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Rationale: High-mobility group box 1 (HMGB1) is a potent inflammatory mediator elevated in sepsis and rheumatoid arthritis, although its role in cystic fibrosis (CF) lung disease is unknown.Objectives: To determine whether HMGB1 contributes to CF lung inflammation, including neutrophil chemotaxis and lung matrix degradation.Methods: We used sputum and serum from subjects with CF and a Scnn1b-transgenic (Scnn1b-Tg) mouse model that overexpresses beta-epithelial Na(+) channel in airways and mimics the CF phenotype, including lung inflammation. Human secretions and murine bronchoalveolar lavage fluid (BALF) was assayed for HMGB1 by Western blot and ELISA. Neutrophil chemotaxis was measured in vitro after incubation with human neutrophils. The collagen fragment proline-glycine-proline (PGP) was measured by tandem mass spectroscopy.Measurements and Main Results: HMGB1 was detected in CF sputum at higher levels than secretions from normal individuals. Scnn1b-Tg mice had elevated levels of HMGB1 by Western blot and ELISA. We demonstrated that dose-dependent chemotaxis of human neutrophils stimulated by purified HMGB1 was partially dependent on CXC chemokine receptors and that this could be duplicated in CF sputum and BALF from Scnn1b-Tg mice. Neutralization by anti-HMGB1 antibody, in both the sputum and BALF-reduced chemotaxis, which suggested that HMGB1 contributed to the chemotactic properties of these samples. Intratracheal administration of purified HMGB1 induced neutrophil influx into the airways of mice and promoted the release of PGP. PGP was also elevated in Scnn1b-Tg mice and CF serum.Conclusions: HMGB1 expression contributes to pulmonary inflammation and lung matrix degradation in CF airway disease and deserves further investigation as a biomarker and potential therapeutic target. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals of increasing concern to human health. PFAS contamination in water systems has been linked to a variety of sources including hydrocarbon fire suppression activities, industrial and military land uses, agricultural applications of biosolids, and consumer products. To assess PFAS in California tap water, we collected 60 water samples from inside homes in four different geographic regions, both urban and rural. We selected mostly small water systems with known history of industrial chemical or pesticide contamination and that served socioeconomically disadvantaged communities. Thirty percent of the tap water samples (18) had a detection of at least one of the 32 targeted PFAS and most detections (89 %) occurred in heavily industrialized Southeast Los Angeles (SELA). The residents of SELA are predominately Latino and low-income. Concentrations of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) ranged from 6.8 to 13.6 ng/L and 9.4-17.8 ng/L, respectively in SELA and were higher than State (PFOA: 0.007 ng/L; PFOS: 1.0 ng/L) and national health-based goals (zero). To look for geographic patterns, we mapped potential sources of PFAS contamination, such as chrome plating facilities, airports, landfills, and refineries, located near the SELA water systems; consistent with the multiple potential sources in the area, no clear spatial associations were observed. The results indicate the importance of systematic testing of PFAS in tap water, continued development of PFAS regulatory standards and advisories for a greater number of compounds, improved drinking-water treatments to mitigate potential health threats to communities, especially in socioeconomically disadvantaged and industrialized areas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Water is an increasingly precious resource in California as years of drought, climate change, pollution, as well as an expanding population have all stressed the state's drinking water supplies. Currently, there are increasing concerns about whether regulated and unregulated contaminants in drinking water are linked to a variety of human-health outcomes particularly in socially disadvantaged communities with a history of health risks. To begin to address this data gap by broadly assessing contaminant mixture exposures, the current study was designed to collect tapwater samples from communities in Gold Country, the San Francisco Bay Area, two regions of the Central Valley (Merced/Fresno and Kern counties), and southeast Los Angeles for 251 organic chemicals and 32 inorganic constituents. Sampling prioritized low-income areas with suspected water quality challenges and elevated breast cancer rates. Results indicated that mixtures of regulated and unregulated contaminants were observed frequently in tapwater throughout the areas studied and the types and concentrations of detected contaminants varied by region, drinking-water source, and size of the public water system. Multiple exceedances of enforceable maximum contaminant level(s) (MCL), non-enforceable MCL goal(s) (MCLG), and other health advisories combined with frequent exceedances of benchmark-based hazard indices were also observed in samples collected in all five of the study regions. Given the current focus on improving water quality in socially disadvantaged communities, our study highlights the importance of assessing mixed-contaminant exposures in drinking water at the point of consumption to adequately address human-health concerns (e.g., breast cancer risk). Data from this pilot study provide a foundation for future studies across a greater number of communities in California to assess potential linkages between breast cancer rates and tapwater contaminants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Rationale: Patients with chronic obstructive pulmonary disease (COPD) exhibit acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. CFTR modulators may improve outcomes in patients with COPD, although recent data regarding magnitude of benefit have been inconclusive and effects on mucociliary clearance are unknown. We conducted a phase 2, randomized, double blind placebo control trial to determine safety and tolerability, and explore the potential mechanism of ivacaftor for the treatment of COPD., Methods: We randomized 40 patients with moderate to severe COPD and symptoms of chronic bronchitis to ivacaftor (N=30) or placebo (N=10) 150mg BID for 12 weeks. Primary endpoints included evaluation of safety of ivacaftor and pharmacokinetics (PK). Secondary endpoints included measures of CFTR activity and clinical outcomes., Results: Ivacaftor was safe and tolerable with similar rates of adverse events rates between groups. Most common adverse event was diarrhea in the ivacaftor group and acute COPD exacerbation in the placebo group. PK analysis found the mean area under the curve over 12 hours (AUC 12 ) to be 72% of the previously reported AUC 12 in cystic fibrosis (CF). Treatment with ivacaftor did not improve sweat chloride, whole lung mucociliary clearance, lung function or respiratory symptoms., Conclusion: Ivacaftor was safe and well tolerated, but did not improve measures of CFTR activity or mucus clearance. As serum concentrations achieved were lower than observed in CF at the same dose, and modulation of wild type CFTR differs from G551D, further dose determination studies are needed to better understand treatment efficacy of CFTR potentiators in COPD. Clinical trial registration available at www., Clinicaltrials: gov, ID: NCT03085485.

The mucociliary transport apparatus is critical for maintaining lung health via the coordinated movement of cilia to clear mucus and particulates. A metachronal wave propagates across the epithelium when cilia on adjacent multiciliated cells beat slightly out of phase along the proximal-distal axis of the airways in alignment with anatomically directed mucociliary clearance. We hypothesized that metachrony optimizes mucociliary transport (MCT) and that disruptions of calcium signaling would abolish metachrony and decrease MCT. We imaged bronchi from human explants and ferret tracheae using micro-optical coherence tomography (µOCT) to evaluate airway surface liquid depth (ASL), periciliary liquid depth (PCL), cilia beat frequency (CBF), MCT, and metachrony in situ. We developed statistical models that included covariates of MCT. Ferret tracheae were treated with BAPTA-AM (chelator of intracellular Ca 2+ ), lanthanum chloride (nonpermeable Ca 2+  channel competitive antagonist), and repaglinide (inhibitor of calaxin) to test calcium dependence of metachrony. We demonstrated that metachrony contributes to mucociliary transport of human and ferret airways. MCT was augmented in regions of metachrony compared with nonmetachronous regions by 48.1%, P = 0.0009 or 47.5%, P < 0.0020 in humans and ferrets, respectively. PCL and metachrony were independent contributors to MCT rate in humans; ASL, CBF, and metachrony contribute to ferret MCT rates. Metachrony can be disrupted by interference with calcium signaling including intracellular, mechanosensitive channels, and calaxin. Our results support that the presence of metachrony augments MCT in a calcium-dependent mechanism. NEW & NOTEWORTHY We developed a novel imaging-based analysis to detect coordination of ciliary motion and optimal coordination, a process called metachrony. We found that metachrony is key to the optimization of ciliary-mediated mucus transport in both ferret and human tracheal tissue. This process appears to be regulated through calcium-dependent mechanisms. This study demonstrates the capacity to measure a key feature of ciliary coordination that may be important in genetic and acquired disorders of ciliary function.

