J Cyst Fibros. 2024 Apr 29:S1569-1993(24)00056-0. doi: 10.1016/j.jcf.2024.04.011. Online ahead of print.

ABSTRACT

BACKGROUND: Sexual dysfunction (erectile dysfunction in males, sexual dissatisfaction, sexual interest/arousal disorders, and dyspareunia in females) has not been the subject of indepth research in people with cystic fibrosis (CF). This study aimed to determine the prevalence of sexual dysfunction in adults with CF, factors associated with sexual dysfunction, and the impact of sexual dysfunction on quality of life.

METHOD: We conducted a multicentre study in adults with cystic fibrosis followed in specialist centres in Western France. We assessed erectile dysfunction and its severity using the IIEF5 self-questionnaire (International Index of Erectile Function); the FSFI (Female Sexual Function Index) was used to assess sexual function in females, and we evaluated quality of life in both sexes using the CFQ-R14+ questionnaire.

RESULTS: In total, 77 males and 74 females completed the sexual function questionnaire (mean age 32+/- 10 and 25+/- 8,5 years respectively). Among them, 21 % of males and 30 % of females reported sexual dysfunction. CFQ-R14+ score was significantly lower in males with erectile dysfunction than those without (p < 0.001). Faecal incontinence was associated with more frequent sexual dysfunction in females and higher severity of erectile dysfunction in males.

CONCLUSION: The prevalence of sexual disorders is relatively high in males and females with cystic fibrosis. Therefore, it seems important to train specialist teams to address the issue of sexuality without embarrassment, and to encourage them to seek out and treat faecal incontinence, which is associated with greater severity or frequency of these symptoms.

PMID:38688746 | DOI:10.1016/j.jcf.2024.04.011

Transplant Proc. 2024 Apr 29:S0041-1345(24)00189-1. doi: 10.1016/j.transproceed.2024.03.017. Online ahead of print.

ABSTRACT

INTRODUCTION: Lung transplantation (LTx) is the last treatment option for children with end-stage respiratory failure. According to the literature, cystic fibrosis remains the most common cause of pediatric LTx. The study aimed to assess the characteristics of pediatric LTx recipients as well as the outcomes of the transplantation.

METHODS: Our study is a single-center retrospective review of clinical data of all 11 patients who underwent a LTx before the age of 18 years between the years 2016 and 2020. Medical records were examined for patients' characteristics, general treatment, and complications.

RESULTS: There were a total of 11 patients (8 males) with a median age 14.5 years (range: 11-17). The primary diseases that led to LTx were: cystic fibrosis in 8 patients (72.73%), hereditary hemorrhagic telangiectasia in 2 patients (18.18%), and idiopathic pulmonary arterial hypertension in 1 patient (9.09%). Median period from qualification to LTx was 235.55 days (range: 11-748). Two patients (18.18%) underwent lung retransplantation after 3 and 5 years. One patient passed away 10 months after surgery due to noncompliance.

CONCLUSIONS: Pediatric lung transplantation is less common than lung transplantation in adults. It also differs in fields of donors accessibility, stronger immune system response and noncompliance that may lead to graft failure.

PMID:38688728 | DOI:10.1016/j.transproceed.2024.03.017

NPJ Antimicrob Resist. 2023;1(1):7. doi: 10.1038/s44259-023-00005-4. Epub 2023 Jul 3.

