Am J Respir Crit Care Med. 2021 Jun 2. doi: 10.1164/rccm.202012-4332LE. Online ahead of print.

NO ABSTRACT

PMID:34077699 | DOI:10.1164/rccm.202012-4332LE

Microb Drug Resist. 2021 Jun 1. doi: 10.1089/mdr.2020.0602. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is associated with frequent pulmonary exacerbations and the need for novel antibiotics against antimicrobial resistance. Cefiderocol is a newly approved therapeutic option active against a variety of multidrug resistant (MDR) bacteria such as gram-negative species commonly encountered by CF patients. This review describes the potential role of cefiderocol against Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cepacia complex. Cefiderocol is a potential therapeutic option for MDR pathogens with minimum inhibitory concentrations (MICs) of ≤4 mg/L. Due to the lack of in vivo evidence in the CF population, cefiderocol may be utilized in patients in which alternative options are lacking due to MDR organisms or rapid pulmonary decline.

PMID:34077286 | DOI:10.1089/mdr.2020.0602

Cerebellum. 2021 Jun 2. doi: 10.1007/s12311-021-01280-5. Online ahead of print.

NO ABSTRACT

PMID:34076863 | DOI:10.1007/s12311-021-01280-5

AJR Am J Roentgenol. 2021 Jun 2:1-10. doi: 10.2214/AJR.19.22694. Online ahead of print.

ABSTRACT

OBJECTIVE. Cystic fibrosis (CF) is a multisystemic life-limiting disorder. The leading cause of morbidity in CF is chronic pulmonary disease. Chest CT is the reference standard for detection of bronchiectasis. Cumulative ionizing radiation limits the use of CT, particularly as treatments improve and life expectancy increases. The purpose of this article is to summarize the evidence on low-dose chest CT and its effect on image quality to determine best practices for imaging in CF. CONCLUSION. Low-dose chest CT is technically feasible, reduces dose, and renders satisfactory image quality. There are few comparison studies of low-dose chest CT and standard chest CT in CF; however, evidence suggests equivalent diagnostic capability. Low-dose chest CT with iterative reconstructive algorithms appears superior to chest radiography and equivalent to standard CT and has potential for early detection of bronchiectasis and infective exacerbations, because clinically significant abnormalities can develop in patients who do not have symptoms. Infection and inflammation remain the primary causes of morbidity requiring early intervention. Research gaps include the benefits of replacing chest radiography with low-dose chest CT in terms of improved diagnostic yield, clinical decision making, and patient outcomes. Longitudinal clinical studies comparing CT with MRI for the monitoring of CF lung disease may better establish the complementary strengths of these imaging modalities.

PMID:34076456 | DOI:10.2214/AJR.19.22694

Transplantation. 2021 May 28. doi: 10.1097/TP.0000000000003839. Online ahead of print.

ABSTRACT

BACKGROUND: The impacts of COVID-19 on lung allograft function, rejection, secondary infection, and clinical outcomes in lung transplant recipients (LTRs) remain unknown.

METHODS: A 1:2 matched case-control study was performed to evaluate re-hospitalization, lung allograft function, and secondary infections up to 90 days after COVID-19 diagnosis (or index dates for controls).

RESULTS: Twenty-four LTRs with COVID-19 (cases) and 48 controls were identified. Cases and controls had similar baseline characteristics and lung allograft function. LTRs with COVID-19 had higher incidence of secondary bacterial infection (29.2% vs 6.3%, p = 0.008), readmission (29.2% vs 10.4%, p = 0.04), and for-cause bronchoscopy (33.3% vs 12.5%, p = 0.04) compared to controls. At day 90, mortality in cases vs controls was 8.3 vs 2.1% (p = 0.21), incidence of invasive fungal infections in cases vs controls was 20.8% vs 8.3% (p = 0.13) and forced expiratory volume in 1 second (FEV1) decline ≥ 10% from baseline occurred in 19% of cases vs 12.2% of controls (p= 0.46). No acute cellular rejection, acute antibody mediated rejection, or new donor specific anti-HLA antibodies were observed among cases or controls within 90 days post index date.

