BACKGROUND:Substance use has increased among people with CF (pwCF), yet communication about use remains understudied between pwCF and their healthcare providers. OBJECTIVE:Investigate pwCF's perceptions regarding their healthcare team's discussions surrounding substance use, comfort level discussing such usage, and barriers encountered during these discussions. METHODS:This cross-sectional study used a one-time electronic survey to assess communication regarding substance use between pwCF aged 13 years and older and their CF healthcare team. RESULTS:Of 226 participants, 74% (n = 167) reported being asked about marijuana, 57% (n = 128) about CBD, 70% (n = 150) about e-cigarettes, and 88% (n = 189) about cigarettes by their CF healthcare team. Fewer providers discussed the risks and benefits of each substance: 47% (n = 107) for marijuana, 40% (n = 90) for CBD, 44% (n = 99) for e-cigarettes, and 61% (n = 138) for cigarettes. Provider knowledge was rated higher for cigarettes and e-cigarettes compared to marijuana and CBD. Most participants felt comfortable discussing substance use, though a minority expressed discomfort, mainly due to concerns about documentation in medical records and perceived lack of support. CONCLUSION:This study highlights variability in communication between pwCF and their healthcare teams regarding substance use, particularly when it comes to marijuana and CBD. The findings suggest a need for standardized guidelines and educational resources to improve recreational substance screening and discussion in CF clinical care, especially given the changing landscape of marijuana regulations and increasing use among pwCF.

Background: As the population of people with CF (pwCF) continues to age, attention is shifting towards addressing the unique challenges teenagers and adults face, including substance use. Changing attitudes and legality regarding marijuana and CBD may influence their use among pwCF, but data on their prevalence, reasons for use, and administration methods are lacking. Objective: Investigate marijuana, cannabidiol (CBD), e-cigarette, and cigarette usage among pwCF and explore differences in demographics, disease severity, and CFTR modulator use between current and non-users. Methods: This cross-sectional study used a one-time electronic survey to assess marijuana, CBD, e-cigarette, and cigarette use in pwCF aged >13 years. Demographic and clinical characteristics were compared between current users and non-users. The association between current substance use and CFTR modulator use was analyzed using logistic regressions. Results: Among 226 participants, 29% used marijuana, 22% used CBD, 27% used e-cigarettes, and 22% used cigarettes. Current users of all substances were more likely to be college-educated, Black, or aged 29-39 years than non-users. Current e-cigarette users were 2.9 times more likely to use CFTR modulators (95% CI 0.98-11.00, p=0.08) and current marijuana users were 2.5 times more likely to use CFTR modulators compared to non-users, adjusted for confounders. Current users of CBD, e-cigarettes, and cigarettes were more likely to have an abnormal mental health screen compared to non-users. A high proportion of never-users of marijuana and CBD expressed interest in using. Conclusion: Substance use is more prevalent among pwCF than previously reported and needs to be addressed by healthcare providers.

