Pediatr Pulmonol. 2021 Sep 1. doi: 10.1002/ppul.25658. Online ahead of print.

ABSTRACT

INTRODUCTION: Newborn screening (NBS) for cystic fibrosis (CF) was implemented in all US states and DC by 2010. This hypothesis generating study was designed to form the basis of additional analyses and to plan quality improvement initiatives. The aims were to describe the outcomes of infants with CF born during the first 9 years of universal NBS.

METHODS: We included participants in the CF Foundation Patient Registry born 2010-2018 with age of recorded CF diagnosis 0-365 days old. We compared age of center-reported diagnosis, age at first CF event (defined as earliest sweat test, clinic visit or hospitalization), demographics, and outcomes between 3 cohorts born between 2010-2012, 2013-2015, and 2016-2018.

RESULTS: In 6354 infants, the median age at first CF event decreased from the 1st to the 3rd cohort. Weight-for-age (WFA) was < 10th percentile in about 40% of infants at the first CF Center visit. Median WFA z-score at 1-2 years was > 0 but height-for-age (HFA) z-score was < 0 through age 5-6 years. The second cohort had a higher HFA z-score than the first cohort at age 5-6 years. Pseudomonas aeruginosa infection was less common in later cohorts. About 1/3 of infants were hospitalized in the first year of life with no changes over time.

CONCLUSION: Over 9 years of CF NBS, median age at first CF event decreased. CF NBS had positive health impacts, but early life nutritional deficits and a high rate of infant hospitalizations persist. This article is protected by copyright. All rights reserved.

PMID:34469079 | DOI:10.1002/ppul.25658

Rev Peru Med Exp Salud Publica. 2021 Apr-Jun;38(2):318-325. doi: 10.17843/rpmesp.2021.382.6108. Epub 2021 Aug 30.

ABSTRACT

Reports of infection and/or disease caused by non-tuberculous mycobacteria (NTM) are becoming increasingly frequent. This scope review describes the epidemiological and clinical trend of infection/disease caused by NTM in Latin America. OVID MEDLINE, Embase and LILACS databases were explored for relevant articles. After filtering, we included 44 articles, representing an overall population of 2,826 subjects diagnosed with NTM infection and disease; the majority of the publications included subjects from Brazil and Colombia (75%), cross-sectional studies were the most common (36.6%), most subjects were male (61.3%) and the median age of subjects was 40.1 years. Disease by NTM was reported in 37 publications, extrapulmonary presentation was the most frequent (54%), main comorbidities were other pulmonary diseases, HIV, cystic fibrosis, diabetes and malnutrition, as reported in 13 studies; tuberculosis diagnosis previous to NTM disease was reported in 15 articles. Aesthetic procedures were reported in 12 articles while clinical procedures were reported in 3 articles. Several NTM species were reported, being Mycobacterium avium (52%), M. abscessus (34%), M. chelonae (18%), M. fortuitum (16%) and M. kansasii (9.1%) the most frequent. Culture and molecular testing were the main methods for diagnosis and identification. Scientific literature on NTM from Latin American countries is scarce. There is an urgent need to conduct studies on the frequency and clinical impact of NTM infections, in order to accurately identify the current morbidity and mortality associated with NTM in Latin American. It is also important to strengthen the local diagnostic capacity and the existing networks focused on studying NTM.

PMID:34468583 | DOI:10.17843/rpmesp.2021.382.6108

Curr Opin Pulm Med. 2021 Aug 30. doi: 10.1097/MCP.0000000000000826. Online ahead of print.

NO ABSTRACT

PMID:34468404 | DOI:10.1097/MCP.0000000000000826

Microbiol Spectr. 2021 Sep 1:e0054921. doi: 10.1128/Spectrum.00549-21. Online ahead of print.

