Pediatr Pulmonol. 2023 Jun 2. doi: 10.1002/ppul.26527. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has been associated with unprecedented clinical improvements, transforming the management of cystic fibrosis (CF). However, side effects with implications for safety and well-being have been reported, including neuropsychiatric changes. This study aimed to better characterize the emerging positive and negative impacts of ETI.

METHODS: The Cystic Fibrosis Foundation's Mental Health Advisory Committee distributed a 26-item survey to US CF care teams to assess clinician observations of patient-reported experiences with ETI. Survey responses measured the prevalence of these effects in five domains: (1) positive physical and psychological effects, (2) sleep difficulties, (3) cognitive difficulties, (4) worsening mental health, and (5) concerns about the future and finances.

RESULTS: Seventy-five healthcare providers responded from a pediatric, adult, and combined centers. Positive physical effects of ETI and increased optimism were reported in the upper quartiles (50%-100%) and rated as having a significant impact on daily functioning. Sleep and cognitive difficulties were reported in 1%-24%, with slight impacts on functioning, and psychological symptoms (e.g., increased stress, depression, anxiety) and new psychiatric medications were reported in 1%-24%, with moderate impacts. Concerns about the future were reported in 1%-24%, with minimal impacts.

CONCLUSION: Across US centers, providers most often observed positive physical effects of ETI. However, a variety of negative side effects were also reported, including sleep disruptions and worsening psychological functioning, which should be systematically monitored by CF teams. These national-level data are a first step in evaluating the prevalence and consequences of these side effects and can directly inform future studies.

PMID:37265418 | DOI:10.1002/ppul.26527

Nutrition. 2023 May 11;112:112073. doi: 10.1016/j.nut.2023.112073. Online ahead of print.

ABSTRACT

OBJECTIVE: The energy demands of individuals with cystic fibrosis (CF) vary depending on pancreatic function, body composition, lung function, and clinical status. In clinical practice, predictive equations are used to determine energy requirements yet do not reliably account for these factors. Research regarding energy requirements during CF pulmonary exacerbation (CFPEx) and clinical stability is conflicting. The aim of this study was to investigate potential within-individual changes in measured resting energy expenditure (mREE) using indirect calorimetry (IC) at the commencement and completion of intravenous antibiotic treatment (IVABx) for CFPEx and during clinical stability. Secondary aims were to investigate potential differences between predicted resting energy expenditure (pREE) using Schofield equation and correlations between clinical factors with mREE.

METHODS: Body composition using bioimpedance analysis and mREE were conducted at three time points: commencement of IVABx; completion of IVABx; and clinically stable period thereafter.

RESULTS: Twenty-eight adults with CF completed at least one valid IC measurement. No significant within-person changes in mREE and body composition parameters were observed across time points. The mREE was positively correlated with fat-free mass (kg; r = 0.6; P = 0.008). The mREE was significantly higher than pREE at all time points with the mREE/pREE ratio elevated at time point 1:118% ± 19.5%; time point 2: 112% ± 13.2%; and time point 3: 122 ± 14.3%.

CONCLUSION: The mREE remained stable during CFPEx and clinical stability. The pREE underestimated mREE and application of injury factor adjustment of 110% to 130% could potentially account for this discrepancy. The potential role of IC and body composition in individualizing CF nutritional assessment and prescription requires further exploration.

PMID:37263161 | DOI:10.1016/j.nut.2023.112073

Adv Med Sci. 2023 May 30;68(2):202-207. doi: 10.1016/j.advms.2023.05.002. Online ahead of print.

ABSTRACT

PURPOSE: The measurement of biomarkers in exhaled breath condensate (EBC) offers a non-invasive way to assess airway disease and can be easily done in a clinical setting among patients with cystic fibrosis (CF). The role of oxidative and nitrosative stress in the complex pathophysiology of CF is widely accepted and biomarkers of oxidative and nitrosative stress can be measured in the serum and EBC. To our knowledge, this is the first study to assess markers of nitrosative stress in EBC and serum, collected simultaneously from the CF patients.

PATIENTS AND METHODS: Paired EBC and serum samples were collected from 36 stable patients with CF and 14 healthy controls. Markers of nitrosative stress ‒ 3-nitrotyrosine and nitrate/nitrite were measured in the EBC and serum using an enzyme-linked immunosorbent assay.

