A Phase 3, Open-Label Study of Lumacaftor/Ivacaftor in Children 1 to Less Than 2 Years of Age with Cystic Fibrosis Homozygous for F508del-CFTR.

Rationale: Previous phase 3 trials showed that treatment with lumacaftor/ivacaftor was safe and efficacious in people aged ⩾2 years with cystic fibrosis (CF) homozygous for the F508del mutation in CFTR (CF transmembrane conductance regulator) (F/F genotype). Objectives: To assess the safety, pharmacokinetics, and pharmacodynamics of lumacaftor/ivacaftor in children aged 1 to <2 years with the F/F genotype. Methods: This open-label, phase 3 study consisted of two parts (part A [n = 14] and part B [n = 46]) in which two cohorts were enrolled on the basis of age (cohort 1, 18 to <24 mo; cohort 2, 12 to <18 mo). For the 15-day treatment period in part A, the lumacaftor/ivacaftor dose was based on weight at screening. Pharmacokinetic data from part A were used to determine dose-based weight boundaries for part B (24-wk treatment period). Measurements and Main Results: The primary endpoint of part A was pharmacokinetics, and the primary endpoint for part B was safety and tolerability. Secondary endpoints for part B were absolute change in sweat chloride concentration from baseline at Week 24 and pharmacokinetics. Analysis of pharmacokinetic data from part A confirmed the appropriateness of part B dosing. In part B, 44 children (95.7%) had adverse events, which for most were either mild (52.2% of children) or moderate (39.1% of children) in severity. The most common adverse events were cough, infective pulmonary exacerbation of CF, pyrexia, and vomiting. At Week 24, mean absolute change from baseline in sweat chloride concentration was -29.1 mmol/L (95% confidence interval, -34.8 to -23.4 mmol/L). Growth parameters (body mass index, weight, length, and associated z-scores) were normal at baseline and remained normal during the 24-week treatment period. Improving trends in some biomarkers of pancreatic function and intestinal inflammation, such as fecal elastase-1, serum immunoreactive trypsinogen, and fecal calprotectin, were observed. Conclusions: Lumacaftor/ivacaftor was generally safe and well tolerated in children aged 1 to <2 years with the F/F genotype, with a pharmacokinetic profile consistent with studies in older children. Efficacy results, including robust reductions in sweat chloride concentration, suggest the potential for CF disease modification with lumacaftor/ivacaftor treatment. These results support the use of lumacaftor/ivacaftor in this population. Clinical trial registered with www.clinicaltrials.gov (NCT03601637).

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis.

BACKGROUND: Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers. METHODS: We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation. RESULTS: From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies. CONCLUSIONS: Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR.

Gastrointestinal Pathologies in Pediatric Patients With Cystic Fibrosis Undergoing Endoscopy: A Single-Center Retrospective Review Over 15 Years.

Introduction Previous studies have demonstrated an increased incidence of gastrointestinal (GI) pathologies, specifically celiac disease (CD) and eosinophilic esophagitis (EoE), in patients with cystic fibrosis (CF). However, there is minimal data available regarding endoscopic findings in pediatric patients with CF and GI mucosal disease.  Methods A retrospective chart review was performed on patients with CF under 18 years of age who underwent esophagogastroduodenoscopy (EGD) or colonoscopy with biopsy over a 15-year period at our institution. Patient characteristics including assigned sex at birth, CF genetic mutations (if identified), and cystic fibrosis transmembrane conductance regulator (CFTR) modulator use were recorded. Data obtained at the time of biopsy included body mass index (BMI), indication for the procedure, exocrine pancreatic status, visual endoscopic findings, and histologic findings. Results A total of 72 patients with CF were included in the study. 24% (n=17) were found to have abnormal endoscopic biopsy results. EoE (13% of all patients, n=9) and CD (6% of all patients, n=4) were the most common GI diagnoses present on endoscopic biopsy. All 3 patients taking CFTR modulator medications at the time of endoscopy had normal biopsy results. Of the 17 patients found to have abnormal pathology results, 14 (82%) were taking proton-pump inhibitor (PPI) medication at the time of endoscopy. Conclusion This study highlights the probable increased frequency of GI disease in the pediatric CF population. These findings underscore the importance of maintaining a broad differential diagnosis while considering utilization of endoscopy with biopsy in pediatric patients with CF who have GI symptoms.

Quality of locally designed surveys in a quality improvement collaborative: review of survey validity and identification of common errors.

