J Clin Immunol. 2023 Jun 21. doi: 10.1007/s10875-023-01539-y. Online ahead of print.

NO ABSTRACT

PMID:37341861 | DOI:10.1007/s10875-023-01539-y

Pediatr Pulmonol. 2023 Jun 21. doi: 10.1002/ppul.26562. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been shown to have a beneficial effect on pulmonary function and nutritional status in patients with cystic fibrosis (CF), but the extent to which they affect glucose tolerance is not fully understood. In the current study, we evaluated the change in glucose tolerance and insulin secretion after first-generation CFTR modulator treatment in adults with CF.

METHODS: We performed a longitudinal observational study with an oral glucose tolerance test performed at baseline and after three and a half years of follow-up. The test comprised glucose, C-peptide and insulin measured at fasting, 1 h, and 2 h, and HbA1c at fasting. We compared changes in parameters of glucose tolerance and insulin secretion from baseline to follow-up.

RESULTS: Among 55 participants, 37 (67%) were treated with a first-generation CFTR modulator for a median of 21 months. Glucose levels were unchanged in both the treated and untreated group. In the treated group, C-peptide levels declined, yet no significant differences in glucose, insulin, and C-peptide levels were observed between the groups. HbA1c increased in both groups, while no significant change in the insulin sensitivity indices was detected in either group. However, homeostatic model assessment for insulin resistance tended to decline in the treated group, whilst tending towards an increase in the untreated group. The difference between the groups reached statistical significance (p = 0.040).

CONCLUSION: Treatment with first-generation CFTR modulators, mainly tezacaftor/ivacaftor, did not seem to be associated with glucose tolerance nor insulin secretion in adults with CF. However, CFTR modulators may still have a beneficial effect on insulin sensitivity.

PMID:37341613 | DOI:10.1002/ppul.26562

Pediatr Pulmonol. 2023 Jun 21. doi: 10.1002/ppul.26556. Online ahead of print.

ABSTRACT

PURPOSE: The purpose of this study was to assess the usefulness of indirect airway hyperresponsiveness (AHR) test using hypertonic saline in determining the dose of inhaled corticosteroids (ICS) to maintain asthma control in children.

METHODS: A group of 104 patients (7-15 years) with mild-moderate atopic asthma were monitored for their asthma control and treatment for 1 year. Patients were randomly assigned to a symptom-only monitored group and a group with therapy changes based on the symptoms and severity of AHR. Spirometry, exhaled nitric oxide, and blood eosinophils (BEos) were assessed on enrollment and every 3 months thereafter.

RESULTS: During the study period, the number of mild exacerbations was lower in the AHR group (44 vs. 85; the absolute rate per patient 0.83 vs. 1.67; relative rate 0.49, 95% confidence interval: 0.346-0.717 (p < 0.001)]. Mean changes from baseline in clinical (except asthma control test), inflammatory, and lung function parameters were similar between groups. Baseline BEos correlated with AHR and was a risk factor for recurrent exacerbation in all patients. There was no significant difference in the final ICS dose between AHR and symptoms group: 287 (SD 255) vs. 243 (158) p = 0.092.

CONCLUSIONS: Adding an indirect AHR test to clinical monitoring of childhood asthma reduced the number of mild exacerbations, with similar current clinical control and final ICS dose as in the symptom-monitored group. The hypertonic saline test appears to be a simple, cheap, and safe tool for monitoring the treatment of mild-to-moderate asthma in children.

PMID:37341585 | DOI:10.1002/ppul.26556

Mol Pharm. 2023 Jun 21. doi: 10.1021/acs.molpharmaceut.3c00323. Online ahead of print.

ABSTRACT

Microorganisms that make up the local microbiota (such as Lactobacillus sp. and Bifidobacterium sp.) play a crucial role in the modulation of diseases and health states by taking place not only in the gut but also in many parts of our body. There is also interference between the gut and the lung via the gut-lung axis. The relationship between respiratory diseases and lung microbiota, which become more of an issue of particular importance in recent years, shows that probiotics play an essential role in maintaining the balance of microorganisms in the respiratory tract. However, studies on probiotics' prophylactic or therapeutic application in chronic lung diseases are limited. In this review, the literature between 1977 and 2022 was surveyed. General information about human microbiota was accessed in earlier sources, and especially in the past decade, research on lung microbiota has been reached. The relationship between lung microbiota and important respiratory diseases such as bronchopulmonary dysplasia, chronic obstructive pulmonary disease, pneumonia, cystic fibrosis, allergy-asthma, influenza, lung cancer, and COVID-19 infection, was scrutinized after mentioning human microbiota, the gut-lung axis, and respiratory tract microbiota. The mechanism of action of probiotics and the formulation approaches of probiotics in terms of pharmaceutical technology were reviewed. Finally, future perspectives on lung-targeted administration of probiotic bacteria with prophylactic or therapeutic potential, or both, were presented.

