Fecal dysbiosis in infants with cystic fibrosis is associated with early linear growth failure.

Nat Med. 2020 Jan 20;:

Authors: Hayden HS, Eng A, Pope CE, Brittnacher MJ, Vo AT, Weiss EJ, Hager KR, Martin BD, Leung DH, Heltshe SL, Borenstein E, Miller SI, Hoffman LR

Abstract
Most infants with cystic fibrosis (CF) have pancreatic exocrine insufficiency that results in nutrient malabsorption and requires oral pancreatic enzyme replacement. Newborn screening for CF has enabled earlier diagnosis, nutritional intervention and enzyme replacement for these infants, allowing most infants with CF to achieve their weight goals by 12 months of age1. Nevertheless, most infants with CF continue to have poor linear growth during their first year of life1. Although this early linear growth failure is associated with worse long-term respiratory function and survival2,3, the determinants of body length in infants with CF have not been defined. Several characteristics of the CF gastrointestinal (GI) tract, including inflammation, maldigestion and malabsorption, may promote intestinal dysbiosis4,5. As GI microbiome activities are known to affect endocrine functions6,7, the intestinal microbiome of infants with CF may also impact growth. We identified an early, progressive fecal dysbiosis that distinguished infants with CF and low length from infants with CF and normal length. This dysbiosis included altered abundances of taxa that perform functions that are important for GI health, nutrient harvest and growth hormone signaling, including decreased abundance of Bacteroidetes and increased abundance of Proteobacteria. Thus, the GI microbiota represent a potential therapeutic target for the correction of low linear growth in infants with CF.

PMID: 31959989 [PubMed - as supplied by publisher]

Culture-enriched metagenomic sequencing enables in-depth profiling of the cystic fibrosis lung microbiota.

Nat Microbiol. 2020 Jan 20;:

Authors: Whelan FJ, Waddell B, Syed SA, Shekarriz S, Rabin HR, Parkins MD, Surette MG

Abstract
Amplicon sequencing (for example, of the 16S rRNA gene) identifies the presence and relative abundance of microbial community members. However, metagenomic sequencing is needed to identify the genetic content and functional potential of a community. Metagenomics is challenging in samples dominated by host DNA, such as those from the skin, tissue and respiratory tract. Here, we combine advances in amplicon and metagenomic sequencing with culture-enriched molecular profiling to study the human microbiota. Using the cystic fibrosis lung as an example, we cultured an average of 82.13% of the operational taxonomic units representing 99.3% of the relative abundance identified in direct sequencing of sputum samples; importantly, culture enrichment identified 63.3% more operational taxonomic units than direct sequencing. We developed the PLate Coverage Algorithm (PLCA) to determine a representative subset of culture plates on which to conduct culture-enriched metagenomics, resulting in the recovery of greater taxonomic diversity-including of low-abundance taxa-with better metagenome-assembled genomes, longer contigs and better functional annotations when compared to culture-independent methods. The PLCA is also applied as a proof of principle to a previously published gut microbiota dataset. Culture-enriched molecular profiling can be used to better understand the role of the human microbiota in health and disease.

PMID: 31959969 [PubMed - as supplied by publisher]

New drug treatments for cystic fibrosis.

BMJ. 2020 Jan 20;368:m118

Authors: Smyth RL

PMID: 31959620 [PubMed - in process]

KMBARC registry: protocol for a multicentre observational cohort study on non-cystic fibrosis bronchiectasis in Korea.

BMJ Open. 2020 Jan 19;10(1):e034090

Authors: Lee H, Choi H, Sim YS, Park S, Kim WJ, Yoo KH, Lee SJ, Kim TH, Yang B, Jeong I, Um SJ, Kim DK, Lee JH, Kwon BS, Cho YJ, Park HY, Lee CH, Rhee CK, Lee SH, Na JO, Jang AS, Jung JY, Ra SW, Lee JH, Kim SH, Kim C, Kim Y, Lee CY, Kim HK, Lee JS, Lee SW, Oh YM, KMBARC

