Examining Tobacco-Related Social Media Research in Government Policy Documents: Systematic Review.

BACKGROUND: Social media data have been used to describe tobacco industry marketing practices, user experiences with tobacco, and youth-oriented protobacco content. OBJECTIVE: Examine the extent to which tobacco-related social media research is cited in government policy documents. SEARCH METHODS: Peer-reviewed tobacco-related social media studies were searched for on Web of Science, PubMed, and other databases from 2004 to 2022. The DOI number for each identified article was then used to search the Overton database to find policy documents citing such research. A secondary, manual search of national and international governmental agency websites was also conducted. SELECTION CRITERIA: Documents were included in this study if they were tobacco-related, written in English, cited social media research in the document text and reference section, and were published by a governmental office or agency. DATA COLLECTION AND ANALYSIS: The analytic sample consisted of (n = 38) government policy documents, and were coded for content themes, agency type, document type, and subsequent citations. MAIN RESULTS: When this research was utilized, it was often in the context of highlighting tobacco industry marketing practices, bringing attention to an issue (eg, youth e-cigarette use), and/or describing how social media platforms can be used as a data source to understand tobacco-related attitudes and behaviors. Agencies that often cited this research were the WHO, FDA, and CDC. The document types included research reports, policy recommendations, industry guidance, legal complaints, and practice-based recommendations. CONCLUSIONS: Tobacco-related social media research has been utilized by government agencies in the last decade to guide the policy process. IMPLICATIONS: Tobacco-related social media research has been used in government policy documents to detail tobacco industry marketing and bring attention to youth exposure to protobacco content online. Continued surveillance of social media may be necessary to track the changing tobacco landscape.

Examining the Peer-Reviewed Literature on Tobacco-Related Social Media Data: Scoping Review.

INTRODUCTION: Tobacco researchers have used social media data to examine tobacco industry marketing practices (eg, influencers), and to document user experience with tobacco products. This study summarized the literature that analyzed tobacco-related social media data, including domain, social media platform, tobacco product type, and themes of findings, among other variables. AIMS AND METHODS: PubMed, PsycINFO, Web of Science, and Communication Source were searched between 2004 and 2022. Peer-reviewed articles were included if they were written in English, included at least one tobacco-related term, and one social media-related term, and analyzed a social media post. Two coders screened all-titles and abstracts. The final sample consisted of (n = 255) articles. Studies were coded for domain, social media platform, tobacco product type, data source, type of data, coding and analytic method, and presence of validation procedure, among other variables. RESULTS: A total of 10 504 820 581 tobacco-related social media posts were assessed across 255 studies. User experience (54.1%) and promotion (23.1%) were the most researched domains. Researchers used data from Twitter the most (42.7%). Text (43.1%) was the most common type of data analyzed. Thematic analysis (80.8%) was the most common analytic technique. Themes of findings from content analyses often pertained to the health effects of tobacco use (61.0%) and promotion (44.2%). CONCLUSIONS: Researchers have analyzed billions of tobacco-related social media posts to describe user experience with, and promotions related to, tobacco products like e-cigarettes on platforms like Twitter. Future research may examine tobacco-related social media data from newer platforms like TikTok. IMPLICATIONS: Real-time surveillance of tobacco-related content on social media can keep the tobacco control community abreast of tobacco industry promotional strategies, user experience with tobacco products, and perceived health effects of tobacco use. A framework may be developed to establish best-practices for social media data collection and analysis, including strategies to identify posts from bot accounts and validate methodological approaches used in thematic analysis.

Content analysis of email marketing communications among online e-cigarette retailers.