ABSTRACT

Despite our best efforts to discover new antimicrobials, bacteria have evolved mechanisms to become resistant. Resistance to antimicrobials can be attributed to innate, inducible, and acquired mechanisms. Mycobacterium abscessus is one of the most antimicrobial resistant bacteria and is known to cause chronic pulmonary infections within the cystic fibrosis community. Previously, we identified epetraborole as an inhibitor against M. abscessus with in vitro and in vivo activities and that the efficacy of epetraborole could be improved with the combination of the non-proteinogenic amino acid norvaline. Norvaline demonstrated activity against the M. abscessus epetraborole resistant mutants thus, limiting resistance to epetraborole in wild-type populations. Here we show M. abscessus mutants with resistance to epetraborole can acquire resistance to norvaline in a leucyl-tRNA synthetase (LeuRS) editing-independent manner. After showing that the membrane hydrophobicity and efflux activity are not linked to norvaline resistance, whole-genome sequencing identified a mutation in the allosteric regulatory domain of α-isopropylmalate synthase (α-IPMS). We found that mutants with the α-IPMSA555V variant incorporated less norvaline in the proteome and produced more leucine than the parental strain. Furthermore, we found that leucine can rescue growth inhibition from norvaline challenge in the parental strain. Our results demonstrate that M. abscessus can modulate its metabolism through mutations in an allosteric regulatory site to upregulate the biosynthesis of the natural LeuRS substrate and outcompete norvaline. These findings emphasize the antimicrobial resistant nature of M. abscessus and describe a unique mechanism of substrate-inhibitor competition.

PMID:38686213 | PMC:PMC11057210 | DOI:10.1038/s44259-023-00005-4

Adv Sci (Weinh). 2024 Apr 29:e2305866. doi: 10.1002/advs.202305866. Online ahead of print.

ABSTRACT

Although the gasotransmitter hydrogen sulfide (H2S) is well known for its vasodilatory effects, H2S also exhibits vasoconstricting properties. Herein, it is demonstrated that administration of H2S as intravenous sodium sulfide (Na2S) increased blood pressure in sheep and rats, and this effect persisted after H2S has disappeared from the blood. Inhibition of the L-type calcium channel (LTCC) diminished the hypertensive effects. Incubation of Na2S with whole blood, red blood cells, methemoglobin, or oxyhemoglobin produced a hypertensive product of H2S, which is not hydrogen thioperoxide, metHb-SH- complexes, per-/poly- sulfides, or thiolsulfate, but rather a labile intermediate. One-electron oxidation of H2S by oxyhemoglobin generated its redox cousin, sulfhydryl radical (HS•). Consistent with the role of HS• as the hypertensive intermediate, scavenging HS• inhibited Na2S-induced vasoconstriction and activation of LTCCs. In conclusion, H2S causes vasoconstriction that is dependent on the activation of LTCCs and generation of HS• by oxyhemoglobin.

PMID:38685626 | DOI:10.1002/advs.202305866

Respir Res. 2024 Apr 29;25(1):190. doi: 10.1186/s12931-024-02778-2.

ABSTRACT

BACKGROUND: Children with advanced pulmonary disease due to cystic fibrosis (CF) are at risk of acute respiratory failure due to pulmonary exacerbations leading to their admission to pediatric intensive care units (PICU). The objectives of this study were to determine short and medium-term outcomes of children with CF admitted to PICU for acute respiratory failure due to pulmonary exacerbation and to identify prognosis factors.

METHODS: This retrospective monocentric study included patients less than 18 years old admitted to the PICU of a French university hospital between 2000 and 2020. Cox proportional hazard regression methods were used to determine prognosis factors of mortality or lung transplant.

RESULTS: Prior to PICU admission, the 29 patients included (median age 13.5 years) had a severe lung disease (median Forced Expiratory Volume in 1 s percentage predicted at 29%). Mortality rates were respectively 17%, 31%, 34%, 41% at discharge and at 3, 12 and 36 months post-discharge. Survival rates free of lung transplant were 34%, 32%, 24% and 17% respectively. Risk factors associated with mortality or lung transplant using the univariate analysis were female sex and higher pCO2 and chloride levels at PICU admission, and following pre admission characteristics: home respiratory and nutritional support, registration on lung transplant list and Stenotrophomonas Maltophilia bronchial colonization.

CONCLUSION: Children with CF admitted to PICU for acute respiratory failure secondary to pulmonary exacerbations are at high risk of death, both in the short and medium terms. Lung transplant is their main chance of survival and should be considered early.