Background: CFTR modulators are approved for approximately 90% of people with cystic fibrosis in the USA and provide substantial clinical benefit. N1303K (Asn1303Lys), one of the most common class 2 CFTR defects, has not been approved for these therapies by any regulatory agency. Preclinical investigation by our laboratories showed N1303K CFTR activation with elexacaftor-tezacaftor-ivacaftor (ETI). In this trial, we evaluate whether ETI improves CFTR function, measured by sweat chloride and other clinical outcomes, in people with cystic fibrosis and CFTR N1303K ., Methods: In this prospective, open-label, single-arm trial, participants aged 12 years or older with cystic fibrosis encoding at least one N1303K variant and at least one CFTR N1303K allele who were ineligible for modulator therapy by US Food and Drug Administration labelling were given ETI for 28 days followed by a 28-day washout period at two cystic fibrosis centres in the USA. Participants received two orally administered pills of 100 mg elexacaftor, 50 mg tezacaftor, and 75 mg ivacaftor once daily in the morning, and 150 mg ivacaftor once daily in the evening. The primary endpoint was mean change in sweat chloride from baseline up to day 28 compared with mixed-effects models. Secondary endpoints were changes in percentage of predicted FEV 1 (ppFEV 1 ), Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain, BMI, and weight after ETI therapy. Safety was assessed in all participants who received at least one dose of the study drug and primary and secondary analyses were performed in all participants who took the study drug per protocol. The trial was registered at ClinicalTrials.gov (NCT03506061) and remains open for reporting purposes., Findings: Between June 7, 2022, and Oct 20, 2023, 20 participants (ten male and ten female) were enrolled and received ETI treatment. One participant was lost to follow-up but was included in intention-to-treat analyses. At 28 days, the mean sweat chloride reduction was -1·1 mmol/L (95% CI -5·3 to 3·1; p=0·61) with only one participant showing a sweat chloride decrease greater than 15 mmol/L. There was a mean increase in ppFEV 1 from baseline at day 28 of 9·5 percentage points (6·7-12·3; p<0·0001) with 15 (75%) participants showing at least a 5% increase in ppFEV 1 . Improvements were also identified in mean CFQ-R respiratory domain score (20·8 increase [95% CI 11·9-29·8]; p<0·0001), BMI (0·4 kg/m 2 increase [0·2-0·7]; p=0·0017), and weight (1·0 kg increase [0·4-1·7]; p=0·0020) after 28 days of ETI treatment. 14 (70%) of 20 participants had adverse events (12 [60%] mild, one [5%] moderate), with one (5%) serious adverse event of hospitalisation attributed to pneumonia. No deaths were recorded in the study., Interpretation: Individuals with CFTR N1303K showed no change in sweat chloride after 28 days of treatment with ETI. However, there were improvements in secondary clinical endpoints, which suggest clinical efficacy. Our approach provides support for the use of in vitro model systems to inform clinical trials for rare CFTR variants., Funding: The Cystic Fibrosis Foundation and the US National Institutes of Health., Competing Interests: Declaration of interest GMS reports funding from the National Institutes of Health (NIH), the Cystic Fibrosis Foundation, the COPD Foundation, and the PCD Foundation; reports grants for clinical trials from Renovion, Vertex, Electromed, Insmed Pharmaceuticals, 4DMT, AstraZeneca, and BiomX for clinical trials; is a paid consultant for Insmed, Electromed, and Genetech; is on the steering committees for clinical trials for AstraZeneca, GlaxoSmithKline, and Genentech; is a member of the steering committee for the Bronchiectasis and NTM Research Registry; and has contracts for laboratory work from Renovion and ReCode, unrelated to the current manuscript. RWL reports grants paid to her institution from the Cystic Fibrosis Foundation and Vertex Pharmaceuticals; consulting fees from Vertex Pharmaceuticals; and support for travel to an investigator meeting from Vertex Pharmaceuticals. AS and EH report funding from the Cystic Fibrosis Foundation. WRH reports funding from NIH and the Cystic Fibrosis Foundation. JJB reports funding from NIH, the Cystic Fibrosis Foundation, and Cure Cystic Fibrosis, and has previously received honoraria for invited lectures from Vertex Pharmaceuticals. AR reports research support from NIH (HL-139876) and the Cystic Fibrosis Foundation. SPB reports grant funding from NIH and the Cystic Fibrosis Foundation. CM-B is a collaborator on the Cystic Fibrosis Foundation grant that funded this work. SS participates and has a key role in studies funded by the NIH and Cystic Fibrosis Foundation, and is an inventor on US Patent number 11 401 510 for the generation of airway basal stem cells from human pluripotent stem cells (issue date Aug 2, 2022). CB participates and has a key role in studies funded by NIH and the Cystic Fibrosis Foundation, and is an inventor on US Patent number 11 401 510. BRD has grants from NIH and the Cystic Fibrosis Foundation, and is an inventor on US Patent number 11 401 510. EJS reports funding from NIH (HL139876), the Cystic Fibrosis Foundation, and the Marcus Foundation; received an honorarium from the University of Iowa (Iowa City, IA, USA) for a talk regarding CFTR theratyping analysis; is working on novel compounds for treatment of cystic fibrosis that are not described or mentioned in this study but might have a future role against many CFTR mutations, including N1303K; and is a non-voting member of the Cystic Fibrosis Foundation board of directors (a not-for-profit organisation with no competing interests with this study). RR, BB, KV, ALW, JH, and CM declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Rationale: Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. Objectives: To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. Methods: Patients in the Bronchiectasis and NTM Research Registry with ⩾5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. Measurements and Main Results: In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline FEV 1 percent predicted, age, hospitalization within 2 years before baseline, body mass index, and sex (all P  < 0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar, regardless of NTM status, except that annual exacerbations were lower in patients with NTM ( P  < 0.05). Conclusions: Outcomes, including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate, were similar across 5 years in patients with bronchiectasis with or without NTM.

Background: Cystic fibrosis associated liver disease (CFLD) carries a significant disease burden with no effective preventive therapies. According to the gut-liver axis hypothesis for CFLD pathogenesis, dysbiosis and increased intestinal inflammation and permeability permit pathogenic bacterial translocation into the portal circulation, leading to hepatic inflammation and fibrosis. Evaluating the effect of CFTR (cystic fibrosis transmembrane conductance regulator) modulation with elexacaftor/tezacaftor/ivacaftor (ETI) may help determine the role of CFTR in CFLD and increase understanding of CFLD pathogenesis, which is critical for developing therapies. We aimed to characterize the fecal microbiota in participants with CF with and without advanced CFLD (aCFLD) before and after ETI., Methods: This is an ancillary analysis of stool samples from participants ages ≥12 y/o enrolled in PROMISE (NCT04038047). Included participants had aCFLD (cirrhosis with or without portal hypertension, or non-cirrhotic portal hypertension) or CF without liver disease (CFnoLD). Fecal microbiota were defined by shotgun metagenomic sequencing at baseline and 1 and 6 months post-ETI., Results: We analyzed 93 samples from 34 participants (11 aCFLD and 23 CFnoLD). Compared to CFnoLD, aCFLD had significantly higher baseline relative abundances of potential pathogens Streptococcus salivarius and Veillonella parvula. Four of 11 aCFLD participants had an initially abnormal fecal calprotectin that normalized 6 months post-ETI, correlating with a significant decrease in S. salivarius and a trend towards decreasing V. parvula., Conclusions: These results support an association between dysbiosis and intestinal inflammation in CFLD with improvements in both post-ETI, lending further support to the gut-liver axis in aCFLD., Competing Interests: Declaration of competing interest JTD – Grant funding from CFF SJS – Grant funding from Vertex, CFF, NIH SMR – Consultant for Vertex; Grant funding from Vertex, CFF, NIH GMS – Consultant for GSK, Genentech, Electromed; Grant funding from Vertex, CFF, NIH DPN – Consultant for Vertex, Genentech; Grant funding from Vertex, CFF, NIH LRH – Grant funding from CFF, NIH MRN – Consultant for UpToDate, Vertex: Grant funding from Gilead, AbbVie, CFF, NIH NG – Grant funding from SCRI-CRSP, (Copyright © 2024. Published by Elsevier B.V.)