Abstract
INTRODUCTION: Despite the significant disease burden of bronchiectasis in Korea, no large-scale, representative prospective cohort studies have been conducted to evaluate the clinical characteristics of Korean patients with bronchiectasis, indicating an urgent need for cohort studies on bronchiectasis.
METHODS AND ANALYSIS: The Korean Multicenter Bronchiectasis Audit and Research Collaboration (KMBARC) is a prospective, non-interventional observational cohort study on bronchiectasis in Korea. The inclusion criteria of this registry are as follows: (1) adult patients (aged ≥18 years) with or without respiratory symptoms (cough, chronic sputum and/or recurrent respiratory infection) and chest computed tomography revealing bronchiectasis affecting one or more lobes and (2) stable status at the time of registration: patients with bronchiectasis who were admitted for a respiratory aetiology can be enrolled at least 4 weeks after hospital discharge. The exclusion criteria are as follows: (1) bronchiectasis due to cystic fibrosis; (2) traction bronchiectasis associated with interstitial lung disease; (3) patients actively being treated for pneumonia, pulmonary tuberculosis or non-tuberculous mycobacterial infection; (4) patients who are unable or unwilling to provide informed consent; and (5) pregnant patients. Although the KMBARC questionnaires for baseline and annual follow-up data are similar to the European Multicentre Bronchiectasis Audit and Research Collaboration questionnaires, KMBARC has distinctive features such as use of Bronchiectasis Health Questionnaires, measurement with fatigue and depression scales, blood tests, use of consensus definition of exacerbations and information on emergency room or hospitalisation.We aim to recruit at least 1200 patients over the study period from more than 26 hospitals in South Korea. Patients will undergo a detailed baseline and yearly assessment for up to 5 years. The study objectives of the KMBARC registry are as follows: (1) uncovering the natural course of bronchiectasis; (2) aiding in establishing evidence-based bronchiectasis guidelines in Korea; and (3) encouraging and facilitating studies on bronchiectasis in Korea.
ETHICS AND DISSEMINATION: This study received necessary approval from the Institutional Review Boards of all participating institutions. The Asan Medical Center Institutional Review Board gave overall approval for the study. Results will be disseminated via peer-reviewed publications and conference presentations.
TRIAL REGISTRATION NUMBER: KCT0003088.

PMID: 31959610 [PubMed - in process]

Organizing pneumonia secondary to Exophiala dermatitidis in cystic fibrosis: A case report.

J Cyst Fibros. 2020 Jan 17;:

Authors: Radonjic A, Pakhale S, Aaron SD, Earlam K, Gaudet E, Gomes MM, Gupta A, Mulpuru S, Chin M

PMID: 31959463 [PubMed - as supplied by publisher]

Autophagy augmentation alleviates cigarette smoke-induced CFTR-dysfunction, ceramide-accumulation and COPD-emphysema pathogenesis.

Free Radic Biol Med. 2019 02 01;131:81-97

Authors: Bodas M, Pehote G, Silverberg D, Gulbins E, Vij N

Abstract
In this study, we aimed to investigate precise mechanism(s) of sphingolipid-imbalance and resulting ceramide-accumulation in COPD-emphysema. Where, human and murine emphysema lung tissues or human bronchial epithelial cells (Beas2b) were used for experimental analysis. We found that lungs of smokers and COPD-subjects with increasing emphysema severity demonstrate sphingolipid-imbalance, resulting in significant ceramide-accumulation and increased ceramide/sphingosine ratio, as compared to non-emphysema/non-smoker controls. Next, we found a substantial increase in emphysema chronicity-related ceramide-accumulation in murine (C57BL/6) lungs, while sphingosine levels only slightly increased. In accordance, the expression of the acid ceramidase decreased after CS-exposure. Moreover, CS-induced (sub-chronic) ceramide-accumulation was significantly (p < 0.05) reduced by treatment with TFEB/autophagy-inducing drug, gemfibrozil (GEM), suggesting that autophagy regulates CS-induced ceramide-accumulation. Next, we validated experimentally that autophagy/lipophagy-induction using an anti-oxidant, cysteamine, significantly (p < 0.05) reduces CS-extract (CSE)-mediated intracellular-ceramide-accumulation in p62 + aggresome-bodies. In addition to intracellular-accumulation, we found that CSE also induces membrane-ceramide-accumulation by ROS-dependent acid-sphingomyelinase (ASM) activation and plasma-membrane translocation, which was significantly controlled (p < 0.05) by cysteamine (an anti-oxidant) and amitriptyline (AMT, an inhibitor of ASM). Cysteamine-mediated and CSE-induced membrane-ceramide regulation was nullified by CFTR-inhibitor-172, demonstrating that CFTR controls redox impaired-autophagy dependent membrane-ceramide accumulation. In summary, our data shows that CS-mediated autophagy/lipophagy-dysfunction results in intracellular-ceramide-accumulation, while acquired CFTR-dysfunction-induced ASM causes membrane ceramide-accumulation. Thus, CS-exposure alters the sphingolipid-rheostat leading to the increased membrane- and intracellular- ceramide-accumulation inducing COPD-emphysema pathogenesis that is alleviated by treatment with cysteamine, a potent anti-oxidant with CFTR/autophagy-augmenting properties.

