Rech Soins Infirm. 2022 Feb 10;(147):42-54. doi: 10.3917/rsi.147.0042.

ABSTRACT

Patient autonomy is an equivocal notion that refers to several intertwined figures. What is expected of young cystic fibrosis patients when speaking to actors (professionals and associations) involved with them ? In this sociological contribution, we show the limits of a medical model of autonomy that does not allow us to think about a whole series of micro-adjustments to the practices of people with cystic fibrosis. The analysis is based on publications by national associations fighting against cystic fibrosis, and on semi-structured interviews with professionals working with people living with this disease. It shows that autonomy is not only thought of by the professionals who support them in terms of an individual management model centered on the patient's medical skills and personal resources, but also as the result of environmental factors. It reveals an innovative characteristic of autonomy in the field of health care, largely supported by the specialized and reinforced medical support of coordinating nurses. This support allows the development of a detailed clinical knowledge of the situations experienced by their patients.

PMID:35485034 | DOI:10.3917/rsi.147.0042

Cell Mol Life Sci. 2022 Apr 28;79(5):265. doi: 10.1007/s00018-022-04287-1.

ABSTRACT

Alcoholic pancreatitis and hepatitis are frequent, potentially lethal diseases with limited treatment options. Our previous study reported that the expression of CFTR Cl- channel is impaired by ethanol in pancreatic ductal cells leading to more severe alcohol-induced pancreatitis. In addition to determining epithelial ion secretion, CFTR has multiple interactions with other proteins, which may influence intracellular Ca2+ signaling. Thus, we aimed to investigate the impact of ethanol-mediated CFTR damage on intracellular Ca2+ homeostasis in pancreatic ductal epithelial cells and cholangiocytes. Human and mouse pancreas and liver samples and organoids were used to study ion secretion, intracellular signaling, protein expression and interaction. The effect of PMCA4 inhibition was analyzed in a mouse model of alcohol-induced pancreatitis. The decreased CFTR expression impaired PMCA function and resulted in sustained intracellular Ca2+ elevation in ethanol-treated and mouse and human pancreatic organoids. Liver samples derived from alcoholic hepatitis patients and ethanol-treated mouse liver organoids showed decreased CFTR expression and function, and impaired PMCA4 activity. PMCA4 co-localizes and physically interacts with CFTR on the apical membrane of polarized epithelial cells, where CFTR-dependent calmodulin recruitment determines PMCA4 activity. The sustained intracellular Ca2+ elevation in the absence of CFTR inhibited mitochondrial function and was accompanied with increased apoptosis in pancreatic epithelial cells and PMCA4 inhibition increased the severity of alcohol-induced AP in mice. Our results suggest that improving Ca2+ extrusion in epithelial cells may be a potential novel therapeutic approach to protect the exocrine pancreatic function in alcoholic pancreatitis and prevent the development of cholestasis in alcoholic hepatitis.

PMID:35484438 | DOI:10.1007/s00018-022-04287-1

Curr Opin Pharmacol. 2022 Apr 25;64:102209. doi: 10.1016/j.coph.2022.102209. Online ahead of print.

ABSTRACT

Disruption of the equilibrium between ion secretion and absorption processes by the airway epithelium is central to many muco-obstructive lung diseases including cystic fibrosis (CF). Besides correction of defective folding and function of CFTR, inhibition of amiloride-sensitive epithelia sodium channels (ENaC) has emerged as a bona fide therapeutic strategy to improve mucociliary clearance in patients with CF. The short half-life of amiloride-based ENaC blockers and hyperosmotic therapies have led to the development of novel RNA-based interventions for targeted and sustained reduction of ENaC expression and function in preclinical models of CF. This review summarizes the recent advances in RNA therapeutics targeting ENaC for mutation-agnostic treatment of CF.

PMID:35483215 | DOI:10.1016/j.coph.2022.102209

J Med Internet Res. 2022 Apr 28;24(4):e36338. doi: 10.2196/36338.