Background: Use of elexacaftor/tezacaftor/ivacaftor (ETI) for treatment of cystic fibrosis (CF) has resulted in unprecedented clinical improvements necessitating development of outcome measures for monitoring disease course. Intranasal micro-optical coherence tomography (μOCT) has previously helped detect and characterize mucociliary abnormalities in patients with CF. This study was done to determine if μOCT can define the effects of ETI on nasal mucociliary clearance and monitor changes conferred to understand mechanistic effects of CFTR modulators beyond CFTR activation., Methods: 26 subjects, with at least 1 F508del mutation were recruited and followed at baseline (visit 1), +1 month (visit 2) and +6 months (visit 4) following initiation of ETI therapy. Clinical outcomes were computed at visits 1, 2 and 4. Intranasal μOCT imaging and functional metrics analysis including mucociliary transport rate (MCT) estimation were done at visits 1 and 2., Results: Percent predicted forced expiratory volume in 1 s (ppFEV 1 ) showed a significant increase of +10.9 % at visit 2, which sustained at visit 4 (+10.6 %). Sweat chloride levels significantly decreased by -36.6 mmol/L and -41.3 mmol/L at visits 2 and 4, respectively. μOCT analysis revealed significant improvement in MCT rate (2.8 ± 1.5, visit 1 vs 4.0 ± 1.5 mm/min, visit 2; P = 0.048)., Conclusions: Treatment with ETI resulted in significant and sustained clinical improvements over 6 months. Functional improvements in MCT rate were evident within a month after initiation of ETI therapy indicating that μOCT imaging is sensitive to the treatment effect of HEMT and suggests improved mucociliary transport as a probable mechanism of action underlying the clinical benefits., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Steven M. Rowe and Guillermo J. Tearney has patent pending to Unlicensed patent on the use of optical coherence tomography., (© 2024 The Authors.)

Spirometry plays a crucial role in the diagnosis of asthma. The hallmark spirometry finding of expiratory airflow variability can be demonstrated in several ways including peak airflow and bronchodilator and bronchoprovocation testing. Challenges of overdiagnosis and underdiagnosis underscore the need to consider clinical context while interpreting these tests. A meticulous and multifaceted approach prioritizing objective testing is imperative while diagnosing asthma., Competing Interests: Disclosure This work was supported by NIH (P30027482-14 and 1K08HL1 to GMS)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Adeno-associated virus (AAV) vector has shown multiple clinical breakthroughs, but its clinical implementation in inhaled gene therapy remains elusive due to difficulty in transducing lung airway cells. We demonstrate here AAV serotype 6 (AAV6) associated with extracellular vesicles (EVs) and secreted from vector-producing HEK-293 cells during vector preparation (EVAAV6) as a safe and highly efficacious gene delivery platform for inhaled gene therapy applications. Specifically, we discovered that EVAAV6 provided markedly enhanced reporter transgene expression in mucus-covered air-liquid interface (ALI) cultures of primary human bronchial and nasal epithelial cells as well as in mouse lung airways compared to standard preparations of AAV6 alone. Of note, AAV6 has been previously shown to outperform other clinically tested AAV serotypes, including those approved by the FDA for treating non-lung diseases, in transducing ALI cultures of primary human airway cells. We provide compelling experimental evidence that the superior performance of EVAAV6 is attributed to the ability of EV to facilitate mucus penetration and cellular entry/transduction of AAV6. The tight and stable linkage between AAV6 and EVs appears essential to exploit the benefits of EVs given that a physical mixture of individually prepared EVs and AAV6 failed to mediate EV-AAV6 interactions or to enhance gene transfer efficacy., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

The coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2 coronavirus, is devastatingly impacting human health. A prominent component of COVID-19 is the infection and destruction of the ciliated respiratory cells, which perpetuates dissemination and disrupts protective mucociliary transport (MCT) function, an innate defense of the respiratory tract. Thus, drugs that augment MCT could improve the barrier function of the airway epithelium and reduce viral replication and, ultimately, COVID-19 outcomes. We tested five agents known to increase MCT through distinct mechanisms for activity against SARS-CoV-2 infection using a model of human respiratory epithelial cells terminally differentiated in an air/liquid interphase. Three of the five mucoactive compounds tested showed significant inhibitory activity against SARS-CoV-2 replication. An archetype mucoactive agent, ARINA-1, blocked viral replication and therefore epithelial cell injury; thus, it was further studied using biochemical, genetic, and biophysical methods to ascertain the mechanism of action via the improvement of MCT. ARINA-1 antiviral activity was dependent on enhancing the MCT cellular response, since terminal differentiation, intact ciliary expression, and motion were required for ARINA-1-mediated anti-SARS-CoV2 protection. Ultimately, we showed that the improvement of cilia movement was caused by ARINA-1-mediated regulation of the redox state of the intracellular environment, which benefited MCT. Our study indicates that intact MCT reduces SARS-CoV-2 infection, and its pharmacologic activation may be effective as an anti-COVID-19 treatment.

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear., Methods: PROMISE is a 56-center prospective, observational study of ETI in PwCF >12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex., Results: 438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change., Conclusions: After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve., Competing Interests: Declaration of Competing Interest SJS-Consultant for UpToDate, Abbvie, Mirium, Nestle; Grant funding from Gilead, Cystic Fibrosis Foundation, NIH. SDF – Consultant for UpToDate, Abbvie, Nestle, Synspira; Grant funding from NIH, Cystic Fibrosis Foundation, Amagma Therapeutics. MRN – Consultant for UpToDate, Vertex: Grant funding from Gilead, AbbVie, Cystic Fibrosis Foundation, NIH SMR: Consultant for Vertex; Grant funding from Vertex, Cystic Fibrosis Foundation, NIH DPN: Consultant for Vertex, Genentech; Grant funding from Vertex, Cystic Fibrosis Foundation, NIH GMS: Consultant for Genentech, Electromed; Grant Funding from Vertex, Cystic Fibrosis Foundation, NIH DG: Consultant for Vertex, Abbvie, Chiesi USA, Eli Lilly AK: Grant funding from NIH, Cystic Fibrosis Foundation, SDS – Grant funding from Cystic Fibrosis Foundation and NIH MSS—Grant funding from Cystic Fibrosis Foundation, (Copyright © 2022. Published by Elsevier B.V.)

Background: Airway clearance therapies (ACTs) are recommended as an integral part of the management of non-cystic fibrosis bronchiectasis (BE) to prevent inflammation, mucus accumulation, and infection that occur because of ineffective secretion clearance. Adherence to ACTs is low, in part because of perceived burden and a lack of standardization of education and training programs for patients. Poor adherence is associated with more frequent exacerbations, worse health outcomes, and worse quality of life. Structured educational programs increase adherence to ACT among people with cystic fibrosis and may show similar results for people with BE., Objective: This pilot study evaluated the feasibility, clinical utility, sustainability, and expert opinions of this educational program addressing gaps in ACT knowledge and skills in people with BE., Methods: The Individual Management of Patient Airway Clearance Therapy- Bronchiectasis (IMPACT BE) was implemented in nine BE centers with 100 patients. Qualitative and quantitative data were collected from patients and providers., Results: The IMPACT BE program demonstrated good uptake in a clinic setting by multidisciplinary team members, with improvements in medical teams' evaluation of their ability to provide education to patients. All healthcare teams indicated that this program could become a sustainable part of their clinic. Qualitative responses from patients indicated the program was comprehensive and easy to use., Conclusion: In this pilot study, IMPACT BE was found to be useful in teaching airway clearance to people with BE. The open-access toolkit was well received by both patients and a diverse array of providers in a clinic setting., (Copyright © 2023 by the American Thoracic Society.)

