Am J Otolaryngol. 2021 Jun 19;42(5):103137. doi: 10.1016/j.amjoto.2021.103137. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine if children with cystic fibrosis (CF) who are otitis media prone and treated with tympanostomy tube placement (TTP) follow the natural course of non-CF children regarding the incidence of tympanostomy tube otorrhea (TTO) (21-34%).

METHODS: All CF patients seen at a large tertiary pediatric hospital were retrospectively reviewed from 2010 to 2019. A total of 483 patients were identified and seventeen met the inclusion criteria and were included in the analysis. Data collected included demographics, CF diagnosis history including date of diagnosis and genotype, TTP notes, and otorrhea found in otolaryngology clinic and pediatrician clinic notes for up to 18 months post-TTP.

RESULTS: CF was diagnosed at a median age of 13 days (0 days to 6 years). In terms of surgical frequency, 14/17 (82.4%) patients had one TTP, 2/17 (11.8%) had two TTPs, and 1/17 (5.9%) had five TTPs. The median (range) age at first TTP was 2 years (3 months to 13 years). After the first TTP, TTO occurred in 5 (29.4%) patients at 3 months, 6 (35.3%) at 6 and 9 months, and 7 (41.2%) at 12 and 18 months at median (range) = 1 (0-5) otolaryngology appointments and median (range) = 0 (0-8) pediatrician appointments.

CONCLUSION: To our knowledge this is the first study to report that CF children are more likely to be severely affected with recurrent acute otitis media (RAOM), to require TTP, and to exhibit a natural history of TTO commensurate with the non-CF population.

PMID:34174638 | DOI:10.1016/j.amjoto.2021.103137

Comp Biochem Physiol A Mol Integr Physiol. 2021 Jun 23:111021. doi: 10.1016/j.cbpa.2021.111021. Online ahead of print.

ABSTRACT

Euryhaline fishes maintain hydromineral balance in a broad range of environmental salinities via the activities of multiple osmoregulatory organs, namely the gill, gastrointestinal tract, skin, kidney, and urinary bladder. Teleosts residing in freshwater (FW) environments are faced with the diffusive loss of ions and the osmotic gain of water, and, therefore, the kidney and urinary bladder reabsorb Na+ and Cl- to support the production of dilute urine. Nonetheless, the regulated pathways for Na+ and Cl- transport by euryhaline fishes, especially in the urinary bladder, have not been fully resolved. Here, we first investigated the ultrastructure of epithelial cells within the urinary bladder of FW-acclimated Mozambique tilapia (Oreochromis mossambicus) by electron microscopy. We then investigated whether tilapia employ Na+/Cl- cotransporter 1 (Ncc1) and Clc family Cl- channel 2c (Clc2c) for the reabsorption of Na+ and Cl- by the kidney and urinary bladder. We hypothesized that levels of their associated gene transcripts vary inversely with environmental salinity. In whole kidney and urinary bladder homogenates, ncc1 and clc2c mRNA levels were markedly higher in steady-state FW- versus SW (seawater)-acclimated tilapia. Following transfer from SW to FW, ncc1 and clc2c in both the kidney and urinary bladder were elevated within 48 h. A concomitant increase in branchial ncc2, and decreases in Na+/K+/2Cl-cotransporter 1a (nkcc1a) and cystic fibrosis transmembrane regulator 1 (cftr1) levels indicated a transition from Na+ and Cl- secretion to absorption by the gills in parallel with the identified renal and urinary bladder responses to FW transfer. Our findings suggest that Ncc1 and Clc2c contribute to the functional plasticity of the kidney and urinary bladder in tilapia.

PMID:34174427 | DOI:10.1016/j.cbpa.2021.111021

Eur Respir J. 2021 Jun 25:2100185. doi: 10.1183/13993003.00185-2021. Online ahead of print.

ABSTRACT

QUESTION: Cystic fibrosis (CF) is characterised by the accumulation of viscous, adherent mucus in the lungs. While several hypotheses invoke a direct relationship with CFTR dysfunction (i.e., acidic airway surface liquid (ASL) pH, low [HCO3 -], airway dehydration), the dominant biochemical alteration of CF mucus remains unknown.