OBJECTIVE: Surveys are a commonly used tool in quality improvement (QI) projects, but little is known about the standards to which they are designed and applied. We aimed to investigate the quality of surveys used within a QI collaborative, and to characterise the common errors made in survey design. METHODS: Five reviewers (two research methodology and QI, three clinical and QI experts) independently assessed 20 surveys, comprising 250 survey items, that were developed in a North American cystic fibrosis lung transplant transition collaborative. Content Validity Index (CVI) scores were calculated for each survey. Reviewer consensus discussions decided an overall quality assessment for each survey and survey item (analysed using descriptive statistics) and explored the rationale for scoring (using qualitative thematic analysis). RESULTS: 3/20 surveys scored as high quality (CVI >80%). 19% (n=47) of survey items were recommended by the reviewers, with 35% (n=87) requiring improvements, and 46% (n=116) not recommended. Quality assessment criteria were agreed upon. Types of common errors identified included the ethics and appropriateness of questions and survey format; usefulness of survey items to inform learning or lead to action, and methodological issues with survey questions, survey response options; and overall survey design. CONCLUSION: Survey development is a task that requires careful consideration, time and expertise. QI teams should consider whether a survey is the most appropriate form for capturing information during the improvement process. There is a need to educate and support QI teams to adhere to good practice and avoid common errors, thereby increasing the value of surveys for evaluation and QI. The methodology, quality assessment criteria and common errors described in this paper can provide a useful resource for this purpose.

Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis.

Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators. Results from 114 participants, including seven on ivacaftor or lumacaftor-ivacaftor, representative of the US CF population during the study period, identified 10 biomarkers associated with future exacerbations mediated by percent predicted forced expiratory volume in 1 s. The findings were not sensitive to anti-inflammatory, antibiotic, and CFTR modulator treatments. The analyses suggest that combination treatments addressing RAGE-axis inflammation, protease-mediated injury, and oxidative stress might prevent pulmonary exacerbations. Our work may apply to other airway inflammatory diseases such as bronchiectasis and the acute respiratory distress syndrome.

Improvement of lipid and lipoprotein profiles in children and adolescents with cystic fibrosis on CFTR modulator therapy.

BACKGROUND: Association of a high-fat diet with increased risks of cardiovascular disease (CVD) and type 2 diabetes, has prompted evaluation of lipids in people with CF (pwCF). However, most evidence on dyslipidemia was published before CF transmembrane conductance regulator (CFTR) modulators became a standard of care. The main goal of this study was to investigate the effect of CFTR modulator therapies on lipid and lipoprotein profiles in children and adolescents with CF. METHODS: Blood samples were collected from 153 pwCF (10.1 ± 4.7 years of age) and 60 age-matched controls. Most pwCF were pancreatic insufficient on pancreatic enzyme replacement therapy. By the end of the study, 65% of CF participants were on CFTR modulator therapy for >1 month. The results of traditional and advanced lipid testing in pwCF were correlated with clinical and dietary information. RESULTS: Total cholesterol and low-density lipoprotein (LDL) cholesterol were significantly lower in pwCF compared to non-CF participants. Those not receiving CFTR modulators also had significantly lower high-density lipoprotein (HDL) cholesterol and HDL particle number than controls. Individuals with CF on modulator therapy had significantly higher concentrations of anti-atherogenic HDL cholesterol and HDL particles along with lower levels of atherogenic large very-low density lipoprotein (VLDL) particles, total and small LDL particles, and triglycerides compared to those without CFTR modulator therapy. CONCLUSION: CFTR modulator therapy has a beneficial effect on dyslipidemia in CF. It remains to be seen if these positive changes translate into decreased CVD risk later in life given the increasing life expectancy in CF.

Implementation of a comprehensive pharmacy-driven immunization care process model in a pediatric cystic fibrosis clinic.

