Respiratory mycobiome and suggestion of inter-kingdom network during acute pulmonary exacerbation in cystic fibrosis.

Sci Rep. 2020 Feb 27;10(1):3589

Authors: Soret P, Vandenborght LE, Francis F, Coron N, Enaud R, Avalos M, Schaeverbeke T, Berger P, Fayon M, Thiebaut R, Delhaes L, Mucofong Investigation Group

Abstract
Lung infections play a critical role in cystic fibrosis (CF) pathogenesis. CF respiratory tract is now considered to be a polymicrobial niche and advances in high-throughput sequencing allowed to analyze its microbiota and mycobiota. However, no NGS studies until now have characterized both communities during CF pulmonary exacerbation (CFPE). Thirty-three sputa isolated from patients with and without CFPE were used for metagenomic high-throughput sequencing targeting 16S and ITS2 regions of bacterial and fungal rRNA. We built inter-kingdom network and adapted Phy-Lasso method to highlight correlations in compositional data. The decline in respiratory function was associated with a decrease in bacterial diversity. The inter-kingdom network revealed three main clusters organized around Aspergillus, Candida, and Scedosporium genera. Using Phy-Lasso method, we identified Aspergillus and Malassezia as relevantly associated with CFPE, and Scedosporium plus Pseudomonas with a decline in lung function. We corroborated in vitro the cross-domain interactions between Aspergillus and Streptococcus predicted by the correlation network. For the first time, we included documented mycobiome data into a version of the ecological Climax/Attack model that opens new lines of thoughts about the physiopathology of CF lung disease and future perspectives to improve its therapeutic management.

PMID: 32108159 [PubMed - in process]

A pathway to keep all lifelong learners up to date: the ERS continuing professional development programme.

Eur Respir J. 2020 Feb;55(2):

Authors: Farr A, Aliberti S, Loukides S, Massard G, Primhak R, Rohde GGU, Tabin N, Pannetier C, Stolz D

PMID: 32108083 [PubMed - in process]

Timing of hypertonic saline inhalation for cystic fibrosis.

Cochrane Database Syst Rev. 2020 Feb 28;2:CD008816

Authors: Elkins M, Dentice R

Abstract
BACKGROUND: Inhalation of hypertonic saline improves sputum rheology, accelerates mucociliary clearance and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane Review.
OBJECTIVES: To determine whether the timing of hypertonic saline inhalation (in relation to airway clearance techniques or in relation to time of day) has an impact on its clinical efficacy in people with cystic fibrosis.
SEARCH METHODS: We identified relevant randomised and quasi-randomised controlled trials from the Cochrane Cystic Fibrosis Trials Register, the Physiotherapy Evidence Database (PEDro), and international cystic fibrosis conference proceedings. Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register: 28 February 2019.
SELECTION CRITERIA: Any trial of hypertonic saline in people with cystic fibrosis where timing of inhalation was the randomised element in the study protocol with either: inhalation up to six hours before airway clearance techniques compared to inhalation during airway clearance techniques compared to inhalation up to six hours after airway clearance techniques; or morning compared to evening inhalation with any definition provided by the author.
DATA COLLECTION AND ANALYSIS: Both authors independently assessed the trials identified by the search for potential inclusion in the review. The certainty of the evidence was assessed using GRADE.
MAIN RESULTS: The searches identified 104 trial reports which represented 51 trials, of which three cross-over trials (providing data on 77 participants) met our inclusion criteria. We present three comparisons: inhalation before versus during airway clearance techniques; inhalation before versus after airway clearance techniques; and inhalation during versus after airway clearance techniques. One trial (50 participants), given its three-arm design, was eligible for all three comparisons. No trials compared morning versus evening inhalation of hypertonic saline. The evidence from the three trials was judged to be of low quality downgraded for limitations (high risk of bias due to blinding) and indirectness (all participants are adults, and therefore not applicable to children). Intervention periods ranged from one treatment to three treatments in one day. There were no clinically important differences between the timing regimens of inhaling hypertonic saline before, during or after airway clearance techniques in the mean amount of improvement in lung function or symptom scores (77 participants), with the between-group comparisons being non-significant (low-certainty evidence). While there may be little or no difference in the rating of satisfaction when hypertonic saline was inhaled before versus during the airway clearance techniques (64 participants) (with the 95% confidence interval including the possibility of both a higher and lower rating of satisfaction), satisfaction may be lower on a 100-mm scale when inhaled after the airway clearance techniques compared to before: mean difference (MD) 20.38 mm (95% confidence interval (CI) 12.10 to 28.66) and when compared to during the techniques, MD 14.80 mm (95% CI 5.70 to 23.90). Perceived effectiveness showed similar results: little or no difference for inhalation before versus during airway clearance techniques (64 participants); may be lower when inhaled after the airway clearance techniques compared to before, MD 10.62 (95% CI 2.54 to 18.70); and also when compared to during the techniques, MD 15.60 (95% CI 7.55 to 23.65). There were no quality of life or adverse events reported in any of the trials.
AUTHORS' CONCLUSIONS: Timing of hypertonic saline inhalation makes little or no difference to lung function (low-certainty evidence). However, inhaling hypertonic saline before or during airway clearance techniques may maximise perceived efficacy and satisfaction. The long-term efficacy of hypertonic saline has only been established for twice-daily inhalations; however, if only one dose per day is tolerated, the time of day at which it is inhaled could be based on convenience or tolerability until evidence comparing these regimens is available. The identified trials were all of very short intervention periods, so longer-term research could be conducted to establish the effects arising from regular use, which would incorporate the influence of changes in adherence with long-term use, as well as generating data on any adverse effects that occur with long-term use.