PMID:38685088 | DOI:10.1186/s12931-024-02778-2

Ital J Pediatr. 2024 Apr 29;50(1):90. doi: 10.1186/s13052-024-01654-5.

ABSTRACT

BACKGROUND: Persistent airway inflammation is a central feature of bronchiectasis. Arachidonate 15-lipoxygenase (ALOX-15) controls production of endogenous lipid mediators, including lipoxins that regulate airway inflammation. Mutations at various positions in ALOX-15 gene can influence airway disease development. We investigated association between ALOX-15,c.-292 C > T gene polymorphism and bronchiectasis unrelated to cystic fibrosis in Egyptian children. Also, lipoxin A4 (LXA4) level in bronchoalveolar lavage (BAL) was studied in relation to polymorphism genotypes and disease phenotypes determined by clinical, pulmonary functions, and radiological severity parameters.

METHODS: This was an exploratory study that included 60 participants. Thirty children with non-cystic fibrosis bronchiectasis (NCFB) were compared with 30 age and sex-matched controls. ALOX-15,c.-292 C > T polymorphism was genotyped using TaqMan-based Real-time PCR. LXA4 was measured in BAL using ELISA method.

RESULTS: There was no significant difference between patients and controls regarding ALOX-15,c.-292 C > T polymorphism genotypes and alleles (OR = 1.75; 95% CI (0.53-5.7), P = 0.35) (OR = 1; 95% CI (0.48-2), p = 1). BAL LXA4 level was significantly lower in patients, median (IQR) of 576.9 (147.6-1510) ng/ml compared to controls, median (IQR) of 1675 (536.8-2542) (p = 0.002). Patients with severe bronchiectasis had a significantly lower LXA4 level (p < 0.001). There were significant correlations with exacerbations frequency (r=-0.54, p = 0.002) and FEV1% predicted (r = 0.64, p = 0.001). Heterozygous CT genotype carriers showed higher LXA4 levels compared to other genotypes(p = 0.005).

CONCLUSIONS: Low airway LXA4 in children with NCFB is associated with severe disease phenotype and lung function deterioration. CT genotype of ALOX-15,c.-292 C > T polymorphism might be a protective genetic factor against bronchiectasis development and/or progression due to enhanced LXA4 production.

PMID:38685084 | DOI:10.1186/s13052-024-01654-5

BMC Pulm Med. 2024 Apr 29;24(1):209. doi: 10.1186/s12890-024-03027-4.

ABSTRACT

BACKGROUND: The pathogenesis of adult non-cystic fibrosis (CF) bronchiectasis is complex, and the relevant molecular mechanism remains ambiguous. Versican (VCAN) is a key factor in inflammation through interactions with adhesion molecules. This study constructs a stable panoramic map of mRNA, reveals the possible pathogenesis of bronchiectasis, and provides new ideas and methods for bronchiectasis.

METHODS: Peripheral blood and tissue gene expression data from patients with bronchiectasis and normal control were selected by bioinformatics analysis. The expression of VCAN in peripheral blood and bronchial tissues of bronchiectasis were obtained by transcriptome sequencing. The protein expression levels of VCAN in serums were verified by the enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of VCAN in co-culture of Pseudomonas aeruginosa and bronchial epithelial cells were verified by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the biological function of VCAN was detected by the transwell assay.

RESULTS: The expression of VCAN was upregulated in the bronchiectasis group by sequencing analysis (P < 0.001). The expression of VCAN in the bronchial epithelial cell line BEAS-2B was increased in P. aeruginosa (P.a), which was co-cultured with BEAS-2B cells (P < 0.05). The concentration of VCAN protein in the serum of patients with bronchiectasis was higher than that in the normal control group (P < 0.05). Transwell experiments showed that exogenous VCAN protein induced the migration of neutrophils (P < 0.0001).