INTRODUCTION: Members of an integrated pharmacy team (pharmacists and pharmacy technicians) have roles that have been identified in the literature as part of the multi-disciplinary cystic fibrosis (CF) care team. One role that has not specifically addressed is the administration of routine and recommended immunizations to people with CF (PwCF). According to care guidelines, PwCF of all ages should be provided all age-appropriate and recommended immunizations. Pharmacists and pharmacy technicians can administer immunizations per state laws. The Primary Children's CF Center decided to implement a comprehensive pharmacy-driven immunization care process model to impact immunization rates. METHODS: A 24-month retrospective analysis was conducted with pediatric (≤18 years) PwCF at the Primary Children's CF Center. The primary outcome measures were the percentage (%) of PwCF who received PPSV23, and/or HPV, and/or meningococcal conjugate vaccine (MCV) immunizations 1-year post-care process model implementation (October 1, 2021, to September 30, 2022) as compared to baseline values. The secondary outcome measures are the total number of immunizations, the number of each immunization provided, and the financial impact of pharmacy-driven immunization care process model 1-year post-implementation. RESULTS: During the 1-year post-care process model implementation (October 1, 2021, to September 30, 2022), a total of 523 immunizations were provided to 243 pediatric PwCF. The most frequent immunizations provided were PPSV23 (160/523, 31%) and Coronavirus Disease 2019 (COVID-19) (154/523, 29%). The baseline percentages of eligible PwCF of PPSV23, HPV, and MCV were 27% (58/217), 43% (32/74), and 24% (8/34), respectively. The 1-year post-implementation percentages of PPSV23, HPV, and MCV were 99% (217/218, p < 0.00001), 91% (67/74, p < 0.00001), and 97% (33/34, p < 0.00001), respectively. For COVID-19 immunizations, 56% of eligible PwCF (181/321) have received their first dose. Of these 181 PwCF, 70% (126/181) have received at least one dose of their primary series or booster during the 1-year post-implementation period. The rate of those PwCF who have received at least one dose of a COVID-19 immunization from the age of 6 months to 4 years, 5-11 years, and 12-18 years, was 37% (30/82), 60% (78/129), and 66% (73/110), respectively. For the financial impact generated during the 1-year immunization care process model post-implementation period, 404 non-VFC immunizations were given for an estimated profit of $11,930. CONCLUSIONS: The implementation of a pharmacy-driven immunization care process model is a way for integrated pharmacy teams to evolve with the CF center care model and have a role expansion in the care provided to PwCF.

Defining and identifying early-onset lung disease in cystic fibrosis with cumulative clinical characteristics.

BACKGROUND: Because of the heterogeneity in cystic fibrosis (CF) lung disease among young children, a clinical method to identify early-onset lung disease is needed. OBJECTIVE: To develop a CF early-onset lung disease (CFELD) scoring system by utilizing prospectively collected longitudinal data on manifestations in the first 3 years of life. DESIGN: We studied 145 infants born during 2012-2017, diagnosed through newborn screening by age 3 months, and followed to 36 months of age. Cough severity, pulmonary exacerbations (PEx), respiratory cultures, and hospitalizations were collected at each CF center visit (every 1-2 months in infancy and quarterly thereafter). These data were used to construct the CFELD system and to classify lung disease into five categories: asymptomatic, minimal, mild, moderate, and severe. RESULTS: The most frequent manifestation of CF early lung disease was MD-reported PEx episodes, PEx hospitalizations, and positive Pseudomonas aeruginosa cultures. Parent-reported cough severity was correlated with the number of respiratory hospitalizations (r = 0.48, p < 0.0001). The distribution of CFELD categories was 10% asymptomatic, 17% minimal, 29% mild, 33% moderate, and 12% severe. The moderate and severe categories occurred threefold higher in pancreatic insufficient (PI, 49%) versus sufficient subjects (16%), p < 0.0001. In addition to PI, gastrointestinal and nutrition-related hospitalizations, plasma cytokines interleukin (IL)-6 and IL-10, duration of CFTR modulator therapy, and type of health insurance were significant predictors of CFELD scores. CONCLUSION: The CFELD scoring system is novel, allows systematic evaluation of lung disease prognosis early, and may aid in therapeutic decision-making particularly in the initiation of CFTR modulator therapy.

