Allergy Asthma Clin Immunol. 2023 Feb 27;19(1):15. doi: 10.1186/s13223-023-00760-z.

ABSTRACT

BACKGROUND: The Cystic Fibrosis Foundation Patient Registry (CFFPR) reports a high prevalence of asthma (34.6%) in people with Cystic Fibrosis (PwCF). While our current understanding of this relationship is limited, a type 2 inflammatory (T2) phenotype has often been identified in CF patients.

RESEARCH QUESTION: This study aimed to evaluate the relationship between the eosinophilic CF T2 inflammatory phenotype and CF-related pulmonary outcomes and microbiological data.

STUDY DESIGN AND METHODS: We conducted a retrospective chart review of adult patients with CF (18 and older; n = 93) receiving their care at University of Virginia Medical Center adult program from January, 2013 through December, 2018. Data collected included demographic data, CFTR (CF transmembrane conductance regulator) mutation, CF comorbidities, medications, Absolute Eosinophil Counts (AEC) in cells/µL and Immunoglobulin E (IgE) levels in IU/mL.

RESULTS: Of 93 patients screened for study eligibility, 74 were included in the final analysis; 19 patients were excluded due to lack of longitudinal data across the study timeline. Lung function decline correlated with increased AEC (p < 0.001) and IgE (p < 0.001) even when adjusting for covariates: age, gender, presence of Pseudomonas spp., MRSA, other bacterial spp., Aspergillus spp., and other fungi (p < 0.001). Univariate analysis demonstrated that people with CF who experienced more than 2 exacerbations requiring hospitalizations and/or intravenous antibiotics a year were more likely to have high AEC (p = 0.018). Logistic regression showed that as AEC increases, the probability that the measurement was taken during a CF exacerbation increases (p = 0.0039). A linear mixed model showed that each additional annual exacerbation event increased on average the log IgE by 0.04. (p = 0.015). This finding remained stable in a multivariate model (p = 0.0145). When adjusted for atopy, log IgE increases as the number of exacerbation events increases (p = 0.022). There was no association between AEC and IgE and microbiological colonization.

INTERPRETATION: This study has shown that in CF patients, T2 inflammation based on serum AEC and IgE correlated with pulmonary exacerbations requiring hospitalizations and/or intravenous antibiotics, independent of bacterial airway colonization. In addition, lung function decline correlated with increased IgE and AEC. Further studies are needed to explore these correlations and potential impact on treatment.

PMID:36849900 | DOI:10.1186/s13223-023-00760-z

J Cyst Fibros. 2023 Feb 25:S1569-1993(23)00062-0. doi: 10.1016/j.jcf.2023.02.010. Online ahead of print.

ABSTRACT

BACKGROUND: An electronic nose (eNose) can be used to detect volatile organic compounds (VOCs). Exhaled breath contains numerous VOCs and individuals' VOCs mixtures create distinct breath profiles. Previous reports have shown that eNose can detect lung infections. Whether eNose can detect Staphylococcus aureus airway infections in breath of children with cystic fibrosis (CF) is currently unclear.

METHODS: In this cross-sectional observational study, a cloud-connected eNose was used for breath profile analysis of clinically stable paediatric CF patients with airway microbiology cultures positive or negative for CF pathogens. Data-analysis involved advanced signal processing, ambient correction and statistics based on linear discriminant and receiver operating characteristics (ROC) analyses.

RESULTS: Breath profiles from 100 children with CF (median predicted FEV1 91%) were obtained and analysed. CF patients with positive airway cultures for any CF pathogen were distinguishable from no CF pathogens (no growth or usual respiratory flora) with accuracy of 79.0% (AUC-ROC 0.791; 95% CI: 0.669-0.913) and between patients positive for Staphylococcus aureus (SA) only and no CF pathogen with accuracy of 74.0% (AUC-ROC 0.797; 95% CI: 0.698-0.896). Similar differences were seen for Pseudomonas aeruginosa (PA) infection vs no CF pathogens (78.0% accuracy, AUC-ROC 0.876, 95% CI: 0.794-0.958). SA- and PA-specific signatures were driven by different sensors in the SpiroNose suggesting pathogen-specific breath signatures.