PMID: 32107770 [PubMed - in process]

Characterization of Pseudomonas lytic phages and their application as a cocktail with antibiotics in controlling Pseudomonas aeruginosa.

J Biosci Bioeng. 2020 Feb 24;:

Authors: Ong SP, Azam AH, Sasahara T, Miyanaga K, Tanji Y

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen that causes nosocomial disease among immunocompromised and chronic cystic fibrosis (CF) patients. We characterized two newly isolated Pseudomonas phages, ϕPA01 and ϕPA02, with different host spectra, and examined their effect as a cocktail with antibiotics against P. aeruginosa, to indicate the possibility of combining a phage cocktail and antibiotics in treating pseudomonal infection. Phages ϕPA01 (66,220 bp) and ϕPA02 (279,095 bp) belong to the genus Pbunalikevirus and Phikzlikevirus, respectively. No virulence or lysogenic associated gene was found in their genomes, thus they are potentially safe for phage therapy. We generated respective phage-resistant strains to investigate cross-resistance between two phages. Slight cross-resistance to ϕPA02 in ϕPA01-resistant strain was observed, while ϕPA02-resistant strain remained susceptible to ϕPA01. A ϕPA01 resistant strain that was cross-resistant to ϕPA02 appeared in round 5 (R5-PA01R), revealed frameshift mutation in phosphoglucomutase (algC), which is important for the synthesis of core lipopolysaccharide (LPS). Knockout of algC was resistant to both phages. Complementation of ΔalgC restored phages' infectivity, suggesting that LPS as host receptor. Phage cocktail suppressed the growth of P. aeruginosa for longer (20 h) hour compared with single phage (8-9 h), further suggesting their potential to be used as a phage cocktail. Furthermore, application of the phage cocktail with ciprofloxacin (0.25 μg/ml) and meropenem (2 μg/ml), respectively managed to suppress the growth of P. aeruginosa up to 96 h. Our results show the potential application of ϕPA01 and ϕPA02 as phage cocktail together with antibiotics for treatment of P. aeruginosa.

PMID: 32107153 [PubMed - as supplied by publisher]

Effect of Sex Differences on Computed Tomography Findings in Adults With Cystic Fibrosis: A Multicenter Study.

Arch Bronconeumol. 2020 Feb 24;:

Authors: Diab Cáceres L, Girón Moreno RM, García Castillo E, Pastor Sanz MT, Olveira C, García Clemente M, Nieto Royo R, Prados Sánchez C, Caballero Sánchez P, Olivera Serrano MJ, Padilla Galo A, Nava Tomas E, Esteban Peris A, Fernández Velilla M, Torres MI, Ancochea Bermúdez J