Voltametric Determination of Zoledronic Acid in a Pharmaceutical Formulation

Objectives: The aim of this study is to study the electroactivity of zoledronic acid (ZOL), optimize the parameters affecting voltametric analysis of ZOL, and make a comparison between voltametric methods used to assay ZOL. Materials and Methods: Three voltametric methods, cyclic voltammetry (CV), square wave voltammetry (SWV), and differential pulse voltammetry (DPV), were used to determine the concentrations of ZOL solutions (0.25-1.2 mg.mL-1). Britton-Robinson universal buffer solutions (BRB) were used as supporting electrolytes with a glassy carbon working electrode. Results: The calibration plots were linear in the range from 0.20 to 1.2 mg.mL-1 for differential DPV and CV and from 0.09 to 1.2 mg.mL-1 for SWV. DPV showed the highest correlation coefficient R2 value of 0.993 and the lowest limit of detection (LOD) of 37.2 µg.mL-1. Furthermore, DPV exhibited the highest precision with the lowest relative standard deviations (RSD) values. For a commercial product of ZOL, DPV showed the best accuracy and precision with 102.32% recovery and 2.88% RSD. Conclusion: ZOL is an electroactive compound. The pH of the BRB supporting the electrolyte is important for ZOL electroactivity. DPV is the recommended method for voltametric analysis of ZOL because of its high-performance regarding accuracy, precision, and LOD compared with other studied methods.

Zinc status and growth in infants and young children with cystic fibrosis.

BACKGROUND: Zinc deficiency is associated with poor growth in children without cystic fibrosis (CF), but its impact on growth in children with CF is unknown. OBJECTIVE: To determine the prevalence of low serum Zn (sZn) and its relationship with growth in the first 3 years of life in children with CF. METHODS: We utilized data from infants with CF who were enrolled in a longitudinal study of nutrition and lung health and had sZn measured as part of clinical care. Cross-sectional correlations between sZn levels and growth z scores were assessed by Pearson's correlation coefficient. To identify factors associated with sZn status and its association to longitudinal growth patterns, multiple regression analysis with repeated measures were performed using generalized estimating equations. RESULTS: A total of 106 sZn measurements from 53 infants were identified. Seventeen infants (32%) had intermittent Zn insufficiency, defined as at least one sZn <70 mcg/dl in their first 3 years of life. There were no significant cross-sectional associations between sZn and growth z scores. However, analysis of longitudinal growth patterns revealed that weight- and length-for-age z scores in children with intermittent Zn insufficiency were lower during early infancy and their weight-for-length z scores at age 3 years were also lower compared to those who were always Zn sufficient. CONCLUSION: Low sZn occurs in one-third of children with CF in the first 3 years of life. Cross-sectional and longitudinal analyses revealed discrepant associations between sZn and growth. Therefore, prospective studies are needed to understand the role of Zn in growth in CF.

Impact of pharmacy technicians as part of an integrated health-system pharmacy team on improvement of medication access in the care of cystic fibrosis patients.

BACKGROUND: Cystic fibrosis (CF) is a genetic disease requiring patients to take multiple medications per day. Multiple barriers exist affecting access and adherence. Studies have demonstrated the positive outcomes of pharmacist involvement in CF care. The purpose of this study is to characterize the impact of pharmacy technicians on medication access in the care of CF patients. METHODS: A retrospective review and analysis of patient medication profiles for patients followed by the integrated pharmacy care process model was performed. Two electronic prescription pathways with pharmacy technician involvement were analyzed. One pathway using a specialty pharmacy CF pharmacy technician (SP technician) examined CF specialty medication delivery times. The other pathway examined the impact of the clinic-based CF pharmacy technician (CB technician) on the number of filling pharmacies for patients. RESULTS: One-hundred and fifty-three patients met inclusion criteria in the CF specialty medication delivery analysis, and 56 patients met inclusion criteria filling pharmacy analysis. The median delivery time for dornase alfa decreased from 8 days to 3 days, p < .00001. The number of patients utilizing one filling pharmacy increased from 8 (14%) to 21 (38%) (p = .005); and utilizing three filling pharmacies decreased from 14 (25%) to 1 (2%) (p = .003). CONCLUSION: The study demonstrated that pharmacy technicians as part of an integrated health-system pharmacy care process model improve medication access in the care of CF patients.

Aspiration in the otherwise healthy Infant-Is there a natural course for improvement?

