TBXA2R signaling in fibroblasts and mediated a myofibroblast activation profile due, at least in part, to potentiation of TGF-β (transforming growth factor-β) signaling. In vivo treatment with the TBXA2R antagonist ifetroban reduced profibrotic signaling in the lungs, protected mice from lung fibrosis in three preclinical models (bleomycin, Hermansky-Pudlak mice, and radiation-induced fibrosis), and markedly enhanced fibrotic resolution after bleomycin treatment. Conclusions: TBXA2R links oxidative stress to fibroblast activation during lung fibrosis. TBXA2R antagonists could have utility in treating pulmonary fibrosis.

Introduction: Infants and children diagnosed with bronchopulmonary dysplasia (BPD) have a higher likelihood of recurrent hospitalizations and asthma-like symptoms. Socio-environmental factors that influence the frequency and severity of pulmonary symptoms in these children during the preschool age are poorly understood. In this study, we used the Area Deprivation Index (ADI) to evaluate the relationship between the socio-environmental exposures in children with BPD and respiratory outcomes during the first few years of life., Methods: A registry of subjects recruited from outpatient BPD clinics at Johns Hopkins University (n = 909) and the Children's Hospital of Philadelphia (n = 125) between January 2008 and October 2021 was used. Subjects were separated into tertiles by ADI scores aggregated to ZIP codes. Caregiver questionnaires were used to assess the frequency of respiratory morbidities and acute care usage for respiratory symptoms., Results: The mean gestational age of subjects was 26.8 ± 2.6 weeks with a mean birthweight of 909 ± 404 g. The highest tertile (most deprived) of ADI was significantly associated with emergency department visits (aOR 1.72; p = 0.009), hospital readmissions (aOR 1.66; p = 0.030), and activity limitations (aOR 1.55; p = 0.048) compared to the lowest tertile. No association was seen with steroid, antibiotic or rescue medication use, trouble breathing, or nighttime symptoms., Conclusion: In this study, children with BPD who lived in areas of higher deprivation were more likely to be rehospitalized and have ED visits for respiratory reasons. Identifying socio-environmental factors that contribute to adverse pulmonary outcomes in children with BPD may provide opportunities for earlier interventions to improve long-term pulmonary outcomes., (© 2022 Wiley Periodicals LLC.)

Pulmonary fibrosis is a disease process associated with significant morbidity and mortality, with limited therapeutic options owing to an incomplete understanding of the underlying pathophysiology. Mechanisms driving the fibrotic cascade have been elucidated through studies of rare and common variants in surfactant-related and telomere-related genes in familial and sporadic forms of pulmonary fibrosis, as well as in multisystem Mendelian genetic disorders that present with pulmonary fibrosis. In this translational review, we outline insights into the pathophysiology of pulmonary fibrosis derived from genetic forms of the disease, with a focus on model systems, shared cellular and molecular mechanisms, and potential targets for therapy.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by improper biogenesis of lysosome-related organelles (LROs). Lung fibrosis is the leading cause of death among adults with HPS-1 and HPS-4 genetic types, which are associated with defects in the biogenesis of lysosome-related organelles complex-3 (BLOC-3), a guanine exchange factor (GEF) for a small GTPase, Rab32. LROs are not ubiquitously present in all cell types, and specific cells utilize LROs to accomplish dedicated functions. Fibroblasts are not known to contain LROs, and the function of BLOC-3 in fibroblasts is unclear. Here, we report that lung fibroblasts isolated from patients with HPS-1 have increased migration capacity. Silencing HPS-1 in normal lung fibroblasts similarly leads to increased migration. We also show that the increased migration is driven by elevated levels of Myosin IIB. Silencing HPS1 or RAB32 in normal lung fibroblasts leads to increased MYOSIN IIB levels. MYOSIN IIB is downstream of p38-MAPK, which is a known target of angiotensin receptor signaling. Treatment with losartan, an angiotensin receptor inhibitor, decreases MYOSIN IIB levels and impedes HPS lung fibroblast migration in vitro. Furthermore, pharmacologic inhibition of angiotensin receptor with losartan seemed to decrease migration of HPS lung fibroblasts in vivo in a zebrafish xenotransplantation model. Taken together, we demonstrate that BLOC-3 plays an important role in MYOSIN IIB regulation within lung fibroblasts and contributes to fibroblast migration., (© 2022. The Author(s).)