Abstract Introduction: Adoptive cellular therapies (ACT) have encountered challenges in solid tumors due in part to the immunosuppressive tumor microenvironment (TME). We have developed OBX-115, TIL engineered to express mbIL15 regulatable using the cytoDRiVE® platform, which allows for TIL expansion, persistence, and anti-tumor efficacy under control of the FDA-approved small-molecule ligand, acetazolamide (ACZ), eliminating the need for co-administration of IL2 (NCT05470283). LIGHT, a tumor necrosis factor family member, interacts with lymphotoxin beta receptor (LTbR) and herpes virus entry mediator (HVEM) found on various TME cell types, including stromal cells such as cancer associated fibroblasts (CAF). In preclinical studies, LIGHT expression within a tumor has been linked to the formation of tertiary lymphoid structures and vascular normalization (Ramachandran Cancer Cell 2023), both associated with better clinical outcomes (Sautès-Fridman Nat Rev Cancer 2019). We hypothesized that engineering TIL with regulatable mbIL15 and LIGHT expression could enhance their efficacy by modifying the TME. Methods: TIL from colorectal (CRC) and head and neck squamous cell carcinoma (HNSCC) were transduced with retroviral vectors to express regulatable mbIL15 and LIGHT. ACZ-induced surface expression of mbIL15 and LIGHT in expanded TIL was examined using flow cytometry. Functional signaling of LIGHT was assessed through co-culture with Jurkat-HVEM-NF-kappaB reporter cells and LTbR+ HUVEC cells. In vitro, engineered TIL were tested in stromal-rich tumor models (CRC and HNSCC) by co-culturing with autologous patient-derived tumor/CAF hybrid spheroids. In vivo, antigen-independent TIL persistence was assessed in NSG mice without exogenous IL2. Syngeneic studies were performed to assess the efficacy of adoptively transferred mbIL15 and LIGHT-engineered Pmel cells (CD8+ T cells transgenic for a gp100-specific T cell receptor) in a subcutaneous cold tumor model (B16-F10). Results: Engineered TIL were successfully expanded without exogenous IL2. ACZ-dependent mbIL15 and LIGHT expression were confirmed, validating co-regulation and functionality in vitro. TIL engineered with mbIL15 and LIGHT displayed significantly increased cytotoxicity against autologous tumor/CAF spheroids compared with TIL expressing mbIL15 alone (p<0.005) in CRC and HNSCC tumor/CAF hybrid models. TIL with mbIL15 and LIGHT expanded in vivo and persisted for ≥42 days without exogenous IL2 support. Moreover, Pmel cells engineered with mbIL15 and LIGHT demonstrated durable anti-tumor efficacy in B16-F10 tumor-bearing mice, which was greater than Pmel cells engineered with mbIL15 alone (p<0.01). Conclusions: These preclinical results suggest that TIL engineered with regulatable mbIL15 and LIGHT using the cytoDRiVE platform have the potential to address the high unmet clinical need in cold tumors with suppressive TME, which are currently not amenable to ACT. Citation Format: Balazs Koscso, Zheng Ao, Carmela Passaro, Nirzari Shah, Ngoc Ly, Patricia Timpug, Bulent A. Aksoy, Dexue Sun, Dan Jun Li, Kerri-Lynn Sheahan, Violet Young, Theresa Ross, Benjamin Primack, Meghan Langley, Jeremy Tchaicha, Dhruv K. Sethi, Jan ter Meulen, Michelle Ols. Tumor-infiltrating lymphocytes (TIL) engineered with regulatable membrane-bound IL15 (mbIL15) and LIGHT (TNFSF14) show enhanced efficacy in fibroblast-containing cold tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB065.

Rationale: Despite lower overall hospitalization rates for asthma in recent years, there has been an increase in the number of pediatric patients receiving intensive care management in the United States. Objectives: To investigate how the use of invasive and noninvasive mechanical ventilation for asthma has changed in the context of an evolving cohort of critically ill pediatric patients with asthma. Methods: We analyzed children admitted to intensive care units for asthma from 2009 through 2019 in the Virtual Pediatric Systems database. Regression analyses were used to evaluate how respiratory support interventions, mortality, and patient characteristics have changed over time. Odds ratios were calculated to determine how patient characteristics were associated with respiratory support needs. Stratified analyses were performed to determine how changing practice patterns may have differed between patient subgroups. Results: There were 67,614 admissions for 56,727 patients analyzed. Intubation occurred in 4.6% of admissions and decreased from 6.9% to 3.4% over time (P < 0.001), whereas noninvasive ventilation as the maximal respiratory support increased from 8.9% to 20.0% (P < 0.001). Over time, the cohort shifted to include more 2- to 6-year-olds and patients of Asian/Pacific Islander or Hispanic race/ethnicity. Although intubation decreased and noninvasive ventilation increased in all subgroups, the changes were most pronounced in the youngest patients and slightly less pronounced for obese patients. Conclusions: In pediatric asthma, use of intubation has halved, whereas use of noninvasive ventilation has more than doubled. This change in practice appears partially related to a younger patient cohort, although other factors merit exploration.