INTRODUCTION: Online e-cigarette retailers use email communications to promote products directly to consumers, which may facilitate e-cigarette use. Little is known about the content of these emails. As such, this study collected emails from online e-cigarette retailers in California to conduct a content analysis. METHODS: This study included 13 online e-cigarette retailers in California using Yelp. To be included in the study, e-cigarette retailers needed a live website, physical retail location (i.e., vape shop), and e-cigarettes available for purchase online. The research team entered each website and signed up (if possible) for an email newsletter. Data were collected from the Gmail Application Programming Interface over a 1-year study period (11/01/21-11/01/22). Members of the research team coded emails for the presence of e-cigarettes, other products, flavors, marketing categories, and promotional activities, among other variables. RESULTS: 749 promotional emails (2.1 avg/per day) were received over the 1-year study period. Second-generation e-cigarettes (n=581, 77.6%) were the most observed product in emails followed by disposable e-cigarettes (n=391, 52.2%). The most common flavor profile was fruit/sweet/liquor (n=424, 56.6%). Emails included links to social media pages (n=366, 48.9%). Online coupons were found in 53.1% (n=398) of the emails. Age warnings were displayed in 8.0% (n=60) of the emails. CONCLUSIONS: E-cigarette retailers' emails promoted new products, flavors, and contained promotional discounts. Future research should examine the impact of exposure to such emails on e-cigarette-related attitudes and behaviors. IMPLICATIONS: Findings from this study may help inform prevention programs and interventions focused on increasing tobacco-related digital media literacy (i.e., evaluate tobacco advertising messages on digital media) among gender and ethnic minorities. Future research should examine if exposure to email marketing is causally linked with e-cigarette use among gender and ethnic minorities.

Feasibility of free-breathing 19 F MRI image acquisition to characterize ventilation defects in CF and healthy volunteers at wash-in.

PURPOSE: To explore the feasibility of measuring ventilation defect percentage (VDP) using 19 F MRI during free-breathing wash-in of fluorinated gas mixture with postacquisition denoising and to compare these results with those obtained through traditional Cartesian breath-hold acquisitions. METHODS: Eight adults with cystic fibrosis and 5 healthy volunteers completed a single MR session on a Siemens 3T Prisma. 1 H Ultrashort-TE MRI sequences were used for registration and masking, and ventilation images with 19 F MRI were obtained while the subjects breathed a normoxic mixture of 79% perfluoropropane and 21% oxygen (O2 ). 19 F MRI was performed during breath holds and while free breathing with one overlapping spiral scan at breath hold for VDP value comparison. The 19 F spiral data were denoised using a low-rank matrix recovery approach. RESULTS: VDP measured using 19 F VIBE and 19 F spiral images were highly correlated (r = 0.84) at 10 wash-in breaths. Second-breath VDPs were also highly correlated (r = 0.88). Denoising greatly increased SNR (pre-denoising spiral SNR, 2.46 ± 0.21; post-denoising spiral SNR, 33.91 ± 6.12; and breath-hold SNR, 17.52 ± 2.08). CONCLUSION: Free-breathing 19 F lung MRI VDP analysis was feasible and highly correlated with breath-hold measurements. Free-breathing methods are expected to increase patient comfort and extend ventilation MRI use to patients who are unable to perform breath holds, including younger subjects and those with more severe lung disease.

An Analysis of Twitter Posts About the U.S. Food and Drug Administration's Menthol Ban.

INTRODUCTION: Although the U.S. Food and Drug Administration (FDA) banned characterizing flavors in cigarettes in 2009, this initial ban exempted menthol. After examining numerous reports on the adverse health effects of menthol cigarettes, the FDA proposed a menthol ban in April 2022. This study analyzed Twitter data to describe public reaction to this announcement. AIMS AND METHODS: Posts containing the word "menthol" and/or "#menthol" were collected from April 21, 2022 to May 5, 2022 from Twitter's Streaming Application Programming Interface (API). A random sampling procedure supplied 1041 tweets for analysis. Following an inductive approach to content analysis, posts were classified into one or more of 11 themes. RESULTS: Posts discussed the FDA announcement (n = 153, 14.7%), racial discrimination (n = 101, 9.7%), distrust in government (n = 67, 6.4%), inconsistencies between policies (n = 52, 5.0%), public health benefits (n = 42, 4%), freedom of choice (n = 22, 2.1%), and health equity (n = 21, 2.0%). Posts contained misinformation (n = 20, 1.9%), and discussed the potential for illicit markets (n = 18, 1.7%) and the need for cessation support (n = 4, 0.4%). 541 (52.0%) tweets did not fit into any of the prescribed themes. CONCLUSIONS: Twitter posts with the word "menthol" commonly discussed distrust in government and mentioned racial discrimination. Findings demonstrated the possibility of near real-time Twitter monitoring of public opinion on a menthol ban. These data may be valuable for designing tobacco control health communication campaigns in the future. IMPLICATIONS: The U.S. FDA proposed a ban on menthol cigarettes in April 2022. This study's content analyzed Twitter posts over a 2-week period to understand the public's response to the proposed menthol ban. Twitter posts with the word "menthol" often discussed distrust in government and mentioned racial discrimination. Findings demonstrated the possibility of near real-time Twitter monitoring of public opinion of regulatory action. Findings underscore the need to educate the public about the potential health benefits of banning menthol from cigarettes, particularly for populations that experience tobacco-related health disparities.