ABSTRACT

In one year of the coronavirus disease 2019 (COVID-19) pandemic, many studies have described the different metabolic changes occurring in COVID-19 patients, linking these alterations to the disease severity. However, a complete metabolic signature of the most severe cases, especially those with a fatal outcome, is still missing. Our study retrospectively analyzes the metabolome profiles of 75 COVID-19 patients with moderate and severe symptoms admitted to Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Lombardy Region, Italy) following SARS-CoV-2 infection between March and April 2020. Italy was the first Western country to experience COVID-19, and the Lombardy Region was the epicenter of the Italian COVID-19 pandemic. This cohort shows a higher mortality rate compared to others; therefore, it represents a unique opportunity to investigate the underlying metabolic profiles of the first COVID-19 patients in Italy and to identify the potential biomarkers related to the disease prognosis and fatal outcome. IMPORTANCE Understanding the metabolic alterations occurring during an infection is a key element for identifying potential indicators of the disease prognosis, which are fundamental for developing efficient diagnostic tools and offering the best therapeutic treatment to the patient. Here, exploiting high-throughput metabolomics data, we identified the first metabolic profile associated with a fatal outcome, not correlated with preexisting clinical conditions or the oxygen demand at the moment of diagnosis. Overall, our results contribute to a better understanding of COVID-19-related metabolic disruption and may represent a useful starting point for the identification of independent prognostic factors to be employed in therapeutic practice.

PMID:34468185 | DOI:10.1128/Spectrum.00549-21

Clin Case Rep. 2021 Aug 25;9(8):e04713. doi: 10.1002/ccr3.4713. eCollection 2021 Aug.

ABSTRACT

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane regulator (CFTR) modulator. It is known to be efficacious in stable patients with severe pneumopathy, but there are few data concerning its effectiveness during acute exacerbations. We here describe its use in a woman with CF and respiratory failure.

PMID:34466263 | PMC:PMC8385458 | DOI:10.1002/ccr3.4713

J Cyst Fibros. 2021 Aug 28:S1569-1993(21)01349-7. doi: 10.1016/j.jcf.2021.08.008. Online ahead of print.

ABSTRACT

In 2017, Nkam et al. published a prognostic score to predict death or lung transplant within 3 years among adult cystic fibrosis (CF) patients. Their model was developed using French CF registry data and was subsequently validated in the Canadian CF registry. We evaluated this prognostic score using data from adult patients with CF in the United States (US) CF Foundation Patient registry, combined with lung transplant records from the United Network for Organ Sharing (UNOS) Registry (2013 to 2016) (n=11,542). We found that the prognostic score had a very good discriminative index predicting death or lung transplant in the US CF population (AUC 0.88, 95% CI 0.88-0.89) with an odds ratio (OR) of 2.83 (95% CI 2.69 - 2.97) for each unit increase in the score. However, it did not provide significant additional utility over an FEV1 ≤30% of predicted as a predictor of death or lung transplant.

PMID:34465539 | DOI:10.1016/j.jcf.2021.08.008

mBio. 2021 Aug 31;12(4):e0215321. doi: 10.1128/mBio.02153-21. Epub 2021 Aug 31.