MATERIALS/METHODS: We characterised a novel cell line (CFTR-KO Calu3 cells) and the responses of human bronchial epithelial (HBE) cells from subjects with G551D or F508del mutations to Ivacaftor and Elexacaftor-Tezacaftor-Ivacaftor (ETI). A spectrum of assays such as short-circuit currents (Isc), qPCR, ASL pH, western blotting (WB), light scattering/refractometry (SEC-MALS), scanning electron microscopy (SEM), % solids, and particle tracking were performed to determine the impact of CFTR function on mucus properties.

RESULTS: Loss of CFTR function in Calu3 cells resulted in ASL pH acidification and mucus hyperconcentration (dehydration). Modulation of CFTR in CF HBE cells did not affect ASL pH or mucin mRNA expression, but decreased mucus concentration, relaxed mucus network ultrastructure, and improved mucus transport. In contrast with modulator-treated cells, a large fraction of airway mucins remained attached to naïve CF cells following short apical washes, as revealed by the use of reducing agents to remove residual mucus from the cell surfaces. Extended hydration, but not buffers alkalised with NaOH or HCO3 -, normalised mucus recovery to modulator-treated cell levels.

CONCLUSION: These results indicate that airway dehydration, not acidic pH and/or low [HCO3 -], is responsible for abnormal mucus properties in CF airways and CFTR modulation predominantly restores normal mucin entanglement.

PMID:34172469 | DOI:10.1183/13993003.00185-2021

J Pediatr Nurs. 2021 Jun 22:S0882-5963(21)00175-5. doi: 10.1016/j.pedn.2021.06.004. Online ahead of print.

ABSTRACT

BACKGROUND: The aim of this study was to survey young adults who participated in either a formal or semi-formal transition program at one cystic fibrosis (CF) care center to compare their self-perceived transition related anxiety, transition readiness and satisfaction with transition teaching and timing.

METHODS: This retrospective cohort study was conducted from 3/1/2015 to 9/30/2016. Study participants met inclusion criteria if they had a diagnosis of CF, received pediatric care from the care center, transitioned to adult care between 1/1/2009 and 3/1/2016 and had at least six months experience in adult care. Participants completed a 43 question Likert-type survey rating their pre-transfer transition related anxiety, transition readiness, and satisfaction with the transition preparation and process.

FINDINGS: Participation in a structured transition program was associated with decreased anxiety at transition time (p < .05), increased transition readiness (p < .01) and increased self-perceived healthcare independence (p < .01). Only 48% of participants were satisfied with their chosen transition time, with 18% wishing they had moved to adult care sooner and 34% wishing they could have delayed their transfer to adult care longer.

DISCUSSION: This study supports that participation in a formalized transition program was associated with significantly lower pre-transfer anxiety and higher post-transition satisfaction in individuals with CF. Age at transfer initiation was not associated with satisfaction or perceived readiness to transfer.

PRACTICE IMPLICATIONS: Disease-specific knowledge acquisition in transition curriculum does not necessarily correlate to task-completion skills. Teams should partner with young adults to choose the right transition time.

PMID:34172371 | DOI:10.1016/j.pedn.2021.06.004

Am J Respir Crit Care Med. 2021 Jun 25. doi: 10.1164/rccm.202102-0451OC. Online ahead of print.

ABSTRACT

RATIONALE: While it is clear that cystic fibrosis airway disease begins at a very young age, the early and subsequent steps in disease pathogenesis and the relative contribution of infection, mucus, and inflammation are not well understood.

OBJECTIVES: As one approach to assessing the early contribution of infection, we tested the hypothesis that early and continuous antibiotics would decrease the airway bacterial burden. We thought that, if it does, it might reveal aspects of the disease that are more or less sensitive to decreasing infection.

METHODS: Three groups of pigs were studied from birth until ~3 weeks of age: 1) wild-type, 2) cystic fibrosis, and 3) cystic fibrosis pigs treated continuously with broad-spectrum antibiotics from birth until study completion. Disease was assessed with chest computed tomography, histopathology, microbiology, and bronchoalveolar lavage.

MEASUREMENTS AND MAIN RESULTS: Disease was present by 3 weeks of age in cystic fibrosis pigs. Continuous antibiotics from birth improved chest computed tomography imaging abnormalities and airway mucus accumulation, but not airway inflammation in the cystic fibrosis pig model. However, reducing bacterial infection did not improve two disease features already present at birth in cystic fibrosis pigs, air trapping and submucosal gland duct plugging. In the cystic fibrosis sinuses, antibiotics did not prevent the development of infection, disease, or the number of bacteria but did alter the bacterial species.