Abstract
BACKGROUND: The survival of women with cystic fibrosis (CF) is lower than that of men by approximately 5 years. While various factors have been put forward to account for this discrepancy, no specific reasons have been established. Our hypothesis was that anatomical-structural involvement is more pronounced in women with CF than in men and that this is reflected in thoracic HRCT findings.
MATERIAL AND METHODS: We performed a prospective multicentre study, in which adult patients were consecutively included over 18 months. Chest HRCT was performed, and findings were scored by 2 thoracic radiologists using the modified Bhalla system. We also studied respiratory function, applied the CFQR 14+ questionnaire, and collected clinical variables.
RESULTS: Of the 360 patients followed up in the participating units, 160 were eventually included. Mean age was 28 years, and 47.5% were women. The mean±SD global score on the modified Bhalla score was 13.7±3.8 in women and 15.2±3.8 in men (p=0.024). The highest scores were observed for sacculations, bronchial generations, and air trapping in women. Women had lower BMI, %FEV1, %FVC, and %DLCO. Similarly, the results for the respiratory domain in CFQR 14+ were worse in women, who also had more annual exacerbations.
CONCLUSIONS: This is the first study to provide evidence of the implication of sex differences in HRCT findings in patients with CF. Women with CF present a more severe form of the disease that results in more frequent exacerbations, poorer functional and nutritional outcomes, deterioration of quality of life, and greater structural damage.

PMID: 32107115 [PubMed - as supplied by publisher]

In vitro activity of Fosfomycin against mucoid and non-mucoid Pseudomonas aeruginosa strains.

J Glob Antimicrob Resist. 2020 Feb 24;:

Authors: Bressan A, Rodio DM, Stangherlin F, Puggioni G, Ambrosi C, Arcari G, Carattoli A, Antonelli G, Pietropaolo V, Trancassini M

Abstract
OBJECTIVES: Pseudomonas aeruginosa is the most frequent infectious agent in cystic fibrosis patients. P. aeruginosa resistance to first line antibiotics limits therapeutic options, but the therapeutic potential of older generation antibiotics, such as fosfomycin is under investigation. Fosfomycin does not belong to any other antibiotic class and acts by inhibiting the biosynthesis of the bacterial cell wall during the initial phases. A major problem for the use of fosfomycin against P. aeruginosa is the absence of a clinical breakpoint, the last one of 32 µg/mL was proposed in 2013 by the CA-SFM (Comité de l'Antibiogramme de la Société Française de Microbiologie).
METHODS: Sixty-one strains ofP. aeruginosa (thirty mucoid and thirty-one non mucoid) were collected from respiratory samples of cystic fibrosis patients. All isolates were identified by MALDI-TOF (Bruker, Bremen, Germany). Fosfomycin MICs against P. aeruginosa were measured using an automated system and confirmed by the gold standard method.
RESULTS: There was no significant difference between mucoid and non-mucoid strains. MIC distribution and susceptibility rates were obtained by agar dilution method and from this data we measured MIC50 and MIC90 which were equal to 32 µg/mL and 64 µg/mL, respectively. From automated method results we measured a very major error (VME), major error (ME) and categorical agreement (CA) which were equal to 0%, 11% and 89%, respectively. Comparing automated and agar dilution methods, a Cohen's kappa equal to 73% (0.726) was measured.
CONCLUSIONS: Our data suggest that fosfomycin has good effect against mucoid and non-mucoid strains of P. aeruginosa and automated systems can be implemented in clinical microbiology laboratories to assess fosfomycin with rapid and reproducible results.

PMID: 32105800 [PubMed - as supplied by publisher]

Uncommon clinical presentation of cystic fibrosis in a patient homozygous for a rare CFTR mutation: a case report.