PMID:37340968 | DOI:10.1021/acs.molpharmaceut.3c00323

Eur Arch Otorhinolaryngol. 2023 Jun 20. doi: 10.1007/s00405-023-08067-w. Online ahead of print.

ABSTRACT

PURPOSE: Allergic and non-allergic rhinorrhea in the forms of acute or chronic rhinosinusitis can mean a watery nasal discharge that is disabling. Primary objective was to review the evidence supporting the hypothesis that rhinorrhea is due to increased chloride secretion through the CFTR chloride channel.

METHODS: The structure of the evidence review followed the EQUATOR Reporting Guidelines. Databases searched from inception to February 2022 included Pubmed, EMBASE and the Cochrane library using keywords "Rhinorrhea", "chloride", "chloride channel", "CFTR" and "randomized controlled trial". Quality assessment was according to the Oxford Centre for Evidence-based Medicine.

RESULTS: 49 articles were included. They included randomized controlled trials out of which subsets of data with the outcome of rhinorrhea on 6038 participants were analysed and in vitro and animal studies. The review revealed that drugs, which activate CFTR are associated with rhinorrhea. Viruses, which cause rhinorrhea like rhinovirus were found to activate CFTR. The chloride concentration in nasal fluid showed an increase in patients with viral upper respiratory tract infection. Increased hydrostatic tissue pressure, which is an activator of CFTR was observed in allergic upper airway inflammation. In this condition exhaled breath condensate chlorine concentration was found to be significantly increased. Drugs, which can reduce CFTR function including steroids, anti-histamines, sympathomimetic and anticholinergic drugs reduced rhinorrhea in randomized controlled trials.

CONCLUSIONS: A model of CFTR activation-mediated rhinorrhea explains the effectiveness of anticholinergic, sympathomimetic, anti-histamine and steroid drugs in reducing rhinorrhea and opens up avenues for further improvement of treatment by already known specific CFTR inhibitors.

PMID:37338585 | DOI:10.1007/s00405-023-08067-w

Mater Horiz. 2023 Jun 20. doi: 10.1039/d3mh00340j. Online ahead of print.

ABSTRACT

Sweat pH is an important indicator for diagnosing disease states, such as cystic fibrosis. However, conventional pH sensors are composed of large brittle mechanical parts and need additional instruments to read signals. These pH sensors have limitations for practical wearable applications. In this study, we propose wearable colorimetric sweat pH sensors based on curcumin and thermoplastic-polyurethane (C-TPU) electrospun-fibers to diagnose disease states by sweat pH monitoring. This sensor aids in pH monitoring by changing color in response to chemical structure variation from enol to di-keto form via H-atom separation. Its chemical structure variation changes the visible color due to light absorbance and reflectance changes. Furthermore, it can rapidly and sensitively detect sweat pH due to its superior permeability and wettability. By O2 plasma activation and thermal pressing, this colorimetric pH sensor can be easily attached to various fabric substrates such as swaddling and patient clothing via surface modification and mechanical interlocking of C-TPU. Furthermore, the diagnosable clothing is durable and reusable enough to neutral washing conditions due to the reversible pH colorimetric sensing performance by restoring the enol form of curcumin. This study contributes to the development of smart diagnostic clothing for cystic fibrosis patients who require continuous sweat pH monitoring.

PMID:37338170 | DOI:10.1039/d3mh00340j

Pathology. 2023 May 22:S0031-3025(23)00123-X. doi: 10.1016/j.pathol.2023.03.009. Online ahead of print.