Background: Hazard identification, risk assessment, regulatory, and policy activity are usually conducted on a chemical-by-chemical basis. Grouping chemicals into categories or classes is an underutilized approach that could make risk assessment and management of chemicals more efficient for regulators., Objective and Methods: While there are some available methods and regulatory frameworks that include the grouping of chemicals (e.g.,same molecular mechanism or similar chemical structure) there has not been a comprehensive evaluation of these different approaches nor a recommended course of action to better consider chemical classes in decision-making. This manuscript: 1) reviews current national and international approaches to grouping; 2) describes how groups could be defined based on the decision context (e.g., hazard/risk assessment, restrictions, prioritization, product development) and scientific considerations (e.g., intrinsic physical-chemical properties); 3) discusses advantages of developing a decision tree approach for grouping; 4) uses ortho-phthalates as a case study to identify and organize frameworks that could be used across agencies; and 5) discusses opportunities to advance the class concept within various regulatory decision-making scenarios., Results: Structural similarity was the most common grouping approach for risk assessment among regulatory agencies (national and state level) and non-regulatory organizations, albeit with some variations in its definition. Toxicity to the same target organ or to the same biological function was also used in a few cases. The phthalates case study showed that a decision tree approach for grouping should include questions about uses regulated by other agencies to encourage more efficient, coherent, and protective chemical risk management., Discussion and Conclusion: Our evaluation of how classes of chemicals are defined and used identified commonalities and differences based on regulatory frameworks, risk assessments, and business strategies. We also identified that using a class-based approach could result in a more efficient process to reduce exposures to multiple hazardous chemicals and, ultimately, reduce health risks. We concluded that, in the absence of a prescribed method, a decision tree approach could facilitate the selection of chemicals belonging to a pre-defined class (e.g., chemicals with endocrine-disrupting activity; organohalogen flame retardants [OFR]) based on the decision-making context (e.g., regulatory risk management)., (© 2022. The Author(s).)

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection., (© 2022. The Author(s).)

Background: Increasing awareness of milder presentations of cystic fibrosis (CF) and greater interest in non-CF bronchiectasis are likely to lead to more CF screening by respiratory clinicians. As a result, adults who may not strictly fulfil CF diagnostic criteria yet display evidence of abnormal CF transmembrane conductance regulator (CFTR) function are being identified. The degree of agreement on diagnosis and care needs in these cases between CF clinicians remains unknown, and has implications for patient care, including access to CFTR modulator therapies., Methods: We surveyed adult CF physicians in Canada, the USA, the UK and Ireland, and presented them with anonymised vignettes of adult patients referred for assessment of possible CF. Diagnostic inter-rater agreement over diagnosis, ease of classifying cases and appropriate follow-up was assessed using Krippendorff's reliability coefficient (α)., Results: Agreement over diagnosis (α=0.282), ease of classification (α= -0.01) and recommended follow-up (α=0.054) was weak. Clinician experience (>10 and 5-10 years versus <5 years) and location (UK and Ireland versus Canada) were associated with higher odds of recommending further testing compared with selecting a formal diagnosis (respectively, OR 2.87; p=0.022, OR 3.74; p=0.013 and OR 3.16; p=0.007). A modified standard of care was recommended in 28.7% of cases labelled as CF. 70% of respondents agreed with the statement that "Accurate distinction between CF and CFTR-related disorder has become significantly more pertinent with the advent of highly effective CFTR modulators"., Conclusions: Our results demonstrate low diagnostic concordance among CF specialists assessing cases of possible adult CF and highlight an area in need of improvement., Competing Interests: Conflict of interest: A.N. Franciosi has received a Michael Smith Health Research BC Research Trainee Award (RT-2020-0493), outside the submitted work. P.G. Wilcox has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Vertex, outside the submitted work; and is member of the CF Foundation DSMB, outside the submitted work. G.M. Solomon has received grants or contracts from the NIH, CF Foundation and Vertex Pharmaceuticals, outside the submitted work; consulting fees from Electromed, Inc. and Spark Healthcare, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Electromed, Inc. and Insmed, outside the submitted work; has participated on a DSMB or advisory board from Electromed, Inc. and Insmed, Inc., outside the submitted work. N.G. McElvaney has received grants or contracts from Grifols (research grant for α1-antitrypsin deficiency), outside the submitted work; consulting fees from Vertex, Intellia and Inhibrx, outside the submitted work; has a patent issued for development of oxidation resistant α1-antitrypsin in CHO cells, outside the submitted work; is President of the Alpha 1 Foundation Ireland, outside the submitted work; has Nuimmune stock options, outside the submitted work; and has received plasma purified for α1-antitrypsin for research from Grifols, outside the submitted work. D.G. Downey has received consulting fees from Vertex Pharmaceuticals and Proteostasis Therapeutics, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Vertex Pharmaceuticals, Proteostasis Therapeutics and Chiesi, outside the submitted work; support for attending meetings and/or travel from Vertex Pharmaceuticals and Proteostasis Therapeutics, outside the submitted work; and has a leadership or fiduciary role in other board, society, committee or advocacy groups for the European CF Society Clinical Trials Network, outside the submitted work. B.S. Quon has received grants or contracts from CF Canada, CF Foundation, Gilead Sciences and BC Lung Association, outside the submitted work; personal speaker fees from Vertex Pharmaceuticals, outside the submitted work; and participated on advisory boards for Proteostasis Therapeutics and AbbVie, outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©The authors 2022.)

The spectrum of disorders involving CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction correlates with a continuous gradient of CFTR function defined by the combination of two allelic CFTR variants. CFTR-related disorders are clinical entities with features of cystic fibrosis (CF) and evidence for presence of CFTR dysfunction but not meeting criteria for diagnosis of CF. Individuals with CFTR-RDs demonstrate a wide range of CFTR activity and are still under-recognized or misclassified. The level of CFTR dysfunction may be measured in vivo (sweat testing, nasal potential difference measurements) and/or by ex vivo tests (intestinal current measurement), or indirectly indicated by CFTR variants, as alteration in sequence of the CFTR gene translates into CFTR dysfunction. CFTR bioassays can aid in the diagnosis of individuals with CF, but we lack parameters to differentiate CF from CFTR-RD. In the era of the CFTR modulators and their potential clinical benefit, it is of utmost importance to diagnose CFTR-RD as unambiguously as possible. We therefore propose the following to define compatible CFTR dysfunction in a person with a suspected diagnosis of CFTR-RD : (1) evidence of CFTR dysfunction in vivo or ex vivo in at least two different CFTR functional test types, or (2) One CFTR variant known to reduce CFTR function and evidence of CFTR dysfunction in vivo or ex vivo in at least two different CFTR functional test types, or (3) Two CFTR variants shown to reduce CFTR function, with at most one CF-causing variant., Competing Interests: Declaration of Competing Interest All the authors have declared their conflict of interests., (Copyright © 2022. Published by Elsevier B.V.)

Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

The COVID-19 pandemic has underscored how underlying disparities in environmental and health conditions exacerbate vulnerability during public health emergencies in low-income and communities of color. Neglected epidemics-high rates of pollution, chronic disease, and racial and socioeconomic health disparities-have continued amid persistent systemic racism and declining investment in public health. Recognized too late due to shortcomings in public health data tracking, COVID-19 has surged through vulnerable communities. Improved public health tracking is critical for informing the country's recovery from COVID-19, and it can be leveraged to measure and reduce health disparities and strengthen community resilience to respond more effectively to the next public health crisis. We emphasize how public health tracking agencies can engage communities in data collection and reporting; we also discuss the complementary role that communities can take to mobilize data to change policies and institutions, strengthening resilience through increased information and capacity driven by community priorities. Success requires the continuous collection of timely data at a community scale, and public health agencies partnering with communities to use the information in decision making and evaluation to ensure progress over time. We highlight community-engaged data collection and reporting-community air monitoring in Imperial County, CA-as an example of working with communities to improve public health data collection and reporting, increase community dialogue and engagement in governmental decision making, and inform public health tracking to reduce health disparities and strengthen community resilience., Competing Interests: Several of the authors are paid staff members of Tracking California, which receives federal funding from CDC's Environmental Public Health Tracking Program and state funding through subcontracts with AB 617 Community Grants recipients. The authors have no other conflicts of interest to disclose., (Copyright 2022, Mary Ann Liebert, Inc., publishers.)

The use of airway clearance strategies as supplementary treatment in respiratory disease has been best investigated in patients with cystic fibrosis (CF) and non-cystic fibrosis bronchiectasis (NCFBE), conditions which are traditionally characterized by excessive mucus stasis and mucociliary dysfunction. A variety of airway clearance therapies both pharmacological and non-pharmacological have been shown to ameliorate disease progression in this population and have hence been assimilated into routine respiratory care. This self-propagating cycle of mucus retention and airway damage leading to chronic inflammation and infections can also be applied to patients with respiratory failure requiring mechanical ventilation. Furthermore, excessive trachea-bronchial secretions have been associated with extubation failure presenting an opportunity for intervention. Evidence for the use of adjunctive mucoactive agents and other therapies to facilitate secretion clearance in these patients are not well defined, and this subgroup still remains largely underrepresented in clinical trials. In this review, we discuss the role of mucus clearance techniques with a proven benefit in patients with CF and NCFBE, and their potential role in patients requiring mechanical ventilation while highlighting the need for standardization and adoption of mucus clearance strategies in these patient populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Goetz, Vijaykumar and Solomon.)

Rationale: The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs in at least 85% of people with CF. Objectives: PROMISE is a postapproval study to understand the broad effects of ETI through 30 months' clinical use in a more diverse U.S. patient population with planned analyses after 6 months. Methods: Prospective, observational study in 487 people with CF age 12 years or older with at least one F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in percent predicted FEV 1 (ppFEV 1 ), sweat chloride concentration, body mass index (BMI), and self-reported respiratory symptoms. Measurements and Main Results: Average age was 25.1 years, and 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor, whereas 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV 1 improved 9.76 percentage points (95% confidence interval [CI], 8.76 to 10.76) from baseline, cystic fibrosis questionnaire-revised respiratory domain score improved 20.4 points (95% CI, 18.3 to 22.5), and sweat chloride decreased -41.7 mmol/L (95% CI, -43.8 to -39.6). BMI also significantly increased. Changes were larger in those naive to modulators but substantial in all groups, including those treated with ivacaftor at baseline. Conclusions: ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naive to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV 1 in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).

Wildfires have destroyed multiple residential communities in California in recent years. After fires in 2017 and 2018, high concentrations of benzene and other volatile organic compounds (VOCs) were found in public drinking water systems in fire-affected areas. The sources of the contamination and appropriate remediation have been urgent matters for investigation. This study characterizes target and non-target VOCs and semi volatile organic compounds (SVOCs) in water from a highly contaminated service line after the 2018 Camp Fire (Paradise, CA). Ninety-five organic compounds were identified or tentatively identified in the service line. Laboratory combustion experiments with drinking water pipes made of polyvinyl chloride (PVC), cross-linked polyethylene (PEX) and high-density polyethylene (HDPE) and a review of the literature were used to evaluate potential sources of the detected chemicals. Among the service line contaminants were thirty-two compounds associated with PVC pyrolysis and twenty-eight organic compounds also associated with the pyrolysis of polyethylene. The service line sample also contained fifty-five compounds associated with uncontrolled burning of biomass and waste materials. The findings support hypotheses that wildfires can contaminate drinking water systems both by thermal damage to plastic pipes and intrusion of smoke. Residual chlorine disinfectant in the water system modifies the contaminant distribution observed.

Background: To date, health-effects research on environmental stressors has rarely focused on behavioral and mental health outcomes. That lack of research is beginning to change. Science and policy experts in the environmental and behavioral health sciences are coming together to explore converging evidence on the relationship-harmful or beneficial-between environmental factors and mental health., Objectives: To organize evidence and catalyze new findings, the National Academy of Sciences, Engineering, and Medicine (NASEM) hosted a workshop 2-3 February 2021 on the interplay of environmental exposures and mental health outcomes., Methods: This commentary provides a nonsystematic, expert-guided conceptual review and interdisciplinary perspective on the convergence of environmental and mental health, drawing from hypotheses, findings, and research gaps presented and discussed at the workshop. Featured is an overview of what is known about the intersection of the environment and mental health, focusing on the effects of neurotoxic pollutants, threats related to climate change, and the importance of health promoting environments, such as urban green spaces., Discussion: We describe what can be gained by bridging environmental and psychological research disciplines and present a synthesis of what is needed to advance interdisciplinary investigations. We also consider the implications of the current evidence for a ) foundational knowledge of the etiology of mental health and illness, b ) toxicant policy and regulation, c ) definitions of climate adaptation and community resilience, d ) interventions targeting marginalized communities, and e ) the future of research training and funding. We include a call to action for environmental and mental health researchers, focusing on the environmental contributions to mental health to unlock primary prevention strategies at the population level and open equitable paths for preventing mental disorders and achieving optimal mental health for all. https://doi.org/10.1289/EHP9889.