PMID: 30500419 [PubMed - indexed for MEDLINE]

Volatile organic compound breath signatures of children with cystic fibrosis by real-time SESI-HRMS.

ERJ Open Res. 2020 Jan;6(1):

Authors: Weber R, Haas N, Baghdasaryan A, Bruderer T, Inci D, Micic S, Perkins N, Spinas R, Zenobi R, Moeller A

Abstract
Early pulmonary infection and inflammation result in irreversible lung damage and are major contributors to cystic fibrosis (CF)-related morbidity. An easy to apply and noninvasive assessment for the timely detection of disease-associated complications would be of high value. We aimed to detect volatile organic compound (VOC) breath signatures of children with CF by real-time secondary electrospray ionisation high-resolution mass spectrometry (SESI-HRMS). A total of 101 children, aged 4-18 years (CF=52; healthy controls=49) and comparable for sex, body mass index and lung function were included in this prospective cross-sectional study. Exhaled air was analysed by a SESI-source linked to a high-resolution time-of-flight mass spectrometer. Mass spectra ranging from m/z 50 to 500 were recorded. Out of 3468 m/z features, 171 were significantly different in children with CF (false discovery rate adjusted p-value of 0.05). The predictive ability (CF versus healthy) was assessed by using a support-vector machine classifier and showed an average accuracy (repeated cross-validation) of 72.1% (sensitivity of 77.2% and specificity of 67.7%). This is the first study to assess entire breath profiles of children with SESI-HRMS and to extract sets of VOCs that are associated with CF. We have detected a large set of exhaled molecules that are potentially related to CF, indicating that the molecular breath of children with CF is diverse and informative.

PMID: 31956658 [PubMed]

UNDERWEIGHT PATIENTS WITH CYSTIC FIBROSIS HAVE ACCEPTABLE SURVIVAL AFTER LUNG TRANSPLANTATION: A UNOS REGISTRY STUDY.

Chest. 2020 Jan 17;:

Authors: Ramos KJ, Kapnadak SG, Bradford MC, Somayaji R, Morrell ED, Pilewski JM, Lease ED, Mulligan MS, Aitken ML, Gries CJ, Goss CH

Abstract
BACKGROUND: Reduced body mass index (BMI) is an absolute contraindication for lung transplantation (LTx) at most centers in the United States (US). Our objective was to quantify post-LTx survival of moderate-to-severely underweight cystic fibrosis (CF) patients (BMI <17 kg/m2) in the US relative to normal-weight CF recipients and other frequently transplanted patient cohorts.
METHODS: Using United Network for Organ Sharing (UNOS) data (transplanted June 2005-November 2015), Kaplan-Meier estimates of median post-transplant survival were calculated for all CF, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF) patients, as well as low and normal-weight CF subgroups. Cox regression modeling stratified by transplant center assessed risk of post-transplant mortality in CF recipients with BMI <17 kg/m2 compared to COPD recipients (reference).
RESULTS: Median post-transplant survival [95% CI] for CF, COPD, and IPF was 7.9 [7.2, 8.6], 5.9 [5.6, 6.2], and 5.5 [5.2, 5.8] years, respectively. While an absolute decrease was noted in post-transplant survival for CF recipients with BMI < 17 kg/m2, compared to those with BMI ≥17 kg/m2 (7.0 years [4.5, 7.9] vs. 8.2 years [7.3, 9.0]), Cox modeling found no increased mortality risk (adjusted HR 1.09 [0.90, 1.32], p=0.38). There was no difference in post-transplant mortality between CF with BMI <17 kg/m2 and COPD recipients of all BMIs (adjusted HR 1.04 [0.86, 1.25], p=0.71).
CONCLUSIONS: CF recipients with BMI <17 kg/m2 had post-transplant survival comparable to other frequently transplanted groups. BMI <17 kg/m2 as a single risk factor in the CF population should not be treated as an absolute contraindication to LTx.