Pediatric PulmonologyVolume 59, Issue 3 p. 791-793 CLINICAL CORRESPONDENCE Cystic fibrosis transmembrane conductance regulator modulator administration to a F508del heterozygous infant with meconium pseudocyst and short bowel syndrome: A case report Sylvia Stoffella PharmD, BCPPS, Corresponding Author Sylvia Stoffella PharmD, BCPPS [email protected] orcid.org/0000-0001-7399-1333 Department of Pharmacy, University of California San Francisco, San Francisco, California, USA Correspondence Sylvia Stoffella, PharmD, BCPPS, Department of Pharmacy, University of California San Francisco, San Francisco, CA, USA. Email: [email protected] Contribution: Writing - review & editing, ​Investigation, Writing - original draftSearch for more papers by this authorNgoc Ly MD, MPH, Ngoc Ly MD, MPH Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editingSearch for more papers by this authorMeghan McGarry MD, MS, Meghan McGarry MD, MS orcid.org/0000-0002-8562-7018 Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editing, ConceptualizationSearch for more papers by this authorFatima Neemuchwala MD, Fatima Neemuchwala MD Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editingSearch for more papers by this authorGwynne Church MD, Gwynne Church MD Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editingSearch for more papers by this authorMarilynn Chan MD, Marilynn Chan MD Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editingSearch for more papers by this authorAddison Cuneo MD, Addison Cuneo MD Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editingSearch for more papers by this authorMakiko Omori RD, Makiko Omori RD Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editingSearch for more papers by this authorElizabeth Gibb MD, MPhil, Elizabeth Gibb MD, MPhil Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editing, ​Investigation, Writing - original draft, ConceptualizationSearch for more papers by this author Sylvia Stoffella PharmD, BCPPS, Corresponding Author Sylvia Stoffella PharmD, BCPPS [email protected] orcid.org/0000-0001-7399-1333 Department of Pharmacy, University of California San Francisco, San Francisco, California, USA Correspondence Sylvia Stoffella, PharmD, BCPPS, Department of Pharmacy, University of California San Francisco, San Francisco, CA, USA. Email: [email protected] Contribution: Writing - review & editing, ​Investigation, Writing - original draftSearch for more papers by this authorNgoc Ly MD, MPH, Ngoc Ly MD, MPH Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editingSearch for more papers by this authorMeghan McGarry MD, MS, Meghan McGarry MD, MS orcid.org/0000-0002-8562-7018 Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editing, ConceptualizationSearch for more papers by this authorFatima Neemuchwala MD, Fatima Neemuchwala MD Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editingSearch for more papers by this authorGwynne Church MD, Gwynne Church MD Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editingSearch for more papers by this authorMarilynn Chan MD, Marilynn Chan MD Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editingSearch for more papers by this authorAddison Cuneo MD, Addison Cuneo MD Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editingSearch for more papers by this authorMakiko Omori RD, Makiko Omori RD Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editingSearch for more papers by this authorElizabeth Gibb MD, MPhil, Elizabeth Gibb MD, MPhil Department of Pediatrics, University of California San Francisco, San Francisco, California, USA Contribution: Writing - review & editing, ​Investigation, Writing - original draft, ConceptualizationSearch for more papers by this author First published: 13 December 2023 https://doi.org/10.1002/ppul.26809Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. Open Research DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. REFERENCES 1Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019; 381(19): 1809-1819. 10.1056/NEJMoa1908639 CASPubMedWeb of Science®Google Scholar 2Heijerman H, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet. 2019; 394(10212): 1940-1948. doi:10.1016/S0140-6736(19)32597-8 10.1016/S0140-6736(19)32597-8 CASPubMedWeb of Science®Google Scholar 3Szentpetery S, Foil K, Hendrix S, et al. A case report of CFTR modulator administration via carrier mother to treat meconium ileus in a F508del homozygous fetus. J Cyst Fibros. 2022; 21(4): 721-724. doi:10.1016/j.jcf.2022.04.005 10.1016/j.jcf.2022.04.005 CASPubMedWeb of Science®Google Scholar 4Fortner CN, Seguin JM, Kay DM. Normal pancreatic function and false-negative CF newborn screen in a child born to a mother taking CFTR modulator therapy during pregnancy. J Cyst Fibros. 2021; 20(5): 835-836. doi:10.1016/j.jcf.2021.03.018 10.1016/j.jcf.2021.03.018 PubMedWeb of Science®Google Scholar Volume59, Issue3March 2024Pages 791-793 ReferencesRelatedInformation