BMC Pediatr. 2020 Feb 27;20(1):90

Authors: Jaworska J, Marach-Mocarska A, Sands D

Abstract
BACKGROUND: Cystic fibrosis (CF) is the most common, life-threatening, autosomal-recessive disorder among Caucasians. To date, approximately 2000 mutations in the CFTR gene have been reported. Some of these mutations are very rare, and some represent individual sequence changes in the gene. The introduction of newborn screening (NBS) in high prevalence countries for CF has considerably changed the diagnosing of this metabolic disease. Currently, in most cases, a diagnosis is made based on NBS, including or expanded with DNA analysis and confirmed with sweat chloride tests, rather than waiting until the child has already developed signs and symptoms. However, in rare cases, NBS does not provide enough information to confirm or reject a CF diagnosis. Not only are there small groups of patients who have false-negative or false-positive NBS results, but there is also a growing number of patients with positive NBS results in whom results of sweat tests and genetic examinations do not provide definite conclusions. Despite all knowledge and modern diagnostic tools at our disposal, sometimes the clinical presentation is so inconclusive, that making a final diagnosis remains a challenge.
CASE PRESENTATION: In this case report, we present a male infant of Polish origin, whose symptoms and laboratory findings (including metabolic acidosis) were strongly suggestive of metabolic disease other than cystic fibrosis. Newborn screening for CF was positive, but the first sweat test results were equivocal, and initial and extended molecular tests were negative. Finally, after considering broad differential diagnosis, introducing treatment specific for CF and excluding other metabolic diseases, a third expanded genetic test revealed the presence of a rare pathogenic mutation in both alleles of the CFTR gene: c.4035_4038dupCCTA (p.Ser1347ProfsX13).
CONCLUSION: Although CF is considered a monogenic disorder, the relationship between genotype and phenotype is very complex. The reported case shows the unusual presentation of the disease. The patient's clinical symptoms and laboratory findings, in combination with molecular test results, provide useful information for further observing the genotype-phenotype correlations in cystic fibrosis.

PMID: 32103733 [PubMed - in process]

Cystic fibrosis: a rare disease emerging in China.

Sci China Life Sci. 2020 Feb 20;:

Authors: Zhang T, Tian X, Xu KF

PMID: 32103413 [PubMed - as supplied by publisher]

Global chemical effects of the microbiome include new bile-acid conjugations.

Nature. 2020 Feb 26;:

Authors: Quinn RA, Melnik AV, Vrbanac A, Fu T, Patras KA, Christy MP, Bodai Z, Belda-Ferre P, Tripathi A, Chung LK, Downes M, Welch RD, Quinn M, Humphrey G, Panitchpakdi M, Weldon KC, Aksenov A, da Silva R, Avila-Pacheco J, Clish C, Bae S, Mallick H, Franzosa EA, Lloyd-Price J, Bussell R, Thron T, Nelson AT, Wang M, Leszczynski E, Vargas F, Gauglitz JM, Meehan MJ, Gentry E, Arthur TD, Komor AC, Poulsen O, Boland BS, Chang JT, Sandborn WJ, Lim M, Garg N, Lumeng JC, Xavier RJ, Kazmierczak BI, Jain R, Egan M, Rhee KE, Ferguson D, Raffatellu M, Vlamakis H, Haddad GG, Siegel D, Huttenhower C, Mazmanian SK, Evans RM, Nizet V, Knight R, Dorrestein PC

Abstract
A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease1-9. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units10), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches11-13 to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry14. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis.

PMID: 32103176 [PubMed - as supplied by publisher]

Disease modification and biomarker development in Parkinson disease: Revision or reconstruction?

Neurology. 2020 Feb 26;:

Authors: Espay AJ, Kalia LV, Gan-Or Z, Williams-Gray CH, Bedard PL, Rowe SM, Morgante F, Fasano A, Stecher B, Kauffman MA, Farrer MJ, Coffey CS, Schwarzschild MA, Sherer T, Postuma RB, Strafella AP, Singleton AB, Barker RA, Kieburtz K, Olanow CW, Lozano A, Kordower JH, Cedarbaum JM, Brundin P, Standaert DG, Lang AE

Abstract
A fundamental question in advancing Parkinson disease (PD) research is whether it represents one disorder or many. Does each genetic PD inform a common pathobiology or represent a unique entity? Do the similarities between genetic and idiopathic forms of PD outweigh the differences? If aggregates of α-synuclein in Lewy bodies and Lewy neurites are present in most (α-synucleinopathies), are they also etiopathogenically significant in each (α-synuclein pathogenesis)? Does it matter that postmortem studies in PD have demonstrated that mixed protein-aggregate pathology is the rule and pure α-synucleinopathy the exception? Should we continue to pursue convergent biomarkers that are representative of the diverse whole of PD or subtype-specific, divergent biomarkers, present in some but absent in most? Have clinical trials that failed to demonstrate efficacy of putative disease-modifying interventions been true failures (shortcomings of the hypotheses, which should be rejected) or false failures (shortcomings of the trials; hypotheses should be preserved)? Each of these questions reflects a nosologic struggle between the lumper's clinicopathologic model that embraces heterogeneity of one disease and the splitter's focus on a pathobiology-specific set of diseases. Most important, even if PD is not a single disorder, can advances in biomarkers and disease modification be revised to concentrate on pathologic commonalities in large, clinically defined populations? Or should our efforts be reconstructed to focus on smaller subgroups of patients, distinguished by well-defined molecular characteristics, regardless of their phenotypic classification? Will our clinical trial constructs be revised to target larger and earlier, possibly even prodromal, cohorts? Or should our trials efforts be reconstructed to target smaller but molecularly defined presymptomatic or postsymptomatic cohorts? At the Krembil Knowledge Gaps in Parkinson's Disease Symposium, the tentative answers to these questions were discussed, informed by the failures and successes of the fields of breast cancer and cystic fibrosis.