PMID: 31958441 [PubMed - as supplied by publisher]

A systematic Cochrane Review of antioxidant supplementation lung disease for cystic fibrosis.

Paediatr Respir Rev. 2019 Dec 12;:

Authors: Ciofu O, Smith S, Lykkesfeldt J

PMID: 31956034 [PubMed - as supplied by publisher]

[Impact of the transition period from childhood to adulthood in cystic fibrosis].

Rev Mal Respir. 2020 Jan 16;:

Authors: Louagé A, Knoop C, Hanssens L

Abstract
INTRODUCTION: The aim of this study was to evaluate the impact of the transition period from childhood to adulthood in patients with cystic fibrosis (CF) being followed up in our reference center.
METHODS: The clinical, functional, inflammatory and microbiological parameters of all transition patients were compared two years before (T-2) and two years after the transfer (T+2) from paediatric to adult centers and further analysed according to whether the transition conditions were optimal or suboptimal.
RESULTS: Twenty-eight patients were included. The mean age at the transfer visit was 19.5 years (±3.5). There were no deaths during the study period. Consultations were more numerous at T-2 [14.5 (±5.9) vs. 12.0 (±5.1), P<0.004]. Chronic colonization with Pseudomonas aeruginosa was more frequent at T+2 (46.4% vs. 17.9%, P=0.021). A progressive decrease in FEV1 and FVC was observed between T-2 and T+2. The number of pulmonary exacerbations was lower in the optimal transition group.
CONCLUSION: The period of transition from childhood to adulthood in patients with CF appears to be associated with functional and microbiological changes.

PMID: 31955962 [PubMed - as supplied by publisher]

The Family of Chloride Channel Regulator, Calcium-activated Proteins in the Feline Respiratory Tract: A Comparative Perspective on Airway Diseases in Man and Animal Models.

J Comp Pathol. 2020 Jan;174:39-53

Authors: Erickson NA, Gruber AD, Mundhenk L

Abstract
Members of the chloride channel regulator, calcium-activated (CLCA) family are considered to be modifiers in inflammatory, mucus-based respiratory conditions such as asthma and cystic fibrosis. Previous work has shown substantial differences between human and murine CLCA orthologues that limit the value of mouse models. As an alternative, the cat is an unfamiliar but powerful model of human asthma. We therefore characterized the expression profiles of CLCA proteins in the feline respiratory tract. Identical to other species, the feline CLCA1 protein was immunohistochemically localized to virtually all goblet cells and found to be secreted into the mucus. However, it was not detected in submucosal glands where it is expressed in other species. In contrast to all other species studied to date, feline CLCA2 was not found in submucosal glands or any other airway cells. Similar to mice, but in contrast to man and pigs, the feline respiratory tract was devoid of CLCA4 expression. In the airways of asthmatic cats, CLCA1 was strongly overexpressed, similar to human patients. Therefore, despite some similarities in CLCA1 protein expression and secretion, substantial differences were identified between several feline CLCA family members and their respective orthologues in man, mice and pigs, which must be considered in comparative medicine.

PMID: 31955802 [PubMed - in process]

Parathyroid hormone increases CFTR expression and function in Caco-2 intestinal epithelial cells.

Biochem Biophys Res Commun. 2020 Jan 15;:

Authors: Jantarajit W, Wongdee K, Lertsuwan K, Teerapornpuntakit J, Aeimlapa R, Thongbunchoo J, Harvey BSJ, Sheppard DN, Charoenphandhu N

Abstract
Parathyroid hormone (PTH) enhances cystic fibrosis transmembrane conductance regulator (CFTR)-mediated anion secretion by the human intestinal epithelial cell line Caco-2. With the patch-clamp and Ussing chamber techniques, we investigated how PTH stimulates CFTR activity in Caco-2 cells. Cell-attached recordings revealed that PTH stimulated the opening of CFTR-like channels, while impedance analysis demonstrated that PTH increased apical membrane capacitance, a measure of membrane surface area. Using ion substitution experiments, the PTH-stimulated increase in short-circuit current (Isc), a measure of transepithelial ion transport, was demonstrated to be Cl-- and HCO3--dependent. However, the PTH-stimulated increase in Isc was unaffected by the carbonic anhydrase inhibitor acetazolamide, but partially blocked by the intermediate-conductance Ca2+-activated K+ channel (IKCa) inhibitor clotrimazole. TRAM-34, a related IKCa inhibitor, failed to directly inhibit CFTR Cl- channels in cell-free membrane patches, excluding its action on CFTR. In conclusion, PTH enhances CFTR-mediated anion secretion by Caco-2 monolayers by increasing the expression and function of CFTR in the apical membrane and IKCa activity in the basolateral membrane.