CONCLUSIONS: These findings suggest that cystic fibrosis airway disease begins immediately following birth, and that early and continuous antibiotics impact some, but not all, aspects of CF lung disease development.

PMID:34170795 | DOI:10.1164/rccm.202102-0451OC

J Cell Mol Med. 2021 Jun 25. doi: 10.1111/jcmm.16729. Online ahead of print.

ABSTRACT

The alteration of the mucociliary clearance is a major hallmark of respiratory diseases related to structural and functional cilia abnormalities such as chronic obstructive pulmonary diseases (COPD), asthma and cystic fibrosis. Primary cilia and motile cilia are the two principal organelles involved in the control of cell fate in the airways. We tested the effect of primary cilia removal in the establishment of a fully differentiated respiratory epithelium. Epithelial barrier integrity was not altered while multiciliated cells were decreased and mucous-secreting cells were increased. Primary cilia homeostasis is therefore paramount for airway epithelial cell differentiation. Primary cilia-associated pathophysiologic implications require further investigations in the context of respiratory diseases.

PMID:34170075 | DOI:10.1111/jcmm.16729

Front Immunol. 2021 Jun 8;12:625922. doi: 10.3389/fimmu.2021.625922. eCollection 2021.

ABSTRACT

Low density neutrophils (LDNs) are described in a number of inflammatory conditions, cancers and infections and associated with immunopathology, and a mechanistic role in disease. The role of LDNs at homeostasis in healthy individuals has not been investigated. We have developed an isolation protocol that generates high purity LDNs from healthy donors. Healthy LDNs were identical to healthy normal density neutrophils (NDNs), aside from reduced neutrophil extracellular trap formation. CD66b, CD16, CD15, CD10, CD54, CD62L, CXCR2, CD47 and CD11b were expressed at equivalent levels in healthy LDNs and NDNs and underwent apoptosis and ROS production interchangeably. Healthy LDNs had no differential effect on CD4+ or CD8+ T cell proliferation or IFNγ production compared with NDNs. LDNs were generated from healthy NDNs in vitro by activation with TNF, LPS or fMLF, suggesting a mechanism of LDN generation in disease however, we show neutrophilia in people with Cystic Fibrosis (CF) was not due to increased LDNs. LDNs are present in the neutrophil pool at homeostasis and have limited functional differences to NDNs. We conclude that increased LDN numbers in disease reflect the specific pathology or inflammatory environment and that neutrophil density alone is inadequate to classify discrete functional populations of neutrophils.

PMID:34168640 | PMC:PMC8217868 | DOI:10.3389/fimmu.2021.625922

Front Physiol. 2021 Jun 8;12:649497. doi: 10.3389/fphys.2021.649497. eCollection 2021.

ABSTRACT

This work presents a new mathematical model of the heat and water exchanges in the human lungs (newborn to adult). This model is based on a local description of the water and energy transports in both the lumen and the surrounding tissues, and is presented in a comprehensive, dimensionless framework with explicitly stated assumptions and a strong physiological background. The model is first used to analyze and quantify the key phenomena and dimensionless numbers governing these heat and water exchanges and then it is applied to an adult in various situations (varying atmospheric conditions, exercising…). The results highlight several interesting physiological elements. They show that the bronchial region of the lungs is able to condition the air in all the considered situations even if, sometimes, for instance when exercising, distal generations have to be involved. The model also shows that these distal generations are super-conditioners. Moreover, the results quantify the key role of the submucosal glands in mucus hydration. They also show that, during expiration, a significant cooling of the air and condensation of water occur along the respiratory tract as the vascularization of the tissues surrounding the airways is not able to maintain these tissues at body temperature during inspiration. Due to the interaction between several phenomena, it appears that the ratio of the amount of water returned to the mucosa during expiration to the amount extracted during inspiration is almost independent of the breathing conditions (around 33%). The results also show that, in acute situations, such as suffering from a pathology with airway dysfunction, when being intubated or when exercising above an intensity threshold, the heat and water exchanges in the lungs may be critical regarding mucus hydration. In proximal generations, the evaporation may overwhelm the ability of the submucosal glands to replenish the airway surface liquid with water. In some situations, the cooling of the mucosa may be very important; it can even become colder than the inspired air, due to evaporative cooling. Finally, the results show that breathing cold air can significantly increase the exchanges between the lungs and the environment, which can be critical regarding disease transmission.