ABSTRACT

The prevalence of Aspergillus fumigatus colonization in individuals with cystic fibrosis (CF) and subsequent fungal persistence in the lung is increasingly recognized. However, there is no consensus for clinical management of A. fumigatus in CF individuals, due largely to uncertainty surrounding A. fumigatus CF pathogenesis and virulence mechanisms. To address this gap in knowledge, a longitudinal series of A. fumigatus isolates from an individual with CF were collected over 4.5 years. Isolate genotypes were defined with whole-genome sequencing that revealed both transitory and persistent A. fumigatus in the lung. Persistent lineage isolates grew most readily in a low-oxygen culture environment, and conidia were more sensitive to oxidative stress-inducing conditions than those from nonpersistent isolates. Closely related persistent isolates harbored a unique allele of the high-osmolarity glycerol (HOG) pathway mitogen-activated protein kinase kinase, Pbs2 (pbs2C2). Data suggest this novel pbs2C2 allele arose in vivo and is necessary for the fungal response to osmotic stress in a low-oxygen environment through hyperactivation of the HOG (SakA) signaling pathway. Hyperactivation of the HOG pathway through pbs2C2 comes at the cost of decreased conidial stress resistance in the presence of atmospheric oxygen levels. These novel findings shed light on pathoadaptive mechanisms of A. fumigatus in CF, lay the foundation for identifying persistent A. fumigatus isolates that may require antifungal therapy, and highlight considerations for successful culture of persistent Aspergillus CF isolates. IMPORTANCE Aspergillus fumigatus infection causes a spectrum of clinical manifestations. For individuals with cystic fibrosis (CF), allergic bronchopulmonary aspergillosis (ABPA) is an established complication, but there is a growing appreciation for A. fumigatus airway persistence in CF disease progression. There currently is little consensus for clinical management of A. fumigatus long-term culture positivity in CF. A better understanding of A. fumigatus pathogenesis mechanisms in CF is expected to yield insights into when antifungal therapies are warranted. Here, a 4.5-year longitudinal collection of A. fumigatus isolates from a patient with CF identified a persistent lineage that harbors a unique allele of the Pbs2 mitogen-activated protein kinase kinase (MAPKK) necessary for unique CF-relevant stress phenotypes. Importantly for A. fumigatus CF patient diagnostics, this allele provides increased fitness under CF lung-like conditions at a cost of reduced in vitro growth under standard laboratory conditions. These data illustrate a molecular mechanism for A. fumigatus CF lung persistence with implications for diagnostics and antifungal therapy.

PMID:34465017 | DOI:10.1128/mBio.02153-21

Antonie Van Leeuwenhoek. 2021 Aug 31. doi: 10.1007/s10482-021-01637-0. Online ahead of print.

ABSTRACT

To improve understanding of the role of Ralstonia in cystic fibrosis (CF), whole genomes of 18 strains from clinical samples were sequenced using Illumina technology. Sequences were analysed by core genome Multi-Locus Sequence Typing, Average Nucleotide Identity based on BLAST (ANIb), RAST annotation, and by ResFinder. Phylogenetic analysis was performed for the 16S rRNA gene, and the OXA-22 and OXA-60 ß-lactamase families. The minimal inhibitory concentrations (MICs) were determined using broth microdilution. ANIb data for the 18 isolates and 54 strains from GenBank, supported by phylogenetic analysis, showed that 8 groups of clusters (A-H), as well as subgroups that should be considered as species or subspecies. Groups A-C contain strains previously identified as Ralstonia solanacearum and Ralstonia pseudosolanacearum. We propose that group A is a novel species. Group B and C are Ralstonia syzygii, Ralstonia solanacearum, respectively. Group D is composed of Ralstonia mannitolilytica and Group E of Ralstonia pickettii. Group F and G should be considered novel species. Group H strains belong to R. insidiosa. OXA-22 and OXA-60 family ß-lactamases were encoded by all strains. Co-trimoxazole generally showed high activity with low MICs (≤1 mg/l) as did ciprofloxacin (≤0.12 mg/l). MICs against the other antibiotics were more variable, but generally high. RAST annotation revealed limited differences between the strains, and virulence factors were not identified. The taxonomy of the genus Ralstonia is in need of revision, but sequencing additional isolates is needed. Antibiotic resistance levels are high. Annotation did not identify potential virulence factors.

PMID:34463860 | DOI:10.1007/s10482-021-01637-0

mSystems. 2021 Aug 31:e0017821. doi: 10.1128/mSystems.00178-21. Online ahead of print.