OBJECTIVES/HYPOTHESIS: Timing and indication for surgical intervention is a major challenge in managing pediatric oropharyngeal dysphagia. No study has evaluated a natural course of swallowing dysfunction in otherwise healthy infants. Our objective was to review the outcomes and time to resolution of abnormal swallow in infants with aspiration. STUDY DESIGN: Retrospective case series at a tertiary children's hospital. METHODS: Fifty patients under 1 year old with aspiration on a modified barium swallow study were included. Patients born <34 weeks, with medical or genetic comorbidities, or who underwent surgical intervention for aspiration were excluded. Patients were followed until aspiration resolved on a swallow study. Kaplan-Meier survival analysis was performed. RESULTS: Forty patients (25 patients [50%] by 6 months, 10 [20%] by 1 year, three [6%] by 2 years, and two [4%] at the end of the follow-up interval) were recommended a normal diet, and 10 patients (20%) were still aspirating by the end of the follow-up interval. Median time to resolution was 202 ± 7 days (range, 19-842 days), probability 48% (95% confidence interval [CI]: 0.34-0.62). The probability of resolution at 6 months was 46% (95% CI: 0.4-0.68), at 1 year was 64% (95% CI: 0.51-0.77), at 2 years was 76% (95% CI: 0.64-0.88), and at the end of the follow-up interval 81.3% (95% CI: 0.7-0.92). CONCLUSIONS: The majority of infants with aspiration and without any other major comorbidities improved within 1 year. Future research should be directed toward better understanding swallowing dysfunction in neurologically normal infants. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:514-520, 2020.

Differences between WHO AND CDC early growth measurements in the assessment of Cystic Fibrosis clinical outcomes.

BACKGROUND: Early childhood growth status has been used to predict long-term clinical outcomes in Cystic Fibrosis (CF) patients. Adulthood CF outcomes based on early weight-for-length (WFL) measurements, using either World Health Organization (WHO) or Centers for Disease Control (CDC) scales, have not been compared. METHODS: Cystic Fibrosis Foundation registry patients were studied (n=3014). Participants were categorized at age two years as WFL <50th percentile on both WHO and CDC scales, ≥50th percentile on WHO but not CDC, or ≥50th percentile on both. Pulmonary function and overall survival were assessed at age 18years. RESULTS: Stepwise gains in pulmonary function and lung transplant-free survival were noted across the three increasing WFL categories. CONCLUSIONS: Children with CF who achieve higher WFL at age two years have improved pulmonary and survival outcomes into adulthood. CF providers should continue to utilize current early growth recommendations, with goal WFL ≥50th percentile on CDC growth charts before age two.

Impact of pharmacy services on cystic fibrosis medication adherence.

OBJECTIVES: The purpose of this study is to characterize the impact of pharmacy services on medication adherence and hospitalizations for pediatric cystic fibrosis (CF) patients. METHODS: A retrospective health insurance claims analysis and patient medical charts review from January 1, 2014 to December 31, 2016 of patients from the Pediatric Intermountain CF Center was performed. Adherence to dornase alfa and hospital admissions for pulmonary exacerbations pre and post the implementation of an integrated pharmacy team were reviewed. Dornase alfa adherence was measured by the medication possession ratio (MPR) both monthly and yearly. RESULTS: Fifty-four patients met inclusion criteria. The mean dornase alfa yearly MPR improved from 0.75 (2014) to 0.92 (2016). Patients were 2.8 times more likely to be adherent to dornase alfa when followed by integrated pharmacy team model (P < 0.001), and 2.4 times more likely to be adherent when followed by a dedicated CF clinic pharmacist only (P = 0.001). CONCLUSION: The study demonstrated that pharmacy services improved adherence to dornase alfa.

Association between follicular tracheitis and gastroesophageal reflux.

OBJECTIVE: Follicular tracheitis (also known as tracheal cobblestoning) is an entity that is poorly described and of unclear significance. The objective of this study was to better define follicular tracheitis and determine the association between the clinical finding of follicular tracheitis on bronchoscopy and objective evidence of gastroesophageal reflux disease. METHODS: Retrospective chart review of children with recurrent croup having undergone a rigid bronchoscopy and an investigation for gastroesophageal reflux between 2001 and 2013. RESULTS: 117 children with recurrent croup children age 6-144 months were included in the study. Follicular tracheitis was noted on 41% of all bronchoscopies. Fifty-nine percent of all children who underwent bronchoscopy were diagnosed with gastroesophageal reflux on at least one investigation. Forty-nine of 117 children underwent a pH probe study, and 51% were found to have evidence of reflux on this study. Nine children were diagnosed with eosinophilic esophagitis. Three patients underwent a biopsy of the follicular tracheitis lesions, which revealed chronic inflammation. There was no evidence of an association between findings of follicular tracheitis and a positive test for gastroesophageal reflux (p=0.52) or a positive pH probe study (p=0.64). There was no association between follicular tracheitis and subglottic stenosis (p=0.33) or an history of asthma and/or atopy (p=0.19). CONCLUSION: In children with recurrent croup, follicular tracheitis remains an unspecific finding associated with an inflammatory disorder of unknown etiology.