Spanish-language tobacco-related posts on Twitter: content analysis.

INTRODUCTION: Twitter data has been used to surveil public sentiment about tobacco products, however, most tobacco-related Twitter research has been conducted with English-language posts. There is a gap in the literature on tobacco-related discussions on Twitter in languages other than English. This study summarized tobacco-related discussions in Spanish on Twitter. METHODS: A set of Spanish terms reflecting electronic cigarettes (e.g., cigarillos electrónicos), cigarettes (e.g., "pitillo"), and cigars (e.g., "cigaro") were identified. A content analysis of tweets (n=1,352) drawn from 2021 was performed to examine themes and sentiment. An initial codebook was developed in English then translated to Spanish and then translated back to English by a bilingual (Spanish and English) member of the research team. Two bilingual members of the research team coded the tweets into themes and sentiment. RESULTS: Themes in the tweets included 1) product promotion (n=168, 12.4%), 2) health warnings (n=161, 11.9%), 3) tobacco use (n=136, 10.1%), 4) health benefits of vaping (n=58, 4.3%), 5) cannabis use (n=50, 3.7%), 6) cessation (n=47, 3.5%), 7) addiction (n=33, 2.4%), 8) policy (n=27, 2.0%), and 9) polysubstance use (n=12, 0.9%). Neutral (n=955, 70.6%) was the most common category of sentiment observed in the data. CONCLUSIONS: Tobacco products are discussed in multiple languages on Twitter and can be summarized by bilingual research teams. Future research should determine if Spanish-speaking individuals are frequently exposed to pro-tobacco content on social media and if such exposure increases susceptibility to use tobacco among never users or sustained use among current users. IMPLICATIONS: Spanish-language pro-tobacco content exists on Twitter, which has implications for Spanish-speaking individuals who may be exposed to this content. Spanish-language pro-tobacco-related posts may help normalize tobacco use among Spanish-speaking populations. As a result, anti-tobacco tweets in Spanish may be necessary to counter areas of the online environment that can be considered pro-tobacco.

Monitoring website marketing among leading e-cigarette brands and vendors in California: content analysis.

BACKGROUND: Electronic cigarette (e-cigarette) brands and vendors use websites to promote pro-tobacco messages that may increase susceptibility to use e-cigarettes among never users or help sustain continued e-cigarette use among current users. E-cigarette website marketing is lightly regulated, and little is known about promotional strategies used on e-cigarette companies' websites. This study conducted a content analysis of website marketing from leading e-cigarette companies selling products in California. METHODS: This study identified 20 e-cigarette vendors and 6 e-cigarette brands that had products available for purchase online in California. Two coders visited 26 websites between 06 February 2022 and 17 April 2022. Websites were coded for marketing themes, promotional and interactive content, availability of flavoured e-cigarette products, presence of health warnings, and reference to tobacco control policies. RESULTS: Marketing themes related to physical health benefits of e-cigarette use were found on 50.0% of the websites. 57.7% of the websites had sales/discounts/coupons. 65.4% of the websites had fruit-flavoured disposable e-cigarettes, while 73.1% of the websites had fruit-flavoured e-liquids available for purchase. 69.2% of the websites allowed users to sign up for email newsletters, and 88.9% of such websites did not require users to create an age-verified account to receive email newsletters. CONCLUSIONS: Findings from this study can be used to inform statewide regulations of promotional communications found on e-cigarette companies' websites and encourage enforcement of age-verification procedures. This may help reduce susceptibility to use, or continued use of, e-cigarette products among price-sensitive populations, such as adolescents and young adults.

Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial.

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 FEV1 (ppFEV1), 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, ppFEV1 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 ppFEV1 in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).

A thematic analysis of Puff Bar-related content on TikTok.

Background: Puff Bar has rapidly captured a large proportion of the disposable e-cigarette market. To stay abreast of the rapidly changing e-cigarette-product landscape, researchers have turned to social media platforms to monitor e-cigarette-related discussions and marketing trends. TikTok is the latest social media platform to capture the attention of adolescents and young adults; however, e-cigarette-related research using TikTok is limited. Objectives: This study examined Puff Bar-related posts on TikTok to identify themes and user engagement. Methods: Data were collected by scraping publicly available TikTok posts that contained the hashtag #puffplus, between January 31, 2020 and May 4, 2021 (n = 581). The research team used an inductive approach to identify 19 themes from the data. User engagement with posts including the number of likes, shares, plays, and comments was also collected. Results: The most prevalent themes included Music at 75.39% (438/581), followed by Flavors at 51.64% (300/581), Youth/Young Adults at 42.86% (249/581), Tobacco Use at 41.14% (239/581), Nicotine Concentration at 35.11% (204/581), Humor at 19.45% (113/581) and Product Review at 19.1% (111/581). Cessation 1.38% (8/581) and Health Warnings 2.58% (15/581) were two themes rarely observed but commonly engaged with by TikTok users. Conclusions: Health communication strategists should prepare to address TikTok's popularity to combat its contribution to the online e-cigarette environment. Future research should determine the impact of exposure to Puff Bar-related content on TikTok on adolescents' and young adults' attitudes and behaviors.

Themes in TikTok Videos Featuring Little Cigars and Cigarillos: Content Analysis.

BACKGROUND: Little cigars and cigarillos (LCCs) are popular tobacco products among youth (ie, adolescents and young adults). A variety of LCC-related promotional and user-generated content is present on social media. However, research on LCC-related posts on social media has been largely focused on platforms that are primarily text- or image-based, such as Twitter and Instagram. OBJECTIVE: This study analyzed LCC-related content on TikTok, an audio and video-based platform popular among youth. METHODS: Publicly available posts (N=811) that contained the LCC-related hashtags #swishersweets or #backwoods were collected on TikTok from January 2019 to May 2021. Metadata were also collected, including numbers of likes, comments, shares, and views per video. Using an inductive approach, a codebook consisting of 26 themes was developed to help summarize the underlying themes evident in the TikTok videos and corresponding captions. A pairwise co-occurrence analysis of themes was also conducted to evaluate connections among themes. RESULTS: Among the 811 posts, the LCC presence theme (ie, a visible LCC) occurred in the most prominent number of posts (n=661, 81.5%), followed by music (n=559, 68.9%), youth (n=332, 40.9%), humor (n=263, 32.4%), LCC use (n=242, 29.8%), flavors (n=232, 28.6%), branding (n=182, 22.4%), paraphernalia (n=137, 16.9%), blunt rolling (n=94, 11.6%), and price (n=84, 10.4%). Product reviews had the highest engagement, with a median 44 (mean 2857, range 36,499) likes and median 491 (mean 15,711, range 193,590) views; followed by product comparisons, with a median 44 (mean 1920, range 36,500) likes and median 671 (mean 11,277, range 193,798) views. Promotions had the lowest engagement, with a median 4 (mean 8, range 34) likes and median 78 (mean 213, range 1131) views. The most prevalent themes co-occurring with LCC presence were (1) music (434/811, 53.5%), (2) youth (264/811, 32.6%), (3) humor (219/811, 27%), (4) flavors (214/811, 26.4%), and (5) LCC use (207/811, 25.5%). CONCLUSIONS: LCC-related marketing and user-generated content was present on TikTok, including videos showing youth discussing, displaying, or using LCCs. Such content may be in violation of TikTok's community guidelines prohibiting the display, promotion, or posting of tobacco-related content on its platform, including the display of possession or consumption of tobacco by a minor. Further improvement in the enforcement of TikTok community guidelines and additional scrutiny from public health policy makers may be necessary for protecting youth from future exposure to tobacco-related posts. Observational and experimental studies are needed to understand the impact of exposure to LCC-related videos on attitudes and behaviors related to LCC use among youth. Finally, there may be a need for engaging antitobacco videos that appeal to youth on TikTok to counter the protobacco content on this platform.