ABSTRACT

The United States has abysmal reproductive health indices that, in part, reflect stark inequities experienced by people of color and those with preexisting medical conditions. The growth of "femtech," or technology-based solutions to women's health issues, in the public and private sectors is promising, yet these solutions are often geared toward health-literate, socioeconomically privileged, and/or relatively healthy white cis-women. In this viewpoint, we propose a set of guiding principles for building technologies that proactively identify and address these critical gaps in health care for people from socially and economically marginalized populations that are capable of pregnancy, as well as people with serious chronic medical conditions. These guiding principles require that such technologies: (1) include community stakeholders in the design, development, and deployment of the technology; (2) are grounded in person-centered frameworks; and (3) address health disparities as a strategy to advance health equity and improve health outcomes.

PMID:35482371 | DOI:10.2196/36338

Antimicrob Agents Chemother. 2022 Apr 28:e0237721. doi: 10.1128/aac.02377-21. Online ahead of print.

ABSTRACT

Extended interval dosing of tobramycin is recommended for treatment of pulmonary exacerbations in adults and older children with cystic fibrosis (CF), but data are limited in patients less than 5 years of age. We performed a retrospective population pharmacokinetic (PK) analysis of hospitalized children with CF <5 years of age prescribed intravenous tobramycin for a pulmonary exacerbation from March 2011 to September 2018 at our hospital. Children with normal renal function who had ≥1 tobramycin concentration available were included. Nonlinear mixed effects population PK modeling was performed using NONMEM using data from the first 48 h of tobramycin treatment. Monte Carlo simulations were implemented to determine the fraction of simulated patients that met published therapeutic targets with regimens of 10-15 mg/kg/day once-daily dosing. Fifty-eight patients received 111 tobramycin courses (range 1-9/patient). A two-compartment model best described the data. Age, glomerular filtration rate, and vancomycin coadministration were significant covariates on tobramycin clearance. The typical values of clearance and central volume of distribution were 0.252 L/hr/kg^0.75 and 0.308 L/kg, respectively. No once-daily regimens achieved all pre-specified targets simultaneously in >75% of simulated subjects. A dosage of 13 mg/kg/dose best met the predefined targets of Cmax >25 mg/L and AUC24 of 80-120 mg·h/L. Based on our population PK analysis and simulations, once-daily dosing of tobramycin would not achieve all therapeutic goals in young patients with CF. However, extended-interval dosing regimens may attain therapeutic targets in the majority of young patients.

PMID:35481751 | DOI:10.1128/aac.02377-21

Oncoimmunology. 2022 Apr 17;11(1):2059878. doi: 10.1080/2162402X.2022.2059878. eCollection 2022.

ABSTRACT

The anticancer immune response is shaped by immunogenic cell stress and death pathways. Thus, cancer cells can release danger-associated molecular patterns that act on pattern recognition receptors expressed by dendritic cells and their precursors to elicit an antitumor immune response. Here, we investigated the impact of single nucleotide polymorphisms (SNPs) in genes affecting this cancer-immunity dialogue in the context of head and neck squamous cell carcinoma (HNSCC). We observed that homozygosity for a loss-of-function SNP (rs2241880, leading to the substitution of a threonine residue in position 300 by an alanine) affecting autophagy related 16 like 1 (ATG16L1) is coupled to poor progression-free survival in platinum-treated HNSCC patients. This result was obtained on a cohort of patients enrolled at the Gustave Roussy Cancer Campus and was validated on an independent cohort of The Cancer Genome Atlas (TCGA). Homozygosity in rs2241880 is well known to predispose to Crohn's disease, and epidemiological associations between Crohn's disease and HNSCC have been reported at the levels of cancer incidence and prognosis. We speculate that rs2241880 might be partially responsible for this association.

PMID:35481288 | PMC:PMC9037530 | DOI:10.1080/2162402X.2022.2059878

RSC Adv. 2022 Apr 19;12(19):11974-11991. doi: 10.1039/d1ra09318e. eCollection 2022 Apr 13.

