Lancet Respir Med. 2023 Jan 13:S2213-2600(23)00002-4. doi: 10.1016/S2213-2600(23)00002-4. Online ahead of print.

NO ABSTRACT

PMID:36646100 | DOI:10.1016/S2213-2600(23)00002-4

J Eur Acad Dermatol Venereol. 2023 Jan 16. doi: 10.1111/jdv.18869. Online ahead of print.

NO ABSTRACT

PMID:36645858 | DOI:10.1111/jdv.18869

FASEB Bioadv. 2022 Oct 31;5(1):13-26. doi: 10.1096/fba.2022-00085. eCollection 2023 Jan.

ABSTRACT

Highly effective modulator therapies for cystic fibrosis (CF) make it a treatable condition for many people. However, although CF respiratory illness occurs after birth, other organ systems particularly in the digestive tract are damaged before birth. We use an ovine model of CF to investigate the in utero origins of CF disease since the sheep closely mirrors critical aspects of human development. Wildtype (WT) and CFTR -/- sheep tissues were collected at 50, 65, 80, 100, and 120 days of gestation and term (147 days) and used for histological, electrophysiological, and molecular analysis. Histological abnormalities are evident in CFTR-/- -/- animals by 80 days of gestation, equivalent to 21 weeks in humans. Acinar and ductal dilation, mucus obstruction, and fibrosis are observed in the pancreas; biliary fibrosis, cholestasis, and gallbladder hypoplasia in the liver; and intestinal meconium obstruction, as seen at birth in all large animal models of CF. Concurrently, cystic fibrosis transmembrane conductance regulator (CFTR)-dependent short circuit current is present in WT tracheal epithelium by 80 days gestation and is absent from CFTR -/- tissues. Transcriptomic profiles of tracheal tissues confirm the early expression of CFTR and suggest that its loss does not globally impair tracheal differentiation.

PMID:36643895 | PMC:PMC9832529 | DOI:10.1096/fba.2022-00085

ACS Omega. 2022 Dec 28;8(1):846-856. doi: 10.1021/acsomega.2c06212. eCollection 2023 Jan 10.

ABSTRACT

Patients with chronic rhinosinusitis (CRS) often show persistent colonization by bacteria in the form of biofilms which are resistant to antibiotic treatment. One of the most commonly isolated bacteria in CRS is Staphylococcus aureus (S. aureus). Nitric oxide (NO) is a potent antimicrobial agent and disperses biofilms efficiently. We hypothesized that S-nitrosoglutathione (GSNO), an endogenous NO carrier/donor, synergizes with gentamicin to disperse and reduce the bacterial biofilm density. We prepared GSNO formulations which are stable up to 12 months at room temperature and show the maximum amount of NO release within 1 h. We examined the effects of this GSNO formulation on the S. aureus biofilm established on the apical surface of the mucociliary-differentiated airway epithelial cell cultures regenerated from airway basal (stem) cells from cystic fibrosis (CF) and CRS patients. We demonstrate that for CF cells, which are defective in producing NO, treatment with GSNO at 100 μM increased the NO levels on the apical surface and reduced the biofilm bacterial density by 2 log units without stimulating pro-inflammatory effects or inducing epithelial cell death. In combination with gentamicin, GSNO further enhanced the killing of biofilm bacteria. Compared to placebo, GSNO significantly increased the ciliary beat frequency (CBF) in both infected and uninfected CF cell cultures. The combination of GSNO and gentamicin also reduced the bacterial density of biofilms grown on sinonasal epithelial cells from CRS patients and improved the CBF. These findings demonstrate that GSNO in combination with gentamicin may effectively reduce the density of biofilm bacteria in CRS patients. GSNO treatment may also enhance the mucociliary clearance by improving the CBF.

PMID:36643497 | PMC:PMC9835527 | DOI:10.1021/acsomega.2c06212

Pediatr Pulmonol. 2023 Jan 15. doi: 10.1002/ppul.26312. Online ahead of print.