Despite growing recognition of the need for increased diversity among students, trainees, and faculty in health care, the medical workforce still lacks adequate representation from groups historically underrepresented in medicine (URiM). The subspecialty field of pediatric pulmonology is no exception. Although there have been efforts to address issues of diversity, equity, and inclusion (DEI) in our own field, gaps persist. To address these gaps, the members of the Diversity, Equity, and Inclusion Advisory Group (DEI-AG) of the American Thoracic Society Pediatrics Assembly created and distributed a Needs Assessment Survey in the United States and Canada to better understand the racial and ethnic demographics of the pediatric pulmonary workforce and to learn more about successes, gaps, and opportunities to enhance how we recruit, train, and retain a diverse workforce. The DEI-AG leadership cochairs convened a workshop to review the findings of the DEI Needs Assessment Survey and to develop strategies to improve the recruitment and retention of URiM fellows and faculty. This Official ATS Workshop Report aims to identify barriers and opportunities for recruitment, training, and career development within the field of pediatric pulmonology. Additionally, we offer useful strategies and resources to improve the recruitment of URiM residents, the mentorship of trainees and junior faculty, and the career development of URiM faculty in academic centers. This Workshop Report is an important first deliverable by the DEI-AG. We hope that this work, originating from within the Pediatrics Assembly, will serve as a model for other Assemblies, disciplines across the ATS, and other fields in Pediatrics.

Background: Hispanic people with CF (pwCF) have increased morbidity than non-Hispanic White pwCF, including increased risk of Pseudomonas aeruginosa. We aimed to determine if Staphylococcus aureus (S. aureus) acquisition varies between Hispanic and non-Hispanic White pwCF.Methods: This longitudinal cohort study of pwCF ages 0-25 years in the CF Foundation Patient Registry compared acquisition of methicillin-sensitive S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), persistent MRSA between Hispanic and non-Hispanic White pwCF. Risk of acquisition was assessed by Kaplan-Meier survival curves and its association with ethnicity was evaluated using Cox regressions. Adjusted associations were evaluated using multivariate Cox models adjusting for sex, age of entry into CFFPR, CFTR variant severity, pancreatic insufficiency, CF-related diabetes, maternal education, insurance status.Results: Of 10,640 pwCF, 7.5% were Hispanic and 92.5% were non-Hispanic White. Hispanic pwCF had a 19% higher risk of acquiring MSSA (HR 1.19, 95% CI 1.10-1.28, p<0.001) and 13% higher risk of acquiring MRSA (HR 1.13, 95% CI 1.02-1.26, p = 0.02) than non-Hispanic White pwCF. The difference in persistent MRSA be-tween ethnicities did not reach statistical significance. After adjusting for confounding variables, only the risk of MSSA was significantly associated with ethnicity. Compared to non-Hispanic White pwCF, Hispanic pwCF acquired MSSA and MRSA at younger median ages (4.9 vs. 3.8 years (p<0.001), 22.4 vs. 20.8 years (p = 0.02).Conclusion: Hispanic pwCF <25 years of age have an increased risk of acquiring MSSA and acquired MSSA and MRSA at an earlier age. Differences in S. aureus acquisition may contribute to increased morbidity in Hispanic pwCF.