PMID:34168568 | PMC:PMC8217871 | DOI:10.3389/fphys.2021.649497

Proc Natl Acad Sci U S A. 2021 Jun 29;118(26):e2017130118. doi: 10.1073/pnas.2017130118.

ABSTRACT

Dual oxidase 1 (DUOX1) is an NADPH oxidase that is highly expre-ssed in respiratory epithelial cells and produces H2O2 in the airway lumen. While a line of prior in vitro observations suggested that DUOX1 works in partnership with an airway peroxidase, lactoperoxidase (LPO), to produce antimicrobial hypothiocyanite (OSCN-) in the airways, the in vivo role of DUOX1 in mammalian organisms has remained unproven to date. Here, we show that Duox1 promotes antiviral innate immunity in vivo. Upon influenza airway challenge, Duox1 -/- mice have enhanced mortality, morbidity, and impaired lung viral clearance. Duox1 increases the airway levels of several cytokines (IL-1β, IL-2, CCL1, CCL3, CCL11, CCL19, CCL20, CCL27, CXCL5, and CXCL11), contributes to innate immune cell recruitment, and affects epithelial apoptosis in the airways. In primary human tracheobronchial epithelial cells, OSCN- is generated by LPO using DUOX1-derived H2O2 and inactivates several influenza strains in vitro. We also show that OSCN- diminishes influenza replication and viral RNA synthesis in infected host cells that is inhibited by the H2O2 scavenger catalase. Binding of the influenza virus to host cells and viral entry are both reduced by OSCN- in an H2O2-dependent manner in vitro. OSCN- does not affect the neuraminidase activity or morphology of the influenza virus. Overall, this antiviral function of Duox1 identifies an in vivo role of this gene, defines the steps in the infection cycle targeted by OSCN-, and proposes that boosting this mechanism in vivo can have therapeutic potential in treating viral infections.

PMID:34168077 | DOI:10.1073/pnas.2017130118

J Clin Invest. 2021 Jun 24:150398. doi: 10.1172/JCI150398. Online ahead of print.

ABSTRACT

Without CFTR-mediated HCO3- secretion, airway epithelia of newborns with cystic fibrosis (CF) produce an abnormally acidic airway surface liquid (ASL), and the decreased pH impairs respiratory host defenses. However, within a few months of birth, ASL pH increases to match that in non-CF airways. Although the physiological basis for the increase is unknown, this time-course matches the development of inflammation in CF airways. To learn whether inflammation alters CF ASL pH, we treated CF epithelia with TNFα and IL-17, two inflammatory cytokines that are elevated in CF airways. TNFα+IL-17 markedly increased ASL pH by upregulating pendrin, an apical Cl-/HCO3- exchanger. Moreover, when CF epithelia were exposed to TNFα+IL-17, clinically approved CFTR modulators further alkalinized ASL pH. As predicted by these results, in vivo data revealed a positive correlation between airway inflammation and CFTR modulator-induced improvement in lung function. These findings suggest that inflammation is a key regulator of HCO3- secretion in CF airways. Thus, they explain earlier observations that ASL pH increases after birth and indicate that for similar levels of inflammation, the pH of CF ASL is abnormally acidic. These results also suggest that a non-cell-autonomous mechanism, airway inflammation, is an important determinant of the response to CFTR modulators.

PMID:34166230 | DOI:10.1172/JCI150398

Endocrinol Diabetes Metab Case Rep. 2021 Jun 1;2021:EDM210010. doi: 10.1530/EDM-21-0010. Online ahead of print.

ABSTRACT

SUMMARY: Systemic pseudohypoaldosteronism type 1 (PHA1) is a rare genetic syndrome of tissue unresponsiveness to aldosterone caused by mutations affecting the epithelial Na channel (ENaC). The classical presentation is life-threatening neonatal/infantile salt-losing crises that mimic congenital adrenal hyperplasia (CAH). Consistently, extra-renal manifestations, including respiratory symptoms that resemble cystic fibrosis, are well reported. Clinical diagnosis is made by the presence of hyponatremia, hyperkalemia, metabolic acidosis, respiratory symptoms, evidence of high renal and extra-renal salt loss in addition to high plasma renin and aldosterone levels. We herein report a novel manifestation of PHA1: episodic dyslipidemia in a 7-month-old Sudanese boy that occurred during the salt-losing crises. Whole exome sequencing of the patient revealed one homozygous missense variant c.1636G>A p.(Asp546Asn) in the SCNN1B gene, confirming our clinical and laboratory findings that were compatible with PHA1. This report aims to highlight the possible explanation of dyslipidemia in PHA1 and its expected consequences in the long term.