CONCLUSIONS: Breath profiles of CF patients with SA in airway cultures are distinct from those with no infection or PA infection, suggesting the utility of eNose technology in the detection of this early CF pathogen in children with CF.

PMID:36849333 | DOI:10.1016/j.jcf.2023.02.010

J Cyst Fibros. 2023 Feb 25:S1569-1993(23)00044-9. doi: 10.1016/j.jcf.2023.02.001. Online ahead of print.

ABSTRACT

BACKGROUND: No data exist to guide antibiotic selection among people with CF (PwCF) with respiratory cultures positive for multiple CF-related bacteria (polymicrobial infections). This study aimed to describe the number of polymicrobial in-hospital treated pulmonary exacerbations (PEx), to determine the proportion of polymicrobial PEx where antibiotics were prescribed with activity against all bacteria detected (termed complete antibiotic coverage), and to determine clinical and demographic factors associated with complete antibiotic coverage.

METHODS: Retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System dataset. Children aged 1-21 years with an in-hospital treated PEx from 2006 to 2019 were eligible for inclusion. Bacterial culture positivity was based on any positive respiratory culture in the 12 months prior to a study PEx.

RESULTS: A total of 4,923 children contributed 27,669 total PEx of which 20,214 were polymicrobial; of these, 68% of PEx had complete antibiotic coverage. In regression modeling, a prior PEx with complete antibiotic coverage for MRSA was associated with a higher likelihood of having complete antibiotic coverage at a subsequent study PEx (OR (95% CI) 3.48 (2.50, 4.83)).

CONCLUSIONS: The majority of children with CF hospitalized for polymicrobial PEx were prescribed complete antibiotic coverage. Prior PEx treatment with complete antibiotic coverage predicted complete antibiotic coverage at a future PEx for all bacteria studied. Studies are needed comparing outcomes of polymicrobial PEx treated with different antibiotic coverages to optimize PEx antibiotic selection.

PMID:36849332 | DOI:10.1016/j.jcf.2023.02.001

J Cyst Fibros. 2023 Feb 25:S1569-1993(23)00048-6. doi: 10.1016/j.jcf.2023.02.004. Online ahead of print.

ABSTRACT

BACKGROUND: A series of phase 3 clinical trials have demonstrated that elexacaftor plus tezacaftor plus ivacaftor (ELX/TEZ/IVA) is safe and efficacious in people with cystic fibrosis (pwCF) aged ≥12 years with ≥1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The impact of this treatment on lifetime clinical outcomes and survival, however, has yet to be assessed.

METHODS: We used a person-level microsimulation model to estimate the survival and lifetime clinical benefits of ELX/TEZ/IVA treatment versus other CFTR modulator combinations (tezacaftor plus ivacaftor [TEZ/IVA] or lumacaftor plus ivacaftor [LUM/IVA]) or best supportive care (BSC) alone in pwCF aged ≥12 years who are homozygous for F508del-CFTR. Disease progression inputs were derived from published literature; clinical efficacy inputs were derived from an indirect treatment comparison conducted using relevant phase 3 clinical trial data and extrapolations of clinical data.

RESULTS: The median projected survival for pwCF homozygous for F508del-CFTR treated with ELX/TEZ/IVA was 71.6 years. This was an increase of 23.2 years versus TEZ/IVA, 26.2 years versus LUM/IVA, and 33.5 years versus BSC alone. Treatment with ELX/TEZ/IVA also reduced disease severity as well as the number of pulmonary exacerbations and lung transplants. In a scenario analysis, the median projected survival for pwCF initiating ELX/TEZ/IVA between the ages of 12 and 17 years was 82.5 years, an increase of 45.4 years compared with BSC alone.

CONCLUSIONS: The results from our model suggest ELX/TEZ/IVA treatment may substantially increase survival for pwCF, with early initiation potentially allowing pwCF to achieve near-normal life expectancy.

PMID:36849331 | DOI:10.1016/j.jcf.2023.02.004

PLOS Digit Health. 2023 Feb 27;2(2):e0000201. doi: 10.1371/journal.pdig.0000201. eCollection 2023 Feb.