ABSTRACT

We collected 163 clinical Pseudomonas aeruginosa isolates at a tertiary hospital specialising in adult cystic fibrosis (CF) and lung transplantation (LTx) in Melbourne, Australia, to explore the activity of ceftolozane-tazobactam (C/T) in populations at high-risk for antimicrobial resistance. Of these, 144 (88.3%) were collected from sputum, and 19 (11.7%) from bronchoalveolar lavage. Most (85.3%) were derived from patients with cystic fibrosis and included a subset of patients that had undergone LTx. These isolates were tested against 11 antibiotics, including C/T, using Sensititre plates for broth microdilution (BMD) testing. Sixty (36.8%) isolates were classified as multidrug resistant (MDR) and 32 (19.6%) were extensively drug resistant (XDR). Overall, 133/163 (81.6%) isolates were susceptible to C/T. For MDR and XDR isolates, 88.3% and 28.1% were C/T susceptible, respectively. Among the non-MDR/XDR isolates, 100% remained susceptible to C/T. Comparisons of C/T susceptibility were made using BioMérieux Etests and Liofilchem MIC test strips (MTS). Categorical agreement to BMD was >93% for both test strips, but essential agreement to BMD was slightly higher with Etest (89.0%) compared to Liofilchem (74.8%). In conclusion, C/T retained activity against most MDR and over a quarter of XDR P. aeruginosa isolates from complex patients with CF and post-LTx.

PMID:37336685 | DOI:10.1016/j.pathol.2023.03.009

Int Microbiol. 2023 Jun 19. doi: 10.1007/s10123-023-00391-9. Online ahead of print.

ABSTRACT

Pseudomonas is a group of bacteria that can cause a wide range of infections, particularly in people with weakened immune systems, such as those with cystic fibrosis or who are hospitalized. It can also cause infections in the skin and soft tissue, including cellulitis, abscesses and wound infections. Antimicrobial peptides (AMPS) are the alternative strategy due to their broad spectrum of activity and act as effective treatment against multi-drug resistance pathogens. In this study, we have used an AMP, RW20 (1RPVKRKKGWPKGVKRGPPKW20). RW20 peptide is derived from the histone acetyltransferases (HATs) of the freshwater teleost, Channa striatus. The antimicrobial prediction tool has been utilized to identify the RW20 sequence from the HATs sequence. We synthesized the peptide to explore its mechanism of action. In an in vitro assay, RW20 was challenged against P. aeruginosa and we showed that RW20 displayed antibacterial properties and damaged the cell membrane. The mechanism of action of RW20 against P. aeruginosa has been established via field emission scanning electron microscopy (FESEM) as well as fluorescence assisted cell sorter (FACS) analysis. Both these experiments established that RW20 caused bacterial membrane disruption and cell death. Moreover, the impact of RW20, in-vivo, was tested against P. aeruginosa-infected zebrafish larvae. In the infected larvae, RW20 showed protective effect against P. aeruginosa by increasing the larval antioxidant enzymes, reducing the excess oxidative stress and apoptosis. Thus, it is possible that HATs-derived RW20 can be an efficient antimicrobial molecule against P. aeruginosa.

PMID:37335389 | DOI:10.1007/s10123-023-00391-9

Hum Gene Ther. 2023 Jun 19. doi: 10.1089/hum.2023.016. Online ahead of print.

ABSTRACT

Gene editing strategies are attractive for treating genetic pulmonary diseases such as cystic fibrosis (CF). However, challenges have included the development of safe and effective vector systems for gene editing of airway epithelia and model systems to report their efficiency and durability. The domestic ferret (Mustela putorius furo) has a high degree of conservation in lung cellular anatomy with humans, and has served as an excellent model for many types of lung diseases including the CF. Here, we evaluated the efficiency of amphiphilic shuttle peptide S10 for protein delivery and gene editing using SpCas9, and AsCas12a (Cpf1) ribonucleoproteins (RNPs). These approaches were evaluated in proliferating ferret airway basal cells, polarized airway epithelia in vitro, and lungs in vivo, by accessing the editing efficiency using reporter ferrets and measuring indels at the ferret CFTR locus. Our results demonstrate that shuttle peptides efficiently enable delivery of reporter proteins/peptides and gene editing SpCas9 or Cpf1 RNP complexes to ferret airway epithelial cells in vitro and in vivo. We measured S10 delivery efficiency of GFP-NLS protein or SpCas9 RNP into ferret airway basal cells and fully differentiated ciliated and non-ciliated epithelial cells in vitro. In vitro and in vivo gene editing efficiencies were determined by Cas/LoxP-gRNA RNP-mediated conversion of a ROSA-TG Cre recombinase reporter using transgenic primary cells and ferrets. S10/Cas9 RNP was more effective relative to S10/Cpf1 RNP at gene editing of the ROSA-TG locus. Intratracheal lung delivery of the S10 shuttle combined with GFP-NLS protein or DRI-NLS peptide demonstrated efficiencies of protein delivery that were ~3-fold or 14-fold greater, respectively, than the efficiency of gene editing at the ROSA-TG locus using S10/Cas9/LoxP-gRNA. Cpf1 RNPs was less effective than SpCas9 at gene editing of LoxP locus. These data demonstrate the feasibility of shuttle peptide delivery of Cas RNPs to the ferret airways and the potential utility for developing ex vivo stem cell-based and in vivo gene editing therapies for genetic pulmonary diseases such as CF.