PMID: 31954520 [PubMed - as supplied by publisher]

Current infection control practices used in Australian and New Zealand cystic fibrosis centers.

BMC Pulm Med. 2020 Jan 17;20(1):16

Authors: Stockwell RE, Wood ME, Ballard E, Moore V, Wainwright CE, Bell SC

Abstract
BACKGROUND: The 2013 update of the Infection Prevention and Control (IP&C) Guideline outlined recommendations to prevent the spread of CF respiratory pathogens. We aimed to investigate the current infection control practices used in Australian and New Zealand (NZ) CF centers.
METHODS: Two online surveys were distributed to Australian and NZ CF centers regarding the uptake of selected IP&C recommendations. One survey was distributed to all the Medical Directors and Lead CF Nurses and the second survey was distributed to all the Lead CF Physiotherapists.
RESULTS: The response rate was 60% (60/100) for medical/nursing and 58% (14/24) for physiotherapy. Over 90% (55/60) of CF centers followed CF-specific infection control guidelines and consistent infection control practices were seen in most CF centers; 76% (41/54) had implemented segregation strategies for ambulatory care and no CF centers housed people with CF in shared inpatient accommodation. However, the application of contact precautions (wearing gloves and apron/gown) by healthcare professionals when reviewing a CF person was variable between CF center respondents but was most often used when seeing CF persons with MRSA infection in both ambulatory care and hospital admission (20/50, 40% and 42/45, 93% of CF centers, respectively). Mask wearing by people with CF was implemented into 61% (36/59) of centers. Hospital rooms were cleaned daily in 79% (37/47) of CF centers and the ambulatory care consult rooms were always cleaned between consults (49/49, 100%) and at the end of the clinic session (51/51, 100%); however the staff member tasked with cleaning changed with 37% (18/49) of CF centers responding that CF multidisciplinary team (MDT) members cleaned between patients whereas at the end of the clinic session, only 12% (6/51) of the CF MDT cleaned the consult room.
CONCLUSIONS: Overall, Australian and NZ CF centers have adopted many recommendations from the IP&C. Although, the application of contact precautions was inconsistent and had overall a low level of adoption in CF centers. In ~ 25% of centers, mixed waiting areas occurred in the ambulatory care. Given the variability of responses, additional work is required to achieve greater consistency between centers.

PMID: 31952502 [PubMed - in process]

Cystic fibrosis and career counselling.

Cent Eur J Public Health. 2019 Dec;27(4):279-284

Authors: Zupanič MV, Škerjanc A

Abstract
OBJECTIVE: Cystic fibrosis is a genetic disorder that affects mostly lungs but also other organs. Modern treatment has transformed once fatal disease of childhood into the chronic disease of adulthood. Hence more patients enter the job market. Very few adolescents with cystic fibrosis receive some formal career guidance. There is still no professional career guidance for them in Slovenia.
METHODS: Literature on workability of patients with cystic fibrosis was reviewed. Following the articles and Slovenian and foreign manuals the guidelines on career counselling of young patients with cystic fibrosis is proposed, as well as the suggestions for professional qualification of these patients.
RESULTS: The results of the studies present that workability of patients with cystic fibrosis is associated to forced expiratory volume in 1 second (FEV1) (p < 0.05), the achieved educational level more than 3 years of faculty study (p < 0.001-p < 0.013), self-assessment of quality of life (p = 0.005), age (p = 0.01), and the number of admissions to the hospital (p = 0.001).
CONCLUSIONS: The interactions among work, quality of life and survival require that healthcare workers strive to help their patients with cystic fibrosis to succeed in their professional lives. The young patients should achieve the highest level of education possible and follow their wishes in line with the realistic possibilities.

PMID: 31951686 [PubMed - in process]

Executive functioning in pediatric cystic fibrosis: A preliminary study and conceptual model.