ABSTRACT

To conduct a systematic review to evaluate the effects of physiotherapy exercises delivered via telemedicine on lung function and quality-of-life in people with Cystic Fibrosis (CF). The databases AMED, CINAHL and MEDLINE were searched from December 2001 until December 2021. Reference lists of included studies were hand-searched. The PRISMA 2020 statement was used to report the review. Studies of any design reported in the English language, included participants with CF, and within outpatient settings were included. Meta-analysis was not deemed appropriate due to the diversity of interventions and heterogeneity of the included studies. Following screening, eight studies with 180 total participants met the inclusion criteria. Sample sizes ranged from 9 to 41 participants. Research designs included five single cohort intervention studies, two randomised control trials and one feasibility study. Telemedicine-based interventions included Tai-Chi, aerobic, and resistance exercise delivered over a study period of six to twelve weeks. All included studies which measured percentage predicted forced expiratory volume in one second found no significant difference. Five studies measuring the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain found improvements, however, did not meet statistical significance. For the CFQ-R physical domain, measured by five studies, two studies found an improvement, although not statistically significant. No adverse events were reported across all studies. The included studies indicate that telemedicine-based exercise over 6-12 weeks does not significantly change lung function or quality-of-life in people with CF. Whilst the role of telemedicine in the care of pwCF is acceptable and promising; further research with standardised outcome measures, larger sample sizes and longer follow-up are required before clinical practice recommendations can be developed.

PMID:36848358 | DOI:10.1371/journal.pdig.0000201

Am J Rhinol Allergy. 2023 Mar;37(2):162-167. doi: 10.1177/19458924221147783.

ABSTRACT

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is comprised of a diverse group of endotypes that cause significant morbidity for afflicted patients. While endoscopic sinus surgery helps ameliorate the disease, polyps frequently recur. Newer strategies are intended to provide access for topical steroid irrigations in attempts to improve the disease process and quality of life, and decrease overall recurrence of polyps.

OBJECTIVE: To review the current literature examining the latest surgical approaches for CRSwNP.

METHODS: Review article.

RESULTS: In dealing with the recalcitrant nature of CRSwNP, surgical techniques have simultaneously become more nuanced and aggressive. Bony resection in anatomically unfavorable areas such as the frontal, maxillary, and sphenoid outflow regions, replacing diseased or denuded mucosa with healthy grafts or flaps at the neo-ostia, and introducing drug-eluting biomaterials to newly opened sinus outflow tracts are highlights in the recent advancements in sinus surgery for CRSwNP. The Draf 3 or modified endoscopic Lothrop procedure has become a standard technique and demonstrated to improve quality of life and decrease polyp recurrence. A number of mucosal grafting or mucosal flap techniques have been described that cover exposed bone of the neo-ostium and evidence shows that this improves healing and diameter of the Draf 3. Partial middle turbinectomy, while controversial, appears to help decrease polyp recurrence in long-term follow-up studies. Modified endoscopic medial maxillectomy improves access to the maxillary sinus mucosa, facilitates debridement and, particularly, in the cystic fibrosis nasal polyp patient, improves overall management of the disease. Sphenoid drill-out procedure provides wider access for topical steroid irrigations and also may improve management of CRSwNP.

CONCLUSION: Surgical intervention remains a mainstay of therapy for CRSwNP. Newer techniques revolve around improving access for topical steroid therapy.

PMID:36848271 | DOI:10.1177/19458924221147783

Infect Immun. 2023 Feb 27:e0053822. doi: 10.1128/iai.00538-22. Online ahead of print.

ABSTRACT

Staphylococcus aureus generates biofilms during many chronic human infections, which contributes to its growth and persistence in the host. Multiple genes and pathways necessary for S. aureus biofilm production have been identified, but knowledge is incomplete, and little is known about spontaneous mutations that increase biofilm formation as infection progresses. Here, we performed in vitro selection of four S. aureus laboratory strains (ATCC 29213, JE2, N315, and Newman) to identify mutations associated with enhanced biofilm production. Biofilm formation increased in passaged isolates from all strains, exhibiting from 1.2- to 5-fold the capacity of parental lines. Whole-genome sequencing identified nonsynonymous mutations affecting 23 candidate genes and a genomic duplication encompassing sigB. Six candidate genes significantly impacted biofilm formation as isogenic transposon knockouts: three were previously reported to impact S. aureus biofilm formation (icaR, spdC, and codY), while the remaining three (manA, narH, and fruB) were newly implicated by this study. Plasmid-mediated genetic complementation of manA, narH, and fruB transposon mutants corrected biofilm deficiencies, with high-level expression of manA and fruB further enhancing biofilm formation over basal levels. This work recognizes genes not previously identified as contributing to biofilm formation in S. aureus and reveals genetic changes able to augment biofilm production by that organism.