PMID:37335046 | DOI:10.1089/hum.2023.016

Front Microbiol. 2023 Jun 2;14:1187708. doi: 10.3389/fmicb.2023.1187708. eCollection 2023.

ABSTRACT

The bacterium Pseudomonas aeruginosa is involved in chronic infections of cystic fibrosis lungs and chronic wounds. In these infections the bacteria are present as aggregates suspended in host secretions. During the course of the infections there is a selection for mutants that overproduce exopolysaccharides, suggesting that the exopolysaccharides play a role in the persistence and antibiotic tolerance of the aggregated bacteria. Here, we investigated the role of individual P. aeruginosa exopolysaccharides in aggregate-associated antibiotic tolerance. We employed an aggregate-based antibiotic tolerance assay on a set of P. aeruginosa strains that were genetically engineered to over-produce a single, none, or all of the three exopolysaccharides Pel, Psl, and alginate. The antibiotic tolerance assays were conducted with the clinically relevant antibiotics tobramycin, ciprofloxacin and meropenem. Our study suggests that alginate plays a role in the tolerance of P. aeruginosa aggregates toward tobramycin and meropenem, but not ciprofloxacin. However, contrary to previous studies we did not observe a role for Psl or Pel in the tolerance of P. aeruginosa aggregates toward tobramycin, ciprofloxacin, and meropenem.

PMID:37333638 | PMC:PMC10272609 | DOI:10.3389/fmicb.2023.1187708

bioRxiv. 2023 Jun 7:2023.06.06.543868. doi: 10.1101/2023.06.06.543868. Preprint.

ABSTRACT

Chronic polymicrobial infections (cPMIs) harbor complex bacterial communities with diverse metabolic capacities, leading to competitive and cooperative interactions. Although the microbes present in cPMIs have been established through culture-dependent and -independent methods, the key functions that drive different cPMIs and the metabolic activities of these complex communities remain unknown. To address this knowledge gap, we analyzed 102 published metatranscriptomes collected from cystic fibrosis sputum (CF) and chronic wound infections (CW) to identify key bacterial members and functions in cPMIs. Community composition analysis identified a high prevalence of pathogens, particularly Staphylococcus and Pseudomonas , and anaerobic members of the microbiota, including Porphyromonas, Anaerococcus, and Prevotella . Functional profiling with HUMANn3 and SAMSA2 revealed that while functions involved in bacterial competition, oxidative stress response, and virulence were conserved across both chronic infection types, ≥40% of the functions were differentially expressed (padj < 0.05, fold-change >2). Higher expression of antibiotic resistance and biofilm functions were observed in CF, while tissue destructive enzymes and oxidative stress response functions were highly expressed in CW samples. Of note, strict anaerobes had negative correlations with traditional pathogens in both CW ( P = -0.43) and CF ( P = -0.27) samples and they significantly contributed to the expression of these functions. Additionally, we show microbial communities have unique expression patterns and distinct organisms fulfill the expression of key functions in each site, indicating the infection environment strongly influences bacterial physiology and that community structure influences function. Collectively, our findings indicate that community composition and function should guide treatment strategies for cPMIs.

IMPORTANCE: The microbial diversity in polymicrobial infections (PMIs) allows for community members to establish interactions with one another which can result in enhanced disease outcomes such as increased antibiotic tolerance and chronicity. Chronic PMIs result in large burdens on health systems, as they affect a significant proportion of the population and are expensive and difficult to treat. However, investigations into physiology of microbial communities in actual human infection sites is lacking. Here, we highlight that the predominant functions in chronic PMIs differ, and anaerobes, often described as contaminants, may be significant in the progression of chronic infections. Determining the community structure and functions in PMIs is a critical step towards understanding the molecular mechanisms that drive microbe-microbe interactions in these environments.