ABSTRACT

Despite attempts to provide medical care with minimal pain, procedural pain remains an important issue in paediatric care. Children with chronic medical conditions such as cystic fibrosis (CF) requires repeated medical procedures, which may amplify distress and increase levels of both pain and anxiety when exposed to subsequent procedures This article is protected by copyright. All rights reserved.

PMID:36642950 | DOI:10.1002/ppul.26312

Respirology. 2023 Jan 15. doi: 10.1111/resp.14450. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Neutrophil elastase (NE), is an important host defence against lung pathogens. Maintaining a homeostatic balance between proteases such as NE and anti-proteases such as secretory leukocyte protease inhibitor (SLPI), is important to prevent tissue damage. In the cystic fibrosis (CF) lung, elevated protease levels and impaired anti-protease defences contribute to tissue destruction.

METHODS: We assessed lung function and sputum SLPI and NE levels from Pseudomonas aeruginosa infected and non-infected CF patients (median age 20 years at recruitment) during different phases of clinical disease. Healthy, never smokers served as healthy controls (HC). Sputum total cell counts (TCC) and colony forming units of P. aeruginosa were also determined in each sputum sample.

RESULTS: Compared to HC, sputum SLPI was significantly reduced and NE increased in all CF subjects whether infected with P. aeruginosa or not, but the presence of P. aeruginosa worsened these parameters. Females with chronic P. aeruginosa infection had significantly lower sputum SLPI levels than males (p < 0.001). Higher sputum SLPI levels were associated with a significantly reduced rate of longitudinal decline in FEV1 % predicted (p < 0.05). Antibiotic treatment in P. aeruginosa-infected patients significantly decreased sputum TCC and increased SLPI levels, which positively correlated with improved lung function.

CONCLUSION: Airway SLPI is deficient in CF, which appears more marked in P. aeruginosa-infected female patients. Importantly, a reduced anti-protease to protease ratio is associated with accelerated lung function decline. Treatment of an exacerbation is accompanied by partial recovery of anti-protease defences and significant improvement in lung function, an important clinical outcome.

PMID:36642534 | DOI:10.1111/resp.14450

Lancet Respir Med. 2023 Jan 12:S2213-2600(23)00003-6. doi: 10.1016/S2213-2600(23)00003-6. Online ahead of print.

NO ABSTRACT

PMID:36642077 | DOI:10.1016/S2213-2600(23)00003-6

Mol Ther. 2023 Jan 13:S1525-0016(23)00014-X. doi: 10.1016/j.ymthe.2023.01.014. Online ahead of print.

ABSTRACT

Nonsense mutations are responsible for around 10% of cases of genetic diseases, including cystic fibrosis. 2,6-diaminopurine (DAP) has recently been shown to promote efficient readthrough of UGA premature stop codons. In this study, we show that DAP can correct a nonsense mutation in the Cftr gene in vivo in a new CF mouse model, in utero, and through breastfeeding, notably thanks to adequate pharmacokinetic properties. DAP turns out to be very stable in plasma and is distributed throughout the body. The ability of DAP to correct various endogenous UGA nonsense mutations in the CFTR gene and to restore its function in mice, in organoids derived from murine or patient cells, and in cells from patients with cystic fibrosis reveals the potential of such readthrough-stimulating molecules in developing a therapeutic approach. The fact that correction by DAP of certain nonsense mutations reaches a clinically relevant level, as judged from previous studies, makes the use of this compound all the more attractive.

PMID:36641622 | DOI:10.1016/j.ymthe.2023.01.014

Infect Dis Health. 2023 Jan 12:S2468-0451(22)00122-5. doi: 10.1016/j.idh.2022.12.002. Online ahead of print.