CONCLUSIONS: We found LTRs with COVID-19 were at risk to develop secondary infections and re-hospitalization post COVID-19, compared to controls. While we did not observe post -viral ACR or AMR, further studies are needed to understand if LTRs with COVID-19 who did not recover baseline lung function within 90 days have developed chronic lung allograft dysfunction stage progression.

PMID:34075005 | DOI:10.1097/TP.0000000000003839

J Pers Med. 2021 May 24;11(6):458. doi: 10.3390/jpm11060458.

ABSTRACT

For many people with cystic fibrosis (pwCF), CFTR modulators will be the cornerstone of their treatment. These modulators show robust treatment effects at group level in pwCF with specific mutations. The individual effect however, is variable. In this review we will explain reasons for reconsideration of dosing regimens of CFTR modulating therapy in order to improve treatment response and prevent side effects. Since the effect of a drug depends on pharmacodynamics and pharmacokinetics, pharmacodynamics and pharmacokinetic properties of CFTR modulators will be discussed. Pharmacokinetic-pharmacodynamic relationships will be used to gain insight in dosage response and exposure response relationships. To understand the cause of variation in drug exposure, pharmacokinetic properties that may change due to CF disease will be explained. We show that with current insight, there are conceivable situations that give reason for reconsideration of dosing regimens, however many questions need to be unravelled.

PMID:34073663 | DOI:10.3390/jpm11060458

Nutrients. 2021 May 26;13(6):1801. doi: 10.3390/nu13061801.

ABSTRACT

Cystic Fibrosis (CF) is a life-long genetic disease, causing increased energy needs and a healthy diet with a specific nutrient distribution. Nutritional status is an indicator of disease prognosis and survival. This study aimed at assessing the effectiveness of a self-management mobile app in supporting patients with CF to achieve the dietary goals set by the CF nutrition guidelines. A clinical trial was conducted in pancreatic insufficient children with CF, followed in six European CF centres, where the self-management app developed within the MyCyFAPP project was used for six months. To assess secondary outcomes, three-day food records were compiled in the app at baseline and after 3 and 6 months of use. Eighty-four subjects (mean 7.8 years old) were enrolled. Compared to baseline, macronutrient distribution better approximated the guidelines, with protein and lipid increasing by 1.0 and 2.1% of the total energy intake, respectively, by the end of the study. Consequently, carbohydrate intake of the total energy intake decreased significantly (-2.9%), along with simple carbohydrate intake (-2.4%). Regarding food groups, a decrease in ultra-processed foods was documented, with a concomitant increase in meat and dairy. The use of a self-management mobile app to self-monitor dietary intake could become a useful tool to achieve adherence to guideline recommendations, if validated during a longer period of time or against a control group.

PMID:34073260 | DOI:10.3390/nu13061801

Toxins (Basel). 2021 May 26;13(6):378. doi: 10.3390/toxins13060378.