Pediatr Pulmonol. 2020 Jan 17;:

Authors: Borschuk AP, Molitor S, Everhart RS, Siracusa C, Filigno SS

Abstract
BACKGROUND: Research has shown that broad cognitive functioning in individuals with CF is intact. Specific executive functioning (EF) deficits have been identified, however, and adults with CF report more symptoms of ADHD than the general population. EF skills are critical to the management of a complex disease like CF although studies have not adequately examined EF mechanisms in CF. This manuscript (a) described EF in a small sample of children with CF, (b) summarized relations found between EF and psychosocial variables, and (c) presented a conceptual model by which to understand EF's impact on adherence in CF.
METHODS: Data for this preliminary study were collected from 19 children with CF and their caregivers (ages, 6-18). Caregivers completed questionnaires assessing their child's physical and mental health, their own functioning, and overall family functioning. EF was measured using a parent-report rating scale. Patient health data were collected from the electronic medical record.
RESULTS: This sample did not demonstrate elevated levels of EF impairment. Worse EF was related to poor family communication/cohesion, as well as higher treatment burden, worse lung function, poorer adherence, and older age. From these findings, a preliminary model was developed describing EF in the context of CF and adherence.
CONCLUSIONS: Findings from this preliminary study suggest that the CF regimen and associated symptoms may overload otherwise adequate EF skills. Reducing disease burden and preventing burnout should be a focus of treatment. A better understanding of EF in CF and the impact on adherence would allow for better clinical management and effective design of interventions.

PMID: 31951324 [PubMed - as supplied by publisher]

Dynamic post-translational modification profiling of M. tuberculosis-infected primary macrophages.

Elife. 2020 Jan 17;9:

Authors: Budzik JM, Swaney DL, Jimenez-Morales D, Johnson JR, Garelis NE, Repasy T, Roberts AW, Popov LM, Parry TJ, Pratt D, Ideker T, Krogan NJ, Cox JS

Abstract
Macrophages are highly plastic cells with critical roles in immunity, cancer, and tissue homeostasis, but how these distinct cellular fates are triggered by environmental cues is poorly understood. To uncover how primary murine macrophages respond to bacterial pathogens, we globally assessed changes in post-translational modifications of proteins during infection with Mycobacterium tuberculosis, a notorious intracellular pathogen. We identified hundreds of dynamically regulated phosphorylation and ubiquitylation sites, indicating that dramatic remodeling of multiple host pathways, both expected and unexpected, occurred during infection. Most of these cellular changes were not captured by mRNA profiling, and included activation of ubiquitin-mediated autophagy, an evolutionarily ancient cellular antimicrobial system. This analysis also revealed that a particular autophagy receptor, TAX1BP1, mediates clearance of ubiquitylated Mtb and targets bacteria to LC3-positive phagophores. These studies provide a new resource for understanding how macrophages shape their proteome to meet the challenge of infection.

PMID: 31951200 [PubMed - as supplied by publisher]

Model-informed drug development in pulmonary delivery: Preclinical pharmacokinetic-pharmacodynamic modelling for evaluation of treatments against chronic Pseudomonas aeruginosa lung infections.

Mol Pharm. 2020 Jan 17;:

Authors: Sou TAS, Kukavica-Ibrulj I, Levesque RC, Friberg LE, Bergström CAS

Abstract
Antibiotic resistance is a major public health threat worldwide and among others, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. Novel treatment strategies are therefore urgently needed. For lung infections, direct delivery of treatments to the site of action in the airway can achieve a higher local concentration with minimal systemic exposure and hence, avoid risks of unwanted systemic adverse effects. Previously, a rat preclinical disease model for PA chronic lung infections has been reported. However, the role of this disease model in the development of new treatment has not been thoroughly evaluated. In this study, tobramycin was used as a model antibiotic to evaluate the application of this preclinical disease model for PA treatments. The obtained data were used for pharmacokinetic-pharmacodynamic (PKPD) modelling. Plasma samples of tobramycin following pulmonary delivery via different types of dosing methods as well as growth and efficacy data from the chronic lung infection disease model following tobramycin treatment were collected for analysis and modelling. The developed PKPD model incorporates a semi-mechanistic description on biofilm development in chronic infections to allow a description of drug action on bacteria in different states (i.e. planktonic, biofilm and latent) and describes the available data from the efficacy study. The PKPD model can be used to support the application of the preclinical lung infection disease model by providing a quantitative description of the drug exposure-response relationship and a mechanistic platform to integrate all available PK and PKPD data with predictive capacity. With the support of appropriate experimental designs, the model can be further extended for other applications to, for instance, study the transition of bacteria between states and describe drug actions on biofilm.