ABSTRACT

BACKGROUND: The avoidance of cross-infection remains of critical importance to prevent the transmission of cystic fibrosis (CF)-related microbial pathogens to persons/people with cystic fibrosis (PwCF). To date, there has been a paucity of infection prevention and control (IPC) guidance relating to infection risk at higher educational institutions. With improvements in treatments, more PwCF are now attending universities/colleges and educational institutions now seek CF-specific guidance on IPC from clinical CF teams/centres.

METHODS: Real world infection-related questions from university students, educators, university support staff and the CF multidisciplinary team were received and collated from various stakeholders, including individual consultations and focus group sessions with two local universities. Subsequently, evidence-based recommendations were compiled from existing peer-reviewed literature and from cystic fibrosis organisations. Glossaries were constructed relating to clinical, microbiological and educational/pedagogical terminology to aid with the understanding amongst these stakeholder groups.

RESULTS: This review addresses CF-related IPC recommendations across five areas of university/college life, including (i) on campus estate, (ii) teaching (lectures/tutorials/small study group work/group assignments), (iii) laboratory practicals, (iv) field trips/study visits/work placements and (v) residential accommodation and lists practical recommendations to help prevent the transmission of infections to PwCF students.

CONCLUSIONS: It is important that the educational institutional environment is safe permitting the PwCF student to enjoy their educational experience and journey through higher education, culminating in achievement of their educational goals, employment and independent living. The guidance presented in this review is intended to equip educational establishments in creating their own bespoke and robust IPC policies relating to PwCF students.

PMID:36641287 | DOI:10.1016/j.idh.2022.12.002

Med J Aust. 2023 Jan 14. doi: 10.5694/mja2.51837. Online ahead of print.

NO ABSTRACT

PMID:36641140 | DOI:10.5694/mja2.51837

J Heart Lung Transplant. 2022 Dec 27:S1053-2498(22)02262-8. doi: 10.1016/j.healun.2022.12.014. Online ahead of print.

ABSTRACT

BACKGROUND: Severe primary graft dysfunction (PGD) is associated with the development of bronchiolitis obliterans syndrome (BOS), the most common form of chronic lung allograft dysfunction (CLAD), in adults. However, PGD associations with long-term outcomes following pediatric lung transplantation are unknown. We hypothesized that PGD grade 3 (PGD 3) at 48- or 72-hours would be associated with shorter CLAD-free survival following pediatric lung transplantation.

METHODS: This was a single center retrospective cohort study of patients ≤ 21 years of age who underwent bilateral lung transplantation between 2005 and 2019 with ≥ 1 year of follow-up. PGD and CLAD were defined by published criteria. We evaluated the association of PGD 3 at 48- or 72-hours with CLAD-free survival by using time-to-event analyses.

RESULTS: Fifty-one patients were included (median age 12.7 years; 51% female). The most common transplant indications were cystic fibrosis (29%) and pulmonary hypertension (20%). Seventeen patients (33%) had PGD 3 at either 48- or 72-hours. In unadjusted analysis, PGD 3 was associated with an increased risk of CLAD or mortality (HR 2.10, 95% CI 1.01-4.37, p=0.047). This association remained when adjusting individually for multiple potential confounders. There was evidence of effect modification by sex (interaction p = 0.055) with the association of PGD 3 and shorter CLAD-free survival driven predominantly by males (HR 4.73, 95% CI 1.44-15.6) rather than females (HR 1.23, 95% CI 0.47-3.20).

CONCLUSIONS: PGD 3 at 48- or 72-hours following pediatric lung transplantation was associated with shorter CLAD-free survival. Sex may be a modifier of this association.

PMID:36639317 | DOI:10.1016/j.healun.2022.12.014

Pediatr Infect Dis J. 2023 Feb 1;42(2):e57-e58. doi: 10.1097/INF.0000000000003765. Epub 2022 Nov 7.

NO ABSTRACT

PMID:36638411 | DOI:10.1097/INF.0000000000003765

Pediatr Phys Ther. 2023 Jan 1;35(1):48. doi: 10.1097/PEP.0000000000000986.