Study Objectives: Obstructive sleep apnea is associated with neurobehavioral dysfunction, but the relationship between disease severity as measured by the apnea-hypopnea index and neurobehavioral morbidity is unclear. The objective of our study is to compare the neurobehavioral morbidity of mild sleep-disordered breathing versus obstructive sleep apnea., Methods: Children 3-12 years old recruited for mild sleep-disordered breathing (snoring with obstructive apnea-hypopnea index < 3) into the Pediatric Adenotonsillectomy Trial for Snoring were compared to children 5-9 years old recruited for obstructive sleep apnea (obstructive apnea-hypopnea 2-30) into the Childhood Adenotonsillectomy Trial. Baseline demographic, polysomnographic, and neurobehavioral outcomes were compared using univariable and multivariable analysis., Results: The sample included 453 participants with obstructive sleep apnea (median obstructive apnea-hypopnea index 5.7) and 459 participants with mild sleep-disordered breathing (median obstructive apnea-hypopnea index 0.5). By polysomnography, participants with obstructive sleep apnea had poorer sleep efficiency and more arousals. Children with mild sleep-disordered breathing had more abnormal executive function scores (adjusted odds ratio 1.96, 95% CI 1.30-2.94) compared to children with obstructive sleep apnea. There were also elevated Conners scores for inattention (adjusted odds ratio 3.16, CI 1.98-5.02) and hyperactivity (adjusted odds ratio 2.82, CI 1.83-4.34) in children recruited for mild sleep-disordered breathing., Conclusions: Abnormal executive function, inattention, and hyperactivity were more common in symptomatic children recruited into a trial for mild sleep-disordered breathing compared to children recruited into a trial for obstructive sleep apnea. Young, snoring children with only minimally elevated apnea-hypopnea levels may still be at risk for deficits in executive function and attention., Trial Registration: Pediatric Adenotonsillectomy for Snoring (PATS), NCT02562040; Childhood Adenotonsillectomy Trial (CHAT), NCT00560859., (Published by Oxford University Press on behalf of Sleep Research Society (SRS) 2022.)

Although increased neuropeptides are often detected in lungs that exhibit respiratory distress, whether they contribute to the condition is unknown. Here, we show in a mouse model of neuroendocrine cell hyperplasia of infancy, a pediatric disease with increased pulmonary neuroendocrine cells (PNECs), excess PNEC-derived neuropeptides are responsible for pulmonary manifestations including hypoxemia. In mouse postnatal lung, prolonged signaling from elevated neuropeptides such as calcitonin gene-related peptide (CGRP) activate receptors enriched on endothelial cells, leading to reduced cellular junction gene expression, increased endothelium permeability, excess lung fluid, and hypoxemia. Excess fluid and hypoxemia were effectively attenuated by either prevention of PNEC formation, inactivation of CGRP gene, endothelium-specific inactivation of CGRP receptor gene, or treatment with CGRP receptor antagonist. Neuropeptides were increased in human lung diseases with excess fluid such as acute respiratory distress syndrome. Our findings suggest that restricting neuropeptide function may limit fluid and improve gas exchange in these conditions., Competing Interests: Declaration of interests X.S. is a member of the advisory board for Developmental Cell. J.X., L.R.Y., and X.S. have one related Patent Cooperation Treaty (PCT) application approved by World Intellectual Property Organization (WIPO) with number WO2020252368., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To characterize postextraction antibiotic prescribing patterns, predictors for antibiotic prescribing and the incidence of and risk factors for postextraction oral infection., Design: Retrospective analysis of a random sample of veterans who received tooth extractions from January 1, 2017 through December 31, 2017., Setting: VA dental clinics., Patients: Overall, 69,610 patients met inclusion criteria, of whom 404 were randomly selected for inclusion. Adjunctive antibiotics were prescribed to 154 patients (38.1%)., Intervention: Patients who received or did not receive an antibiotic were compared for the occurrence of postextraction infection as documented in the electronic health record. Multivariable logistic regression was performed to identify factors associated with antibiotic receipt., Results: There was no difference in the frequency of postextraction oral infection identified among patients who did and did not receive antibiotics (4.5% vs 3.2%; P = .59). Risk factors for postextraction infection could not be identified due to the low frequency of this outcome. Patients who received antibiotics were more likely to have a greater number of teeth extracted (aOR, 1.10; 95% CI, 1.03-1.18), documentation of acute infection at time of extraction (aOR, 3.02; 95% CI, 1.57-5.82), molar extraction (aOR, 1.78; 95% CI, 1.10-2.86) and extraction performed by an oral maxillofacial surgeon (aOR, 2.29; 95% CI, 1.44-3.58) or specialty dentist (aOR, 5.77; 95% CI, 2.05-16.19)., Conclusion: Infectious complications occurred at a low incidence among veterans undergoing tooth extraction who did and did not receive postextraction antibiotics. These results suggest that antibiotics have a limited role in preventing postprocedural infection; however, future studies are necessary to more clearly define the role of antibiotics for this indication.