PMID:36847490 | DOI:10.1128/iai.00538-22

Front Microbiol. 2023 Feb 9;14:1119703. doi: 10.3389/fmicb.2023.1119703. eCollection 2023.

ABSTRACT

INTRODUCTION: Airway infection and inflammation lead to the progression of obstructive lung disease in persons with cystic fibrosis (PWCF). However, cystic fibrosis (CF) fungal communities, known drivers of CF pathophysiology, remain poorly understood due to the shortcomings of traditional fungal culture. Our objective was to apply a novel small subunit rRNA gene (SSU-rRNA) sequencing approach to characterize the lower airway mycobiome in children with and without CF.

METHODS: Bronchoalveolar lavage fluid (BALF) samples and relevant clinical data were collected from pediatric PWCF and disease control (DC) subjects. Total fungal load (TFL) was measured using quantitative PCR, and SSU-rRNA sequencing was used for mycobiome characterization. Results were compared across groups, and Morisita-Horn clustering was performed.

RESULTS: 161 (84%) of the BALF samples collected had sufficient load for SSU-rRNA sequencing, with amplification being more common in PWCF. BALF from PWCF had increased TFL and increased neutrophilic inflammation compared to DC subjects. PWCF exhibited increased abundance of Aspergillus and Candida, while Malassezia, Cladosporium, and Pleosporales were prevalent in both groups. CF and DC samples showed no clear differences in clustering when compared to each other or to negative controls. SSU-rRNA sequencing was used to profile the mycobiome in pediatric PWCF and DC subjects. Notable differences were observed between the groups, including the abundance of Aspergillus and Candida.

DISCUSSION: Fungal DNA detected in the airway could represent a combination of pathogenic fungi and environmental exposure (e.g., dust) to fungus indicative of a common background signature. Next steps will require comparisons to airway bacterial communities.

PMID:36846802 | PMC:PMC9948248 | DOI:10.3389/fmicb.2023.1119703

Transpl Int. 2023 Feb 8;36:10690. doi: 10.3389/ti.2023.10690. eCollection 2023.

ABSTRACT

Donation after cardiac death (DCD) donors are still subject of studies. In this prospective cohort trial, we compared outcomes after lung transplantation (LT) of subjects receiving lungs from DCD donors with those of subjects receiving lungs from donation after brain death (DBD) donors (ClinicalTrial.gov: NCT02061462). Lungs from DCD donors were preserved in-vivo through normothermic ventilation, as per our protocol. We enrolled candidates for bilateral LT ≥14 years. Candidates for multi-organ or re-LT, donors aged ≥65 years, DCD category I or IV donors were excluded. We recorded clinical data on donors and recipients. Primary endpoint was 30-day mortality. Secondary endpoints were: duration of mechanical ventilation (MV), intensive care unit (ICU) length of stay, severe primary graft dysfunction (PGD3) and chronic lung allograft dysfunction (CLAD). 121 patients (110 DBD Group, 11 DCD Group) were enrolled. 30-day mortality and CLAD prevalence were nil in the DCD Group. DCD Group patients required longer MV (DCD Group: 2 days, DBD Group: 1 day, p = 0.011). ICU length of stay and PGD3 rate were higher in DCD Group but did not significantly differ. LT with DCD grafts procured with our protocols appears safe, despite prolonged ischemia times.

PMID:36846600 | PMC:PMC9945516 | DOI:10.3389/ti.2023.10690

Biofilm. 2023 Feb 6;5:100106. doi: 10.1016/j.bioflm.2023.100106. eCollection 2023 Dec.