Comparison of single breath hyperpolarized 129 Xe MRI with dynamic 19 F MRI in cystic fibrosis lung disease.

PURPOSE: To quantitatively compare dynamic 19 F and single breath hyperpolarized 129 Xe MRI for the detection of ventilation abnormalities in subjects with mild cystic fibrosis (CF) lung disease. METHODS: Ten participants with stable CF and a baseline FEV1 > 70% completed a single imaging session where dynamic 19 F and single breath 129 Xe lung ventilation images were acquired on a 3T MRI scanner. Ventilation defect percentages (VDP) values between 19 F early-breath, 19 F maximum-ventilation, 129 Xe low-resolution, and 129 Xe high-resolution images were compared. Dynamic 19 F images were used to determine gas wash-in/out rates in regions of ventilation congruency and mismatch between 129 Xe and 19 F. RESULTS: VDP values from high-resolution 129 Xe images were greater than from low-resolution images (P = .001), although these values were significantly correlated (r = 0.68, P = .03). Early-breath 19 F VDP and max-vent 19 F VDP also showed significant correlation (r = 0.75, P = .012), with early-breath 19 F VDP values being significantly greater (P < .001). No correlation in VDP values were detected between either 19 F method or high-res 129 Xe images. In addition, the location and volume of ventilation defects were often different when comparing 129 Xe and 19 F images from the same subject. Areas of ventilation congruence displayed the expected ventilation kinetics, while areas of ventilation mismatch displayed abnormally slow gas wash-in and wash-out. CONCLUSION: In CF subjects, ventilation abnormalities are identified by both 19 F and HP 129 Xe imaging. However, these ventilation abnormalities are not entirely congruent. 19 F and HP 129 Xe imaging provide complementary information that enable differentiation of normally ventilated, slowly ventilated, and non-ventilated regions in the lungs.

Airway Mucus Hyperconcentration in Non-Cystic Fibrosis Bronchiectasis.

Rationale: Non-cystic fibrosis bronchiectasis is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these abnormalities has not been characterized.Objectives: This study was designed to: 1) measure mucus concentration and biophysical properties of bronchiectasis mucus; 2) identify the secreted mucins contained in bronchiectasis mucus; 3) relate mucus properties to airway epithelial mucin RNA/protein expression; and 4) explore relationships between mucus hyperconcentration and disease severity.Methods: Sputum samples were collected from subjects with bronchiectasis, with and without chronic erythromycin administration, and healthy control subjects. Sputum percent solid concentrations, total and individual mucin concentrations, osmotic pressures, rheological properties, and inflammatory mediators were measured. Intracellular mucins were measured in endobronchial biopsies by immunohistochemistry and gene expression. MUC5B (mucin 5B) polymorphisms were identified by quantitative PCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline-induced sputa were collected, and mucus/mucin concentrations were measured.Measurements and Main Results: Bronchiectasis sputum exhibited increased percent solids, total and individual (MUC5B and MUC5AC) mucin concentrations, osmotic pressure, and elastic and viscous moduli compared with healthy sputum. Within subjects with bronchiectasis, sputum percent solids correlated inversely with FEV1 and positively with bronchiectasis extent, as measured by high-resolution computed tomography, and inflammatory mediators. No difference was detected in MUC5B rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced non-cystic fibrosis bronchiectasis mucus concentration by 5%.Conclusions: Hyperconcentrated airway mucus is characteristic of subjects with bronchiectasis, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy.

Inhibition of ATP hydrolysis restores airway surface liquid production in cystic fibrosis airway epithelia.