ABSTRACT

Respiratory infection during childhood is a key risk factor in early cystic fibrosis (CF) lung disease progression. Haemophilus influenzae and Haemophilus parainfluenzae are routinely isolated from the lungs of children with CF; however, little is known about the frequency and characteristics of Haemophilus colonization in this context. Here, we describe the detection, antimicrobial resistance (AMR), and genome sequencing of H. influenzae and H. parainfluenzae isolated from airway samples of 147 participants aged ≤12 years enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program, Melbourne, Australia. The frequency of colonization per visit was 4.6% for H. influenzae and 32.1% for H. parainfluenzae, 80.3% of participants had H. influenzae and/or H. parainfluenzae detected on at least one visit, and using genomic data, we estimate 15.6% of participants had persistent colonization with the same strain for at least two consecutive visits. Isolates were genetically diverse and AMR was common, with 52% of H. influenzae and 82% of H. parainfluenzae displaying resistance to at least one drug. The genetic basis for AMR could be identified in most cases; putative novel determinants include a new plasmid encoding blaTEM-1 (ampicillin resistance), a new inhibitor-resistant blaTEM allele (augmentin resistance), and previously unreported mutations in chromosomally carried genes (pbp3, ampicillin resistance; folA/folP, cotrimoxazole resistance; rpoB, rifampicin resistance). Acquired AMR genes were more common in H. parainfluenzae than H. influenzae (51% versus 21%, P = 0.0107) and were mostly associated with the ICEHin mobile element carrying blaTEM-1, resulting in more ampicillin resistance in H. parainfluenzae (73% versus 30%, P = 0.0004). Genomic data identified six potential instances of Haemophilus transmission between participants, of which three involved participants who shared clinic visit days. IMPORTANCE Cystic fibrosis (CF) lung disease begins during infancy, and acute respiratory infections increase the risk of early disease development and progression. Microbes involved in advanced stages of CF are well characterized, but less is known about early respiratory colonizers. We report the population dynamics and genomic determinants of AMR in two early colonizer species, namely, Haemophilus influenzae and Haemophilus parainfluenzae, collected from a pediatric CF cohort. This investigation also reveals that H. parainfluenzae has a high frequency of AMR carried on mobile elements that may act as a potential reservoir for the emergence and spread of AMR to H. influenzae, which has greater clinical significance as a respiratory pathogen in children. This study provides insight into the evolution of AMR and the colonization of H. influenzae and H. parainfluenzae in a pediatric CF cohort, which will help inform future treatment.

PMID:34463568 | DOI:10.1128/mSystems.00178-21

Biomed Pharmacother. 2021 Aug 27;142:112090. doi: 10.1016/j.biopha.2021.112090. Online ahead of print.

ABSTRACT

BACKGROUND: MicroRNAs play an important role in health and disease. TGF-β signaling, upregulated by HIV Tat, and in chronic airway diseases and smokers upregulates miR-145-5p to suppress cystic fibrosis transmembrane conductance regulator (CFTR). CFTR suppression in chronic airway diseases like Cystic Fibrosis, COPD and smokers has been associated with suppressed MCC and recurrent lung infections and inflammation. This can explain the emergence of recurrent lung infections and inflammation in people living with HIV.

METHODS: Tat-induced aberrant microRNAome was identified by miRNA expression analysis. microRNA mimics and antagomirs were used to validate the identified miRNAs involved in Tat mediated CFTR mRNA suppression. CRISPR-based editing of the miRNA target sites in CFTR 3'UTR was used to determine rescue of CFTR mRNA and function in airway epithelial cell lines and in primary human bronchial epithelial cells exposed to TGF-β and Tat.

FINDINGS: HIV Tat upregulates miR-145-5p and miR-509-3p. The two miRNAs demonstrate co-operative effects in suppressing CFTR. CRISPR-based editing of the miRNA target site preserves CFTR mRNA and function in airway epithelial cells INTERPRETATION: Given the important roles of TGF-β signaling and the multitude of genes regulated by miRNAs, we demonstrate that CRISPR-based gene-specific microRNA antagonism approach can preserve CFTR mRNA and function in the context of HIV Tat and TGF-β signaling without suppressing expression of other genes regulated by miR-145-5p.