ABSTRACT

The B subunit pentamer verotoxin (VT aka Shiga toxin-Stx) binding to its cellular glycosphingolipid (GSL) receptor, globotriaosyl ceramide (Gb3) mediates internalization and the subsequent receptor mediated retrograde intracellular traffic of the AB5 subunit holotoxin to the endoplasmic reticulum. Subunit separation and cytosolic A subunit transit via the ER retrotranslocon as a misfolded protein mimic, then inhibits protein synthesis to kill cells, which can cause hemolytic uremic syndrome clinically. This represents one of the most studied systems of prokaryotic hijacking of eukaryotic biology. Similarly, the interaction of cholera AB5 toxin with its GSL receptor, GM1 ganglioside, is the key component of the gastrointestinal pathogenesis of cholera and follows the same retrograde transport pathway for A subunit cytosol access. Although both VT and CT are the cause of major pathology worldwide, the toxin-receptor interaction is itself being manipulated to generate new approaches to control, rather than cause, disease. This arena comprises two areas: anti neoplasia, and protein misfolding diseases. CT/CTB subunit immunomodulatory function and anti-cancer toxin immunoconjugates will not be considered here. In the verotoxin case, it is clear that Gb3 (and VT targeting) is upregulated in many human cancers and that there is a relationship between GSL expression and cancer drug resistance. While both verotoxin and cholera toxin similarly hijack the intracellular ERAD quality control system of nascent protein folding, the more widespread cell expression of GM1 makes cholera the toxin of choice as the means to more widely utilise ERAD targeting to ameliorate genetic diseases of protein misfolding. Gb3 is primarily expressed in human renal tissue. Glomerular endothelial cells are the primary VT target but Gb3 is expressed in other endothelial beds, notably brain endothelial cells which can mediate the encephalopathy primarily associated with VT2-producing E. coli infection. The Gb3 levels can be regulated by cytokines released during EHEC infection, which complicate pathogenesis. Significantly Gb3 is upregulated in the neovasculature of many tumours, irrespective of tumour Gb3 status. Gb3 is markedly increased in pancreatic, ovarian, breast, testicular, renal, astrocytic, gastric, colorectal, cervical, sarcoma and meningeal cancer relative to the normal tissue. VT has been shown to be effective in mouse xenograft models of renal, astrocytoma, ovarian, colorectal, meningioma, and breast cancer. These studies are herein reviewed. Both CT and VT (and several other bacterial toxins) access the cell cytosol via cell surface ->ER transport. Once in the ER they interface with the protein folding homeostatic quality control pathway of the cell -ERAD, (ER associated degradation), which ensures that only correctly folded nascent proteins are allowed to progress to their cellular destinations. Misfolded proteins are translocated through the ER membrane and degraded by cytosolic proteosome. VT and CT A subunits have a C terminal misfolded protein mimic sequence to hijack this transporter to enter the cytosol. This interface between exogenous toxin and genetically encoded endogenous mutant misfolded proteins, provides a new therapeutic basis for the treatment of such genetic diseases, e.g., Cystic fibrosis, Gaucher disease, Krabbe disease, Fabry disease, Tay-Sachs disease and many more. Studies showing the efficacy of this approach in animal models of such diseases are presented.

PMID:34073185 | DOI:10.3390/toxins13060378

Diagnostics (Basel). 2021 May 31;11(6):1002. doi: 10.3390/diagnostics11061002.

ABSTRACT

We appreciate the interest in our review and we are grateful for the comment by Gambazza S. [...].

PMID:34072667 | DOI:10.3390/diagnostics11061002

Diagnostics (Basel). 2021 May 31;11(6):1001. doi: 10.3390/diagnostics11061001.

ABSTRACT

We read with great interest the paper entitled "Impact of physical activity of cognitive functions: a new field for research and management of Cystic Fibrosis" by Elce et al. [...].

PMID:34072648 | DOI:10.3390/diagnostics11061001

Sensors (Basel). 2021 May 29;21(11):3776. doi: 10.3390/s21113776.

ABSTRACT

A plasmonic sensing platform was developed as a noninvasive method to monitor gas-phase biomarkers related to cystic fibrosis (CF). The nanohole array (NHA) sensing platform is based on localized surface plasmon resonance (LSPR) and offers a rapid data acquisition capability. Among the numerous gas-phase biomarkers that can be used to assess the lung health of CF patients, acetaldehyde was selected for this investigation. Previous research with diverse types of sensing platforms, with materials ranging from metal oxides to 2-D materials, detected gas-phase acetaldehyde with the lowest detection limit at the µmol/mol (parts-per-million (ppm)) level. In contrast, this work presents a plasmonic sensing platform that can approach the nmol/mol (parts-per-billion (ppb)) level, which covers the required concentration range needed to monitor the status of lung infection and find pulmonary exacerbations. During the experimental measurements made by a spectrometer and by a smartphone, the sensing examination was initially performed in a dry air background and then with high relative humidity (RH) as an interferent, which is relevant to exhaled breath. At a room temperature of 23.1 °C, the lowest detection limit for the investigated plasmonic sensing platform under dry air and 72% RH conditions are 250 nmol/mol (ppb) and 1000 nmol/mol (ppb), respectively.