ABSTRACT

Porcine Pancreatic Elastase (PPE) is a serine protease that is homologous to trypsin and chymotrypsin that are involved in various pathologies like inflammatory disease, Chronic Obstructive Pulmonary Disease (COPD), acute respiratory distress syndrome, cystic fibrosis, and atherosclerosis. PPE if remained uninhibited would lead to digestion of important connective tissue. We developed new structurally diverse series of adamantyl-iminothiazolidinone hybrids to divulge elastase inhibition assay. To identify potent derivatives, in silico screening was conducted and in vitro studies disclosed that the compounds 5a, 5f, 5g, and 5h showed excellent binding energies and low IC50 values. In silico studies including molecular docking, DFT studies (using the B3LYP/SVP basis set in the gas phase) drug likeness scores and molecular dynamic simulation studies were conducted to evaluate protein-ligand interactions and to determine the stability of top ranked conformation. In silico studies further supported the results of in vitro experiments and suggest these derivatives as novel inhibitors of elastase enzyme.

PMID:35481107 | PMC:PMC9016748 | DOI:10.1039/d1ra09318e

Pediatr Pulmonol. 2022 Apr 28. doi: 10.1002/ppul.25942. Online ahead of print.

ABSTRACT

BACKGROUND: Inhaled antibiotics are an important part of cystic fibrosis (CF) airway disease management and should be individualized to fit the microorganism and match patient needs. To investigate the implementation of personalised treatment, this study mapped the use of different types of inhaled antibiotics and adherence patterns.

METHOD: We performed individual structured interviews in a cross-sectional study at the CF Centre in Copenhagen, Denmark. Patients with CF older than 15 years attending clinical consultations were included. Clinical data were obtained from centralized databases.

RESULTS: Among 149 participants, 107 (72%) had indication for treatment with inhaled antibiotics. In this group, 97 (91%) reported use of inhaled antibiotics within the last 12 months. Change from one inhaled antibiotic to another during that period was reported by 31 (29%), and 17 (25%) with Pseudomonas aeruginosa had used off-label antibiotics. Adherence to minimum one daily dose of antibiotic was reported by 78%, whilst adherence to all daily doses was 28 percentage-points lower. Skipping inhalations was due to side effects and doubt about the effect in less than 5% of cases.

CONCLUSION: Change of inhaled antibiotics and use of off-label antibiotics for inhalation were common and side effects were a rare cause of non-adherence. This suggests satisfactory implementation of the principle of tailored antibiotic inhalation prescription in the Copenhagen CF-population. Adherence to at least one daily inhalation dose was markedly higher than adherence to multiple daily inhalations. This article is protected by copyright. All rights reserved.

PMID:35478387 | DOI:10.1002/ppul.25942

mSphere. 2022 Apr 28:e0010422. doi: 10.1128/msphere.00104-22. Online ahead of print.

ABSTRACT

Nontuberculous mycobacterial (NTM) pulmonary infections in people with cystic fibrosis (CF) are associated with significant morbidity and mortality and are increasing in prevalence. Host risk factors for NTM infection in CF are largely unknown. We hypothesize that the airway microbiota represents a host risk factor for NTM infection. In this study, 69 sputum samples were collected from 59 people with CF; 42 samples from 32 subjects with NTM infection (14 samples collected before incident NTM infection and 28 samples collected following incident NTM infection) were compared to 27 samples from 27 subjects without NTM infection. Sputum samples were analyzed with 16S rRNA gene sequencing and metabolomics. A supervised classification and correlation analysis framework (sparse partial least-squares discriminant analysis [sPLS-DA]) was used to identify correlations between the microbial and metabolomic profiles of the NTM cases compared to the NTM-negative controls. Several metabolites significantly differed in the NTM cases compared to controls, including decreased levels of tryptophan-associated and branched-chain amino acid metabolites, while compounds involved in phospholipid metabolism displayed increased levels. When the metabolome and microbiome data were integrated by sPLS-DA, the models and component ordinations showed separation between the NTM and control samples. While this study could not determine if the observed differences in sputum metabolites between the cohorts reflect metabolic changes that occurred as a result of the NTM infection or metabolic features that contributed to NTM acquisition, it is hypothesis generating for future work to investigate host and bacterial community factors that may contribute to NTM infection risk in CF. IMPORTANCE Host risk factors for nontuberculous mycobacterial (NTM) infection in people with cystic fibrosis (CF) are largely unclear. The goal of this study was to help identify potential host and bacterial community risk factors for NTM infection in people with CF, using microbiome and metabolome data from CF sputum samples. The data obtained in this study identified several metabolic profile differences in sputum associated with NTM infection in CF, including 2-methylcitrate/homocitrate and selected ceramides. These findings represent potential risk factors and therapeutic targets for preventing and/or treating NTM infections in people with CF.