RESULTS: We found no differences in 3-nitrotyrosine and nitrate/nitrite in the EBC of patients with CF as compared to healthy controls (125.37 ​± ​3.29 vs. 126.24 ​± ​2.21 ​nmol/L, p ​= ​0.218; 12.66 ​± ​7.23 vs. 8.79 ​± ​4.83 ​μmol/L, p ​= ​0.133, respectively). Furthermore, 3-nitrotyrosine and nitrate/nitrite were significantly higher in the serum of patients with CF as compared to the healthy controls (0.13 ​± ​0.02 vs. 0.11 ​± ​0.01 ​nmol/mg protein, p ​= ​0.003; 70.78 ​± ​22.55 vs. 53.08 ​± ​8.5 ​μmol/L, p ​= ​0.009, respectively). No correlations were found between the markers determined in the EBC and serum.

CONCLUSIONS: The results of the EBC nitrosative stress biomarkers should be interpreted with caution, especially in patients with stable disease, as the EBC values may be independent on levels of circulating markers that are elevated in the serum of patients with stable CF.

PMID:37263097 | DOI:10.1016/j.advms.2023.05.002

BMC Pulm Med. 2023 Jun 1;23(1):190. doi: 10.1186/s12890-023-02463-y.

ABSTRACT

BACKGROUND: The present study evaluates personality traits in adult patients with cystic fibrosis (CF) and correlates these results with health-related quality of life (HRQoL) and other clinical parameters indicative of disease severity.

METHODS: Seventy adults completed the Cystic Fibrosis Questionnaire-Revised (CFQ-R 14+), a CF-specific measure of HRQoL, and a self-administered questionnaire about personality traits and disorders. Mean subscale scores and the prevalence of extreme personality traits on the `Persönlichkeits-Stil- und Störungs-Inventar (PSSI)´ were compared to the norming sample. Moreover, a cluster analysis was conducted to identify personality styles among people with cystic fibrosis (pwCF). The relationship between mean PSSI subscale scores and personality clusters with HRQoL and clinical outcomes, e.g., percent predicted forced expiratory volume in one second (ppFEV1), and body mass index (BMI), was studied by regression analysis considering important confounders.

RESULTS: On several of the subscales of the personality questionnaire, people with cystic fibrosis (pwCF) showed either significantly higher or lower scores than the norm sample. In further analyses, two personality clusters could be identified. PwCF from the cluster with predominantly low scores on the subscales 'negativistic', 'schizoid', 'borderline', 'depressed', and 'paranoid' showed better HRQoL than pwCF from the other cluster with mainly high normal or elevated scores. The studied health outcomes proved to be independent of the respective personality clusters.

CONCLUSIONS: In pwCF, HRQoL is mainly determined by psychological factors, including personality. Since more recent personality theories assume that personality is modifiable, our findings imply that patients with accentuated personality traits may benefit from psychosocial support.

PMID:37264349 | DOI:10.1186/s12890-023-02463-y

Sci Rep. 2023 Jun 1;13(1):8910. doi: 10.1038/s41598-023-35942-7.

ABSTRACT

Cystic fibrosis (CF) is a progressive multi-organ disease with significant morbidity placing extensive demands on the healthcare system. Little is known about those individuals with CF who continually incur high costs over multiple years. Understanding their characteristics may help inform opportunities to improve management and care, and potentially reduce costs. The purpose of this study was to identify and understand the clinical and demographic attributes of frequent high-costing CF individuals and characterize their healthcare utilization and costs over time. A longitudinal study of retrospective data was completed in British Columbia, Canada by linking the Canadian CF Registry with provincial healthcare administrative databases for the period between 2009 and 2017. Multivariable Cox regression models were employed to identify baseline factors associated with becoming a frequent high-cost CF user (vs. not a frequent high-cost CF user) in the follow-up period. We found that severe lung impairment (Hazard Ratio [HR]: 3.71, 95% confidence interval [CI], 1.49-9.21), lung transplantation (HR: 4.23, 95% CI, 1.68-10.69), liver cirrhosis with portal hypertension (HR: 10.96, 95% CI: 3.85-31.20) and female sex (HR: 1.97, 95% CI: 1.13-3.44) were associated with becoming a frequent high-cost CF user. Fifty-nine (17% of cohort) frequent high-cost CF users accounted for more than one-third of the overall total healthcare costs, largely due to inpatient hospitalization and outpatient medication costs.