PMID:34072374 | DOI:10.3390/s21113776

Genes (Basel). 2021 May 28;12(6):837. doi: 10.3390/genes12060837.

ABSTRACT

Cystic fibrosis (CF) is the most common monogenic autosomal recessive disease, associated with pathogenic variants in the CFTR gene. The splicing variant c.3140-16T>A (3272-16T>A) has been described previously and, according to the Russian CF Patients Registry, occurs with a frequency of 0.34%. The phenotypic features of CF patients with the c.3140-16T>A variant were compared with those of patients with the genotype F508del/F508del. Patients with the allele c.3140-16T>A had higher average age and age at diagnosis, and the allele was present in a greater proportion of adults. Patients carrying the c.3140-16T>A allele were characterised by better physical development indicators, both in adults and in children, had preserved pancreatic function, as well as the absence of a number of complications, and required pancreatic enzyme replacement therapy less often than patients with the F508del/F508del genotype. Sweat test values also were lower in patients with the c.3140-16T>A genotype. According to the results of clinical and laboratory studies, the phenotype of patients with the genetic variant c.3140-16T>A can be considered "mild". Functional CFTR protein activity in the presence of c.3140-16T>A was evaluated using intestinal current measurements (ICM) and the forskolin-induced swelling assay on organoids obtained from patients' rectal biopsies. c.3140-16T>A had high residual CFTR channel activity and was amenable to effective pharmacological correction with thea VX-770 potentiator. To evaluate the effect of the variant on CFTR pre-mRNA splicing we performed a minigene assay, as well as RT-PCR analysis of RNA isolated from the nasal epithelium and rectal biopsy of patients. We showed that the c.3140-16T>A variant creates a novel acceptor AG dinucleotide within CFTR intron 19, resulting in a 14-nucleotide extension of exon 20. This frameshift produces a premature termination codon and triggers mRNA degradation by the nonsense-mediated decay (NMD) mechanism. Moreover, we observed that the c.3140-16T>A allele could produce a residual amount of normally spliced transcript, thus explaining the patient's mild phenotype.

PMID:34071719 | DOI:10.3390/genes12060837

Int J Mol Sci. 2021 May 28;22(11):5793. doi: 10.3390/ijms22115793.

ABSTRACT

Sphingolipids are a specialized group of lipids essential to the composition of the plasma membrane of many cell types; however, they are primarily localized within the nervous system. The amphipathic properties of sphingolipids enable their participation in a variety of intricate metabolic pathways. Sphingoid bases are the building blocks for all sphingolipid derivatives, comprising a complex class of lipids. The biosynthesis and catabolism of these lipids play an integral role in small- and large-scale body functions, including participation in membrane domains and signalling; cell proliferation, death, migration, and invasiveness; inflammation; and central nervous system development. Recently, sphingolipids have become the focus of several fields of research in the medical and biological sciences, as these bioactive lipids have been identified as potent signalling and messenger molecules. Sphingolipids are now being exploited as therapeutic targets for several pathologies. Here we present a comprehensive review of the structure and metabolism of sphingolipids and their many functional roles within the cell. In addition, we highlight the role of sphingolipids in several pathologies, including inflammatory disease, cystic fibrosis, cancer, Alzheimer's and Parkinson's disease, and lysosomal storage disorders.

PMID:34071409 | DOI:10.3390/ijms22115793

Genes (Basel). 2021 May 25;12(6):803. doi: 10.3390/genes12060803.