PMID:34463266 | DOI:10.1016/j.biopha.2021.112090

Clin Nutr. 2021 Aug 8;40(9):5162-5168. doi: 10.1016/j.clnu.2021.07.032. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Bronchiectasis is a heterogeneous, chronic respiratory condition, in which the role of nutrition remains unclear and nutritional guidance is lacking. Few studies have explored the role of nutrition in disease management, and little is known about nutritional requirements during periods of stability or metabolic stress. The aim of this study was to characterise nutritional status and intakes in a cohort of patients and identify potential associations with body composition and functional capacity.

METHODS: A prospective observational cohort study was undertaken in an adult population (>17 years). Bronchiectasis was confirmed by high-resolution computerised tomography (HRCT). Anthropometric (weight, height, Body Mass Index (BMI), triceps skinfold thickness (TSF), mid upper-arm circumference (MUAC) and mid arm muscle circumference (MAMC)] lung function and nutritional intakes were measured. Results were analysed as a whole and by disease aetiology [primary ciliary dyskinesia (PCD), Idiopathic cause (IC), bronchiectasis in association with asthma and other] and associations tested.

RESULTS: In total, 128 participants (65.5% female) completed the study. Median handgrip strength (HGS) in the total sample was only 66.5% (IQR 60.5-89.8) of reference population norms and was low for those with PCD [58.0% (IQR 43.5-70.0))]. Univariate regression indicated that BMI was a statistically significant predictor of lung function in the whole population with HGS and weight identified as statistically significant predictors of lung function in PCD. The total population and each sub-group failed to meet estimated average requirements for energy but exceeded the Reference nutrient intake (RNI) for protein. Vitamin D was consistently <35% of the RNI.

CONCLUSION: BMI lay within normal to overweight ranges within the whole population and sub-groups, but masked important functional, body composition and nutritional deficits. This was particularly so within a younger sub-group with PCD, who had impaired muscle function, when compared to other causal and associative diseases.

PMID:34461590 | DOI:10.1016/j.clnu.2021.07.032

JMIR Res Protoc. 2021 Apr 19. doi: 10.2196/28728. Online ahead of print.

ABSTRACT

BACKGROUND: The acute nature of COVID-19 epidemic puts a strain on the health resources usually dedicated to chronic illness. Induced changes of care practices and networks had major repercussions on the experience of chronically ill people. This paper presents the research protocol PARCOURS-COVID, and aims to study the effects of such a reorganization on their usual care network which fosters and qualify its quality and continuum.

OBJECTIVE: Our first objective is to document chronically ill people experience through its transformations and adaptations, both in its practical dimension - daily life and care - and subjective dimension (psychosocial experience of illness and relationship to the health system). The second objective of the study is to identify and reconstruct these reorganizations during the lockdown and the post-lockdown period, in order to grasp their repercussions chronologically and structurally. The last objective is to produce recommendations for adapting the healthcare system to future crises by better acknowledging the experience of chronic patients, their involvement and consultation in the preparation and management of a health crisis.

METHODS: The PARCOURS-COVID study is a qualitative and participatory research involving patient organizations as research partners and members of patient organizations as part of the research team. Three group of chronic diseases have been selected regarding the specificities of the care network they mobilise: cystic fibrosis and kidney disease, haemophilia and mental disorders. Four consecutive phases will be conducted: i) preparatory interviews; ii) in-depth individual interviews with patients of each pathology will be analysed using a qualitative method of thematic analysis; iii) results of these both latter will be triangulated through interviews with members of each patient's care ecosystem; iv) focus-groups will be organized to discuss the results with research participants ie. representatives of chronic disease associations, patients, actors of the medical, psycho-social and family care network in a research-action frame.

RESULTS: The protocol study has undergone a peer-review by the French National Research Agency's scientific committee and has been approved by the Research Ethical Committee of the Université de Paris (registration number: IRB 00012020-59 June 28th, 2020). The project was funded from August 2020 through April 2021. Expected results will be disseminated in 2021 and 2022.