CONCLUSIONS: Our findings indicate that VCAN may be involved in the development of bronchiectasis by increasing the migration of neutrophils and play an important role in bronchial pathogenesis.

PMID:38685004 | DOI:10.1186/s12890-024-03027-4

Heliyon. 2024 Apr 16;10(8):e29188. doi: 10.1016/j.heliyon.2024.e29188. eCollection 2024 Apr 30.

ABSTRACT

BACKGROUND: Use of elexacaftor/tezacaftor/ivacaftor (ETI) for treatment of cystic fibrosis (CF) has resulted in unprecedented clinical improvements necessitating development of outcome measures for monitoring disease course. Intranasal micro-optical coherence tomography (μOCT) has previously helped detect and characterize mucociliary abnormalities in patients with CF. This study was done to determine if μOCT can define the effects of ETI on nasal mucociliary clearance and monitor changes conferred to understand mechanistic effects of CFTR modulators beyond CFTR activation.

METHODS: 26 subjects, with at least 1 F508del mutation were recruited and followed at baseline (visit 1), +1 month (visit 2) and +6 months (visit 4) following initiation of ETI therapy. Clinical outcomes were computed at visits 1, 2 and 4. Intranasal μOCT imaging and functional metrics analysis including mucociliary transport rate (MCT) estimation were done at visits 1 and 2.

RESULTS: Percent predicted forced expiratory volume in 1 s (ppFEV1) showed a significant increase of +10.9 % at visit 2, which sustained at visit 4 (+10.6 %). Sweat chloride levels significantly decreased by -36.6 mmol/L and -41.3 mmol/L at visits 2 and 4, respectively. μOCT analysis revealed significant improvement in MCT rate (2.8 ± 1.5, visit 1 vs 4.0 ± 1.5 mm/min, visit 2; P = 0.048).

CONCLUSIONS: Treatment with ETI resulted in significant and sustained clinical improvements over 6 months. Functional improvements in MCT rate were evident within a month after initiation of ETI therapy indicating that μOCT imaging is sensitive to the treatment effect of HEMT and suggests improved mucociliary transport as a probable mechanism of action underlying the clinical benefits.

PMID:38681615 | PMC:PMC11052906 | DOI:10.1016/j.heliyon.2024.e29188

Endosc Int Open. 2024 Apr 26;12(4):E629-E638. doi: 10.1055/a-2251-3372. eCollection 2024 Apr.

ABSTRACT

Background and study aims Currently available polyethylene glycol (PEG)-based preparations continue to represent a challenge in children. The aim of this study was to compare the efficacy and safety of a new low-volume PEG preparation with a conventional PEG-electrolyte solution (PEG-ES) in children and adolescents. Patients and methods This was a multicenter, randomized, observer-blind, parallel-group, phase 3 clinical trial, where patients were randomized between PMF104 (Clensia) and a conventional PEG-ES (Klean-Prep), and stratified by age stratum (2 to <6; 6 to < 12;12 to <18 years). The primary endpoint was to test the non-inferiority of PMF104 versus PEG-ES, in terms of colon cleansing. Safety, tolerability, acceptability, palatability, and compliance were also assessed. Efficacy endpoints were analyzed in the per protocol set (PPS) and full analysis set (FAS) and safety and tolerability endpoints in the safety set (SAF). Results Of the 356 patients enrolled, 258 were included in the PPS, 346 in the FAS, and 351 in the SAF. Non-inferiority of PMF104 was confirmed for children aged > 6 years and for all age groups in PPS and FAS, respectively. Optimal compliance was reported more frequently in the PMF104 than in the PEG-ES group, in both PPS (86.1% vs. 68.4%) and FAS (82.9% vs. 65.3%). Both preparations were equally safe and tolerable. Palatability and acceptability were considered better in the PMF104 group than in the PEG-ES group (27.1% vs. 15.3% and 15.3% vs. 3.5%, respectively). Conclusions In children aged 6 to 17 years, the new low-volume product PMF104 is non-inferior to the reference PEG-ES in terms of bowel cleansing, safety, and tolerability, with slightly better results in compliance, palatability, and acceptability.