ABSTRACT

Cystic fibrosis (CF) lung disease has the greatest impact on the morbidity and mortality of patients suffering from this autosomal-recessive multiorgan disorder. Although CF is a monogenic disorder, considerable phenotypic variability of lung disease is observed in patients with CF, even in those carrying the same mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or CFTR mutations with comparable functional consequences. In most patients with CF, lung disease progresses from childhood to adulthood, but is already present in infants soon after birth. In addition to the CFTR genotype, the variability of early CF lung disease can be influenced by several factors, including modifier genes, age at diagnosis (following newborn screening vs. clinical symptoms) and environmental factors. The early onset of CF lung disease requires sensitive, noninvasive measures to detect and monitor changes in lung structure and function. In this context, we review recent progress with using multiple-breath washout (MBW) and lung magnetic resonance imaging (MRI) to detect and quantify CF lung disease from infancy to adulthood. Further, we discuss emerging data on the impact of variability of lung disease severity in the first years of life on long-term outcomes and the potential use of this information to improve personalized medicine for patients with CF.

PMID:34070354 | DOI:10.3390/genes12060803

Int J Environ Res Public Health. 2021 May 18;18(10):5375. doi: 10.3390/ijerph18105375.

ABSTRACT

The purpose of this study was to examine differences in sports participation and the levels of physical activity (PA) and sedentary behaviour (SB) between schoolchildren with cystic fibrosis (CF) and a healthy control group (CG) taking into account the gender variable. PA and SB were measured with an accelerometer for 7 consecutive days in 44 children (24 girls; 11.0 (3.2) years) with CF and 45 age-, sex-, and socioeconomic status-matched controls (24 girls; 11.1 (3.0) years). CF patients and CG did not differ in moderate-to-vigorous PA (54 (31) vs. 59 (27) min/day respectively) or in SB (558 (106) vs. 553 (92) min/day respectively). There were no differences in meeting the PA guidelines between both groups (CF: 36.4% vs. CG: 42.4%). Gender analysis revealed that boys were more active and met more PA guidelines than girls regardless of the group (CF or CG), girls with CF being the least active group (only 16.7% met PA guidelines). A possible compensatory effect was found between SB and PA only in the CF sample, as for each minute/day spent in SB the odds of meeting PA guidelines decreased by 34%. These findings suggest that promoting a reduction in SB is as important as promoting PA in the CF population, especially in girls. Health caregivers, coaches, teachers, or parents could offer appealing supervised and unsupervised physical activities, foster the adoption of active lifestyles, or incorporate PA into daily routines to improve the health of CF schoolchildren.

PMID:34070042 | DOI:10.3390/ijerph18105375

Pathogens. 2021 May 18;10(5):618. doi: 10.3390/pathogens10050618.

ABSTRACT

Fungi are frequently recovered from lower airway samples from people with cystic fibrosis (CF), yet the role of fungi in the progression of lung disease is debated. Recent studies suggest worsening clinical outcomes associated with airway fungal detection, although most studies to date are retrospective or observational. The presence of fungi can elicit a T helper cell type 2 (Th-2) mediated inflammatory reaction known as allergic bronchopulmonary aspergillosis (ABPA), particularly in those with a genetic atopic predisposition. In this review, we discuss the epidemiology of fungal infections in people with CF, risk factors associated with development of fungal infections, and microbiologic approaches for isolation and identification of fungi. We review the spectrum of fungal disease presentations, clinical outcomes after isolation of fungi from airway samples, and the importance of considering airway co-infections. Finally, we discuss the association between fungi and airway inflammation highlighting gaps in knowledge and future research questions that may further elucidate the role of fungus in lung disease progression.

PMID:34069863 | DOI:10.3390/pathogens10050618

Biomedicines. 2021 May 14;9(5):550. doi: 10.3390/biomedicines9050550.