PMID:37264136 | DOI:10.1038/s41598-023-35942-7

Sci Rep. 2023 Jun 1;13(1):8876. doi: 10.1038/s41598-023-35919-6.

ABSTRACT

The high antibiotic resistance of Pseudomonas aeruginosa (PA) makes it critical to develop alternative antimicrobial agents that are effective and affordable. One of the many applications of silver nanoparticles (Ag NPs) is their use as an antimicrobial agent against bacteria resistant to common antibiotics. The key purpose of this research was to assess the antibacterial and antibiofilm effectiveness of biosynthesized Ag NPs against six biofilm-forming clinically isolated strains of PA and one reference strain (ATCC 27853). Ag NPs were biosynthesized using a seed extract of Peganum harmala as a reducing agent. Ag NPs were characterized by Ultraviolet-visible (UV-Vis) spectroscopy and scanning transmission electron microscopy (STEM). The effect of Ag NPs on biofilm formation and eradication was examined through micro-titer plate assays, and the minimal inhibitory (MIC) and minimum bactericidal (MBC) concentrations determined. In addition, real-time polymerase chain reactions (RT-PCR) were performed to examine the effects of Ag NPs on the expression of seven PA biofilm-encoding genes (LasR, LasI, LssB, rhIR, rhII, pqsA and pqsR). The biosynthesized Ag NPs were spherically-shaped with a mean diameter of 11 nm. The MIC for each PA strain was 15.6 µg/ml, while the MBC was 31.25 µg/ml. All PA strains exposed to Ag NPs at sub-inhibitory concentrations (0.22-7.5 µg/ml) showed significant inhibitory effects on growth and biofilm formation. Biomass and biofilm metabolism were reduced dependent on Ag NP concentration. The expression of the quorum-sensing genes of all strains were significantly reduced at an Ag NP concentration of 7.5 µg/ml. The results demonstrate the extensive in-vitro antibacterial and antibiofilm performance of Ag NPs and their potential in the treatment of PA infection. It is recommended that future studies examine the possible synergy between Ag NPs and antibiotics.

PMID:37264060 | DOI:10.1038/s41598-023-35919-6

Vaccine. 2023 May 22:S0264-410X(23)00590-X. doi: 10.1016/j.vaccine.2023.05.041. Online ahead of print.

ABSTRACT

People with cystic fibrosis (pwCF) were considered to be clinically vulnerable to COVID-19 and were therefore given priority in the vaccination campaign. Vaccines induced a humoral response in these patients that was comparable to the response observed among the general population. However, the role of the cell-mediated immune response in providing long-term protection against SARS-CoV-2 in pwCF has not yet been defined. In this study, humoral (antibody titre) and cell-mediated immune responses (interferon-γ release) to the BNT162b2 vaccine were measured at different time points, from around 6-8 months after the 2nd dose and up to 8 months after the 3rd dose, in 118 CF patients and 26 non-CF subjects. Subjects were sampled between November 2021 and September 2022 and followed-up for breakthrough infection through October 2022. pwCF mounted a cell-mediated response that was similar to that observed in non-CF subjects. Low antibody titres (<1st quartile) were associated with a higher risk of breakthrough infection (HR: 2.39, 95 % CI: 1.17-4.88), while there was no significant association with low INF-γ levels (<0.3 IU/mL) (HR: 1.38, 95 % CI: 0.64-2.99). Further studies are needed in subgroup of pwCF receiving immunosuppressive therapy, such as organ transplant recipients. This data is important for tailoring vaccination strategies for this clinically vulnerable population.

PMID:37263872 | DOI:10.1016/j.vaccine.2023.05.041

J Cyst Fibros. 2023 May 30:S1569-1993(23)00175-3. doi: 10.1016/j.jcf.2023.05.016. Online ahead of print.