PMID:38681144 | PMC:PMC11052644 | DOI:10.1055/a-2251-3372

Qatar Med J. 2024 Mar 25;2024(2):7. doi: 10.5339/qmj.2024.qitc.7. eCollection 2024.

NO ABSTRACT

PMID:38680415 | PMC:PMC11046136 | DOI:10.5339/qmj.2024.qitc.7

Qatar Med J. 2024 Apr 8;2024(2):4. doi: 10.5339/qmj.2024.qitc.4. eCollection 2024.

NO ABSTRACT

PMID:38680409 | PMC:PMC11046103 | DOI:10.5339/qmj.2024.qitc.4

J Cyst Fibros. 2024 Apr 27:S1569-1993(24)00058-4. doi: 10.1016/j.jcf.2024.04.012. Online ahead of print.

ABSTRACT

BACKGROUND: Over the past four decades, numerous case reports and clinical studies have highlighted the presence of heart disease in individuals with cystic fibrosis. Given the limited information in this field and the imperative to identify early changes during childhood, our study aims to explore cardiac dysfunction in patients with cystic fibrosis using echocardiography.

METHODS: In this case-control study, we examined echocardiographic findings from thirty-three patients with cystic fibrosis and sixty healthy children. Demographic information for both groups was recorded, and the disease severity in patients was assessed using the Schawachman criterion. M-mode, Doppler flow velocity, and Tissue Doppler Imaging echocardiography were performed for all participants, with subsequent data analysis using SPSS 24.

RESULTS: Our study encompassed thirty-three CF patients and sixty healthy children. The estimated pulmonary artery blood pressure (systolic and mean) in patients with cystic fibrosis was significantly higher than in the control group (P < 0.05). Additionally, the mean trans-tricuspid peak early to late diastolic flow velocity (E/A) was significantly lower in the case group than the control group (P < 0.05), along with a significantly lower mean tricuspid valve deceleration time (DT) (P < 0.05). Similarly, the mean TAPSE in the case group was notably lower than in the control group (P < 0.05). No significant difference in Mean left ventricular Ejection Fraction (EF) and Fractional Shortening (FS) existed between the two groups (P > 0.05). Furthermore, Trans-mitral peak early to late diastolic flow velocity (E/A) in the case group was significantly lower than in the control group (P < 0.05), and the mean mitral valve DT in the case group was also significantly lower (P < 0.05).

CONCLUSION: Our study findings indicate the presence of some degree of right ventricular dysfunction in children with cystic fibrosis. This finding may have implications for the development or modification of clinical guidelines for managing cystic fibrosis in children. Further investigations are recommended to elucidate the underlying mechanisms and contributing factors, providing valuable insights for clinical management.

PMID:38679549 | DOI:10.1016/j.jcf.2024.04.012

Biochim Biophys Acta Gene Regul Mech. 2024 Apr 27:195031. doi: 10.1016/j.bbagrm.2024.195031. Online ahead of print.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes an anion-selective channel found in epithelial cell membranes. Mutations in CFTR cause cystic fibrosis (CF), an inherited disorder that impairs epithelial function in multiple organs. Most men with CF are infertile due to loss of intact genital ducts. Here we investigated a novel epididymis-selective cis-regulatory element (CRE), located within a peak of open chromatin at -9.5 kb 5' to the CFTR gene promoter. Activation of the -9.5 kb CRE alone by CRISPRa had no impact on CFTR gene expression. However, CRISPRa co-activation of the -9.5 kb CRE and the CFTR gene promoter in epididymis cells significantly augmented CFTR mRNA and protein expression when compared to promoter activation alone. This increase was accompanied by enhanced chromatin accessibility at both sites. Furthermore, the combined CRISPRa strategy activated CFTR expression in other epithelial cells that lack open chromatin at the -9.5 kb site and in which the locus is normally inactive. However, the -9.5 kb CRE does not function as a classical enhancer of the CFTR promoter in transient reporter gene assays. These data provide a novel mechanism for activating/augmenting CFTR expression, which may have therapeutic utility for mutations that perturb CFTR transcription.