ABSTRACT

Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms of action (MoA) have emerged: RNase H-dependent degradation of mRNA directed by short chimeric antisense oligonucleotides (gapmers), correction of splicing defects via splice-modulation oligonucleotides, and interference of gene expression via short interfering RNAs (siRNAs). These antisense-based mechanisms can tackle several genetic disorders in a gene-specific manner, primarily by gene downregulation (gapmers and siRNAs) or splicing defects correction (exon-skipping oligos). Still, the challenge remains for the repair at the single-nucleotide level. The emerging field of epitranscriptomics and RNA modifications shows the enormous possibilities for recoding the transcriptome and repairing genetic mutations with high specificity while harnessing endogenously expressed RNA processing machinery. Some of these techniques have been proposed as alternatives to CRISPR-based technologies, where the exogenous gene-editing machinery needs to be delivered and expressed in the human cells to generate permanent (DNA) changes with unknown consequences. Here, we review the current FDA-approved antisense MoA (emphasizing some enabling technologies that contributed to their success) and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2'-O-methylation.

PMID:34068948 | DOI:10.3390/biomedicines9050550

Int J Mol Sci. 2021 May 17;22(10):5262. doi: 10.3390/ijms22105262.

ABSTRACT

Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta®/Kaftrio®) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60-70% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties.

PMID:34067708 | DOI:10.3390/ijms22105262

J Pers Med. 2021 May 17;11(5):422. doi: 10.3390/jpm11050422.

ABSTRACT

There are insufficient data regarding the relationship between non-cystic fibrosis bronchiectasis and incident aspergillosis. We performed a population-based, matched cohort study using data from the Korean National Health Insurance database between 2003 and 2013. The incidence of aspergillosis was 50/100,000 person-years in the bronchiectasis cohort and 11/100,000 person-years in the matched cohort (subdistribution hazard ratio, 4.53; 95% confidence interval (CI), 3.25-6.32). Among the bronchiectasis cohort, chronic obstructive pulmonary disease (adjusted HR, 1.95; 95% CI, 1.07-3.57), previous pulmonary tuberculosis (adjusted HR, 3.67; 95% CI, 2.03-6.64), and non-tuberculous mycobacterial pulmonary disease (adjusted HR, 11.25; 95% CI, 1.49-85.18) increased the risk of incident aspergillosis. The incidence of aspergillosis in patients with bronchiectasis was approximately 4.5-fold that in those without bronchiectasis. Comorbid pulmonary diseases-chronic obstructive pulmonary disease, previous pulmonary tuberculosis, and non-tuberculous mycobacterial pulmonary disease-significantly increased the risk of aspergillosis in patients with bronchiectasis. Our study indicates that close monitoring is warranted for aspergillosis in patients with bronchiectasis.

PMID:34067607 | DOI:10.3390/jpm11050422

Microorganisms. 2021 May 22;9(6):1123. doi: 10.3390/microorganisms9061123.

ABSTRACT

Burkholderia gladioli has high versatility and adaptability to various ecological niches. Here, we constructed a pan-genome using 14 genome sequences of B. gladioli, which originate from different niches, including gladiolus, rice, humans, and nature. Functional roles of core and niche-associated genomes were investigated by pathway enrichment analyses. Consequently, we inferred the uniquely important role of niche-associated genomes in (1) selenium availability during competition with gladiolus host; (2) aromatic compound degradation in seed-borne and crude oil-accumulated environments, and (3) stress-induced DNA repair system/recombination in the cystic fibrosis-niche. We also identified the conservation of the rhizomide biosynthetic gene cluster in all the B. gladioli strains and the concentrated distribution of this cluster in human isolates. It was confirmed the absence of complete CRISPR/Cas system in both plant and human pathogenic B. gladioli and the presence of the system in B. gladioli living in nature, possibly reflecting the inverse relationship between CRISPR/Cas system and virulence.

PMID:34067383 | DOI:10.3390/microorganisms9061123