Background: People living with cystic fibrosis (PwCF) face a lifetime of potentially traumatic illness related experiences that can lead to posttraumatic stress symptoms. Existing criteria for this type of post traumatic stress, called medical traumatic stress (MTS), may not fully capture the CF experience. In this study we aimed to explore: 1) illness-related experiences perceived as traumatic in the setting of CF, 2) perceived MTS symptoms in PwCF, and 3) perceived health-related functional impairments from MTS. Methods: Informed by our aims, we developed and piloted guides for semi-structured interviews and focus groups with PwCF, family members of PwCF, and CF medical providers. We then conducted a series of interviews and focus groups. The qualitative analytical process followed Deterding and Waters' three stages of flexible coding for in-depth interviews, generating key themes and sub-themes in each domain of study inquiry. Results: We recruited 51 participants, including 24 PwCF, 7 family members of PwCF, and 20 CF care team members. Illness-related experiences perceived as traumatic were often characterized by themes of loss of agency, threats of bodily harm, and shifts in identity. Prominent MTS symptoms included shame, survivor guilt, burden guilt, germaphobia, and symptom panic. Health-related themes of functional impairments perceived to result from MTS included poor adherence and strained relationships between providers and patients/families. Conclusions: This is the first study to explore the specific experiences of MTS in PwCF. It highlights the need for screening that includes these specific exposure types and symptoms, which may be mitigatable with medical trauma-focused interventions. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Objective To inform approaches to pediatric medical traumatic stress (PMTS) by exploring providers' (1) perception of the impact of PMTS on the medical care of patients with pediatric-onset chronic illnesses, (2) self-reported competencies and practices of PMTS prevention, treatment, and counseling, and (3) perception of the barriers influencing the adoption of these practices. Study design A convenience sample of multidisciplinary healthcare providers was recruited through a multi-modal recruitment strategy to participate in an electronic survey adapted from the Trauma-Informed Care Provider Survey. Results Among participants (n = 304), 99% agreed that PMTS impacts patient health. Participants report altering medical care plans due to PMTS, including deferring or stopping treatments (n = 98 [32%]) and changing medication regimens (n = 88 [29%]). Sixty-eight percent (n = 208) report negative impact of PMTS on patient implementation of medical care plans, including medication nonadherence (n = 153 [50%]) and missed appointments (n = 119 [39%]). Although participants agreed it is their job to decrease patient stress (n = 292 [96%]) and perform PMTS assess-ments (n = 268 [88%]), few practiced PMTS-focused trauma informed care. Systems-level barriers to practice included insufficient training, absent clinical workflows, and lack of access to mental health experts. Conclusions Our findings have helped inform a conceptual framework for understanding the relationship be-tween PMTS and health outcomes. Systems-level opportunities to optimize PMTS-focused trauma-informed care include (1) dissemination of provider training, (2) integrated workflows for PMTS mitigation, and (3) enhanced accessibility to mental health providers. Further work is required to determine if these interventions can improve health outcomes in patients with pediatric-onset chronic illnesses.

Background: Children with asthma are at risk for low lung function extending into adulthood, but understanding of clinical predictors is incomplete. Objective: We sought to determine phenotypic factors associated with FEV1 throughout childhood in the Severe Asthma Research Program 3 pediatric cohort. Methods: Lung function was measured at baseline and annually. Multivariate linear mixed-effects models were constructed to assess the effect of baseline and time-varying predictors of prebronchodilator FEV1 at each assessment for up to 6 years. All models were adjusted for age, predicted FEV1 by Global Lung Function Initiative reference equations, race, sex, and height. Secondary outcomes included postbronchodilator FEV1 and prebronchodilator FEV1/forced vital capacity. Results: A total of 862 spirometry assessments were performed for 188 participants. Factors associated with FEV1 include baseline FENO (B, -49 mL/log2 PPB; 95% CI, -92 to -6), response to a characterizing dose of triamcinolone acetonide (B, -8.4 mL/1% change FEV1 posttriamcinolone; 95% CI, -12.3 to -4.5), and maximal bronchodilator reversibility (B, -27 mL/ 1% change postbronchodilator FEV1; 95% CI,-37 to-16). Annually assessed time-varying factors of age, obesity, and exacerbation frequency predicted FEV1 over time. Notably, there was a significant age and sex interaction. Among girls, there was no exacerbation effect. For boys, however, moderate (1-2) exacerbation frequency in the previous 12 months was associated with-20 mL (95% CI,-39 to-2) FEV1 at each successive year. High exacerbation frequency (>_3) 12 to 24 months before assessment was associated with-34 mL (95% CI,-61 to-7) FEV1 at each successive year. Conclusions: In children with severe and nonsevere asthma, several clinically relevant factors predict FEV1 over time. Boys with recurrent exacerbations are at high risk of lower FEV1 through childhood. (J Allergy Clin Immunol 2023;151:138-46.)

OBJECTIVES:Known as pediatric medical traumatic stress (PMTS), posttraumatic stress symptoms from medical experiences have not been explored in children with chronic gastrointestinal diseases. This cross-sectional study of children and adolescents with inflammatory bowel disease, chronic pancreatitis and cystic fibrosis, aimed to (1) estimate the prevalence of medical potentially traumatic events (PTEs) and PMTS, (2) explore potential risk factors for PMTS, and (3) explore potential consequences of PMTS.METHODS:This cross-sectional study used validated, self-report measures to evaluate PTEs and PMTS. Descriptive statistics and regression analyses were used to achieve study objectives.RESULTS:Over two-thirds of children reported a medical potentially traumatic event (91 of 132, 69%). Forty-eight had PMTS symptoms (36%). PMTS was associated with medication burden, emergency and intensive care visits, and parent posttraumatic stress disorder in multivariate analysis. Potential consequences associated with PMTS included school absenteeism, home opioid use, poor quality of life, and parent missed work.CONCLUSIONS:A substantial portion of our cohort reported medical PTEs and PMTS. The exploratory analysis identified potential associations between PMTS and illness factors, parent posttraumatic stress disorder, and functional impairments. Further studies of PMTS detection, prevention and treatment are integral to optimizing these children's health and quality of life.