Plasticized Polymer Composite Single-Ion Conductors for Lithium Batteries.

Lithium bis(trifluoromethane) sulfonamide (TFSI) is a promising electrolyte salt in lithium batteries, due to its good conductivity and high dissociation between the lithium cation and its anion. By tethering N-pentane trifluoromethane sulfonamide (C5NHTf), a TFSI analogue molecule, onto the surface of silica nanoparticle as a monolayer coverage should increase the Li(+) transference number to unity since anions bound to particles have reduced mobilities. Silica polymer composite has better mechanical property than that of the pure PEO. Analogously trifluoromethane sulfonic aminoethyl methacrylate (TfMA), a TFSI analogue vinyl monomer, was polymerized on silica nanoparticle surface as a multilayer coverage. Anchored polyelectrolytes to particle surfaces offer multiple sites for anions, and in principle the carrier concentration would increase arbitrarily and approach the carrier concentration of the bulk polyelectrolyte. Monolayer grafted nanoparticles have a lithium content of 1.2 × 10(-3) g Li/g, and multilayer grafted nanoparticles have a lithium content over an order higher at 2 × 10(-2) g Li/g. Electrolytes made from monolayer grafted particles exhibit a weak conductivity dependence on temperature, exhibiting an ionic conductivity in the range of 10(-6) S/cm when temperatures increase to 80 °C. While electrolytes made from multilayer grafted particles show a steep increase in conductivity with temperature with an ionic conductivity increase to 3 × 10(-5) S/cm at 80 °C, with an O/Li ratio of 32.

Ferrous iron is a significant component of bioavailable iron in cystic fibrosis airways.

UNLABELLED: ABSTRACT Chronic, biofilm-like infections by the opportunistic pathogen Pseudomonas aeruginosa are a major cause of mortality in cystic fibrosis (CF) patients. While much is known about P. aeruginosa from laboratory studies, far less is understood about what it experiences in vivo. Iron is an important environmental parameter thought to play a central role in the development and maintenance of P. aeruginosa infections, for both anabolic and signaling purposes. Previous studies have focused on ferric iron [Fe(III)] as a target for antimicrobial therapies; however, here we show that ferrous iron [Fe(II)] is abundant in the CF lung (-39 µM on average for severely sick patients) and significantly correlates with disease severity (ρ = -0.56, P = 0.004), whereas ferric iron does not (ρ = -0.28, P = 0.179). Expression of the P. aeruginosa genes bqsRS, whose transcription is upregulated in response to Fe(II), was high in the majority of patients tested, suggesting that increased Fe(II) is bioavailable to the infectious bacterial population. Because limiting Fe(III) acquisition inhibits biofilm formation by P. aeruginosa in various oxic in vitro systems, we also tested whether interfering with Fe(II) acquisition would improve biofilm control under anoxic conditions; concurrent sequestration of both iron oxidation states resulted in a 58% reduction in biofilm accumulation and 28% increase in biofilm dissolution, a significant improvement over Fe(III) chelation treatment alone. This study demonstrates that the chemistry of infected host environments coevolves with the microbial community as infections progress, which should be considered in the design of effective treatment strategies at different stages of disease. IMPORTANCE: Iron is an important environmental parameter that helps pathogens thrive in sites of infection, including those of cystic fibrosis (CF) patients. Ferric iron chelation therapy has been proposed as a novel therapeutic strategy for CF lung infections, yet until now, the iron oxidation state has not been measured in the host. In studying mucus from the infected lungs of multiple CF patients from Europe and the United States, we found that ferric and ferrous iron change in concentration and relative proportion as infections progress; over time, ferrous iron comes to dominate the iron pool. This information is relevant to the design of novel CF therapeutics and, more broadly, to developing accurate models of chronic CF infections.

Micropatterned thin film honeycomb materials from regiospecifically modified cellulose.

Thin film honeycomb materials were prepared from regioselectively modified celluloses. The method uses water condensation at the surface of a cellulosic solution as an ordered template to form honeycomb structures. Pore size and distribution is controlled by several factors, one of which is the hydrophilicity of the cellulosic used. The amphiphilic nature of the celluloses was modified with varying lengths of ethylene glycol side chains using 2,6-thexyldimethylsilyl cellulose. It was found that the side chains do affect the honeycomb formation, with longer ethylene glycol chains leading to increased pore uniformity but having little influence on the pore size.