LEARNING POINTS: A child presenting with features that mimic salt-losing congenital adrenal hyperplasia (CAH) crises that do not respond to glucocorticoid and mineralocorticoid therapy should alert the pediatricians to the possibility of end-organ resistance to aldosterone. Pseudohypoaldosteronism type 1 (PHA1) can be diagnosed even in the absence of advanced laboratory investigations. To our knowledge, this is the first case of systemic PHA1 to have a documented episodic dyslipidemia (primarily as marked hypertriglyceridemia).

PMID:34165441 | DOI:10.1530/EDM-21-0010

ERJ Open Res. 2021 Jun 21;7(2):00883-2020. doi: 10.1183/23120541.00883-2020. eCollection 2021 Apr.

ABSTRACT

Childhood lung infection is often associated with prominent neutrophilic airway inflammation and excess production of proteases such as neutrophil elastase (NE). The mechanisms responsible for this inflammation are not well understood. One potentially relevant pathway is the production of extracellular traps by neutrophils (NETs) and macrophages (METs). The aim of this study was to measure NET and MET expression in children and the effect of deoxyribonculease (DNase) 1 and α1-antitrypsin (AAT) on this process. We studied 76 children (median age of 4.0 years) with cystic fibrosis or chronic cough who underwent investigational bronchoscopy. NETs, METs and neutrophil elastase activity in bronchoalveolar lavage (BAL) samples were measured using confocal microscopy and functional assays. The effects of DNase 1 and AAT on NET/MET expression and neutrophil elastase activity were examined in vitro. Both subject groups had airway neutrophilia with prominent BAL production of NETs with neutrophil elastase co-expression; the mean %±standard error of the mean of neutrophils expressing NETs in the cystic fibrosis group was 23.3±2.8% and in the non-cystic fibrosis group was 28.4±3.9%. NET expression was higher in subjects who had detectable neutrophil elastase activity (p≤0.0074). The percentage of macrophages expressing METs in the cystic fibrosis group was 10.7±1.2% and in the non-cystic fibrosis group was 13.2±1.9%. DNase 1 decreased NET/MET expression (p<0.0001), but increased neutrophil elastase activity (p≤0.0137). The combination of AAT and DNase 1 reduced neutrophil elastase activity (p≤0.0049). We observed prominent extracellular trap formation in symptomatic children with and without cystic fibrosis. This innate inflammatory response was down-regulated by a combination of currently available therapeutics.

PMID:34164555 | PMC:PMC8215332 | DOI:10.1183/23120541.00883-2020

Front Physiol. 2021 Jun 7;12:652513. doi: 10.3389/fphys.2021.652513. eCollection 2021.

ABSTRACT

Altered cholesterol homeostasis in cystic fibrosis patients has been reported, although controversy remains. As a major membrane lipid component, cholesterol modulates the function of multiple ion channels by complicated mechanisms. However, whether cholesterol directly modulates cystic fibrosis transmembrane conductance regulator (CFTR) channel function remains unknown. To answer this question, we determined the effects of changing plasma membrane cholesterol levels on CFTR channel function utilizing polarized fischer rat thyroid (FRT) cells and primary human bronchial epithelial (HBE) cells. Treatment with methyl-β-cyclodextrin (MβCD) significantly reduced total cholesterol content in FRT cells, which significantly decreased forskolin (FSK)-mediated activation of both wildtype (WT-) and P67L-CFTR. This effect was also seen in HBE cells expressing WT-CFTR. Cholesterol modification by cholesterol oxidase and cholesterol esterase also distinctly affected activation of CFTR by FSK. In addition, alteration of cholesterol increased the potency of VX-770, a clinically used potentiator of CFTR, when both WT- and P67L-CFTR channels were activated at low FSK concentrations; this likely reflects the apparent shift in the sensitivity of WT-CFTR to FSK after alteration of membrane cholesterol. These results demonstrate that changes in the plasma membrane cholesterol level significantly modulate CFTR channel function and consequently may affect sensitivity to clinical therapeutics in CF patients.