ABSTRACT

People living with cystic fibrosis (PLwCF) experience high symptom burden. 146 clinicians completed online surveys regarding barriers and solutions to symptom management between September and October 2020. The surveys contained both closed-ended and free-text entries. The symptom management specialists that CF clinicians most wished to consult included mental health (88, 65%), palliative care (59, 41%), and pain specialists (48, 33%). Barriers to symptom management included concerns about controlled substances prescribed for symptom control causing addiction and precluding transplantation, a lack of trust and collaboration among clinical specialties, a lack of symptom management specialists with CF expertise, and a worry about the affordability of specialist-level symptom management care. Potential solutions included non-pharmacological approaches, expanding access to affordable specialist symptom management care, the creation of clinical care guidelines for symptom management in CF, and having CF clinicians and symptom management specialists work alongside each other in CF clinic to build interdisciplinary trust and education.

PMID:37263825 | DOI:10.1016/j.jcf.2023.05.016

Med Mycol. 2023 Jun 1:myad051. doi: 10.1093/mmy/myad051. Online ahead of print.

ABSTRACT

Scedosporium and Lomentospora species rank second among the filamentous fungi colonizing the airways of Cystic Fibrosis (CF) patients. These fungi could be responsible for allergic bronchopulmonary mycoses (ABPM) and bronchitis before lung transplantation and invasive infections after. However, their role in CF lung disease is debated. The present study aimed to identify clinical or environmental factors associated with an airway colonization by Scedosporium/Lomentospora species in patients with CF over a period of 7 years. A longitudinal cohort study was conducted from 2008 to 2014 in the CF reference centre in Lyon, France, to compare the characteristics of patients with Scedosporium/Lomentospora colonized and non-colonized patients. During the study period, 283 patients completed the clinical and microbiological follow-up. The analysis revealed that a higher number and duration of hospitalizations, an increased number of courses of parenteral antibiotic therapy, an history of ABPA and treatment by itraconazole were significantly associated with an airway colonization by Scedosporium/Lomentospora species. The rate of decline of FEV1 was not statistically different between colonized and non-colonized patients. This study provides evidence that patients colonized by Scedosporium/Lomentospora species require more medical cares than non-colonized patients. Additional cares could be in part explained by the management of Scedosporium/Lomentospora-related diseases such as ABPM or bronchitis. However, we did not demonstrate a faster rate of decline of respiratory function or BMI in colonized patients, suggesting, as previously reported, that colonization of the airways by these fungi does not play a significant role in the progression of CF disease.

PMID:37263788 | DOI:10.1093/mmy/myad051

J Appl Physiol (1985). 2023 Jun 1. doi: 10.1152/japplphysiol.00744.2022. Online ahead of print.

ABSTRACT

This study explored the use of computed cardiopulmonography (CCP) to assess lung function in early stage cystic fibrosis (CF). CCP has two components. The first is a particularly accurate technique for measuring gas exchange. The second is a computational cardiopulmonary model where patient-specific parameters can be estimated from the measurements of gas exchange. Twenty-five participants (14 healthy controls, 11 early stage CF) were studied with CCP. They were also studied with a standard clinical protocol to measure the lung clearance index (LCI2.5). Ventilation inhomogeneity, as quantified though CCP parameter σlnCL, was significantly greater (p<0.005) in CF than in controls, and anatomical deadspace relative to predicted functional residual capacity (DS/FRCpred) was significantly more variable (p<0.002). Participant-specific parameters were used with the CCP model to calculate idealised values for LCI2.5 (iLCI2.5) where extrapulmonary influences on the LCI2.5, such as breathing pattern, had all been standardised. Both LCI2.5 and iLCI2.5 distinguished clearly between CF and control participants. LCI2.5 values were mostly higher than iLCI2.5 values in a manner dependent on the participant's respiratory rate (r=0.46, p<0.05). The within-participant reproducibility for iLCI2.5 appeared better than for LCI2.5, but this did not reach statistical significance (F-ratio=2.2, p=0.056). Both a sensitivity analysis on iLCI2.5 and a regression analysis on LCI2.5 revealed that these depended primarily on an interactive term between CCP parameters of the form σlnCL*(DS/FRC). In conclusion, the LCI2.5 (or iLCI2.5) probably reflect an amalgam of different underlying lung changes in early-stage CF that would require a multi-parameter approach, such as potentially CCP, to resolve.

PMID:37262105 | DOI:10.1152/japplphysiol.00744.2022

Microbiol Spectr. 2023 Jun 1:e0077723. doi: 10.1128/spectrum.00777-23. Online ahead of print.