Objectives. To assess the US food industry's response to calls from public health authorities to reduce portion sizes by comparing current with past sizes of selected examples of single-serve ultra-processed packaged and fast foods. Methods. We obtained manufacturers' information about current portion sizes and compared it with sizes when first introduced and in 2002. Results. Few companies in our sample reduced portion sizes since 2002; all still sold portions of ultra-processed foods in up to 5-times-larger sizes than when first introduced. Conclusions. Policies and practices focused on reducing portion size could help discourage the consumption of excessive amounts of ultra-processed foods. ( Am J Public Health . 2021;111(12):2223-2226. https://doi.org/10.2105/AJPH.2021.306513).

Alveolar epithelial type 2 cell (AEC2) dysfunction is implicated in the pathogenesis of adult and pediatric interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF); however, identification of disease-initiating mechanisms has been impeded by inability to access primary AEC2s early on. Here, we present a human in vitro model permitting investigation of epithelial-intrinsic events culminating in AEC2 dysfunction, using patient-specific induced pluripotent stem cells (iPSCs) carrying an AEC2-exclusive disease-associated variant (SFTPC I73T ). Comparing syngeneic mutant versus gene-corrected iPSCs after differentiation into AEC2s (iAEC2s), we find that mutant iAEC2s accumulate large amounts of misprocessed and mistrafficked pro-SFTPC protein, similar to in vivo changes, resulting in diminished AEC2 progenitor capacity, perturbed proteostasis, altered bioenergetic programs, time-dependent metabolic reprogramming, and nuclear factor κB (NF-κB) pathway activation. Treatment of SFTPC I73T -expressing iAEC2s with hydroxychloroquine, a medication used in pediatric ILD, aggravates the observed perturbations. Thus, iAEC2s provide a patient-specific preclinical platform for modeling the epithelial-intrinsic dysfunction at ILD inception., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Childhood interstitial lung disease (chILD) comprises >200 rare respiratory disorders, with no currently approved therapies and variable prognosis. Nintedanib reduces the rate of forced vital capacity (FVC) decline in adults with progressive fibrosing interstitial lung diseases (ILDs). We present the design of a multicentre, prospective, double-blind, randomised, placebo-controlled clinical trial of nintedanib in patients with fibrosing chILD (1199-0337 or InPedILD; ClinicalTrials.gov: NCT04093024). Male or female children and adolescents aged 6-17 years (≥30; including ≥20 adolescents aged 12-17 years) with clinically significant fibrosing ILD will be randomised 2:1 to receive oral nintedanib or placebo on top of standard of care for 24 weeks (double-blind), followed by variable-duration nintedanib (open-label). Nintedanib dosing will be based on body weight-dependent allometric scaling, with single-step dose reductions permitted to manage adverse events. Eligible patients will have evidence of fibrosis on high-resolution computed tomography (within 12 months of their first screening visit), FVC ≥25% predicted, and clinically significant disease (Fan score of ≥3 or evidence of clinical progression over time). Patients with underlying chronic liver disease, significant pulmonary arterial hypertension, cardiovascular disease, or increased bleeding risk are ineligible. The primary endpoints are pharmacokinetics and the proportion of patients with treatment-emergent adverse events at week 24. Secondary endpoints include change in FVC% predicted from baseline, Pediatric Quality of Life Questionnaire, oxygen saturation, and 6-min walk distance at weeks 24 and 52. Additional efficacy and safety endpoints will be collected to explore long-term effects., Competing Interests: Conflict of interest: R. Deterding reports scientific advisory and consulting fees paid to the University of Colorado, and manuscript preparation assistance from Boehringer Ingelheim Pharmaceuticals Inc., during the conduct of the study. Conflict of interest: M. Griese reports personal fees from Boehringer Ingelheim during the conduct of the study and grants from Boehringer Ingelheim outside the submitted work. Conflict of interest: G. Deutsch reports consulting fees paid to Seattle Children's Hospital by Boehringer Ingelheim during the conduct of the study. Conflict of interest: D. Warburton serves in an advisory role for Boehringer Ingelheim on the evaluation of nintedanib as a potential treatment for childhood ILD, and has received reimbursement for travel and consultation in this role. Conflict of interest: E.M. DeBoer reports consulting fees from Boehringer Ingelheim and Parexel, and consulting fees from and stock in EvoEndoscopy, outside the submitted work. Conflict of interest: S. Cunningham reports consultancy fees paid to the University of Edinburgh by Boehringer Ingelheim during the conduct of the study. Conflict of interest: A. Clement has nothing to disclose. Conflict of interest: N. Schwerk reports consulting fees from Boehringer Ingelheim outside the submitted work. Conflict of interest: K.R. Flaherty reports grants and personal fees from Boehringer Ingelheim, and personal fees from Roche/Genentech, Bellerophan, Respivant and Blade Therapeutics, outside the submitted work. Conflict of interest: K.K. Brown reports, outside the submitted work, grants from NHLBI, personal fees from Biogen and advisory board participation for Blade, Boehringer Ingelheim, Galapagos, Galecto, Genoa, Lifemax, MedImmune, OSIC (Open Source Imaging Consortium), Pliant, ProMetic, Third Pole, Theravance, Three Lakes Partners and Veracyte. Conflict of interest: F. Voss is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. Conflict of interest: U. Schmid is an employee of Boehringer Ingelheim. Conflict of interest: R. Schlenker-Herceg is an employee of Boehringer Ingelheim. Conflict of interest: D. Verri is an employee of Boehringer Ingelheim Italia S.p.A. Conflict of interest: M. Dumistracel is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. Conflict of interest: M. Schiwek is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. Conflict of interest: S. Stowasser is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: K. Tetzlaff is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: E. Clerisme-Beaty is an employee of Boehringer Ingelheim. Conflict of interest: L.R. Young reports personal fees for advisory board participation from Boehringer Ingelheim, and grants from the NIH, during the conduct of the study. All authors disclose third-party writing assistance contracted and funded by Boehringer Ingelheim International GmbH., (Copyright ©The authors 2021.)