PMID: 32102975 [PubMed - as supplied by publisher]

PKA phosphorylation potentiates CFTR gating by relieving auto-inhibition on the stimulatory C terminus of the regulatory domain.

J Biol Chem. 2020 Feb 26;:

Authors: Chen JH

Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel activated by PKA phosphorylation on the regulatory (R) domain. Phosphorylation at several R domain residues stimulates ATP-dependent channel openings and closings, termed channel gating. To explore the protein segment responsible for channel potentiation and PKA-dependent activation, deletion mutations were constructed by removing 1 to 3 protein segments of the R domain, including residues 708-759 (ΔR708-759), R760-783 and R784-835, each of which contains one or two PKA phosphorylation sites. Deletion of R708-759 or R760-783 had little effect on CFTR gating, whereas all mutations lacking R784-835 reduced CFTR activity by decreasing the mean burst duration (MBD) and increasing the interburst interval (IBI). The data suggest that R784-835 plays a major role in stimulating CFTR gating. For ATP-associated regulation, ∆R784-835 had minor impact on gating potentiation by 2'dATP, CaATP and pyrophosphate. Interestingly, introducing a phosphorylated peptide matching R809-835 shortened the IBI of ΔR708-835-CFTR. Consistently, ΔR815-835, but not ΔR784-814, enhanced IBI, whereas both reduced MBD. These data suggest that entire R784-835 is required for stabilizing the open state of CFTR; however, R815-835 through interactions with the channel is dominant for enhancing the opening rate. Of note, PKA markedly decreased the IBI of ΔR708-783-CFTR. Conversely, the IBI of ΔR708-814-CFTR was short and PKA-independent. These data reveal that for stimulating CFTR gating, PKA phosphorylation may relieve R784-814-mediated auto-inhibition that prevents IBI shortening by R815-835 This mechanism may elucidate how the R domain potentiates channel gating and may unveil CFTR stimulation by other protein kinases.

PMID: 32102849 [PubMed - as supplied by publisher]

Comparison of International Growth Standards for Assessing Nutritional Status in Cystic Fibrosis: The GreeCF Study.

J Pediatr Gastroenterol Nutr. 2020 Feb 25;:

Authors: Poulimeneas D, Grammatikopoulou MG, Petrocheilou A, Kaditis AG, Troupi E, Doudounakis SE, Laggas D, Vassilakou T

Abstract
OBJECTIVE: To compare three international growth references and explore their differences in assessing growth in Greek school-aged Cystic Fibrosis (CF) patients.
METHODS: Sample included 114 patients (50 boys, age 11.5 ± 3.9 years), provided care at Aghia Sofia Children's Hospital, Greece. Anthropometrics and Forced Expiratory Volume at 1-second (FEV1%) were measured. Body Mass Index (BMI) and height z-scores were computed according to the Center for Disease Control (CDC), World Health Organization (WHO) and International Obesity Task Force (IOTF) references. Agreement between methods were analyzed with kappa statistics, repeated-measures ANOVA and Bland-Altman analysis. The relationship between FEV1% and BMI was explored with linear regression.
RESULTS: Mean CDC BMI z-score was lowest (0.06 ± 1.08), followed by WHO (0.17 ± 1.14) and IOTF (0.35 ± 1.05) (p≤0.001 for all). The CDC and WHO growth references highly agreed for most weight status strata and stunting; all other comparisons produced lower agreements. Except for CDC and IOTF BMI z-scores, all other comparisons produced wide levels of agreement and proportional bias. CDC reference classified more children as attaining low or normal weight, against WHO or IOTF (p≤0.001 for all). Lowest prevalence of ideal and excess weight was recorded by CDC, compared to all other standards (p≤0.001 for all). All BMI z-scores provided moderate associations with FEV1%.
CONCLUSION: Large variations across weight status classification were present when employing three growth standards in school-aged CF patients. Given than BMI z-scores from all references provided comparable associations with pulmonary function, our data indicate that no studied reference is better than others in assessing growth in CF.