ABSTRACT

The presence of Pseudomonas aeruginosa biofilms in cystic fibrosis (CF) patients suffering from chronic lung infections contributes to the failure of antimicrobial therapy. Conventionally, the minimal inhibitory concentration (MIC) is determined to assess the antimicrobial susceptibility of a pathogen, however this parameter fails to predict success in treating biofilm-associated infections. In the present study we developed a high throughput method to determine the antimicrobial concentration required to prevent P. aeruginosa biofilm formation, using a synthetic cystic fibrosis sputum medium (SCFM2). Biofilms were grown in SCFM2 for 24 h in the presence of antibiotics (tobramycin, ciprofloxacin or colistin), whereafter biofilms were disrupted and a resazurin staining was used to quantify the number of surviving metabolically active cells. In parallel, the content of all wells was plated to determine the number of colony forming units (CFU). Biofilm preventing concentrations (BPCs) were compared to MICs and minimal bactericidal concentrations (MBCs) determined according to EUCAST guidelines. Correlations between the resazurin-derived fluorescence and CFU counts were assessed with Kendall's Tau Rank tests. A significant correlation between fluorescence and CFU counts was observed for 9 out of 10 strains investigated, suggesting the fluorometric assay is a reliable alternative to plating for most P. aeruginosa isolates to determine biofilm susceptibility in relevant conditions. For all isolates a clear difference between MICs and BPCs of all three antibiotics was observed, with the BPCs being consistently higher than the MICs. Additionally, the extent of this difference appeared to be antibiotic-dependent. Our findings suggest that this high throughput assay could be a valuable addition to evaluate the antimicrobial susceptibility in P. aeruginosa biofilms in the context of CF.

PMID:36845825 | PMC:PMC9945637 | DOI:10.1016/j.bioflm.2023.100106

Front Cell Infect Microbiol. 2023 Feb 13;13:1127786. doi: 10.3389/fcimb.2023.1127786. eCollection 2023.

ABSTRACT

BACKGROUND: Pseudomonas aeruginosa is a grave nosocomial pathogen that persistently inhabits the lungs of patients with cystic fibrosis (CF) and causes various chronic infections. The bacterial toxin-antitoxin (TA) system is associated with latent and long-term infections, but the underlying mechanisms remain to be fully characterized.

METHODS: We here investigated the diversity and function of five genomic type II TA systems widely distributed among P. aeruginosa clinical isolates. We also examined the distinct structural features of the toxin protein from different TA systems and characterized their contributions to persistence, invasion ability, and intracellular infection caused by P. aeruginosa.

RESULTS: ParDE, PA1030/PA1029, and HigBA could modulate persister cell formation under treatment with specific antibiotics. Furthermore, cell-based transcriptional and invasion assays revealed that PA1030/PA1029 and HigBA TA systems were critical for intracellular survival.

DISCUSSION: Our results highlight the prevalence and diverse roles of type II TA systems in P. aeruginosa and evaluate the possibility of using PA1030/PA1029 and HigBA TA pairs as targets for novel antibiotic treatments.

PMID:36844395 | PMC:PMC9948252 | DOI:10.3389/fcimb.2023.1127786

J Glob Antimicrob Resist. 2023 Feb 24:S2213-7165(23)00027-9. doi: 10.1016/j.jgar.2023.02.010. Online ahead of print.

ABSTRACT

OBJECTIVES: The old antimicrobial nitroxoline is approved to treat urinary tract infection (UTI) and is currently rediscovered for treatment of drug resistant pathogens. Mycobacteria of the Mycobacterium abscessus complex (MYABS) are rapid-growing nontuberculous mycobacteria that are associated with difficult to treat infections of the lungs in patients with pulmonary disorders such as cystic fibrosis. In this study we assessed the in vitro activity of nitroxoline against molecularly characterized drug resistant MYABS isolates from clinical samples to address potential repurposing of nitroxoline in difficult to treat MYABS infection.

METHODS: The isolates originated from clinical samples collected between 2010 and 2019 at the University Hospital of Cologne, Germany (N=16; 10/16 M. abscessus spp. abscessus, 4/16 M. abscessus spp. massiliense, 2/16 M. abscessus spp. bolletii). Nitroxoline activity was compared to standard antimicrobials recommended for treatment of MYABS infection. For drug susceptibility testing of nitroxoline and comparators broth microdilution was performed based on current CLSI guidelines.