Airway surface dehydration is a pathological feature of cystic fibrosis (CF) lung disease. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR), a cyclic AMP-regulated Cl- channel controlled in part by the adenosine A2B receptor. An alternative CFTR-independent mechanism of fluid secretion is regulated by ATP via the P2Y2 receptor (P2Y2R) that activates Ca2+-regulated Cl- channels (CaCC/TMEM16) and inhibits Na+ absorption. However, due to rapid ATP hydrolysis, steady-state ATP levels in CF airway surface liquid (ASL) are inadequate to maintain P2Y2R-mediated fluid secretion. Therefore, inhibiting airway epithelial ecto-ATPases to increase ASL ATP levels constitutes a strategy to restore airway surface hydration in CF. Using [γ32P]ATP as radiotracer, we assessed the effect of a series of ATPase inhibitory compounds on the stability of physiologically occurring ATP concentrations. We identified the polyoxometalate [Co4(H2O)2(PW9O34)2]10- (POM-5) as the most potent and effective ecto-ATPase inhibitor in CF airway epithelial cells. POM-5 caused long-lasting inhibition of ATP hydrolysis in airway epithelia, which was reversible upon removal of the inhibitor. Importantly, POM-5 markedly enhanced steady-state levels of released ATP, promoting increased ASL volume in CF cell surfaces. These results provide proof of concept for ecto-ATPase inhibitors as therapeutic agents to restore hydration of CF airway surfaces. As a test of this notion, cell-free sputum supernatants from CF subjects were studied and found to have abnormally elevated ATPase activity, which was markedly inhibited by POM-5.

An Improved Inhaled Mucolytic to Treat Airway Muco-obstructive Diseases.

RATIONALE: Airways obstruction with thick, adherent mucus is a pathophysiologic and clinical feature of muco-obstructive respiratory diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis (CF). Mucins, the dominant biopolymer in mucus, organize into complex polymeric networks via the formation of covalent disulfide bonds, which govern the viscoelastic properties of the mucus gel. For decades, inhaled N-acetylcysteine (NAC) has been used as a mucolytic to reduce mucin disulfide bonds with little, if any, therapeutic effects. Improvement of mucolytic therapy requires the identification of NAC deficiencies and the development of compounds that overcome them. OBJECTIVES: Elucidate the pharmacological limitations of NAC and test a novel mucin-reducing agent, P3001, in preclinical settings. METHODS: The study used biochemical (e.g., Western blotting, mass spectrometry) and biophysical assays (e.g., microrheology/macrorheology, spinnability, mucus velocity measurements) to test compound efficacy and toxicity in in vitro and in vivo models and patient sputa. MEASUREMENTS AND MAIN RESULTS: Dithiothreitol and P3001 were directly compared with NAC in vitro and both exhibited superior reducing activities. In vivo, P3001 significantly decreased lung mucus burden in ßENaC-overexpressing mice, whereas NAC did not (n = 6-24 mice per group). In NAC-treated CF subjects (n = 5), aerosolized NAC was rapidly cleared from the lungs and did not alter sputum biophysical properties. In contrast, P3001 acted faster and at lower concentrations than did NAC, and it was more effective than DNase in CF sputum ex vivo. CONCLUSIONS: These results suggest that reducing the viscoelasticity of airway mucus is an achievable therapeutic goal with P3001 class mucolytic agents.

Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR.

RATIONALE: Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor. OBJECTIVES: To evaluate the safety and efficacy of tezacaftor monotherapy and of tezacaftor/ivacaftor combination therapy in subjects with cystic fibrosis homozygous for F508del or compound heterozygous for F508del and G551D. METHODS: This was a randomized, placebo-controlled, double-blind, multicenter, phase 2 study (NCT01531673). Subjects homozygous for F508del received tezacaftor (10 to 150 mg) every day alone or in combination with ivacaftor (150 mg every 12 h) in a dose escalation phase, as well as in a dosage regimen testing phase. Subjects compound heterozygous for F508del and G551D, taking physician-prescribed ivacaftor, received tezacaftor (100 mg every day). MEASUREMENTS AND MAIN RESULTS: Primary endpoints were safety through Day 56 and change in sweat chloride from baseline through Day 28. Secondary endpoints included change in percent predicted FEV1 (ppFEV1) from baseline through Day 28 and pharmacokinetics. The incidence of adverse events was similar across treatment arms. Tezacaftor (100 mg every day)/ivacaftor (150 mg every 12 h) resulted in a 6.04 mmol/L decrease in sweat chloride and 3.75 percentage point increase in ppFEV1 in subjects homozygous for F508del, and a 7.02 mmol/L decrease in sweat chloride and 4.60 percentage point increase in ppFEV1 in subjects compound heterozygous for F508del and G551D from baseline through Day 28 (P < 0.05 for all). CONCLUSIONS: These results support continued clinical development of tezacaftor (100 mg every day) in combination with ivacaftor (150 mg every 12 h) in subjects with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT01531673).