PMID: 32102088 [PubMed - as supplied by publisher]

Salivary biomarkers in the context of gingival inflammation in children with cystic fibrosis.

J Periodontol. 2020 Feb 25;:

Authors: Keles Yucel ZP, Silbereisen A, Emingil G, Tokgoz Y, Kose T, Sorsa T, Tsilingaridis G, Bostanci N

Abstract
BACKGROUND: Cystic fibrosis (CF) is a life-threatening chronic inflammatory disease in children due to respiratory complications. Saliva could serve as reservoir of bacterial colonization and potentially reflect systemic inflammation. This study investigated whether salivary triggering receptor expressed on myeloid cells 1 (TREM-1), peptidoglycan recognition protein 1 (PGLYRP1), interleukin (IL)-1β and calprotectin are associated with CF or reflect concomitant gingival inflammation.
METHODS: Ten CF (age:3-12yrs) and ten systemically healthy age-and-gender-matched children (C) were enrolled in the study. Individuals with CF underwent routine laboratory determinations. Probing pocket depth (PPD), gingival index (GI), plaque index (PI) and bleeding on probing (BOP) were recorded on fully erupted teeth and saliva samples collected. Salivary TREM-1, PGLYRP1, IL-1β and calprotectin were analysed by ELISA.
RESULTS: Children with CF had significantly higher BOP scores (P = 0.001) and calprotectin levels (P = 0.017) compared to the C group. TREM-1, PGLYRP1 and IL-1β could not distinguish between CF and SH but showed positive correlation with GI, PI and BOP in both groups. Calprotectin levels positively correlated with procalcitonin (P = 0.014), thrombocyte counts (P = 0.001), mean platelet volume (P = 0.030) and with PGLYRP1 (P = 0.019) and IL-1β (P = 0.013) in CF children. Receiver operating characteristic curve analysis for calprotectin (CFvsC) showed an area under the curve of 0.79 (95% CI 0.58-0.99, P = 0.034).
CONCLUSIONS: CF children presented with higher gingival inflammation scores and salivary calprotectin levels, that correlated with systemic inflammatory markers. Salivary calprotectin levels were not associated with periodontal parameters. Hence, preliminary data demonstrate that salivary calprotectin might have a chairside diagnostic potential for CF in children. This article is protected by copyright. All rights reserved.

PMID: 32100289 [PubMed - as supplied by publisher]

Staphylococcal lung abscess in a child with cystic fibrosis: Case report & review of literature.

Respir Med Case Rep. 2020;29:101024

Authors: Edwards P, Brener M, Isles A, Kapur N

Abstract
With contemporary cystic fibrosis (CF) care, a lung abscess is an uncommon occurrence. We describe a case of a staphylococcal lung abscess in a teenage girl with CF who presented with a two-week history of non-specific malaise followed by two days of left posterior chest pain and fever. A chest radiograph was consistent with a left sided pulmonary abscess, which was confirmed on a CT scan of the chest. The abscess was drained under ultrasound guidance and cultured methicillin-sensitive Staphylococcus aureus. The patient responded well to antibiotic treatment with the abscess cavity showing complete radiological resolution by six weeks post drainage.

PMID: 32099785 [PubMed]

Misunderstandings, misperceptions, and missed opportunities: Perspectives on adherence barriers from people with CF, caregivers, and CF team members.

Patient Educ Couns. 2020 Feb 19;:

Authors: Eaton CK, Beachy S, McLean KA, Nicolais CJ, Bernstein R, Sáez-Clarke E, Quittner AL, Riekert KA