RESULTS: Nitroxoline yielded a MIC90 of 4 mg/L (range 2-4 mg/L), which is two twofold dilutions below the current EUCAST susceptibility breakpoint of ≤ 16 mg/L (limited to uncomplicated UTI and E. Coli). Resistance to other antimicrobials was common in our cohort (16/16 isolates resistant to ciprofloxacin, imipenem and doxycycline; 12/16 isolates resistant to tobramycin; 9/16 isolates resistant to cefoxitin; 7/16 isolates resistant to clarithromycin; 2/16 isolates resistant to amikacin).

CONCLUSION: Nitroxoline has a promising in vitro-activity against drug resistant MYABS isolates. Future studies should investigate this finding with macrophage and in vivo models.

PMID:36842457 | DOI:10.1016/j.jgar.2023.02.010

Lancet Respir Med. 2023 Feb 23:S2213-2600(23)00001-2. doi: 10.1016/S2213-2600(23)00001-2. Online ahead of print.

NO ABSTRACT

PMID:36842448 | DOI:10.1016/S2213-2600(23)00001-2

Lancet Respir Med. 2023 Feb 23:S2213-2600(22)00504-5. doi: 10.1016/S2213-2600(22)00504-5. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing.

METHODS: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor-tezacaftor-deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor-tezacaftor-deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor-deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)-tezacaftor-deutivacaftor or tezacaftor-ivacaftor active control for 4 weeks, following a 4-week tezacaftor-ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete.

FINDINGS: In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI -0·8 to 7·0) and 2·7 percentage points (-1·0 to 6·5) from baseline at week 12, respectively, versus -0·8 percentage points (-6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)-tezacaftor-deutivacaftor (n=9), vanzacaftor (10 mg)-tezacaftor-deutivacaftor (n=19), vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (-1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (-4·1 to 8·0), respectively, in sweat chloride concentration of -42·8 mmol/L (-51·7 to -34·0), -45·8 mmol/L (95% CI -51·9 to -39·7), -49·5 mmol/L (-55·9 to -43·1), and 2·3 mmol/L (-7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (-10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=18) and tezacaftor-ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor-ivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and -0·1 percentage points (-6·4 to 6·1), respectively, in sweat chloride concentration of -45·5 mmol/L (-49·7 to -41·3) and -2·6 mmol/L (-8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and -5·0 points (-16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor-tezacaftor-deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity.

INTERPRETATION: Once-daily dosing with vanzacaftor-tezacaftor-deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor-tezacaftor-deutivacaftor in phase 3 clinical trials compared with elexacaftor-tezacaftor-ivacaftor.

FUNDING: Vertex Pharmaceuticals.

PMID:36842446 | DOI:10.1016/S2213-2600(22)00504-5

Metabolites. 2023 Jan 29;13(2):198. doi: 10.3390/metabo13020198.

ABSTRACT

Physical activity can be effective in preventing some of the adverse effects of aging on health. High-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) are beneficial interventions for the quality of life of obese older individuals. The understanding of all possible metabolic mechanisms underlying these beneficial changes has not yet been established. The aim of this study was to analyze changes in the serum metabolome after 12 weeks of HIIT and MICT in obese older adults. Thirty-eight participants performed either HIIT (n = 26) or MICT (n = 12) three times per week for 12 weeks. Serum metabolites as well as clinical and biological parameters were assessed before and after the 12-week intervention. Among the 364 metabolites and ratio of metabolites identified, 51 metabolites changed significantly following the 12-week intervention. Out of them, 21 significantly changed following HIIT intervention and 18 significantly changed following MICT. Associations with clinical and biological adaptations revealed that changes in acyl-alkyl-phosphatidylcholine (PCae) (22:1) correlated positively with changes in handgrip strength in the HIIT group (r = 0.52, p < 0.01). A negative correlation was also observed between 2-oxoglutaric acid and HOMA-IR (r = -0.44, p < 0.01) when considering both groups together (HIIT and MICT). This metabolite also correlated positively with quantitative insulin-sensitivity check index (QUICKI) in both groups together (r = 0.46, p < 0.01) and the HIIT group (r = 0.51, p < 0.01). Additionally, in the MICT group, fumaric acid was positively correlated with triglyceride levels (r = 0.73, p < 0.01) and acetylcarnitine correlated positively with low-density lipoprotein (LDL) cholesterol (r = 0.81, p < 0.01). These four metabolites might represent potential metabolites of interest concerning muscle strength, glycemic parameters, as well as lipid profile parameters, and hence, for a potential healthy aging. Future studies are needed to confirm the association between these metabolites and a healthy aging.