Childhood asthma is a heterogeneous condition with multiple endophenotypes, with most treatments focused on type 2 allergic/eosinophilic inflammation. Despite the use of treatments targeting type 2 inflammation, a subset of children continue to have asthma exacerbations. A cross-sectional analysis of adults enrolled into the National Institutes of Health/National Heart, Lung, and Blood Institute–sponsored Severe Asthma Research Program-3 (SARP-3) cohort study by Peters et al1 demonstrated that high plasma IL-6 is associated with metabolic dysfunction, reduced lung function, and greater asthma severity, independent of body mass index (BMI).

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

Background: For unknown reasons, Hispanic patients with cystic fibrosis (CF) have more severe pulmonary disease than non-Hispanic white patients. In CF, the pulmonary pathogen Pseudomonas aeruginosa is associated with worse outcomes. We sought to determine if Hispanic patients with CF are at an increased risk of acquiring P. aeruginosa or acquire it earlier than non-Hispanic white patients. Methods: This is a longitudinal study comparing the timing and risk of acquisition of different forms of P. aeruginosa between Hispanic and non-Hispanic white patients aged 0-21 years old with CF in the CF Foundation Patient Registry (CFFPR) in 2008-2013. The age at the initial acquisition of P. aeruginosa (initial acquisition, mucoid, chronic, multidrug-resistant) was summarized using Kaplan-Meier survival curves and analyzed using Cox proportional hazards regression models. Results: Of 10,464 patients, 788 (7.5%) were Hispanic and 9,676 (92.5%) were non-Hispanic white. Hispanic patients acquired all forms of P. aeruginosa at a younger age than non-Hispanic white patients. Hispanic patients had a higher risk of acquiring P. aeruginosa than non-Hispanic white patients: the hazard ratio (HR) was 1.26 (95% CI 1.16-1.38, p < 0.001) for initial P. aeruginosa , 1.59 (95% CI 1.43-1.77, p < 0.001) for mucoid P. aeruginosa , 1.91 (95% CI 1.64-2.23, p < 0.001) for multidrug-resistant P. aeruginosa , and 1.39 (95% CI 1.25-1.55, p < 0.001) for chronic P. aeruginosa . Conclusions: Hispanic patients have an increased risk of acquiring P. aeruginosa and acquire it at an earlier age than non-Hispanic white patients in the United States. This may contribute to increased morbidity and mortality in Hispanic patients with CF. (c) 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

In longitudinal analysis of this well-characterized cohort, half of the children with severe asthma no longer had severe asthma after 3 years; there was a stepwise decrease in the proportion meeting severe asthma criteria. Surprisingly, asthma severity decreased equally in male and female subjects. Peripheral eosinophilia predicted resolution. These data will be important for planning clinical trials in this population.

Relative enlargement of the pulmonary artery (PA) on chest CT imaging is associated with respiratory exacerbations in patients with COPD or cystic fibrosis. We sought to determine whether similar findings were present in patients with asthma and whether these findings were explained by differences in ventricular size.We measured the PA and aorta diameters in 233 individuals from the Severe Asthma Research Program III cohort. We also estimated right, left, and total epicardial cardiac ventricular volume indices (eERVVI, eELVVI, and eETVVI, respectively). Associations between the cardiac and PA measures (PA-to-aorta [PA/A] ratio, eERVVI-to-eELVVI [eRV/eLV] ratio, eERVVI, eELVVI, eETVVI) and clinical measures of asthma severity were assessed by Pearson correlation, and associations with asthma severity and exacerbation rate were evaluated by multivariable linear and zero-inflated negative binomial regression.Asthma severity was associated with smaller ventricular volumes. For example, those with severe asthma had 36.1 mL/m2 smaller eETVVI than healthy control subjects (P = .003) and 14.1 mL/m2 smaller eETVVI than those with mild/moderate disease (P = .011). Smaller ventricular volumes were also associated with a higher rate of asthma exacerbations, both retrospectively and prospectively. For example, those with an eETVVI less than the median had a 57% higher rate of exacerbations during follow-up than those with eETVVI greater than the median (P = .020). Neither PA/A nor eRV/eLV was associated with asthma severity or exacerbations.In patients with asthma, smaller cardiac ventricular size may be associated with more severe disease and a higher rate of asthma exacerbations.ClinicalTrials.gov; No.: NCT01761630; URL: www.clinicaltrials.gov.