Abstract
OBJECTIVE: To identify differences in perspectives of people with cystic fibrosis (PwCF) and caregivers versus healthcare providers on adherence barriers. Mismatched perspectives may lead to miscommunication and missed opportunities to reduce barriers and improve CF outcomes.
METHODS: PwCF, caregivers, and CF providers completed audio-taped, semi-structured interviews about adherence barriers. Interviews were transcribed and coded for themes. Themes were reviewed to identify when PwCF-caregiver perspectives differed from providers'.
RESULTS: Participants included 14 adolescents with CF (mean age = 15.89 years, 64 % female, 71 % Caucasian), 14 adults with CF (mean age = 30.03 years, 64 % female, 57 % Caucasian), 29 caregivers (76 % female; 72 % Caucasian), and 42 providers. Four barriers were identified that could generate miscommunication between PwCF-caregivers and providers: Tired = Fatigued/Sleepy versus Tired = Burnout, Vacation and Travel, Knowledge and Skills About CF Regimen, and Daily Habits or Routines. PwCF and caregivers used similar words as providers, but conceptualized barriers differently. PwCF and caregivers discussed barriers pragmatically, however, providers viewed certain barriers more abstractly or unidimensionally, or did not discuss them.
CONCLUSIONS: PwCF-caregivers and providers may not align in how they discuss barriers, which may contribute to miscommunication about adherence challenges.
PRACTICE IMPLICATIONS: Patient-centered communication strategies may enhance providers' understandings of PwCF-caregiver perspectives on barriers and facilitate adherence interventions.

PMID: 32098744 [PubMed - as supplied by publisher]

Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways.

Int J Mol Sci. 2020 Feb 21;21(4):

Authors: Karatas E, Bouchecareilh M

Abstract
Human cells express large amounts of different proteins continuously that must fold into well-defined structures that need to remain correctly folded and assemble in order to ensure their cellular and biological functions. The integrity of this protein balance/homeostasis, also named proteostasis, is maintained by the proteostasis network (PN). This integrated biological system, which comprises about 2000 proteins (chaperones, folding enzymes, degradation components), control and coordinate protein synthesis folding and localization, conformational maintenance, and degradation. This network is particularly challenged by mutations such as those found in genetic diseases, because of the inability of an altered peptide sequence to properly engage PN components that trigger misfolding and loss of function. Thus, deletions found in the ΔF508 variant of the Cystic Fibrosis (CF) transmembrane regulator (CFTR) triggering CF or missense mutations found in the Z variant of Alpha 1-Antitrypsin deficiency (AATD), leading to lung and liver diseases, can accelerate misfolding and/or generate aggregates. Conversely to CF variants, for which three correctors are already approved (ivacaftor, lumacaftor/ivacaftor, and most recently tezacaftor/ivacaftor), there are limited therapeutic options for AATD. Therefore, a more detailed understanding of the PN components governing AAT variant biogenesis and their manipulation by pharmacological intervention could delay, or even better, avoid the onset of AATD-related pathologies.

PMID: 32098273 [PubMed - in process]

Small Molecule Anion Carriers Correct Abnormal Airway Surface Liquid Properties in Cystic Fibrosis Airway Epithelia.

Int J Mol Sci. 2020 Feb 21;21(4):

Authors: Gianotti A, Capurro V, Delpiano L, Mielczarek M, García-Valverde M, Carreira-Barral I, Ludovico A, Fiore M, Baroni D, Moran O, Quesada R, Caci E

Abstract
Cystic fibrosis (CF) is a genetic disease characterized by the lack of cystic fibrosis transmembrane conductance regulator (CFTR) protein expressed in epithelial cells. The resulting defective chloride and bicarbonate secretion and imbalance of the transepithelial homeostasis lead to abnormal airway surface liquid (ASL) composition and properties. The reduced ASL volume impairs ciliary beating with the consequent accumulation of sticky mucus. This situation prevents the normal mucociliary clearance, favouring the survival and proliferation of bacteria and contributing to the genesis of CF lung disease. Here, we have explored the potential of small molecules capable of facilitating the transmembrane transport of chloride and bicarbonate in order to replace the defective transport activity elicited by CFTR in CF airway epithelia. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into a mucociliated epithelia in order to assess the effects of our compounds on some key properties of ASL. The treatment of these functional models with non-toxic doses of the synthetic anionophores improved the periciliary fluid composition, reducing the fluid re-absorption, correcting the ASL pH and reducing the viscosity of the mucus, thus representing promising drug candidates for CF therapy.

PMID: 32098269 [PubMed - in process]

Comparative Genomics and Evolutionary Analysis of RNA-Binding Proteins of Burkholderia cenocepacia J2315 and Other Members of the B. cepacia Complex.