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Introduction: Research shows that cognitive performance and emotional well-being can be significantly strengthened. A high-performance brain training protocol, Strategic Memory Advanced Reasoning Training (SMART), was developed by cognitive neuroscientists at The University of Texas at Dallas Center for BrainHealth based on 25-plus years of scientific study. Randomized controlled trials with various populations have shown that training and use of nine "SMART" strategies for processing information can improve cognitive performance and psychological health. However, the multi-week intensive training used in the laboratory is not practical for widespread use outside the laboratory. This article examines the efficacy of SMART when translated outside the laboratory to two populations (military/veterans and law enforcement) that received SMART in condensed time frames., Materials and Methods: In two translation studies with healthy military personnel and veterans, 425 participants received between 6 and 10 hours of SMART over 2 days. In a third translation study, 74 healthy police officers received 9 hours of SMART over 3 days. Training was conducted by clinicians who taught the nine "SMART" strategies related to three core areas-strategic attention, integrated reasoning, and innovation-to groups of up to 25 participants. In all three translation studies, cognitive performance and psychological health data were collected before and immediately following the training. In one of the military/veteran studies, psychological health data were also collected 1 and 4 months following the training., Results: In both translations to military personnel and veterans, there were improvements in the complex cognitive domains of integrated reasoning (P < .0001) and innovation (P < .0001) immediately after undergoing SMART. In the translation to police officers, there were improvements in the cognitive domains of innovation (P = .02) and strategic attention (P = .005). Participants in all three translations saw statistically significant improvements in self-reported symptoms of psychological health. The improvements continued among a subset of participants who responded to the later requests for information., Conclusions: The results of translating to these two populations provide evidence supporting the efficacy of SMART delivered in an abbreviated time frame. The improvements in two major domains of cognitive function demonstrate that strategies can be taught and immediately applied by those receiving the training. The immediate psychological health improvements may be transient; however, the continued improvements in psychological health observed in a subset of the participants suggest that benefits may be sustainable even at later intervals., (© The Association of Military Surgeons of the United States 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Emerging evidence indicates that early life events can increase the risk for developing chronic obstructive pulmonary disease (COPD). Using an inducible transgenic mouse model for NF-κB activation in the airway epithelium, we found that a brief period of inflammation during the saccular stage (P3-P5) but not alveolar stage (P10-P12) of lung development disrupted elastic fiber assembly, resulting in permanent reduction in lung function and development of a COPD-like lung phenotype that progressed through 24 months of age. Neutrophil depletion prevented disruption of elastic fiber assembly and restored normal lung development. Mechanistic studies uncovered a role for neutrophil elastase (NE) in downregulating expression of critical elastic fiber assembly components, particularly fibulin-5 and elastin. Further, purified human NE and NE-containing exosomes from tracheal aspirates of premature infants with lung inflammation downregulated elastin and fibulin-5 expression by saccular-stage mouse lung fibroblasts. Together, our studies define a critical developmental window for assembling the elastin scaffold in the distal lung, which is required to support lung structure and function throughout the lifespan. Although neutrophils play a well-recognized role in COPD development in adults, neutrophilic inflammation may also contribute to early-life predisposition to COPD.