ABSTRACT

Mycobacterium abscessus, an intracellular nontuberculous mycobacterium, is considered the most pathogenic species among the group of rapidly growing mycobacteria. The resistance of M. abscessus to the host innate response contributes to its pathogenicity in addition to several virulence factors. We have recently shown in Drosophila that antimicrobial peptides (AMPs), whose production is induced by M. abscessus, are unable to control mycobacterial infection. This could be due to their inability to kill mycobacteria and/or the hidden location of the pathogen in phagocytic cells. Here, we demonstrate that the rapid internalization of M. abscessus by Drosophila macrophages allows it to escape the AMP-mediated humoral response. By depleting phagocytes in AMP-deficient flies, we found that several AMPs were required for the control of extracellular M. abscessus. This was confirmed in the Tep4 opsonin-deficient flies, which we show can better control M. abscessus growth and have increased survival through overproduction of some AMPs, including Defensin. Furthermore, Defensin alone was sufficient to kill extracellular M. abscessus both in vitro and in vivo and control its infection. Collectively, our data support that Tep4-mediated opsonization of M. abscessus allows its escape and resistance toward the Defensin bactericidal action in Drosophila. IMPORTANCE Mycobacterium abscessus, an opportunistic pathogen in cystic fibrosis patients, is the most pathogenic species among the fast-growing mycobacteria. How M. abscessus resists the host innate response before establishing an infection remains unclear. Using Drosophila, we have recently demonstrated that M. abscessus resists the host innate response by surviving the cytotoxic lysis of the infected phagocytes and the induced antimicrobial peptides (AMPs), including Defensin. In this work, we demonstrate that M. abscessus resists the latter response by being rapidly internalized by Drosophila phagocytes. Indeed, by combining in vivo and in vitro approaches, we show that Defensin is able to control extracellular M. abscessus infection through a direct bactericidal action. In conclusion, we report that M. abscessus escapes the host AMP-mediated humoral response by taking advantage of its internalization by the phagocytes.

PMID:37260399 | DOI:10.1128/spectrum.00777-23

J Bacteriol. 2023 Jun 1:e0002923. doi: 10.1128/jb.00029-23. Online ahead of print.

ABSTRACT

Most Pseudomonas aeruginosa strains produce bacteriocins derived from contractile or noncontractile phage tails known as R- and F-type pyocins, respectively. These bacteriocins possess strain-specific bactericidal activity against P. aeruginosa and likely increase evolutionary fitness through intraspecies competition. R-type pyocins have been studied extensively and show promise as alternatives to antibiotics. Although they have similar therapeutic potential, experimental studies on F-type pyocins are limited. Here, we provide a bioinformatic and experimental investigation of F-type pyocins. We introduce a systematic naming scheme for genes found in R- and F-type pyocin operons and identify 15 genes invariably found in strains producing F-type pyocins. Five proteins encoded at the 3' end of the F-type pyocin cluster are divergent in sequence and likely determine bactericidal specificity. We use sequence similarities among these proteins to define eleven distinct F-type pyocin groups, five of which had not been previously described. The five genes encoding the variable proteins associate in two modules that have clearly reassorted independently during the evolution of these operons. These proteins are considerably more diverse than the specificity-determining tail fibers of R-type pyocins, suggesting that F-type pyocins may have emerged earlier. Experimental studies on six F-type pyocin groups show that each displays a distinct spectrum of bactericidal activity. This activity is strongly influenced by the lipopolysaccharide O-antigen type, but other factors also play a role. F-type pyocins appear to kill as efficiently as R-type pyocins. These studies set the stage for the development of F-type pyocins as antibacterial therapeutics. IMPORTANCE Pseudomonas aeruginosa is an opportunistic pathogen that causes antibiotic-resistant infections with high mortality rates, particularly in immunocompromised individuals and cystic fibrosis patients. Due to the increasing frequency of multidrug-resistant P. aeruginosa infections, there is great need for the development of alternative therapeutics. In this study, we investigate one such potential therapeutic: F-type pyocins, which are bacteriocins naturally produced by P. aeruginosa that resemble noncontractile phage tails. We show that they are potent killers of P. aeruginosa and identify their probable bactericidal specificity determinants, which opens up the possibility of engineering them to precisely target strains of pathogenic bacteria. The resemblance of F-type pyocins to well-characterized phage tails will greatly facilitate their development into effective antibacterials.