PMID:37333206 | PMC:PMC10274682 | DOI:10.1101/2023.06.06.543868

Front Pharmacol. 2023 Jun 2;14:1178009. doi: 10.3389/fphar.2023.1178009. eCollection 2023.

ABSTRACT

Introduction: Seminal clinical trials with the triple combination of elexacaftor-tezacaftor-ivacaftor (ETI) demonstrated clinical efficacy in people with cystic fibrosis (pwCF) who carry at least one F508del mutation. However, due to exclusion criteria of these clinical trials, the effect of ETI was not studied in a substantial number of pwCF. Thus, we ran a single center trial to evaluate a clinical efficacy of ETI treatment in adult pwCF who were ineligible for enrollment in registration studies. Methods: PwCF on ETI with prior lumacaftor-ivacaftor therapy, severe airway obstruction, well-preserved lung function, or with airway infection with pathogens at risk of more rapid decline in lung function formed the study group, while all the others on ETI formed the control group. Lung function, nutritional status and sweat chloride concentration were assessed before and after initialization of ETI therapy over a 6-month period. Results: Approximately a half of the ETI-treated pwCF at the adult Prague CF center (49 of 96) were assigned to the study group. Their mean changes in body mass index ( + 1.04 kg/m2) and in sweat chloride concentration (-48.4 mmol/L) were similar to the control group ( + 1.02 kg/m2; -49.7 mmol/L), while the mean change in percent predicted forced expiratory volume in 1 s (ppFEV1; + 10.3 points) was significantly lower than in the control group ( + 15.8 points) (p = 0.0015). In the subgroup analysis, pwCF with severe airway obstruction (ppFEV1 <40) and pwCF with well-preserved lung function (ppFEV1 >90) showed a less potential for improvement in lung function during the ETI treatment than controls (median change in ppFEV1 + 4.9 points and + 9.5 points, respectively). Conclusion: PwCF not eligible for inclusion in clinical trials demonstrated improvement in lung function and nutritional status following the initiation of treatment with the ETI combination. Moderate increase in ppFEV1 was observed in those with severe airway obstruction or well-preserved lung function.

PMID:37332357 | PMC:PMC10275572 | DOI:10.3389/fphar.2023.1178009

Ther Adv Infect Dis. 2023 Jun 12;10:20499361231179668. doi: 10.1177/20499361231179668. eCollection 2023 Jan-Dec.

ABSTRACT

BACKGROUND: Select circumstances require outpatient parenteral antimicrobial therapy (OPAT). The potency of OPAT agents presents an increased risk of adverse events and unscheduled medical care. We analyzed these outcomes among OPAT recipients as part of the implementation of a collaborative OPAT program.

METHODS: Adult patients discharged home from an academic hospital with OPAT between January 2019 and June 2021 were included in this retrospective cohort; participants discharged between June 2020 and June 2021 were part of the collaborative OPAT program. Patients with cystic fibrosis were excluded. Data on patient characteristics and outcomes were collected from electronic medical records by two reviewers. Multivariable analysis was conducted to identify predictors of vascular access device (VAD) complications, adverse drug events (ADEs), and OPAT-related emergency department (ED) visits and rehospitalizations.

RESULTS: Among 265 patients included in the cohort, 57 (21.5%) patients experienced a VAD complication; obesity [odds ratio (OR): 3.32; 95% confidence interval (CI): 1.38-8.73; p = 0.01) and multi-drug therapy (OR: 2.56; 95% CI: 1.21-5.39; p = 0.01) were associated with an increased odds of VAD complication. Eighty-two (30.9%) participants experienced an ADE; 30 (11.3%) experienced a severe/serious ADE. Lipo/glycopeptide receipt, (OR: 5.28; 95% CI: 1.89-15.43; p < 0.01) and Black/African American race (OR: 4.85; 95% (CI): 1.56-15.45; p < 0.01) were associated with an increased odds of severe/serious ADE. Inclusion in the OPAT collaborative was associated with a decreased odds of severe/serious ADE (OR: 0.26; 95% CI: 0.08-0.77; p = 0.01). Fifty-eight (21.9%) patients experienced an OPAT-related ED visit and 53 (20.0%) experienced an OPAT-related rehospitalization. VAD complication (OR: 2.37; 95% (CI): 1.15-4.86, p = 0.02) and ADEs (OR: 2.19; CI: 1.13-4.22; p = 0.02) were associated with OPAT-related ED visits. ADE was associated with 90-day OPAT-related rehospitalization (OR: 3.21; (CI): 1.59-6.58; p < 0.01).