CONCLUSIONS: Our findings will better inform the stakes of the current health crisis on the management of the chronically ill and, more broadly, any future crisis for a population deemed to be at risk. They will improve health democracy by supporting a better transferability of knowledge between the scientific and citizen communities.

CLINICALTRIAL: Trial registration: IRB n° 00012020-59 (June, 28th, 2020).

PMID:34460413 | DOI:10.2196/28728

Infect Immun. 2021 Aug 30:IAI0041221. doi: 10.1128/IAI.00412-21. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is one of the principal pathogens implicated in respiratory infections of patients with cystic fibrosis (CF) and non-CF bronchiectasis. Previously, we demonstrated that impaired serum-mediated killing of P. aeruginosa was associated with increased severity of respiratory infections in patients with non-CF bronchiectasis. This inhibition was mediated by high titres of O-antigen-specific IgG2 antibodies that cloak the surface of the bacteria, blocking access to the membrane. Infection related symptomatology was ameliorated in patients by using plasmapheresis to remove the offending antibodies. To determine if these inhibitory 'cloaking antibodies' were prevalent in patients with CF, we investigated 70 serum samples from patients with P. aeruginosa infection, and five without P. aeruginosa infection. Thirty-two percent of patients had serum that inhibited the ability of healthy control serum to kill P. aeruginosa. Here we demonstrate that this inhibition of killing requires O-antigen expression. Furthermore, we reveal that while IgG alone can inhibit the activity of healthy control serum, O-antigen specific IgA in patient sera can also inhibited serum-killing. We found that antibody affinity, not just titre, was also important in the inhibition of serum-mediated killing. These studies provide novel insight into cloaking antibodies in human infection and may provide further options in CF and other diseases for treatment of recalcitrant P. aeruginosa infections.

PMID:34460286 | DOI:10.1128/IAI.00412-21

J Antimicrob Chemother. 2021 Aug 30:dkab312. doi: 10.1093/jac/dkab312. Online ahead of print.

ABSTRACT

OBJECTIVES: To investigate the population pharmacokinetics of posaconazole gastroresistant tablets in children with cystic fibrosis (CF) and perform simulations to recommend optimal doses.

PATIENTS AND METHODS: Children from a paediatric CF centre who had received posaconazole tablets and underwent therapeutic drug monitoring were identified from pharmacy records. Relevant clinical data were collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A stepwise covariate model-building exercise evaluated the influence of interacting medicines and liver function.

RESULTS: One hundred posaconazole serum concentrations were collected from 37 children with a median age of 14 years (range 7-17). Posaconazole pharmacokinetics were adequately described by a one-compartment model with inter-individual variability on clearance. Dose simulations demonstrated a 77%-83% probability of attaining a trough target of 1 mg/L with a dose of 300 mg every 12 h for two doses then 300 mg once daily (OD) in children aged 6-11 years; and 86%-88% with a dose of 400 mg every 12 h for two doses then 400 mg OD in adolescents aged 12-17 years. This dose scheme also yielded a 90% probability of achieving an AUC of 30 mg·h/L. AUC and trough concentration were highly correlated (r2 = 0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30 mg·h/L in 90% of patients.

CONCLUSIONS: A starting dose of 300 mg OD in those aged 6-11 years and 400 mg OD in those aged 12-17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg·h/L.

PMID:34458906 | DOI:10.1093/jac/dkab312

Mol Ther Nucleic Acids. 2021 Jun 24;25:293-301. doi: 10.1016/j.omtn.2021.06.010. eCollection 2021 Sep 3.