NO ABSTRACT

PMID:36638026 | DOI:10.1097/PEP.0000000000000986

Pediatr Pulmonol. 2023 Jan 12. doi: 10.1002/ppul.26314. Online ahead of print.

ABSTRACT

We are hopeful that CTFR modulation does have a positive impact of bone health, but we have concerns about this study design being used to support the hypothesis This article is protected by copyright. All rights reserved.

PMID:36635953 | DOI:10.1002/ppul.26314

Sci Rep. 2023 Jan 12;13(1):600. doi: 10.1038/s41598-022-24429-6.

ABSTRACT

Cystic fibrosis is a hereditary metabolic disorder characterized by impaired traffic of chloride ions and water through membranes of the respiratory and gastrointestinal, that causes inadequate hydration of airway surfaces, dehydrated mucous secretions and a high-sodium chloride sweat. Although the classical presentation of the condition is well known, a better characterization of metabolic alterations related is need. In particular, the metabolic composition alterations of biological fluids may be influence by the disease state and could be captured as putative signature to set targeted therapeutic strategies. A targeted comprehensive mass spectrometry-based platform was employed to dissect the lipid content of saliva samples form CF patients, in order to investigate alterations in the lipid metabolic homeostasis related to the pathology, chronic obstructive pulmonary disease, Pseudomonas Aeruginosa infection, pancreatic insufficiency, liver disfunction and diabetes-related complications.

PMID:36635275 | DOI:10.1038/s41598-022-24429-6

J Cyst Fibros. 2023 Jan 10:S1569-1993(22)01432-1. doi: 10.1016/j.jcf.2022.12.012. Online ahead of print.

ABSTRACT

BACKGROUND: With improvement in supportive therapies and the introduction of cystic fibrosis transmembrane conductance regulator (CFTR)-modulator treatment in patients with cystic fibrosis (CF), milder disease courses are expected. Therefore, sensitive parameters are needed to monitor disease course and effects of CFTR-modulators. Functional lung MRI using matrix-pencil decomposition (MP-MRI) is a promising tool for assessing ventilation and perfusion quantitatively. This study aimed to assess the treatment effect of elexacaftor/tezacaftor/ivacaftor combination regimen (ELX/TEZ/IVA) on measures of structural and functional lung abnormalities.

METHODS: 24 children with CF underwent lung function tests (multiple breath washout, spirometry), functional and structural MRI twice (one year apart) before and once after at least two weeks (mean 4.7 ± 2.6 months) on ELX/TEZ/IVA. Main outcomes were changes (Δ) upon ELX/TEZ/IVA in lung function, defect percentage of ventilation (VDP) and perfusion (QDP), defect distribution index of ventilation and perfusion (DDIV, DDIQ), and Eichinger score. Statistical analyses were performed using paired t-tests and multilevel regression models with bootstrapping.

RESULTS: We observed a significant improvement in lung function, structural and functional MRI parameters upon ELX/TEZ/IVA treatment (mean; 95%-CI): ΔLCI2.5 (TO) -0.84 (-1.62 to -0.06); ΔFEV1 (z-score) 1.05 (0.56 to 1.55); ΔVDP (% of impairment) -6.00 (-8.44 to -3.55); ΔQDP (% of impairment) -3.90 (-5.90 to -1.90); ΔDDIV -1.38 (-2.22 to -0.53); ΔDDIQ -0.31 (-0.73 to 0.12); ΔEichinger score -3.89 (-5.05 to -2.72).

CONCLUSIONS: Besides lung function tests, functional and structural MRI is a suitable tool to monitor treatment response of ELX/TEZ/IVA therapy, and seems promising as outcome marker in the future.

PMID:36635199 | DOI:10.1016/j.jcf.2022.12.012

Eur J Intern Med. 2023 Jan 5:S0953-6205(23)00003-1. doi: 10.1016/j.ejim.2023.01.003. Online ahead of print.