PMID:35477313 | DOI:10.1128/msphere.00104-22

Proc Natl Acad Sci U S A. 2022 May 3;119(18):e2117633119. doi: 10.1073/pnas.2117633119. Epub 2022 Apr 27.

ABSTRACT

SignificanceBacteria must respond quickly to environmental changes to survive. One way bacteria can respond to environmental stress is by undergoing a lifestyle transition from individual, free-swimming cells to a surface-associated community called a biofilm characterized by aggregative growth. The opportunistic pathogen Pseudomonas aeruginosa uses the Wsp chemosensory system to sense an unknown surface-associated cue. Here we show that the Wsp system senses cell envelope stress, specifically conditions that promote unfolded or misregulated periplasmic and inner membrane proteins. This work provides direct evidence that cell envelope stress is an important feature of surface sensing in P. aeruginosa.

PMID:35476526 | DOI:10.1073/pnas.2117633119

MCN Am J Matern Child Nurs. 2022 May-Jun 01;47(3):147-153. doi: 10.1097/NMC.0000000000000812.

ABSTRACT

PURPOSE: Cystic fibrosis (CF) is no longer a disease limited to childhood. With medical advancements, many of those with CF live into adulthood and have similar life goals as their non-CF peers. Most women with CF want to become mothers. However, available options and the related decision-making process is not well understood. The purpose of this study was to explore the decision-making framework of women with CF to better understand the factors they consider when deciding on a path to motherhood.

STUDY DESIGN AND METHODS: Qualitative interviews were performed using a grounded theory approach. Inclusion criteria were women with CF who became mothers through biological pregnancy, adoption, or gestational surrogacy. Results: Twenty-five mothers with CF were interviewed. A distinct decision-making process was identified through which women started with a desire for motherhood, assessed several factors, then eventually took the path they felt was right for them and their family.

CLINICAL IMPLICATIONS: Our findings provide women with CF a framework that other women with CF have used to assist in making decisions about their reproductive options. Conversations about family planning should occur early and regularly between women with CF and their health care providers. The decision-making process to achieve motherhood for women with a chronic illness, such as CF, includes consideration of unique factors that should be included in clinical conversations.

PMID:35475925 | DOI:10.1097/NMC.0000000000000812

Clin Infect Dis. 2022 Apr 27:ciac333. doi: 10.1093/cid/ciac333. Online ahead of print.

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are closely monitored in people with cystic fibrosis (pwCF), with a special emphasis on severe cases. Previous studies used hospitalization rates as proxy for severity.

METHODS: We evaluated data from coronavirus disease 2019 (COVID-19) cases diagnosed in French pwCF followed in one of the 47 French CF center over the first year of the pandemic.

OBJECTIVE: criteria were applied for defining severity (e.g., respiratory failure and/or death). Data were compared to those from all French pwCF using the French CF Registry.