PMID:37260386 | DOI:10.1128/jb.00029-23

Expert Opin Drug Metab Toxicol. 2023 May 31. doi: 10.1080/17425255.2023.2220960. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is characterized by mucus accumulation impairing the lungs, gastrointestinal tract, and other organs. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators (ivacaftor, tezacaftor, elexacaftor, lumacaftor) significantly improve lung function and nutritional status; however, they are substrates, inhibitors, and/or inducers of certain CYP enzymes and transporters, raising the risk of drug-drug interactions (DDI) with common CF medications.

AREAS COVERED: A literature search was conducted for DDIs involving CFTR modulators by reviewing new drug applications, drug package inserts, clinical studies, and validated databases of substrates, inhibitors, and inducers. Clinically, CYP3A inducers and inhibitors significantly decrease and increase systemic concentrations of elexacaftor/tezacaftor/ivacaftor respectively. Additionally, lumacaftor and ivacaftor alter concentrations of CYP3A and P-gp substrates. Potential DDIs without current clinical evidence include ivacaftor and elexacaftor's effect on CYP2C9 and OATP1B1/3 substrates, respectively, and OATP1B1/3 and P-gp inhibitors' effect on tezacaftor. A literature review was conducted using PubMed.

EXPERT OPINION: Dosing recommendations for CFTR modulators with DDIs are relatively comprehensive; however, recommendations on timing of dosing transition of CFTR modulators when CYP3A inhibitors are initiated or discontinued is incomplete. Certain drug interactions may be managed by choosing an alternative treatment to avoid/minimize DDIs. Next generation CFTR modulator therapies under development are expected to provide increased activity with reduced DDI risk.

PMID:37259485 | DOI:10.1080/17425255.2023.2220960

Pharmaceuticals (Basel). 2023 Feb 1;16(2):220. doi: 10.3390/ph16020220.

ABSTRACT

Human Mesenchymal Stem Cell (hMSC) immunotherapy has been shown to provide both anti-inflammatory and anti-microbial effectiveness in a variety of diseases. The clinical potency of hMSCs is based upon an initial direct hMSC effect on the pro-inflammatory and anti-microbial pathophysiology as well as sustained potency through orchestrating the host immunity to optimize the resolution of infection and tissue damage. Cystic fibrosis (CF) patients suffer from a lung disease characterized by excessive inflammation and chronic infection as well as a variety of other systemic anomalies associated with the consequences of abnormal cystic fibrosis transmembrane conductance regulator (CFTR) function. The application of hMSC immunotherapy to the CF clinical armamentarium is important even in the era of modulators when patients with an established disease still need anti-inflammatory and anti-microbial therapies. Additionally, people with CF mutations not addressed by current modulator resources need anti-inflammation and anti-infection management. Furthermore, hMSCs possess dynamic therapeutic properties, but the potency of their products is highly variable with respect to their anti-inflammatory and anti-microbial effects. Due to the variability of hMSC products, we utilized standardized in vitro and in vivo models to select hMSC donor preparations with the greatest potential for clinical efficacy. The models that were used recapitulate many of the pathophysiologic outcomes associated with CF. We applied this strategy in pursuit of identifying the optimal donor to utilize for the "First in CF" Phase I clinical trial of hMSCs as an immunotherapy and anti-microbial therapy for people with cystic fibrosis. The hMSCs screened in this study demonstrated significant diversity in antimicrobial and anti-inflammatory function using models which mimic some aspects of CF infection and inflammation. However, the variability in activity between in vitro potency and in vivo effectiveness continues to be refined. Future studies require and in-depth pursuit of hMSC molecular signatures that ultimately predict the capacity of hMSCs to function in the clinical setting.

PMID:37259368 | DOI:10.3390/ph16020220

Pharmaceuticals (Basel). 2023 Jan 28;16(2):192. doi: 10.3390/ph16020192.