ABSTRACT

Life-long expression of a gene therapy agent likely requires targeting stem cells. Here we ask the question: does viral vector transduction or ectopic expression of a therapeutic transgene preclude airway stem cell function? We used a lentiviral vector containing a GFP or cystic fibrosis transmembrane conductance regulator (CFTR) transgene to transduce primary airway basal cells from human cystic fibrosis (CF) or non-CF lung donors and monitored expression and function after differentiation. Ussing chamber measurements confirmed CFTR-dependent chloride channel activity in CF donor cells. Immunostaining, quantitative real-time PCR, and single-cell sequencing analysis of cell-type markers indicated that vector transduction or CFTR expression does not alter the formation of pseudostratified, fully differentiated epithelial cell cultures or cell type distribution. These results have important implications for use of gene addition or gene editing strategies as life-long curative approaches for lung genetic diseases.

PMID:34458011 | PMC:PMC8379527 | DOI:10.1016/j.omtn.2021.06.010

Front Cell Neurosci. 2021 Aug 11;15:726605. doi: 10.3389/fncel.2021.726605. eCollection 2021.

ABSTRACT

The strength and sign of synapses involving ionotropic GABA and glycine receptors are dependent upon the Cl- gradient. We have shown that nitric oxide (NO) elicits the release of Cl- from internal acidic stores in retinal amacrine cells (ACs); temporarily altering the Cl- gradient and the strength or even sign of incoming GABAergic or glycinergic synapses. The underlying mechanism for this effect of NO requires the cystic fibrosis transmembrane regulator (CFTR) but the link between NO and CFTR activation has not been determined. Here, we test the hypothesis that NO-dependent Ca2+ elevations activate the Ca2+-dependent adenylate cyclase 1 (AdC1) leading to activation of protein kinase A (PKA) whose activity is known to open the CFTR channel. Using the reversal potential of GABA-gated currents to monitor cytosolic Cl-, we established the requirement for Ca2+ elevations. Inhibitors of AdC1 suppressed the NO-dependent increases in cytosolic Cl- whereas inhibitors of other AdC subtypes were ineffective suggesting that AdC1 is involved. Inhibition of PKA also suppressed the action of NO. To address the sufficiency of this pathway in linking NO to elevations in cytosolic Cl-, GABA-gated currents were measured under internal and external zero Cl- conditions to isolate the internal Cl- store. Activators of the cAMP pathway were less effective than NO in producing GABA-gated currents. However, coupling the cAMP pathway activators with the release of Ca2+ from stores produced GABA-gated currents indistinguishable from those stimulated with NO. Together, these results demonstrate that cytosolic Ca2+ links NO to the activation of CFTR and the elevation of cytosolic Cl-.

PMID:34456687 | PMC:PMC8385318 | DOI:10.3389/fncel.2021.726605

Biologics. 2021 Aug 21;15:353-361. doi: 10.2147/BTT.S326422. eCollection 2021.

ABSTRACT

Clustered regularly interspaced short palindromic repeat (CRISPR) and their associated protein (Cas-9) is the most effective, efficient, and accurate method of genome editing tool in all living cells and utilized in many applied disciplines. Guide RNA (gRNA) and CRISPR-associated (Cas-9) proteins are the two essential components in CRISPR/Cas-9 system. The mechanism of CRISPR/Cas-9 genome editing contains three steps, recognition, cleavage, and repair. The designed sgRNA recognizes the target sequence in the gene of interest through a complementary base pair. While the Cas-9 nuclease makes double-stranded breaks at a site 3 base pair upstream to protospacer adjacent motif, then the double-stranded break is repaired by either non-homologous end joining or homology-directed repair cellular mechanisms. The CRISPR/Cas-9 genome-editing tool has a wide number of applications in many areas including medicine, agriculture, and biotechnology. In agriculture, it could help in the design of new grains to improve their nutritional value. In medicine, it is being investigated for cancers, HIV, and gene therapy such as sickle cell disease, cystic fibrosis, and Duchenne muscular dystrophy. The technology is also being utilized in the regulation of specific genes through the advanced modification of Cas-9 protein. However, immunogenicity, effective delivery systems, off-target effect, and ethical issues have been the major barriers to extend the technology in clinical applications. Although CRISPR/Cas-9 becomes a new era in molecular biology and has countless roles ranging from basic molecular researches to clinical applications, there are still challenges to rub in the practical applications and various improvements are needed to overcome obstacles.

