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In human airways diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), host defense is compromised and airways inflammation and infection often result. Mucus clearance and trapping of inhaled pathogens constitute key elements of host defense. Clearance rates are governed by mucus viscous and elastic moduli at physiological driving frequencies, whereas transport of trapped pathogens in mucus layers is governed by diffusivity. There is a clear need for simple and effective clinical biomarkers of airways disease that correlate with these properties. We tested the hypothesis that mucus solids concentration, indexed as weight percent solids (wt%), is such a biomarker. Passive microbead rheology was employed to determine both diffusive and viscoelastic properties of mucus harvested from human bronchial epithelial (HBE) cultures. Guided by sputum from healthy (1.5-2.5 wt%) and diseased (COPD, CF; 5 wt%) subjects, mucus samples were generated in vitro to mimic in vivo physiology, including intermediate range wt% to represent disease progression. Analyses of microbead datasets showed mucus diffusive properties and viscoelastic moduli scale robustly with wt%. Importantly, prominent changes in both biophysical properties arose at ∼4 wt%, consistent with a gel transition (from a more viscous-dominated solution to a more elastic-dominated gel). These findings have significant implications for: (1) penetration of cilia into the mucus layer and effectiveness of mucus transport; and (2) diffusion vs. immobilization of micro-scale particles relevant to mucus barrier properties. These data provide compelling evidence for mucus solids concentration as a baseline clinical biomarker of mucus barrier and clearance functions.

\"Explores the challenges and rewards faced by literary biographers. Details the author's experiences writing the lives of writers including Edwin Arlington Robinson, Ernest Hemingway, F. Scott Fitzgerald, John Cheever, and Archibald MacLeish\"--Provided by publisher.

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. This study analyzed LCC-related content on TikTok, an audio and video–based platform popular among youth. 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. 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%). 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.

Use the methodology in this study guide to design, manage, and operate a balanced enterprise cybersecurity program that is pragmatic and realistic in the face of resource constraints and other real-world limitations. This guide is an instructional companion to the book \"Enterprise cybersecurity : how to build a successful cyberdefense program against advanced threats\". The study guide will help you understand the book's ideas and put them to work. The guide can be used for self-study or in the classroom.

No detailed description available for \"Fitzgerald and the War Between the Sexes\".

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. 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. 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). Primary endpoints were safety through Day 56 and change in sweat chloride from baseline through Day 28. Secondary endpoints included change in percent predicted FEV (ppFEV ) 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 ppFEV in subjects homozygous for F508del, and a 7.02 mmol/L decrease in sweat chloride and 4.60 percentage point increase in ppFEV in subjects compound heterozygous for F508del and G551D from baseline through Day 28 (P < 0.05 for all). 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).

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation. To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers. We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor. Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.

The pathogenesis of mucoinfective lung disease in cystic fibrosis (CF) patients likely involves poor mucus clearance. A recent model of mucus clearance predicts that mucus flow depends on the relative mucin concentration of the mucus layer compared with that of the periciliary layer; however, mucin concentrations have been difficult to measure in CF secretions. Here, we have shown that the concentration of mucin in CF sputum is low when measured by immunologically based techniques, and mass spectrometric analyses of CF mucins revealed mucin cleavage at antibody recognition sites. Using physical size exclusion chromatography/differential refractometry (SEC/dRI) techniques, we determined that mucin concentrations in CF secretions were higher than those in normal secretions. Measurements of partial osmotic pressures revealed that the partial osmotic pressure of CF sputum and the retained mucus in excised CF lungs were substantially greater than the partial osmotic pressure of normal secretions. Our data reveal that mucin concentration cannot be accurately measured immunologically in proteolytically active CF secretions; mucins are hyperconcentrated in CF secretions; and CF secretion osmotic pressures predict mucus layer-dependent osmotic compression of the periciliary liquid layer in CF lungs. Consequently, mucin hypersecretion likely produces mucus stasis, which contributes to key infectious and inflammatory components of CF lung disease.

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.