CONCLUSION: Adverse safety events and OPAT-related unscheduled care occurred often in our cohort. A structured OPAT program that includes ID pharmacist antibiotic reconciliation may reduce rates of ADEs.

PMID:37332294 | PMC:PMC10272639 | DOI:10.1177/20499361231179668

J Cyst Fibros. 2023 Jun 16:S1569-1993(23)00178-9. doi: 10.1016/j.jcf.2023.06.001. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303K-CFTR activity. Based on the in vitro response, eight patients commenced treatment with ELX/TEZ/IVA.

METHODS: Two homozygotes; and six compound heterozygotes N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from 5 study patients and an additional patient carrying N1303K that is not receiving treatment.

RESULTS: Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 26.5% relative to baseline, mean BMI increased by 0.79 Kg/m2, and mean lung clearance index decreased by 3.6 points and 22.2%. There was no significant change in sweat chloride. Nasal potential difference normalized in four patients and remained abnormal in three. Results in 3D intestinal organoids and 2D nasal epithelial cultures showed a response in CFTR channel activity.

CONCLUSIONS: This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation have a significant clinical benefit by ELX/TEZ/IVA treatment.

PMID:37331863 | DOI:10.1016/j.jcf.2023.06.001

Respir Res. 2023 Jun 17;24(1):164. doi: 10.1186/s12931-023-02451-0.

ABSTRACT

BACKGROUND: The introduction of the novel therapy, Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been effective in improving weight gain in both clinical trials and real-world studies. However, the magnitude of this effect appears to be heterogeneous across patient subgroups. This study aims to identify potential determinants of heterogeneity in weight gain following 6-month ETI therapy.

METHODS: We conducted a multicenter, prospective cohort study enrolling 92 adults with CF at two major CF centers in Italy with follow-up visit at one month and six months from ETI initiation. The treatment's effect on weight changes was evaluated using mixed effect regression models that included subject-specific random intercepts and fixed effects for potential predictors of treatment response, time and a predictor-by-time interaction term.

RESULTS: The mean weight gain at six months from the start of treatment was 4.6 kg (95% CI: 2.3-6.9) for the 10 patients with underweight, 3.2 kg (95% CI: 2.3-4.0) for the 72 patients with normal weight, and 0.7 kg (95% CI: -1.6-3.0) for the 10 patients with overweight. After six months of ETI treatment, 8 (80%) of the patients with underweight transitioned to the normal weight category, while 11 (15.3%) of the normal-weight patients became overweight. The major determinants of heterogeneity in weight gain were the baseline BMI and the presence of at least one CFTR residual function mutation, explaining 13% and 8% of the variability, respectively.

CONCLUSIONS: Our results indicate that ETI is highly effective in improving weight gain in underweight subjects with CF. However, our data also suggests the need for close monitoring of excess weight gain to prevent potential cardiometabolic complications.

PMID:37330504 | DOI:10.1186/s12931-023-02451-0

Ann Am Thorac Soc. 2023 Jun 16. doi: 10.1513/AnnalsATS.202301-078OC. Online ahead of print.

ABSTRACT

Rationale/Objective: Antibiotic selection for in-hospital treated pulmonary exacerbations (PEx) in people with cystic fibrosis (PwCF) is typically guided by previous respiratory culture results or past PEx antibiotic treatment. In the absence of clinical improvement during PEx treatment, antibiotics are frequently changed in search of a regimen that better alleviates symptoms and restores lung function. The clinical benefits of changing antibiotics during PEx treatment are largely uncharacterized.

METHODS: This was a retrospective cohort study utilizing the CF Foundation Patient Registry-Pediatric Health Information System. PEx were included if they occurred in children with CF from 6 to 21 years old who had been treated with IV antibiotics between January 1st, 2006, through December 31st, 2018. PEx with lengths of stay <5 or >21 days or where treatment was delivered in an intensive care unit were excluded. An antibiotic change was defined as addition or subtraction of any IV antibiotic between hospital day 6 and the day prior to hospital discharge. Inverse probability of treatment weighting was used to adjust for disease severity and indication bias, which might influence a decision to change antibiotics.