PMID:34456559 | PMC:PMC8388126 | DOI:10.2147/BTT.S326422

J Cyst Fibros. 2021 Aug 26:S1569-1993(21)01338-2. doi: 10.1016/j.jcf.2021.07.019. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) was historically a disease largely afflicting children. Due to therapeutic advancements, there are now more adults with CF than children. In the past decade, medications including Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators became available that treat the underlying cause of CF and are dramatically improving lung function as well as quality and quantity of life for people with CF. As a result, more women with CF are becoming pregnant. We gathered a panel of experts in CF care, family planning, high risk obstetrics, nutrition, genetics and women with CF to review current literature on pregnancies and to provide care recommendations for this unique population.

PMID:34456158 | DOI:10.1016/j.jcf.2021.07.019

J Cyst Fibros. 2021 Aug 26:S1569-1993(21)01350-3. doi: 10.1016/j.jcf.2021.08.009. Online ahead of print.

ABSTRACT

BACKGROUND: Multiple factors affect incident infection rates (IIR) for Pseudomonas aeruginosa (PA) and methicillin resistant Staphylococcus aureus (MRSA) at CF care centers. We assessed changes in IIR across CF centers temporally associated with the 2013 Infection/Prevention & Control guidelines controlling for center-specific factors.

METHODS: Using the CF Foundation Patient Registry we defined and measured changes in IIR between 2010-2012 and 2014-2016. Data were compared to non-CF rates of MRSA and resistant PA in geographically similar regions. Characteristics of each CF center (n centers: Adult 54 in 2010 to 82 in 2016. Pediatric ∼106) and their respective population were evaluated for associations with IIR and with changes in IIR between the study periods.

RESULTS: Across the years 35613 patients were included. Incident-infection rates for PA (mean 19.2±0.04% Pediatric, 21.2±0.07% Adult centers) were higher than for MRSA (mean 9.4±0.03% Pediatric, 7.8±0.03% Adult). The IIR decreased for MRSA (-1.54±0.54%, p<0.001) and PA (-4.77±0.63%, p<0.001) at Pediatric but only for PA (-3.20±1.31, p=0.02) at Adult centers. Except for Adult CF, MRSA rates (CF and non-CF) were highest in the South. In 2014-2016, private insurance and a higher proportion of LatinX patients at a center were associated with lower MRSA IIR while larger center size, higher proportion of LatinX, and lower mean center-wide lung function were associated with higher PA IIR. Higher IIR in 2010-2012, were predictive of a more pronounced decrease in IIR in 2014-2016 for MRSA and PA (p<0.001). Different factors indicative of lower social status (smoking, insurance, education) in 2010-2012 predicted decreases in MRSA or PA IIR.

CONCLUSION: Comparisons of IIR across U.S. CF centers should consider location, ethnic background and socio-economic variables of a center's population.

PMID:34456157 | DOI:10.1016/j.jcf.2021.08.009

Am Surg. 2021 Aug 30:31348211041560. doi: 10.1177/00031348211041560. Online ahead of print.

ABSTRACT

Here we present the case of a cystic fibrosis (CF) patient with preserved pulmonary function who developed acute liver failure requiring liver transplant following an episode of binge drinking and ingestion of a modest amount of acetaminophen. Cystic Fibrosis Liver Disease (CFLD) is the third most common cause of death among CF patients. The pathogenesis of CFLD is complex and still not fully understood. It is important that patients suffering from CF know about the possible dangers associated with acetaminophen and ethanol ingestion. Our case report highlights the need for more research that needs to be done to truly understand the underlying pathogenesis of CFLD and the significant risk factors that play a part in the development of acute liver failure in patients with CF.

PMID:34455828 | DOI:10.1177/00031348211041560