Genes (Basel). 2020 Feb 21;11(2):

Authors: Feliciano JR, Seixas AMM, Pita T, Leitão JH

Abstract
RNA-binding proteins (RBPs) are important regulators of cellular functions, playing critical roles on the survival of bacteria and in the case of pathogens, on their interaction with the host. RBPs are involved in transcriptional, post-transcriptional, and translational processes. However, except for model organisms like Escherichia coli, there is little information about the identification or characterization of RBPs in other bacteria, namely in members of the Burkholderia cepacia complex (Bcc). Bcc is a group of bacterial species associated with a poor clinical prognosis in cystic fibrosis patients. These species have some of the largest bacterial genomes, and except for the presence of two-distinct Hfq-like proteins, their RBP repertoire has not been analyzed so far. Using in silico approaches, we identified 186 conventional putative RBPs in Burkholderia cenocepacia J2315, an epidemic and multidrug resistant pathogen of cystic fibrosis patients. Here we describe the comparative genomics and phylogenetic analysis of RBPs present in multiple copies and predicted to play a role in transcription, protein synthesis, and RNA decay in Bcc bacteria. In addition to the two different Hfq chaperones, five cold shock proteins phylogenetically close to E. coli CspD protein and three distinct RhlE-like helicases could be found in the B. cenocepacia J2315 genome. No RhlB, SrmB, or DeaD helicases could be found in the genomes of these bacteria. These results, together with the multiple copies of other proteins generally involved in RNA degradation, suggest the existence, in B. cenocepacia and in other Bcc bacteria, of some extra and unexplored functions for the mentioned RBPs, as well as of alternative mechanisms involved in RNA regulation and metabolism in these bacteria.

PMID: 32098200 [PubMed - in process]

Burkholderia cenocepacia-host cell contact controls the transcription activity of the trimeric autotransporter adhesin BCAM2418 gene.

Microbiologyopen. 2020 Feb 25;:e998

Authors: Pimenta AI, Mil-Homens D, Fialho AM

Abstract
Cell-to-cell early contact between pathogens and their host cells is required for the establishment of many infections. Among various surface factors produced by bacteria that allow an organism to become established in a host, the class of adhesins is a primary determinant. Burkholderia cenocepacia adheres to the respiratory epithelium of cystic fibrosis patients and causes chronic inflammation and disease. Cell-to-cell contacts are promoted by various kinds of adhesins, including trimeric autotransporter adhesins (TAAs). We observed that among the 7 TAA genes found in the B. cenocepacia K56-2 genome, two of them (BCAM2418 and BCAS0236) express higher levels of mRNA following physical contact with host cells. Further analysis revealed that the B. cenocepacia K56-2 BCAM2418 gene shows an on-off switch after an initial colonization period, exhibits a strong expression dependent on the host cell type, and enhances its function on cell adhesion. Furthermore, our analysis revealed that adhesion to mucin-coated surfaces dramatically increases the expression levels of BCAM2418. Abrogation of mucin O-glycans turns BCAM2418 gene expression off and impairs bacterial adherence. Overall, our findings suggest that glycosylated extracellular components of host membrane might be a binding site for B. cenocepacia and a signal for the differential expression of the TAA gene BCAM2418.

PMID: 32097539 [PubMed - as supplied by publisher]

Hepatic manifestations of cystic fibrosis.

Curr Opin Gastroenterol. 2020 Feb 20;:

Authors: Dana J, Girard M, Debray D

Abstract
PURPOSE OF REVIEW: Liver disease in cystic fibrosis (CF) usually develops before puberty, is often asymptomatic and slowly progressive. Multilobular cirrhosis develops in approximately 5-10% of patients by the age of 18, and is a significant contributor to the morbidity and mortality. No therapy, including ursodeoxycholic acid and cystic fibrosis transmembrane conductance regulator correctors or potentiators, has proven effective to prevent or halt the progression of liver disease towards cirrhosis and portal hypertension. This review provides the current knowledge in the epidemiology of CF liver disease and development of noninvasive tools to assess liver disease severity and progression overtime in order to optimize clinical management and therapeutic options.
RECENT FINDINGS: Liver disease not only develops during childhood but also later in the lifetime of patients with CF; the incidence of cirrhosis with portal hypertension increases progressively reaching 10% by age 30. Several noninvasive tools to measure liver stiffness as an indirect measure of fibrosis are being investigated, and show promising results for the assessment of early stages of liver fibrosis and disease progression.
SUMMARY: Identifying noninvasive biomarkers is fundamental to improving early diagnosis, monitoring disease evolution and measuring treatment effects. A prerequisite is the use of consistent definitions for CF- liver disease (LD) in clinical trials.

PMID: 32097175 [PubMed - as supplied by publisher]