PMID: 31951139 [PubMed - as supplied by publisher]

Streamlining care in cystic fibrosis: survey of otolaryngologist, pulmonologist, and patient experiences.

Int Forum Allergy Rhinol. 2020 Jan 17;:

Authors: Farzal Z, Dean KM, Sreenath SB, Hodge SE, Thorp BD, Ebert CS, Zanation AM, Senior BA, Kimple AJ

Abstract
BACKGROUND: Care coordination for cystic fibrosis (CF) is essential. The objectives of this study were to: (1) compare otolaryngologists' and pulmonlogists' understanding of long-term chronic rhinosinusitis (CRS) management; and (2) query patient perceptions of otolaryngologic care and CRS.
METHODS: A cross-sectional survey was administered by the Cystic Fibrosis Foundation in 2018 to patients with CF or their caregivers, otolaryngologists, and pulmonologists. Statistical analysis was performed comparing specialists. Descriptive statistics were computed for patient/caregiver-reported data.
RESULTS: Respondents included 126 otolaryngologists, 115 pulmonologists, and 186 patients with CF or their caregivers. Pulmonologists had greater experience caring for CF patients compared with otolaryngologists (66.7% vs 43.2% with 13+ years of experience, respectively), but more otolaryngologists cared for both adult and pediatric CF patients (39.2% vs 10.4%, respectively). Significantly more otolaryngologists advocated for establishing otolaryngologic care at time of CF diagnosis (64.8%) compared with pulmonologists (14.4%, p < 0.001), of whom 60.4% recommended otolaryngologist referral when sinonasal symptoms affect quality of life. More otolaryngologists perceived sinus surgery as beneficial for pulmonary function (74.5% vs 57.7%, p = 0.009); 60.8% of patients first sought otolaryngologic care in infancy or childhood (<13 years). Median number of sinus surgeries was 3 (interquartile range, 2-5). The most common perceived benefits of surgery according to patients/caregivers included improved breathing (31.2%) and improved sinonasal symptoms (23.7%). Top patients/caregiver otolaryngologic priorities included symptom/infection control (49.0%) and care coordination (15.0%).
CONCLUSION: Our results highlight variable patient/caregiver experiences, and suggest that otolaryngologist and pulmonologist perceptions of CF otolaryngologic care also differ in some respects requiring improved interspecialty coordination/education.

PMID: 31951081 [PubMed - as supplied by publisher]

Dr Jeffrey S. Wagener: An impactful career and life.

Pediatr Pulmonol. 2020 Jan 17;:

Authors: Deterding RR, Morgan WJ

PMID: 31951079 [PubMed - as supplied by publisher]

High-resolution imaging of the actin cytoskeleton and epithelial sodium channel, CFTR, and aquaporin-9 localization in the vas deferens.

Mol Reprod Dev. 2020 Jan 17;:

Authors: Sharma S, Kumaran GK, Hanukoglu I

Abstract
Vas deferens is a conduit for sperm and fluid from the epididymis to the urethra. The duct is surrounded by a thick smooth muscle layer. To map the actin cytoskeleton of the duct and its epithelium, we reacted sections of the proximal and distal regions with fluorescent phalloidin. Confocal microscopic imaging showed that the cylinder-shaped epithelium of the proximal region has a thick apical border of actin filaments that form microvilli. The epithelium of the distal region is covered with tall stereocilia (13-18 µm) that extend from the apical border into the lumen. In both regions, the lateral and basal cell borders showed a thin lining of actin cytoskeleton. The vas deferens epithelium contains various channels to regulate the fluid composition in the lumen. We mapped the localization of the epithelial sodium channel (ENaC), aquaporin-9 (AQP9), and cystic fibrosis transmembrane conductance regulator (CFTR) in the rat and mouse vas deferens. ENaC and AQP9 immunofluorescence were localized on the luminal surface and stereocilia and also in the basal and smooth muscle layers. CFTR immunofluorescence appeared only on the luminal surface and in smooth muscle layers. The localization of all three channels on the apical surface of the columnar epithelial cells provides clear evidence that these channels are involved concurrently in the regulation of fluid and electrolyte balance in the lumen of the vas deferens. ENaC allows the flow of Na+ ions from the lumen into the cytoplasm, and the osmotic gradient generated provides the driving force for the passive flow of water through AQP channels.

PMID: 31950584 [PubMed - as supplied by publisher]