ABSTRACT

Lactoferrin (LF) is a multifunctional iron-binding glycoprotein that exhibits a variety of properties, such as immunomodulatory, anti-inflammatory, antimicrobial, and anticancer, that can be used to treat numerous diseases. Lung diseases continue to be the leading cause of death and disability worldwide. Many of the therapies currently used to treat these diseases have limited efficacy or are associated with side effects. Therefore, there is a constant pursuit for new drugs and therapies, and LF is frequently considered a therapeutic agent and/or adjunct to drug-based therapies for the treatment of lung diseases. This article focuses on a review of the existing and most up-to-date literature on the contribution of the beneficial effects of LF on the treatment of lung diseases, including asthma, viral infections, cystic fibrosis, or lung cancer, among others. Although in vitro and in vivo studies indicate significant potency of LF in the treatment of the listed diseases, only in the case of respiratory tract infections do human studies seem to confirm them by demonstrating the effectiveness of LF in reducing episodes of illness and shortening the recovery period. For lung cancer, COVID-19 and sepsis, the reports are conflicting, and for other diseases, there is a paucity of human studies conclusively confirming the beneficial effects of LF.

PMID:37259341 | DOI:10.3390/ph16020192

Nature. 2023 May 31. doi: 10.1038/s41586-023-06133-1. Online ahead of print.

ABSTRACT

Nonsense mutations are the underlying cause of approximately 11% of all inherited genetic diseases1. Nonsense mutations convert a sense codon that is decoded by tRNA into a premature termination codon (PTC), resulting in an abrupt termination of translation. One strategy to suppress nonsense mutations is to use natural tRNAs with altered anticodons to base-pair to the newly emerged PTC and promote translation2-7. However, tRNA-based gene therapy has not yielded an optimal combination of clinical efficacy and safety and there is presently no treatment for individuals with nonsense mutations. Here we introduce a strategy based on altering native tRNAs into efficient suppressor tRNAs (sup-tRNAs) by individually fine-tuning their sequence to the physico-chemical properties of the amino acid that they carry. Intravenous and intratracheal lipid nanoparticle (LNP) administration of sup-tRNA in mice restored the production of functional proteins with nonsense mutations. LNP-sup-tRNA formulations caused no discernible readthrough at endogenous native stop codons, as determined by ribosome profiling. At clinically important PTCs in the cystic fibrosis transmembrane conductance regulator gene (CFTR), the sup-tRNAs re-established expression and function in cell systems and patient-derived nasal epithelia and restored airway volume homeostasis. These results provide a framework for the development of tRNA-based therapies with a high molecular safety profile and high efficacy in targeted PTC suppression.

PMID:37258671 | DOI:10.1038/s41586-023-06133-1

Infect Dis Health. 2023 May 29:S2468-0451(23)00033-0. doi: 10.1016/j.idh.2023.05.002. Online ahead of print.

ABSTRACT

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a significant pathogen in people with cystic fibrosis (PwCF). There is a paucity of reports on MRSA infection dynamics within CF. It was the aim to examine the utility of Time-To-FirstIsolation (TTFI) metric and to correlate this with patient gender and CF transmembrane conductance regulator (CFTR) mutation type.

METHODS: The microbiology of respiratory specimens from 100 adult (≥18 years) PwCF was examined (50 females; 50 males; mean age 24.6 years ±6.25 (SD)) from birth to present, equating to 2455 patient years. TTFI was determined in relation to (i) presence/absence of MRSA, (ii) CFTR mutation type and (iii) PwCF gender.

RESULTS: MRSA was noted in 23% patients (10 female/13 males); (i) F508del/F508del homozygous (43.5%) and (ii) F508del/other heterozygous (56.5%). No non-F508del CFTR mutations types were noted. The median and mean TTFI was 137 months and 127.4 months respectively, shortest time was 23 months, longest time 211 months. There was no statistical significance in TTFI in relation to CFTR mutation group (p = 0.39) or gender (p = 0.71).

CONCLUSIONS: TTFI is useful and applicable to the chronic infection model, where patients with a specific underlying disease are predisposed to acquire infections and where these infections are likely to become chronic. Intelligence offered by TTFI provides a window of opportunity to target IPC interventions, to help prevent MRSA acquisition. CF multidisciplinary teams, microbiologists and infection prevention specialists should utilise such TTFI data from their respective centres to help inform and plan intervention strategies to help prevent MRSA acquisition.

PMID:37258345 | DOI:10.1016/j.idh.2023.05.002

Eur Respir J. 2023 May 31;61(5):23E6105. doi: 10.1183/13993003.E6105-2023. Print 2023 May.