NO ABSTRACT

PMID:36635129 | DOI:10.1016/j.ejim.2023.01.003

Appl Microbiol Biotechnol. 2023 Jan 12. doi: 10.1007/s00253-022-12347-6. Online ahead of print.

ABSTRACT

Pseudmonas aeruginosa is a Gram-negative bacterium known to be ubiquitous and recognized as one of the leading causes of infections such as respiratory, urinary tract, burns, cystic fibrosis, and in immunocompromised individuals. Failure of antimicrobial therapy has been documented to be attributable due to the development of various resistance mechanisms, with a proclivity to develop additional resistance mechanisms rapidly. P. aeruginosa virulence attenuation is an alternate technique for disrupting pathogenesis without impacting growth. The iron-scavenging siderophores (pyoverdine and pyochelin) generated by P. aeruginosa have various properties like scavenging iron, biofilm formation, quorum sensing, increasing virulence, and toxicity to the host. As a result, developing an antivirulence strategy, specifically inhibiting the P. aeruginosa siderophore, has been a promising therapeutic option to limit their infection. Several natural, synthetic compounds and nanoparticles have been identified as potent inhibitors of siderophore production/biosynthesis, function, and transport system. The current review discussed pyoverdine and pyochelin's synthesis and transport system in P. aeruginosa. Furthermore, it is also focused on the role of several natural and synthetic compounds in reducing P. aeruginosa virulence by inhibiting siderophore synthesis, function, and transport. The underlying mechanism involved in inhibiting the siderophore by natural and synthetic compounds has also been explained. KEY POINTS: • Pseudomonas aeruginosa is an opportunistic pathogen linked to chronic respiratory, urinary tract, and burns infections, as well as cystic fibrosis and immunocompromised patients. • P. aeruginosa produces two virulent siderophores forms: pyoverdine and pyochelin, which help it to survive in iron-deficient environments. • The inhibition of siderophore production, transport, and activity using natural and synthesized drugs has been described as a potential strategy for controlling P. aeruginosa infection.

PMID:36633626 | DOI:10.1007/s00253-022-12347-6

Neonatal Netw. 2023 Jan 1;42(1):31-36. doi: 10.1891/NN-2022-0012.

ABSTRACT

We present a case of an infant born to a mother with COVID-19, who at 24 hours of life was treated with a glycerin suppository for failure to pass meconium and went on to develop bilious emesis and abdominal distention as feeding continued over the next several hours. After a barium enema identified the distal obstruction, the pediatric surgical team used rectal irrigation to remove a large meconium plug, which mimicked the appearance of the descending colon on plain film, in a case of small left colon syndrome. Although intestinal obstruction in the newborn is rare, it is imperative that it is promptly diagnosed and treated appropriately to avoid negative outcomes; which, even in perhaps the mildest form of functional distal obstruction, meconium plug syndrome, can lead to an impressive clinical illness with risk of intestinal perforation and subsequent meconium peritonitis if the obstruction is not relieved.

PMID:36631261 | DOI:10.1891/NN-2022-0012

Neonatal Netw. 2023 Jan 1;42(1):23-30. doi: 10.1891/NN-2022-0007.

ABSTRACT

Cystic fibrosis (CF) is the most common genetic disorder in Caucasian individuals, with an incidence of 1/2,500-3,500 live births. When CF was first described in 1938, most children died in infancy. Currently, the average lifespan is 28-47.7 years. Although new breakthroughs have occurred, CF is still incurable. Both early diagnosis and treatment by multidisciplinary teams are essential to optimize short- and long-term outcomes. It is imperative for neonatal clinicians to keep up to date on the most current research, treatment, and management of CF to provide the best outcomes. This article offers clinicians an updated review of the pathophysiology and clinical manifestations of CF, as well as current evidence-based diagnostics and treatment regimens.

PMID:36631257 | DOI:10.1891/NN-2022-0007