Background: Cystic fibrosis (CF) programs and people with CF (PwCF) employed various monitoring methods for virtual care during the COVID-19 pandemic. This paper characterizes experiences with remote monitoring across the U.S. CF community., Methods: The CF Foundation (CFF) sponsored distribution of home spirometers (April 2020 to May 2021), surveys to PwCF and CF programs (July to September 2020), and a second program survey (April to May 2021). We used mixed methods to explore access, use, and perspectives regarding the use of remote monitoring in future care., Results: By October 2020, 13,345 spirometers had been distributed, and 19,271 spirometers by May 2021. Programs (n=286) estimated proportions of PwCF with home devices increased over seven months: spirometers (30% to 70%), scales (50% to 70%), oximeters (5% to 10%) with higher estimates in adult programs for spirometers and oximeters. PwCF (n=378) had access to scales (89%), followed by oximeters (48%) and spirometers (47%), often using scales and oximeters weekly, and spirometers monthly. Over both surveys, some programs had no method to collect respiratory specimens for cultures associated with telehealth visits (47%, n=132; 41%, n=118). Most programs (81%) had a process for phlebotomy associated with a telehealth visit, primarily through off-site labs. Both PwCF and programs felt future care should advance remote monitoring and recommended improvements for access, training, and data collection systems., Conclusions: PwCF and programs experienced unprecedented access to remote monitoring and raised its importance for future care. Improvements to current systems may leverage these shared experiences to augment future care models., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Background: During the COVID-19 pandemic, CF centers shifted to a telehealth delivery model. Our study aimed to determine how people with CF (PwCF) and their families experienced telehealth and assessed its quality and acceptability for future CF care., Methods: The CF Patient and Family State of Care Survey (PFSoC) was fielded from August 31-October 30, 2020. The PFSoC explored themes of overall telehealth quality, ease of use, desirability, and preference for a future mix of in-person and telehealth care. Demographic covariates considered included: gender, age, CFTR modulator status, and region of residence., Results: 424 PwCF and parents of PwCF responded (47% parents). Most (81%) reported a telehealth visit which included a MD/APP and nurse team members. 91% found telehealth easy to use, and 66% reported similar/higher quality than in-person care. One-third (34%) reported the highest desire for future telehealth care, with 45% (n =212) desiring 50% or more of visits conducted via telehealth. Adults were more likely than parents to report highest desire for future telehealth (64% vs. 36%). Respondents who perceived telehealth as similar/higher quality were more likely to desire future telehealth compared to those who perceived telehealth as lower quality (96% vs. 50%). Mixed methods analysis revealed themes affecting perceptions of telehealth., Conclusions: PwCF desire for future telehealth was influenced by perception of quality and age. Several themes emerged that need to be explored as telehealth is adapted into the CF chronic care model, especially when thinking about integration into pediatric care., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Background: Riociguat is a first-in-class soluble guanylate cyclase stimulator for which preclinical data suggested improvements in cystic fibrosis transmembrane conductance regulator (CFTR) function., Methods: This international, multicenter, two-part, Phase II study of riociguat enrolled adults with cystic fibrosis (CF) homozygous for Phe508del CFTR. Part 1 was a 28-day, randomized, double-blind, placebo-controlled study in participants not receiving CFTR modulator therapy. Twenty-one participants were randomized 1:2 to placebo or oral riociguat (0.5 mg three times daily [tid] for 14 days, increased to 1.0 mg tid for the subsequent 14 days). The primary and secondary efficacy endpoints were change in sweat chloride concentration and percent predicted forced expiratory volume in 1 second (ppFEV 1 ), respectively, from baseline to Day 14 and Day 28 with riociguat compared with placebo., Results: Riociguat did not alter CFTR activity (change in sweat chloride) or lung function (change in ppFEV 1 ) at doses up to 1.0 mg tid after 28 days. The most common drug-related adverse event (AE) was headache occurring in three participants (21%); serious AEs occurred in one participant receiving riociguat (7%) and one participant receiving placebo (14%). This safety profile was consistent with the underlying disease and the known safety of riociguat for its approved indications., Conclusions: The Rio-CF study was terminated due to lack of efficacy and the changing landscape of CF therapeutic development. The current study⁠, within its limits of a small sample size, did not provide evidence that riociguat could be a valid treatment option for CF., Clinical Trial Registration Number: NCT02170025., Competing Interests: Declaration of Competing Interest N. Derichs received a speaker honorarium from Vertex Pharmaceuticals, Inc. for participation in a symposium, and served as a consultant for Vertex Pharmaceuticals, Inc. at educational activities and advisory boards. J.L. Taylor-Cousar reports grants paid to her institution from the Cystic Fibrosis Foundation; grants paid to her institution and consulting and speaking fees from Vertex Pharmaceuticals, Inc.; grants paid to her institution from Bayer; grants, consulting, and speaking fees from Celtaxys; grants paid to her institution and consulting fees from Proteostasis Therapeutics, Inc.; consulting fees from Santhera, 4DMT, AbbVie, and Polarean; and grants paid to her institution from Eloxx Pharmaceuticals. J.C. Davies reports grants from the CF Trust and other funding from Algipharma AS, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Galapagos NV, ImevaX GmbH, Nivalis Therapeutics, Inc., ProQR Therapeutics III B.V., Proteostasis Therapeutics, Inc., Raptor Pharmaceuticals, Inc., Vertex Pharmaceuticals, Inc., Enterprise, Novartis, Pulmocide, Flatley, Nivalis Therapeutics, Inc., and Teva. I. Fajac received speaker honoraria from Vertex Pharmaceuticals, Inc. for participation in symposia and served as a consultant for Novartis, Proteostasis Therapeutics, Inc., and Vertex Pharmaceuticals, Inc. E. Tullis reports grants paid to her institution from Vertex Pharmaceuticals, Inc., Proteostasis Therapeutics, Bayer AG, Boehringer Ingelheim, AbbVie, Celtaxis, Corbus, and Spyryx, and consultancy fees and honoraria from Vertex Pharmaceuticals, Proteostasis Therapeutics, Astra Zeneca and Horizon. D. Nazareth has nothing to disclose. D.G. Downey reports grants from Vertex Pharmaceuticals, Inc., Proteostasis Therapeutics, Inc., Gilead, and Chiesi; and honoraria or speaker fees from Vertex Pharmaceuticals, Inc., Proteostasis Therapeutics, Inc., and Chiesi. D. Rosenbluth has nothing to disclose. A. Malfroot has nothing to disclose. C. Saunders has nothing to disclose. R. Jensen has nothing to disclose. G.M. Solomon reports work on advisory boards for Bayer and Electromed. F. Vermeulen has nothing to disclose. A. Kaiser is an employee of Bayer AG. S. Willmann is an employee of Bayer AG. S. Saleh is an employee of Bayer AG. K. Droebner is an employee of Bayer AG. P. Sandner is an employee of Bayer AG. C.E. Bear has nothing to disclose. A. Hoffmann is an employee of Bayer AG. F. Ratjen reports other consultancy fees from Vertex Pharmaceuticals, Inc., Bayer, Talecris, CSL Behring, Roche, and Gilead; grants and consultancy from Novartis; and developed speaker bureau for Genentech outside the submitted work. S.M. Rowe reports grants and consulting fees from Arrowhead, Bayer, Celtaxsys, Galapagos/AbbVie, Novartis, Renovion, Synedgen/Synspira, andVertex Pharmaceuticals Inc.; consulting fees from Arcturus, and Cysteic Medicines; and grants from AstraZeneca, Eloxx, N30 Pharmaceuticals, PTC Therapeutics, Translate Bio, and Proteostasis Therapeutics, Inc., (Copyright © 2021. Published by Elsevier B.V.)

We investigated patterns of volatile organic compound (VOC) contamination in drinking water systems affected by the California 2018 Camp Fire. We performed spatial analysis of over 5000 water samples collected over a 17 month period by a local water utility, sampled tap water for VOCs in approximately 10% ( N = 136) of standing homes, and conducted additional nontargeted chemical analysis of 10 samples. Benzene contamination was present in 29% of service connections to destroyed structures and 2% of service connections to standing homes. A spatial pattern was apparent. Tap water in standing homes 11 months after the fire contained low concentrations of benzene in 1% of samples, but methylene chloride was present in 19% of samples, including several above regulatory limits. Elevated methylene chloride was associated with greater distance from the water meter to the tap, longer stagnation time, and the presence of a destroyed structure on the service connection; it was inversely associated with certain trihalomethanes. Nontargeted analysis identified multiple combustion byproducts in the water at 2/10 homes. Our findings support the hypothesis that pyrolysis and smoke intrusion from depressurization contributed to the benzene contamination. Further research is needed to test the hypothesis that methylene chloride may be generated from the dehalogenation of disinfection byproducts stagnating in galvanized iron pipes., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Infertility and subfertility are commonly faced by females with cystic fibrosis (FwCF) and resulting in decreased contraceptive use and increased utilization of reproductive technologies. Elexacaftor-tezacaftor-ivacaftor (ETI) is a CFTR modulator that affects common causes of subfertility. Two CF centers conducted a retrospective chart review on females with CF who were receiving ETI and became pregnant. We analyzed obstetrical-gynecological history, genotype, and clinical response to ETI therapy. Fourteen FwCF on ETI became pregnant. Half (7) of the FwCFs were previously attempting to conceive, but only three were using contraceptives. Four FwCF had a history of infertility; two were reconsidering use of reproductive technologies (IUI). Patients achieved conception at mean 8 weeks after initiating ETI. ETI may lessen CF-associated factors that affect fertility; however, its exact mechanism is unknown. This warrants counseling on contraceptive use and family planning prior to initiation of therapy and at routine intervals while utilizing ETI., Competing Interests: Declarations of Competing Interest None, (Copyright © 2020. Published by Elsevier B.V.)