NO ABSTRACT

PMID:37257907 | DOI:10.1183/13993003.E6105-2023

Anatol J Cardiol. 2023 Jun;27(6):319-327. doi: 10.14744/AnatolJCardiol.2023.2864.

ABSTRACT

BACKGROUND: Right heart functions are affected in patients with bronchiectasis as a result of pulmonary hypertension induced by chronic hypoxemia. Pulmonary artery wall thickness has recently been introduced as a sign of intensive and prolonged inflammation. The aim of this study was to analyze right ventricular and right atrial functions and to mea-sure pulmonary artery wall thickness in patients with cystic fibrosis-bronch iecta sis in comparison to those with noncystic fibrosis-bronchiectasis and healthy individuals.

METHODS: We studied 36 patients with cystic fibrosis-bronchiectasis, 34 patients with noncystic fibrosis-bronchiectasis, and 32 age- and sex-matched control subjects. Lung function tests were performed. All subjects underwent comprehensive echocardiographic evaluation including conventional, tissue Doppler, speckle-tracking, and pulmonary artery wall thickness measurements.

RESULTS: Right ventricular global longitudinal strain and global longitudinal right atrial strain during ventricular systole decreased in cystic fibrosis-bronchiectasis group compared with noncystic fibrosis-bronchiectasis and control groups (P <.001, both). Conversely, pulmonary artery wall thickness was increased in cystic fibrosis-bronchiectasis group in comparison to other groups (P <.001). Moreover, right ventricular global longitudinal strain was lower and pulmonary artery wall thickness was higher in patients with airflow obstruction (P <.001 and P =.025, respectively) than in those without. Only right ventricular global longitudinal strain was significantly correlated with pulmonary function test parameters. The negative effect of cystic fibrosis on right ventricular and right atrial functions was independent of age, gender, and disease duration.

CONCLUSION: Our study showed that right ventricular and right atrial functions were deteriorated and pulmonary artery wall was thickened in cystic fibrosis-bronchiectasis patients more than noncystic fibrosis-bronchiectasis patients. Right ventricular global longitudinal strain detected subclinical right ventricular dysfunction and was associated with the severity of pulmonary disease.

PMID:37257004 | DOI:10.14744/AnatolJCardiol.2023.2864

Am J Physiol Lung Cell Mol Physiol. 2023 May 31. doi: 10.1152/ajplung.00150.2022. Online ahead of print.

ABSTRACT

Lung infections caused by antibiotic resistant strains of Pseudomonas aeruginosa are difficult to eradicate in immunocompromised hosts such as those with cystic fibrosis. We previously demonstrated that extracellular vesicles (EVs) secreted by primary human airway epithelial cells (AEC) delivermiRNA let-7b-5p to P. aeruginosa to suppress biofilm formation and increase sensitivity to beta-lactam antibiotics. In this study, we show that EVs secreted by AEC transfer multiple distinct sRNA fragments to P. aeruginosa that are predicted to target the three subunits of the fluoroquinolone efflux pump MexHI-OpmD, thus increasing antibiotic sensitivity. Exposure of P. aeruginosa to EVs resulted in a significant reduction in the protein levels of MexH (-48%), MexI (-50%) and OpmD (-35%). Moreover, EVs reduced planktonic growth of P. aeruginosa in the presence of the fluoroquinolone antibiotic ciprofloxacin by 20%. A mexGHI-opmD deletion mutant of P. aeruginosa phenocopied this increased sensitivity to ciprofloxacin. Finally, we found that a fragment of an 18S rRNA external transcribed spacer that was transferred to P. aeruginosa by EVs reduced planktonic growth of P. aeruginosa in the presence of ciprofloxacin, reduced the minimum inhibitory concentration (MIC) of P. aeruginosa for ciprofloxacin by over 50%, and significantly reduced protein levels of both MexH and OpmD. In conclusion, an rRNA fragment secreted by AEC in EVs that targets the fluoroquinolone efflux pump MexHI-OpmD down-regulated these proteins and increased the ciprofloxacin sensitivity of P. aeruginosa. A combination of rRNA fragments and ciprofloxacin packaged in nanoparticles or EVs may benefit patients with antibiotic-resistant P. aeruginosa infections.

PMID:37256658 | DOI:10.1152/ajplung.00150.2022