RESULTS: In all, 4099 children with CF contributed 18,745 PEx for analysis, of which 8,169 PEx (43.6%) included a change in IV antibiotics on or after day 6. The mean change in in pre- to post-treatment percent predicted forced expiratory volume in one second (ppFEV1) was 11.3 (standard error 0.21) among events in which an IV antibiotic change occurred versus 12.2 (0.18) among PEx without an IV antibiotic change (p=0.001). Similarly, the odds of return to ≥90% of baseline ppFEV1 were less for PEx with antibiotic changes than those without changes (odds ratio (OR) 0.89; [95% Confidence Interval (CI): 0.80-0.98]). Odds of returning to ≥100% of baseline ppFEV1 did not differ between PEx with versus without antibiotic changes (OR 0.94; [0.86-1.03]). In addition, PEx treated with IV antibiotic changes were associated with higher odds of future PEx (OR 1.17 [1.12-1.22]).

CONCLUSIONS: In this retrospective study, changing IV antibiotics during PEx treatment in children with CF was common and not associated with improved clinical outcomes.

PMID:37327485 | DOI:10.1513/AnnalsATS.202301-078OC

Front Mol Biosci. 2023 May 31;10:1201630. doi: 10.3389/fmolb.2023.1201630. eCollection 2023.

ABSTRACT

Opportunistic infections from multidrug-resistant pathogens such as Burkholderia cenocepacia are a threatening risk for hospital-bound patients suffering from immunocompromised conditions or cystic fibrosis. B. cenocepacia BC2L-C lectin has been linked to bacterial adhesion and biofilm formation, thus hindering its activity is seen as a promising strategy to reduce the severity of the infection. We recently described the first bifunctional ligands of the trimeric N-terminal domain of BC2L-C (BC2L-C-Nt), capable of simultaneously engaging its fucose-specific sugar binding site and a vicinal region at the interface between two monomers. Here, we report a computational workflow for the study of these glycomimetic bifunctional ligands in complex with BC2L-C-Nt, aimed at investigating the molecular basis of ligand binding and the dynamics of glycomimetic/lectin interactions. In particular, we evaluated the use of molecular docking in the protein trimer, followed by refinement using MM-GBSA re-scoring and MD simulations in explicit water. Computational results were compared to experimental data derived from X-ray crystallography and isothermal titration calorimetry. The computational protocol proved suitable to provide a reliable description of the interactions between the ligands and BC2L-C-Nt, highlighting the contribution of MD simulations in explicit solvent for a good fit with the experimental observations. The information achieved in the study and the whole workflow appear promising for the structure-based design of improved BC2L-C-Nt ligands as novel antimicrobials with antiadhesive properties.

PMID:37325481 | PMC:PMC10264699 | DOI:10.3389/fmolb.2023.1201630

Front Mol Biosci. 2023 Jun 1;10:1148501. doi: 10.3389/fmolb.2023.1148501. eCollection 2023.

ABSTRACT

Background: Cystic fibrosis (CF) is caused by a wide spectrum of mutations in the CF transmembrane conductance regulator (CFTR) gene, with some leading to non-classical clinical presentations. We present an integrated in vivo, in silico and in vitro investigation of an individual with CF carrying the rare Q1291H-CFTR allele and the common F508del allele. At age 56 years, the participant had obstructive lung disease and bronchiectasis, qualifying for Elexacaftor/Tezacaftor/Ivacaftor (ETI) CFTR modulator treatment due to their F508del allele. Q1291H CFTR incurs a splicing defect, producing both a normally spliced but mutant mRNA isoform and a misspliced isoform with a premature termination codon, causing nonsense mediated decay. The effectiveness of ETI in restoring Q1291H-CFTR is largely unknown. Methods: We collected clinical endpoint measurements, including forced expiratory volume in 1 s percent predicted (FEV1pp) and body mass index (BMI), and examined medical history. In silico simulations of the Q1291H-CFTR were compared to Q1291R, G551D, and wild-type (WT)-CFTR. We quantified relative Q1291H CFTR mRNA isoform abundance in patient-derived nasal epithelial cells. Differentiated pseudostratified airway epithelial cell models at air liquid interface were created and ETI treatment impact on CFTR was assessed by electrophysiology assays and Western blot. Results: The participant ceased ETI treatment after 3 months due to adverse events and no improvement in FEV1pp or BMI. In silico simulations of Q1291H-CFTR identified impairment of ATP binding similar to known gating mutants Q1291R and G551D-CFTR. Q1291H and F508del mRNA transcripts composed 32.91% and 67.09% of total mRNA respectively, indicating 50.94% of Q1291H mRNA was misspliced and degraded. Mature Q1291H-CFTR protein expression was reduced (3.18% ± 0.60% of WT/WT) and remained unchanged with ETI. Baseline CFTR activity was minimal (3.45 ± 0.25 μA/cm2) and not enhanced with ETI (5.73 ± 0.48 μA/cm2), aligning with the individual's clinical evaluation as a non-responder to ETI. Conclusion: The combination of in silico simulations and in vitro theratyping in patient-derived cell models can effectively assess CFTR modulator efficacy for individuals with non-classical CF manifestations or rare CFTR mutations, guiding personalized treatment strategies and optimizing clinical outcomes.