PMID:34163370 | PMC:PMC8215275 | DOI:10.3389/fphys.2021.652513

Int J Gen Med. 2021 Jun 14;14:2513-2521. doi: 10.2147/IJGM.S274196. eCollection 2021.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease characterized by an accumulation of thick layers of mucus, leading to airway obstruction and air trapping. Poorly cleared mucus leads to frequent respiratory infections that produce chronic cough and dyspnea. The presence of infected mucus induces progressive inflammation. The resulting damage anatomically distorts airways leading to development of bronchiectasis. Bronchiectasis is irreversible and results in progressive respiratory function decline over time. Impaired mucociliary clearance together with tenacious mucus makes expectoration with cough alone problematic. Clinicians providing effective care for CF patients must have knowledge of the wide variety of treatment options currently available. Knowledge of these techniques will enable clinicians to prescribe airway clearance therapy (ACT) where necessary and provide treating physicians the ability to adapt to changing patient treatments as necessary. Training programs frequently do not provide in-depth knowledge of ACT technologies in CF patients resulting in knowledge gaps once physicians are in practice. This paper reviews strategies for ACT. It is specifically targeted for clinicians who frequently provide care for patients with CF.

PMID:34163219 | PMC:PMC8214208 | DOI:10.2147/IJGM.S274196

J Multidiscip Healthc. 2021 Jun 15;14:1423-1429. doi: 10.2147/JMDH.S313209. eCollection 2021.

ABSTRACT

PURPOSE: The aim of this cross-sectional study was to identify the major factors influencing pulmonary function in CF patients from western side of Romania.

PATIENTS AND METHODS: The study enrolled 51 patients with CF between the ages of 6 and 27.8 years who were monitored at regular visits to the National Cystic Fibrosis Centre and Pius Branzeu County Hospital in Timisoara, Romania, over a period of 2 years. The relationships between lung function, as measured by forced expiratory volume in 1 s (FEV1), with patient age, sex, body mass index (BMI), pancreatic insufficiency (PI), microbial infection, CF-related diabetes (CFRD), CF-associated liver disease (CFLD), and physical activity <30 min/day, were evaluated by multivariate regression analysis.

RESULTS: The results showed that FEV1 was 0.32% higher for each increase in percentile of BMI (95% confidence interval: 0.034-0.619). In addition, mean FEV1 was 1.52% lower with every year rise of age. PI and female sex increased the risk of impaired lung function (FEV1 <60%). The factors most closely correlated with pulmonary function in pediatric CF patients were current age (negative) and BMI (positive).

CONCLUSION: The findings of this study, in combination with what is known from other studies in CF, suggest that a better nutritional status and infection prophylaxis should be part of a comprehensive clinical management strategy for pediatric CF in Romania.

PMID:34163170 | PMC:PMC8214515 | DOI:10.2147/JMDH.S313209

Am J Case Rep. 2021 Jun 24;22:e930867. doi: 10.12659/AJCR.930867.

ABSTRACT

BACKGROUND Individuals with cystic fibrosis (CF) constituted approximately 10% of organ transplants in 2019, with the majority of transplants consisting of bilateral lung transplant. Multiorgan transplantation in individuals with cystic fibrosis (CF) is rare, and usually involves the liver and lung combined. Since kidney disease is not a common sequela of CF, the need for renal transplant in individuals who have not previously undergone lung transplant is uncommon. CASE REPORT We report a case of successful liver-lung-kidney transplant in a 23-year-old man with CF-related liver and lung disease, who developed renal failure due to IgA nephropathy. He required renal replacement therapy during the months before transplantation. After discussions among the liver, lung, and renal transplant teams, the patient was listed for multiorgan transplantation. An appropriate single donor for all organs was identified, and the patient underwent transplantation. The patient required extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) perioperatively, with total operative time of 23 h and 1 min. Postoperative course was notable for hemothorax and medication-induced acute tubular necrosis, which resolved without the need for renal replacement therapy. Liver and lung graft function was normal at 6 months, and renal function was minimally reduced. CONCLUSIONS Triple organ transplantation in CF is a viable option for individuals with multiorgan failure who may otherwise not qualify for single/dual organ transplantation. Use of ECMO and CRRT can be necessary during the long operative procedure. Optimal immunosuppression protocols for this group of patients has not yet been established, and ethical concerns regarding multiorgan transplantation exist.