PMID:36837817 | PMC:PMC9967246 | DOI:10.3390/metabo13020198

Clin Ther. 2023 Feb 23:S0149-2918(23)00036-X. doi: 10.1016/j.clinthera.2023.01.016. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a genetic disorder that occurs in people of all genetic ancestries. CF is caused by variants in the CF transmembrane conductance regulator (CFTR) gene that result in decreased, absent, or nonfunctional CFTR protein at the cell surface of the mucous membranes. Clinical manifestations include chronic respiratory disease, malabsorption, and decreased fertility. Historically, therapies for CF were focused on the signs and symptoms of the disease. However, more recently, CFTR modulators, therapies directed at the basic defect, are improving the quality and duration of the lives of people with CF. The predicted survival of people with CF in the United States is now 53 years of age. With the hope of longer, healthier lives, female individuals with CF (fwCF) are expressing the desire to discuss fertility, pregnancy, and parenthood. Furthermore, pregnancy rates are increasing substantially. Understanding the impact of use or discontinuation of highly effective modulator therapy on the reproductive health of fwCF is critical. Finally, fwCF and their providers must consider preventative cancer screening. (Clin Ther. 2023;45:XXX-XXX) © 2023 Elsevier HS Journals, Inc.

PMID:36841738 | DOI:10.1016/j.clinthera.2023.01.016

Eur J Nutr. 2023 Feb 25. doi: 10.1007/s00394-023-03121-z. Online ahead of print.

ABSTRACT

BACKGROUND: Choline deficiency leads to pathologies particularly of the liver, brain and lung. Adequate supply is important for preterm infants and patients with cystic fibrosis. We analysed the assimilation of four different enterally administered deuterium-labelled (D9-) choline supplements in adults.

METHODS: Prospective randomised cross-over study (11/2020-1/2022) in six healthy men, receiving four single doses of 2.7 mg/kg D9-choline equivalent each in the form of D9-choline chloride, D9-phosphorylcholine, D9-alpha-glycerophosphocholine (D9-GPC) or D9-1-palmitoyl-2-oleoyl-glycero-3-phosphoryl-choline (D9-POPC), in randomised order 6 weeks apart. Plasma was obtained at baseline (t = - 0.1 h) and at 0.5 h to 7d after intake. Concentrations of D9-choline and its D9-labelled metabolites were analysed by tandem mass spectrometry. Results are shown as median and interquartile range.

RESULTS: Maximum D9-choline and D9-betaine concentrations were reached latest after D9-POPC administration versus other components. D9-POPC and D9-phosphorylcholine resulted in lower D9-trimethylamine (D9-TMAO) formation. The AUCs (0-7d) of plasma D9-PC concentration showed highest values after administration of D9-POPC. D9-POPC appeared in plasma after fatty acid remodelling, predominantly as D9-1-palmitoyl-2-linoleyl-PC (D9-PLPC), confirming cleavage to 1-palmitoyl-lyso-D9-PC and re-acylation with linoleic acid as the most prominent alimentary unsaturated fatty acid.

CONCLUSION: There was a delayed increase in plasma D9-choline and D9-betaine after D9-POPC administration, with no differences in AUC over time. D9-POPC resulted in a higher AUC of D9-PC and virtually absent D9-TMAO levels. D9-POPC is remodelled according to enterocytic fatty acid availability. D9-POPC seems best suited as choline supplement to increase plasma PC concentrations, with PC as a carrier of choline and targeted fatty acid supply as required by organs. This study was registered at Deutsches Register Klinischer Studien (DRKS) (German Register for Clinical Studies), DRKS00020498, 22.01.2020.