PMID:37325471 | PMC:PMC10267335 | DOI:10.3389/fmolb.2023.1148501

Food Sci Nutr. 2023 Mar 28;11(6):3348-3357. doi: 10.1002/fsn3.3323. eCollection 2023 Jun.

ABSTRACT

Inflammation may develop due to internal dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein or external factors in patients with cystic fibrosis (CF). This prospective randomized clinical trial aimed to ascertain the effects of nano-curcumin as an anti-inflammatory agent and a CFTR modulator on clinical and inflammatory markers in children with CF. Children with CF were randomly assigned to receive daily curcumin or a placebo for 3 months. The primary outcome measure was to evaluate inflammatory indices, nasopharyngeal swab analysis, and clinical assessments via spirometry, anthropometric measurements, and quality of life (QOL) analysis. Sixty children were included. Intra-group changes comparison showed that curcumin decreased the level of high-sensitivity C-reactive protein (hs-CRP) (median: -0.31 mg/L, IQR: -1.53 to 0.81; p = .01) and fecal calprotectin level (-29 μg/g, -57.5 to 11.5; p = .03), also increased the level of interleukin (IL)-10 (6.1 pg/mL, 4.5-9; p = .01). Moreover, curcumin improved the overall QOL and the subscales of the questionnaire. Inter-group changes comparison depicted the number of Pseudomonas colonies reduced by about 52% in the curcumin group and gained weight by about 16% (p > .05). Nano-curcumin seems to be considered as an effective nutritional supplement on hs-CRP, IL-10, fecal calprotectin levels, and improving QOL in patients with CF.

PMID:37324924 | PMC:PMC10261803 | DOI:10.1002/fsn3.3323

Front Pharmacol. 2023 May 30;14:1188051. doi: 10.3389/fphar.2023.1188051. eCollection 2023.

ABSTRACT

Rationale: Lumacaftor/ivacaftor was approved for the treatment of patients with cystic fibrosis who are homozygous for F508del aged 2 years and older following positive results from phase three trials. However, the improvement in CFTR function associated with lumacaftor/ivacaftor has only been studied in patients over 12 years of age, while the rescue potential in younger children is unknown. Methods: In a prospective study, we aimed to evaluate the effect of lumacaftor/ivacaftor on the CFTR biomarkers sweat chloride concentration and intestinal current measurement as well as clinical outcome parameters in F508del homozygous CF patients 2-11 years before and 8-16 weeks after treatment initiation. Results: A total of 13 children with CF homozygous for F508del aged 2-11 years were enrolled and 12 patients were analyzed. Lumacaftor/ivacaftor treatment reduced sweat chloride concentration by 26.8 mmol/L (p = 0.0006) and showed a mean improvement in CFTR activity, as assessed by intestinal current measurement in the rectal epithelium, of 30.5% compared to normal (p = 0.0015), exceeding previous findings of 17.7% of normal in CF patients homozygous for F508del aged 12 years and older. Conclusion: Lumacaftor/ivacaftor partially restores F508del CFTR function in children with CF who are homozygous for F508del, aged 2-11 years, to a level of CFTR activity seen in patients with CFTR variants with residual function. These results are consistent with the partial short-term improvement in clinical parameters.

PMID:37324488 | PMC:PMC10266342 | DOI:10.3389/fphar.2023.1188051