PMID:34162826 | DOI:10.12659/AJCR.930867

J Cyst Fibros. 2021 Jun 21:S1569-1993(21)00160-0. doi: 10.1016/j.jcf.2021.05.009. Online ahead of print.

NO ABSTRACT

PMID:34162524 | DOI:10.1016/j.jcf.2021.05.009

PLoS Pathog. 2021 Jun 23;17(6):e1009681. doi: 10.1371/journal.ppat.1009681. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa (PA) is an opportunistic pathogen that causes diverse human infections including chronic airway infection in patients with cystic fibrosis (CF). Comparing the genomes of CF and non-CF PA isolates has great potential to identify the genetic basis of pathogenicity. To gain a deeper understanding of PA adaptation in CF airways, we performed a genome-wide association study (GWAS) on 1,001 PA genomes. Genetic variations identified among CF isolates were categorized into (i) alterations in protein-coding regions, either large- or small-scale, and (ii) polymorphic variation in intergenic regions. We introduced each CF-associated genetic alteration into the genome of PAO1, a prototype PA strain, and validated the outcomes experimentally. Loci readily mutated among CF isolates included genes encoding a probable sulfatase, a probable TonB-dependent receptor (PA2332~PA2336), L-cystine transporter (YecS, PA0313), and a probable transcriptional regulator (PA5438). A promoter region of a heme/hemoglobin uptake outer membrane receptor (PhuR, PA4710) was also different between the CF and non-CF isolate groups. Our analysis highlights ways in which the PA genome evolves to survive and persist within the context of chronic CF infection.

PMID:34161396 | DOI:10.1371/journal.ppat.1009681

Am J Respir Crit Care Med. 2021 Jun 23. doi: 10.1164/rccm.202103-0674ED. Online ahead of print.

NO ABSTRACT

PMID:34161195 | DOI:10.1164/rccm.202103-0674ED

mSphere. 2021 Jun 23:e0041621. doi: 10.1128/mSphere.00416-21. Online ahead of print.

ABSTRACT

Microbe-microbe interactions can strongly influence growth and biofilm formation kinetics. For Pseudomonas aeruginosa and Candida albicans, which are found together in diverse clinical sites, including urinary and intravenous catheters and the lungs of individuals with cystic fibrosis (CF), we compared the kinetics of biofilm formation by each species in dual-species and single-species biofilms. We engineered fluorescent protein constructs for P. aeruginosa (producing mKO-κ) and C. albicans (producing mKate2) that did not alter growth and enabled single-cell resolution imaging by live-sample microscopy. Using these strains in an optically clear derivative of synthetic CF sputum medium, we found that both P. aeruginosa and C. albicans displayed increased biovolume accumulation-by three- and sixfold, respectively-in dual-species biofilms relative to single-species biofilms. This result was specific to the biofilm environment, as enhanced growth was not observed in planktonic cocultures. Stimulation of C. albicans biofilm formation occurred regardless of whether P. aeruginosa was added at the time of fungal inoculation or 24 h after the initiation of biofilm development. P. aeruginosa biofilm increases in cocultures did not require the Pel extracellular polysaccharide, phenazines, and siderophores known to influence C. albicans. P. aeruginosa mutants lacking Anr, LasR, and BapA were not significantly stimulated by C. albicans, but they still promoted a significant enhancement of biofilm development of the fungus, suggesting a fungal response to the presence of bacteria. Last, we showed that a set of P. aeruginosa clinical isolates also prompted an increase of biovolume by C. albicans in coculture. IMPORTANCE There is an abundance of work on both P. aeruginosa and C. albicans in isolation, and quite some work as well on the way these two microbes interact. These studies do not, however, consider biofilm environments under flow, and our results here show that the expected outcome of interaction between these two pathogens can actually be reversed under flow, from pure antagonism to an increase in biomass on the part of both. Our work also highlights the importance of cellular-scale spatial structure in biofilms for understanding multispecies population dynamics.

PMID:34160236 | DOI:10.1128/mSphere.00416-21