Highly effective CFTR modulator drug therapy is increasingly available to those with cystic fibrosis. Multiple observational research studies are now being conducted to better understand the impacts of this important therapeutic milestone on long-term outcomes, patient care needs, and future research priorities. PROMISE is a large, multi-disciplinary academic study focused on the broad impacts of starting elexacaftor/tezacaftor/ivacaftor in the US population age 6 years and older. The many areas of investigation and rationale for each are discussed by organ systems, along with recognition of remaining important questions that will not be addressed by this study alone. Knowledge gained through this and multiple complementary studies around the world will help to understand important health outcomes, clinical care priorities, and research needs for a large majority of people treated with these or similarly effective medications targeting the primary cellular impairment in cystic fibrosis., Competing Interests: Declaration of Competing Interest The primary author declares no conflict of interest with the content of this manuscript. Any potential conflicts of interest among all authors related to funding or other financial agreements will be collected and updated during the review process., (Copyright © 2021. Published by Elsevier B.V.)

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion transporter that regulates mucus hydration, viscosity and acidity of the airway epithelial surface. Genetic defects in CFTR impair regulation of mucus homeostasis, causing severe defects of mucociliary clearance as seen in cystic fibrosis. Recent work has established that CFTR dysfunction can be acquired in chronic obstructive pulmonary disease (COPD) and may also contribute to other diseases that share clinical features of cystic fibrosis, such as asthma, allergic bronchopulmonary aspergillosis and bronchiectasis. Protean causes of CFTR dysfunction have been identified including cigarette smoke exposure, toxic metals and downstream effects of neutrophil activation pathways. Recently, CFTR modulators, small molecule agents that potentiate CFTR or restore diminished protein levels at the cell surface, have been successfully developed for various CFTR gene defects, prompting interest in their use to treat diseases of acquired dysfunction. The spectrum of CFTR dysfunction, strategies for CFTR modulation, and candidate diseases for CFTR modulation beyond cystic fibrosis will be reviewed in this manuscript., Competing Interests: Conflict of interest: S.D. Patel has nothing to disclose. Conflict of interest: T.R. Bono has nothing to disclose. Conflict of interest: S.M. Rowe reports grants from Bayer, Forest Research Institute, AstraZeneca, N30/Nivalis, Novartis, Galapagos/AbbVie, Proteostasis, Eloxx and PTC Therapeutics, grants and personal fees from Celtaxsys, grants, personal fees and non-financial support from Vertex Pharmaceuticals Incorporated, and personal fees from Bayer and Novartis, outside the submitted work. Conflict of interest: G.M. Solomon reports grants from NIH and the CF Foundation, during the conduct of the study; grants and personal fees from Vertex Pharamceuticals, Electromed, Inc. and Insmed Inc., and grants from Saavara, Inc. and Parion Sciences, outside the submitted work., (Copyright ©ERS 2020.)

Background: Despite evidence of exercise benefits to lung function, adherence to routine exercise in adults with cystic fibrosis (CF) is low. The incorporation of interactive virtual reality video exergame activities in home-based programs as an incentive may help improve motivation and adherence to exercise. This proposed study will attempt to improve the physical fitness and respiratory function of sedentary adults with CF by engaging them in a Nintendo Wii Fit Plus™ home-based exercise program., Methods: A single group pretest-posttest design will be used to examine the immediate (12-weeks) and long-term effect (24-weeks) of a home-based exergame program on improving pulmonary-related function (physical fitness and respiratory function) in sedentary adults with CF. Participants will receive a one-time orientation to the Wii Fit Plus, and will be requested to use it to exercise according to the recommended guidelines 3 times a week for 30 min in the following 24 weeks. Monthly phone monitoring will be conducted during the first 12 weeks. Besides evaluating the efficacy of a home-based exergame program on improving aerobic capacity, physical activity, and respiratory-related symptoms, we will examine the impact of the exergame on airway ion transport as measured by nasal potential difference, which will be collected at baseline and at the end of 12-weeks only., Discussion: This is the first study to evaluate the feasibility, acceptability and potential effectiveness of a low-cost exercise avenue (i.e., exergames) for adults with CF to improve their pulmonary-related function, which is important for CF disease management and prevention of complications. In addition, the proposed study will be the first to investigate the therapeutic efficacy of home-based exergames on airway ion transport among adults with CF. Through an increase in physical activity, it is expected that participants will improve their physical fitness and respiratory function at the end of the study., Trial Registration: ClinicalTrials.gov ID: NCT02277860.

Background: Numerous types of rapid toxicity or exposure assays and platforms are providing information relevant to human hazard and exposure identification. They offer the promise of aiding decision-making in a variety of contexts including the regulatory management of chemicals, evaluation of products and environmental media, and emergency response. There is a need to consider both the scientific validity of the new methods and the values applied to a given decision using this new information to ensure that the new methods are employed in ways that enhance public health and environmental protection. In 2018, a National Academies of Sciences, Engineering, and Medicine (NASEM) workshop examined both the toxicological and societal aspects of this challenge., Objectives: Our objectives were to explore the challenges of adopting new data streams into regulatory decision-making and highlight the need to align new methods with the information and confidence needs of the decision contexts in which the data may be applied., Methods: We go beyond the NASEM workshop to further explore the requirements of different decision contexts. We also call for the new methods to be applied in a manner consistent with the core values of public health and environmental protection. We use the case examples presented in the NASEM workshop to illustrate a range of decision contexts that have applied or could benefit from these new data streams. Organizers of the NASEM workshop came together to further evaluate the main themes from the workshop and develop a joint assessment of the critical needs for improved use of emerging toxicology tools in decision-making. We have drawn from our own experience and individual decision or research contexts as well as from the case studies and panel discussions from the workshop to inform our assessment., Discussion: Many of the statutes that regulate chemicals in the environment place a high priority on the protection of public health and the environment. Moving away from the sole reliance on traditional approaches and information sources used in hazard, exposure, and risk assessment, toward the more expansive use of rapidly acquired chemical information via in vitro , in silico , and targeted testing strategies will require careful consideration of the information needed and values considerations associated with a particular decision. In this commentary, we explore the ability and feasibility of using emerging data streams, particularly those that allow for the rapid testing of a large number of chemicals across numerous biological targets, to shift the chemical testing paradigm to one in which potentially harmful chemicals are more rapidly identified, prioritized, and addressed. Such a paradigm shift could ultimately save financial and natural resources while ensuring and preserving the protection of public health. https://doi.org/10.1289/EHP4745.

Background: Mucociliary clearance is a main defense mechanism of the airway and is impaired in ciliary dyskinesia. The objective of this study was to evaluate the prevalence of chronic rhinosinusitis (CRS) and its characteristics in bronchiectasis patients suspected of harboring ciliary dyskinesia., Methods: Bronchiectasis patients referred to a rhinology clinic for nasal brush biopsy (NBB) were included in this study. NBB was performed using a curettage technique whereby ciliated epithelial cells were obtained from the surface of the inferior nasal turbinate. Results of transmission electron microscopy findings, primary ciliary dyskinesia (PCD) gene (35 genes) analyses (Invitae), and sinus computed tomography (CT) scans were reviewed., Results: Twenty-three patients (age, 54 ± 2.9 years) were referred for NBB between 2015 and 2018. Thirteen patients (56.5%) met the criteria for diagnosis of CRS. Nineteen patients had ciliary ultrastructural defects. The most common finding was compound cilia (n = 11, 47.8%). Five patients (21.7%) had central microtubule defects (CMD) with higher forced expiratory volume in 1 second (FEV 1 ) at the time of referral than those without CMD (CMD + , 91 ± 3.7%; CMD - , 73.5 ± 5.7%; p = 0.023). Of 15 subjects with a PCD gene panel, 67% (9 of 15) carried at least 1 gene associated with PCD. Only 1 patient reached diagnosis of PCD. Approximately 50% of non-PCD carriers had a smoking history (p < 0.05). Lund-Mackay scores did not significantly differ between PCD and non-PCD carriers (p = 0.72)., Conclusion: Nearly half of bronchiectasis patients referred for NBB had concurrent CRS. The presence of ciliary abnormalities was not amplified in bronchiectasis patients with CRS compared to those without CRS. Extrinsic factors may be related to ciliary structural abnormalities in non-PCD gene carriers., (© 2019 ARS-AAOA, LLC.)