PMID:38679287 | DOI:10.1016/j.bbagrm.2024.195031

Diagn Microbiol Infect Dis. 2024 Apr 4;109(3):116294. doi: 10.1016/j.diagmicrobio.2024.116294. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a progressive and inherited disease that affects approximately 70000 individuals all over the world annually. A mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene serves as its defining feature. Bacterial infections have a significant impact on the occurrence and development of CF. In this manuscript, we discuss the role and virulence factors of Staphylococcus aureus as an important human pathogen with the ability to induce respiratory tract infections. Recent studies have reported S. aureus as the first isolated bacteria in CF patients. Methicillin-resistant Staphylococcus aureus (MRSA) pathogens are approximately resistant to all β-lactams. CF patients are colonized by MRSA expressing various virulence factors including toxins, and Staphylococcal Cassette Chromosome mec (SCCmec) types, and have the potential for biofilm formation. Therefore, variations in clinical outcomes will be manifested. SCCmec type II has been reported in CF patients more than in other SCCmec types from different countries. The small-colony variants (SCVs) as specific morphologic subtypes of S. aureus with slow growth and unusual properties can also contribute to persistent and difficult-to-treat infections in CF patients. The pathophysiology of SCVs is complicated and not fully understood. Patients with cystic fibrosis should be aware of the intrinsic risk factors for complex S. aureus infections, including recurring infections, physiological issues, or coinfection with P. aeruginosa.

PMID:38678689 | DOI:10.1016/j.diagmicrobio.2024.116294

Respir Res. 2024 Apr 27;25(1):187. doi: 10.1186/s12931-024-02794-2.

ABSTRACT

BACKGROUND: Modulator therapies that seek to correct the underlying defect in cystic fibrosis (CF) have revolutionized the clinical landscape. Given the heterogeneous nature of lung disease progression in the post-modulator era, there is a need to develop prediction models that are robust to modulator uptake.

METHODS: We conducted a retrospective longitudinal cohort study of the CF Foundation Patient Registry (N = 867 patients carrying the G551D mutation who were treated with ivacaftor from 2003 to 2018). The primary outcome was lung function (percent predicted forced expiratory volume in 1 s or FEV1pp). To characterize the association between ivacaftor initiation and lung function, we developed a dynamic prediction model through covariate selection of demographic and clinical characteristics. The ability of the selected model to predict a decline in lung function, clinically known as an FEV1-indicated exacerbation signal (FIES), was evaluated both at the population level and individual level.

RESULTS: Based on the final model, the estimated improvement in FEV1pp after ivacaftor initiation was 4.89% predicted (95% confidence interval [CI]: 3.90 to 5.89). The rate of decline was reduced with ivacaftor initiation by 0.14% predicted/year (95% CI: 0.01 to 0.27). More frequent outpatient visits prior to study entry and being male corresponded to a higher overall FEV1pp. Pancreatic insufficiency, older age at study entry, a history of more frequent pulmonary exacerbations, lung infections, CF-related diabetes, and use of Medicaid insurance corresponded to lower FEV1pp. The model had excellent predictive accuracy for FIES events with an area under the receiver operating characteristic curve of 0.83 (95% CI: 0.83 to 0.84) for the independent testing cohort and 0.90 (95% CI: 0.89 to 0.90) for 6-month forecasting with the masked cohort. The root-mean-square errors of the FEV1pp predictions for these cohorts were 7.31% and 6.78% predicted, respectively, with standard deviations of 0.29 and 0.20. The predictive accuracy was robust across different covariate specifications.

CONCLUSIONS: The methods and applications of dynamic prediction models developed using data prior to modulator uptake have the potential to inform post-modulator projections of lung function and enhance clinical surveillance in the new era of CF care.