OBJECTIVES:Data on outcomes of children with cystic fibrosis admitted to PICUs are limited and outdated. Prior studies cite PICU mortality rates ranging from 37.5% to 100%. Given the advances made in cystic fibrosis care, we expect outcomes for these patients to have changed significantly since last studied. We provide an updated report on PICU mortality and the factors associated with death among critically ill children with cystic fibrosis.DESIGN:Retrospective multicenter cohort analysis utilizing data from the Virtual Pediatric Systems database.SETTING:Data were collected from 135 PICUs from January 1, 2009, to June 20, 2018.PATIENTS:One-thousand six-hundred thirty-three children with cystic fibrosis accounting for 2,893 PICU admissions were studied.INTERVENTIONS:None.MEASUREMENTS AND MAIN RESULTS:The primary outcome was mortality during PICU admission. Predictors included demographics, anthropometrics, diagnoses, clinical characteristics, and critical care interventions. Odds ratios of mortality were calculated in univariate and multivariable analyses to assess differences in mortality associated with predictor variables. Generalized estimating equation models were used to account for multiple admissions per patient. The overall PICU mortality rate was 6.6%. Factors associated with increased odds of mortality included hemoptysis/pulmonary hemorrhage, pneumothorax, gastrointestinal bleeding, bacterial/fungal infections, lower body mass index/malnutrition, and need for noninvasive or invasive respiratory support. Intubation/mechanical ventilation occurred in 26.4% of the 2,893 admissions and was associated with a 19.1% mortality rate. Of the nonsurvivors, 20.7% died without receiving mechanical ventilation.CONCLUSIONS:The mortality rate during PICU admissions for patients with cystic fibrosis is lower than has been reported in prior studies, both in the overall cohort and in the subset requiring invasive mechanical ventilation. These data provide updated insight into the prognosis for cystic fibrosis patients requiring critical care.

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients' biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy.

Functional profiling of CFTR-directed therapeutics offers the potential to provide significant benefits to young people with cystic fibrosis (CF). However, the development of 2D airway epithelial cell models for individual response tests in CF children remains a central task. The objective of this study was to determine the utility of EpiXTM technology for expansion of nasal epithelial cells for use in electrophysiological CFTR function measurements. An initial harvest of as few as 20,000 cells was sufficient to expand up to 50 million cells that were used to generate air-liquid interface (ALI) cultures for ion transport studies with the Ussing assay. CFTR function was assessed by measuring responses to forskolin and the CFTR potentiator VX-770 (ivacaftor) in ALI cultures generated from passage 3 and 4 cells. Short-circuit current (Isc) measurements of blocked CFTR currents (ΔICFTRinh) discriminated CFTR function between healthy control (wild type, WT) and patients with intermediate (F508del/R117H-7T: 56% WT) and severe (F508del/F508del: 12% WT) CF disease. For the mixed genotypes, CFTR activity for F508del/c.850dupA was 12% WT, R334W/406-1G>A was 24% WT, and CFTRdele2,3(21 kb)/CFTRdele2,3(21 kb) was 9% WT. The CFTR correctors VX-809 (lumacaftor) and VX-661 (tezacaftor) significantly increased CFTR currents for F508del/R117H to 73 and 67% WT, respectively. Cultures with the large deletion mutation CFTRdele2,3(21 kb) unexpectedly responded to VX-661 treatment (20% WT). Amiloride-sensitive sodium currents were robust and ranged between 20-80 μA/cm2 depending on the subject. In addition to characterizing the electrophysiological profile of mutant CFTR activity in cultures for five genotypes, our study exemplifies the promising paradigm of bed-to-bench side cooperation and personalized medicine.