STUDY REGISTRATION: This study was registered at Deutsches Register Klinischer Studien (DRKS) (German Register for Clinical Studies), DRKS00020498.

PMID:36840817 | DOI:10.1007/s00394-023-03121-z

Pharmaceutics. 2023 Feb 6;15(2):545. doi: 10.3390/pharmaceutics15020545.

ABSTRACT

A fatal hereditary condition, cystic fibrosis (CF) causes severe lung problems. Ibuprofen (IBU), a non-steroidal anti-inflammatory drug, slows the progression of disease without causing significant side effects. Considering the poor water-solubility of the drug, IBU nanoparticles are beneficial for local pulmonary administration. We aimed to formulate a carrier-free dry powder inhaler containing nanosized IBU. We combined high-performance ultra-sonication and nano spray-drying. IBU was dissolved in ethyl acetate; after that, it was sonicated into a polyvinyl alcohol solution, where it precipitated as nanoparticles. Mannitol and leucine were added when producing dry particles using nano-spray drying. The following investigations were implemented: dynamic light scattering, laser diffraction, surface tension measurement, scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry, Fourier-transform infrared spectroscopy, in vitro dissolution test, and in vitro aerodynamic assessment (Andersen Cascade Impactor). The particle diameter of the IBU was in the nano range. The spray-dried particles showed a spherical morphology. The drug release was rapid in artificial lung media. The products represented large fine particle fractions and proper aerodynamic diameters. We successfully created an inhalable powder, containing nano-sized IBU. Along with the exceptional aerodynamic performance, the ideal particle size, shape, and drug-release profile might offer a ground-breaking local therapy for CF.

PMID:36839867 | DOI:10.3390/pharmaceutics15020545

Pharmaceutics. 2023 Feb 2;15(2):502. doi: 10.3390/pharmaceutics15020502.

ABSTRACT

Targeting pathogenic mechanisms, rather than essential processes, represents a very attractive approach for the development of new antimycobacterial drugs. In this context, iron acquisition routes have recently emerged as potentially druggable pathways. However, the importance of siderophore biosynthesis in the virulence and pathogenicity of M. abscessus (Mab) is still poorly understood. In this study, we investigated the Salicylate Synthase (SaS) of Mab as an innovative molecular target for the development of inhibitors of siderophore production. Notably, Mab-SaS does not have any counterpart in human cells, making it an interesting candidate for drug discovery. Starting from the analysis of the binding of a series of furan-based derivatives, previously identified by our group as inhibitors of MbtI from M. tuberculosis (Mtb), we successfully selected the lead compound 1, exhibiting a strong activity against Mab-SaS (IC50 ≈ 5 µM). Computational studies characterized the key interactions between 1 and the enzyme, highlighting the important roles of Y387, G421, and K207, the latter being one of the residues involved in the first step of the catalytic reaction. These results support the hypothesis that 5-phenylfuran-2-carboxylic acids are also a promising class of Mab-SaS inhibitors, paving the way for the optimization and rational design of more potent derivatives.

PMID:36839823 | DOI:10.3390/pharmaceutics15020502

Pathogens. 2023 Jan 24;12(2):181. doi: 10.3390/pathogens12020181.

ABSTRACT

Staphylococci are broadly adaptable and their ability to grow in unique environments has been widely established, but the most common and clinically relevant staphylococcal niche is the skin and mucous membranes of mammals and birds. S. aureus causes severe infections in mammalian tissues and organs, with high morbidities, mortalities, and treatment costs. S. epidermidis is an important human commensal but is also capable of deadly infections. Gold-standard diagnostic methods for staph infections currently rely upon retrieval and characterization of the infectious agent through various culture-based methods. Yet, obtaining a viable bacterial sample for in vitro identification of infection etiology remains a significant barrier in clinical diagnostics. The development of volatile organic compound (VOC) profiles for the detection and identification of pathogens is an area of intensive research, with significant efforts toward establishing breath tests for infections. This review describes the limitations of existing infection diagnostics, reviews the principles and advantages of VOC-based diagnostics, summarizes the analytical tools for VOC discovery and clinical detection, and highlights examples of how VOC biomarkers have been applied to diagnosing human and animal staph infections.

PMID:36839453 | DOI:10.3390/pathogens12020181