PMID:38678203 | DOI:10.1186/s12931-024-02794-2

Gene Ther. 2024 Apr 27. doi: 10.1038/s41434-024-00453-1. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa poses a significant threat to immunocompromised individuals and those with cystic fibrosis. Treatment relies on antibiotics, but persistent infections occur due to intrinsic and acquired resistance of P. aeruginosa towards multiple classes of antibiotics. To date, there are no licensed vaccines for this pathogen, prompting the urgent need for novel treatment approaches to combat P. aeruginosa infection and persistence. Here we validated AAV vectored immunoprophylaxis as a strategy to generate long-term plasma and mucosal expression of highly protective monoclonal antibodies (mAbs) targeting the exopolysaccharide Psl (Cam-003) and the PcrV (V2L2MD) component of the type-III secretion system injectosome either as single mAbs or together as a bispecific mAb (MEDI3902) in a mouse model. When administered intramuscularly, AAV-αPcrV, AAV-αPsl, and AAV-MEDI3902 significantly protected mice challenged intranasally with a lethal dose of P. aeruginosa strains PAO1 and PA14 and reduced bacterial burden and dissemination to other organs. While all AAV-mAbs provided protection, AAV-αPcrV and AAV-MEDI3902 provided 100% and 87.5% protection from a lethal challenge with 4.47 × 107 CFU PAO1 and 87.5% and 75% protection from a lethal challenge with 3 × 107 CFU PA14, respectively. Serum concentrations of MEDI3902 were ~10× lower than that of αPcrV, but mice treated with this vector showed a greater reduction in bacterial dissemination to the liver, lung, spleen, and blood compared to other AAV-mAbs. These results support further investigation into the use of AAV vectored immunoprophylaxis to prevent and treat P. aeruginosa infections and other bacterial pathogens of public health concern for which current treatment strategies are limited.

PMID:38678160 | DOI:10.1038/s41434-024-00453-1

J Cyst Fibros. 2024 Apr 27:S1569-1993(24)00047-X. doi: 10.1016/j.jcf.2024.04.004. Online ahead of print.

ABSTRACT

Pulmonary exacerbations in people with cystic fibrosis are associated with significant morbidity and reduced quality of life. Pulmonary exacerbation treatment guidelines, published by an expert panel assembled by the Cystic Fibrosis Foundation nearly 15 years ago, were primarily consensus-based as there were several gaps in the evidence base. In particular, limited evidence existed regarding optimal pulmonary exacerbation treatment strategies, including duration of antibiotic therapy, treatment location, antibiotic selection, and the role of systemic corticosteroids. Over the last decade, results from observational studies and large multi-center randomized controlled trials have begun to answer important questions related to pulmonary exacerbation treatment. This review focuses on the diagnosis, etiology, and changing epidemiology of pulmonary exacerbations, and also summarizes the most recent and up-to-date studies describing pulmonary exacerbation treatment. Finally, this review provides consideration for future pulmonary exacerbation research priorities, particularly in the current highly effective modulator therapy era.

PMID:38677887 | DOI:10.1016/j.jcf.2024.04.004

J Mol Biol. 2024 Apr 25:168591. doi: 10.1016/j.jmb.2024.168591. Online ahead of print.