Microorganisms play a central role in the biology of vinegar flies such as Drosophila suzukii and Drosophila melanogaster : serving as a food source to both adults and larvae, and influencing a range of traits including nutrition, behavior, and development. The niches utilized by the fly species partially overlap, as do the microbiota that sustain them, and interactions among these players may drive the development of crop diseases. To learn more about how the microbiota of one species may affect the other, we isolated and identified microbes from field-caught D. suzukii , and then characterized their effects on D. melanogaster larval development time in the laboratory. We found that the D. suzukii microbiota consistently included both yeasts and bacteria. It was dominated by yeasts of the genus Hanseniaspora , and bacteria from the families Acetobacteraceae and Enterobacteriaceae. Raising D. melanogaster under gnotobiotic conditions with each microbial isolate individually, we found that some bacteria promoted larval development relative to axenic conditions, but most did not have a significant effect. In contrast, nearly all the yeasts tested significantly accelerated larval development. The one exception was Starmerella bacillaris , which had the opposite effect: significantly slowing larval developmental rate. We investigated the basis for this effect by examining whether S. bacillaris cells could sustain larval growth, and measuring the survival of S. bacillaris and other yeasts in the larval gut. Our results suggest S. bacillaris is not digested by D. melanogaster and therefore cannot serve as a source of nutrition. These findings have interesting implications for possible interactions between the two Drosophilia species and their microbiota in nature. Overall, we found that microbes isolated from D. suzukii promote D. melanogaster larval development, which is consistent with the model that infestation of fruit by D. suzukii can open up habitat for D. melanogaster . We propose that the microbiome is an important dimension of the ecological interactions between Drosophila species., Competing Interests: The authors declare there are no competing interests., (©2019 Solomon et al.)

Background: In US cystic fibrosis (CF) patients, methicillin-resistant Staphylococcus aureus (MRSA) rates have tripled in the past 2 decades. Known clinical risk factors include exposure to a healthcare setting, Pseudomonas aeruginosa and CF-related diabetes. Area-level socio-environmental exposures have not been evaluated. We explored the association of area-level deprivation with MRSA prevalence in a pediatric CF Center in the Southeastern United States., Methods: Patients' residential addresses were geocoded and linked to a composite Area Deprivation Index and Rural-Urban Commuting Area scores. The association of MRSA with Area Deprivation Index and Rural-Urban Commuting Area scores was evaluated using logistic regression with robust standard errors adjusted for sociodemographic covariates (age, sex, race, mother's and father's education and household income), clinical risk factors (P. aeruginosa, CF-related diabetes, hospitalizations and number of clinic visits) and clustering., Results: The study included all pediatric patients (N = 231; mean age 12) at a single CF Center. MRSA was present in 44% of subjects. Higher area-level deprivation was correlated with rural residence, lack of parental college education and lower household income (P < 0.001 for each). In a multiple regression model fully adjusted for patient-level sociodemographic covariates, clinical risk factors and clustering, neighborhood deprivation was associated with more than 2-fold increase in the odds of having MRSA [OR 2.26 (1.14-4.45), P < 0.05]., Conclusions: Neighborhood deprivation is a risk factor for MRSA in pediatric CF, doubling the odds of infection. Community-level socioeconomic risk factors should be considered when developing prevention strategies and treatment plans for MRSA infection in pediatric patients with CF.

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality worldwide and is characterized by an excessive airway neutrophilic response. The neutrophil chemoattractant proline-glycine-proline (PGP) and its more potent acetylated form (acPGP) have been found to be elevated in patients with COPD and act via CXCR2. Here, we investigated the impact of neutralizing PGP peptides in a murine model for emphysema. The PGP-neutralizing peptide l-arginine-threonine-arginine (RTR) was used first in a 6-week model of cigarette smoke exposure, where it attenuated lung inflammation. Then, in a model of chronic smoke exposure, mice were exposed to cigarette smoke and RTR treatment was initiated after 10 weeks of smoke exposure. This treatment was continued together with smoke exposure for another 13 weeks, for a total of 23 weeks of smoke exposure. RTR significantly inhibited neutrophil and macrophage influx into the lungs in the 6-week model of exposure. RTR also attenuated the development of emphysema, normalized lung volumes, and reduced right ventricular hypertrophy in the chronic exposure model. Murine epithelia expressed CXCR2, and this expression was increased after smoke exposure. In vitro , human bronchial epithelial cells also demonstrated robust expression of CXCR2, and stimulation of primary human bronchial epithelial cells with acPGP led to increased release of MMP-9 and IL-8. Overall, these results provide evidence that acPGP plays a critical role during the development of emphysema in cigarette smoke-induced injury, and highlight a new epithelial mechanism by which acPGP augments neutrophilic inflammation.

We have developed a human bronchial epithelial (HBE) cell and endothelial cell co-cultured microfluidic model to mimic the in vivo human airway. This airway-on-a-chip was designed with a central epithelial channel and two flanking endothelial channels, with a three-dimensional monolayers of cells growing along the four walls of the channel, forming central clear lumens. These cultures mimic airways and microvasculature in vivo . The central channel cells are grown at air-liquid interface and show features of airway differentiation including tight-junction formation, mucus production, and ciliated cells. Combined with novel micro-optical coherence tomography, this chip enables functional imaging of the interior of the lumen, which includes quantitation of cilia motion including beat frequency and mucociliary transport. This airway-on-a chip is a significant step forward in the development of microfluidics models for functional imaging., Competing Interests: Dr. Rowe reports grants from Bayer (F), grants from Forest Research Institute (F), grants from AstraZeneca (F), grants from N30/Nivalis (F), grants from Novartis (F), grants from Galapagos/AbbVie (F), grants from Proteostasis (F), grants from Eloxx (F), grants and personal fees from Celtaxsys (F,C), grants from PTC Therapeutics (F), grants, personal fees and non-financial support from Vertex Pharmaceuticals Incorporated (F,C,S), personal fees from Bayer (C), personal fees from Novartis (C), personal fees from Renovion (C), outside the submitted work. All other authors declare no conflicts of interest. The microfluidic device will be available commercially from SynVivo Inc., (© 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although impairment of mucociliary clearance contributes to severe morbidity and mortality in people with CF, a clear understanding of the pathophysiology is lacking. This is, in part, due to the absence of clinical imaging techniques capable of capturing CFTR-dependent functional metrics at the cellular level. Here, we report the clinical translation of a 1-μm resolution micro-optical coherence tomography (μOCT) technology to quantitatively characterize the functional microanatomy of human upper airways. Using a minimally invasive intranasal imaging approach, we performed a clinical study on age- and sex-matched CF and control groups. We observed delayed mucociliary transport rate at the cellular level, depletion of periciliary liquid layer, and prevalent loss of ciliation in subjects with CF. Distinctive morphological differences in mucus and various forms of epithelial injury were also revealed by μOCT imaging and had prominent effects on the mucociliary transport apparatus. Elevated mucus reflectance intensity in CF, a proxy for viscosity in situ, had a dominant effect. These results demonstrate the utility of μOCT to determine epithelial function and monitor disease status of CF airways on a per-patient basis, with applicability for other diseases of mucus clearance., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)