SPLUNC1 degradation by the cystic fibrosis mucosal environment drives airway surface liquid dehydration.

The multi-organ disease cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator gene (CFTR) that lead to diminished transepithelial anion transport. CF lungs are characterised by airway surface liquid (ASL) dehydration, chronic infection/inflammation and neutrophilia. Dysfunctional CFTR may upregulate the epithelial Na+ channel (ENaC), further exacerbating dehydration. We previously demonstrated that short palate lung and nasal epithelial clone 1 (SPLUNC1) negatively regulates ENaC in normal airway epithelia.Here, we used pulmonary tissue samples, sputum and human bronchial epithelial cells (HBECs) to determine whether SPLUNC1 could regulate ENaC in a CF-like environment.We found reduced endogenous SPLUNC1 in CF secretions, and rapid degradation of recombinant SPLUNC1 (rSPLUNC1) by CF secretions. Normal sputum, containing SPLUNC1 and SPLUNC1-derived peptides, inhibited ENaC in both normal and CF HBECs. Conversely, CF sputum activated ENaC, and rSPLUNC1 could not reverse this phenomenon. Additionally, we observed upregulation of ENaC protein levels in human CF bronchi. Unlike SPLUNC1, the novel SPLUNC1-derived peptide SPX-101 resisted protease degradation, bound apically to HBECs, inhibited ENaC and prevented ASL dehydration following extended pre-incubation with CF sputum.Our data indicate that CF mucosal secretions drive ASL hyperabsorption and that protease-resistant peptides, e.g. SPX-101, can reverse this effect to rehydrate CF ASL.

Effects of inhaled high-molecular weight hyaluronan in inflammatory airway disease.

Cystic fibrosis (CF) is a chronic inflammatory disease that is affecting thousands of patients worldwide. Adjuvant anti-inflammatory treatment is an important component of cystic fibrosis treatment, and has shown promise in preserving lung function and prolonging life expectancy. Inhaled high molecular weight hyaluronan (HMW-HA) is reported to improve tolerability of hypertonic saline and thus increase compliance, and has been approved in some European countries for use as an adjunct to hypertonic saline treatment in cystic fibrosis. However, there are theoretical concerns that HMW-HA breakdown products may be pro-inflammatory. In this clinical pilot study we show that sputum cytokines in CF patients receiving HMW-HA are not increased, and therefore HMW-HA does not appear to adversely affect inflammatory status in CF airways.

UDP-glucose promotes neutrophil recruitment in the lung.

In addition to their role in glycosylation reactions, UDP-sugars are released from cells and activate widely distributed cell surface P2Y14 receptors (P2Y14R). However, the physiological/pathophysiological consequences of UDP-sugar release are incompletely defined. Here, we report that UDP-glucose levels are abnormally elevated in lung secretions from patients with cystic fibrosis (CF) as well as in a mouse model of CF-like disease, the ßENaC transgenic (Tg) mouse. Instillation of UDP-glucose into wild-type mouse tracheas resulted in enhanced neutrophil lung recruitment, and this effect was nearly abolished when UDP-glucose was co-instilled with the P2Y14R antagonist PPTN [4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl-2-naphthoic acid]. Importantly, administration of PPTN to ßENaC-Tg mice reduced neutrophil lung inflammation. These results suggest that UDP-glucose released into the airways acts as a local mediator of neutrophil inflammation.