ABSTRACT

De novo protein folding into a native three-dimensional structure is indispensable for biological function, is instructed by its amino acid sequence, and occurs along a vectorial trajectory. The human proteome contains thousands of membrane-spanning proteins, whose biosynthesis begins on endoplasmic reticulum-associated ribosomes. Nearly half of all membrane proteins traverse the membrane more than once, including therapeutically important protein families such as solute carriers, G-protein-coupled receptors, and ABC transporters. These mediate a variety of functions like signal transduction and solute transport and are often of vital importance for cell function and tissue homeostasis. Missense mutations in multispan membrane proteins can lead to misfolding and cause disease; an example is the ABC transporter Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Even though our understanding of multispan membrane-protein folding still is rather rudimental, the cumulative knowledge of 20 years of basic research on CFTR folding has led to development of drugs that modulate the misfolded protein. This has provided the prospect of a life without CF to the vast majority of patients. In this review we describe our understanding of the folding pathway of CFTR in cells, which is modular and tolerates many defects, making it effective and robust. We address how modulator drugs affect folding and function of CFTR, and distinguish protein stability from its folding process. Since the domain architecture of (mammalian) ABC transporters are highly conserved, we anticipate that the insights we discuss here for folding of CFTR may lay the groundwork for understanding the general rules of ABC-transporter folding.

PMID:38677493 | DOI:10.1016/j.jmb.2024.168591

J Heart Lung Transplant. 2024 Apr 25:S1053-2498(24)01566-3. doi: 10.1016/j.healun.2024.04.005. Online ahead of print.

ABSTRACT

BACKGROUND: Inconsistent data exists regarding the risk factors for bronchoalveolar lavage (BAL) positivity in lung donors, the incidence of donor-derived infections (DDI), and the effect of BAL positivity on lung transplant (LuTx) recipients' outcome.

METHODS: A retrospective analysis was conducted on consecutive LuTx at a single center from January 2016 to December 2022. Donors' data, including characteristics, graft function and BAL samples were collected pre-procurement. Recipients underwent BAL before LuTx and about the 3rd, 7th and 14th day after LuTx. A DDI was defined as BAL positivity (bacterial growth ≥104 colony forming units) for identical bacterial species between donor and recipient. Recipients' pre-operative characteristics, intra-operative management, and post-operative outcomes were assessed. Two recipient cohorts were identified based on lung colonization status before undergoing LuTx.

RESULTS: Out of 188 LuTx procedures performed, 169 were analyzed. Thirty-six percent of donors' BAL tested positive. Donors' characteristics and graft function at procurement were not associated with BAL positivity. Fourteen DDI were detected accounting for 23% of recipients receiving a graft with a positive BAL. Only among uncolonized recipients, receiving a graft with positive BAL is associated with higher likelihood of requiring invasive ventilation at 72 hours after LuTx on higher positive end-expiratory pressure levels having lower PaO2/FiO2, prolonged duration of mechanical ventilation and longer ICU stay. No difference in hospital length of stay was observed.

CONCLUSIONS: Receiving a graft with a positive BAL, which is poorly predicted by donors' characteristics, carries the risk of developing a DDI and is associated to a worse early graft function among uncolonized recipients.

PMID:38677352 | DOI:10.1016/j.healun.2024.04.005

Diagn Microbiol Infect Dis. 2024 Apr 26;109(3):116321. doi: 10.1016/j.diagmicrobio.2024.116321. Online ahead of print.

ABSTRACT

Cystic fibrosis patients' lungs are chronically colonized by multiple microbial species capable of forming biofilms. This study aimed to characterize the polymicrobial biofilm formed by Candida spp. and S. aureus, co-isolated from sputum samples of cystic fibrosis patients regarding microbial density, metabolic activity, and structure. 67 samples from 28 patients were collected with a 96% alteration rate. 34% showed alterations by both Candida spp. and Gram-positive bacteria, predominantly Candida spp. and S. aureus in 77% of cases, accounting for 6 associations. Biofilm biomass was quantified using the crystal violet assay, and metabolic activity was assessed using the MTT reduction assay. Scanning electron microscopy analyzed the C. tropicalis/S. aureus24 biofilm architecture. Candida spp. isolates demonstrated the ability to form mixed biofilms with S. aureus. The C. tropicalis/S. aureus24 association exhibited the highest production of biofilm and metabolic activity, along with the C. albicans17/C. rugosa/S. aureus7 in both single and mixed biofilms.

PMID:38677054 | DOI:10.1016/j.diagmicrobio.2024.116321