RESULTS: As of April 30, 2021, 223 pwCF were diagnosed with COVID-19, with higher risks in adults (≥18 years, odds ratio [OR] = 2.52, 95% confidence interval [CI] = 1.82-3.48) and post-transplant individuals (OR = 2.68, 95% CI = 1.98-3.63). Sixty (26.9%) patients were hospitalized, with an increased risk in post-transplant individuals (OR = 4.74, 95% CI = 2.49-9.02). In 34 (15%) cases, COVID-19 was considered severe; 28/60 (46.7%) hospitalizations occurred in patients without objective criteria of severity. Severe cases occurred mostly in adults (85.3%) and post-transplant pwCF (61.8%, OR = 6.02, 95% CI = 2.77-13.06). In non-transplanted pwCF, risk factors for severity included low lung function (median ppFEV1 54.6% vs. 75.1%, OR = 1.04, 95% CI = 1.01-1.08) and CF-associated diabetes (OR = 3.26, 95% CI = 1.02-10.4). While most cases recovered without sequelae (n = 204, 91.5%), 16 (13%) were followed for possible sequelae, and three post-transplant females died.

CONCLUSIONS: Severe COVID-19 cases occurred infrequently during the first year of the pandemic in French pwCF. Non-transplanted adults with severe respiratory disease or diabetes and post-transplant individuals were at risk for severe COVID-19. Thus, specific preventive measures should be proposed.

PMID:35475917 | DOI:10.1093/cid/ciac333

J Bras Pneumol. 2022 Apr 20;48(2):e20220069. doi: 10.36416/1806-3756/e20220069.

NO ABSTRACT

PMID:35475871 | DOI:10.36416/1806-3756/e20220069

J Bras Pneumol. 2022 Apr 20;48(2):e20210307. doi: 10.36416/1806-3756/e20210307. eCollection 2022.

ABSTRACT

OBJECTIVE: To determine whether abnormal continuous glucose monitoring (CGM) readings (hypoglycemia/hyperglycemia) can predict the onset of cystic fibrosis-related diabetes (CFRD) and/or clinical impairment (decline in BMI and/or FEV1) in pediatric patients with cystic fibrosis (CF).

METHODS: This was a longitudinal prospective cohort study involving CF patients without diabetes at baseline. The mean follow-up period was 3.1 years. The patients underwent 3-day CGM, performed oral glucose tolerance test (OGTT), and had FEV1 and BMI determined at baseline. OGTT, FEV1, and BMI were reassessed at the end of the follow-up period.

RESULTS: Thirty-nine CF patients (10-19 years of age) had valid CGM readings at baseline, and 34 completed the follow-up period (mean = 3.1 ± 0.5 years). None of the study variables predicted progression to CFRD or were associated with hypoglycemic events. CGM could detect glucose abnormalities not revealed by OGTT. Patients with glucose levels ≥ 140 mg/dL, as compared with those with lower levels, on CGM showed lower BMI values and z-scores at baseline-17.30 ± 3.91 kg/m2 vs. 19.42 ± 2.07 kg/m2; p = 0.043; and -1.55 ± 1.68 vs. -0.17 ± 0.88; p = 0.02, respectively-and at the end of follow-up-17.88 ± 3.63 kg/m2 vs. 19.95 ± 2.56 kg/m2; p = 0.039; and -1.65 ± 1.55 vs. -0.42 ± 1.08; p = 0.039. When comparing patients with and without CFRD, the former were found to have worse FEV1 (in % of predicted)-22.67 ± 5.03 vs. 59.58 ± 28.92; p = 0.041-and a greater decline in FEV1 (-36.00 ± 23.52 vs. -8.13 ± 17.18; p = 0.041) at the end of follow-up.

CONCLUSIONS: CGM was able to identify glucose abnormalities not detected by OGTT that were related to early-stage decreases in BMI. CGM was ineffective in predicting the onset of diabetes in this CF population. Different diagnostic criteria for diabetes may be required for individuals with CF.

PMID:35475864 | DOI:10.36416/1806-3756/e20210307

Pediatr Pulmonol. 2022 Apr 26. doi: 10.1002/ppul.25945. Online ahead of print.

ABSTRACT

Primary ciliary dyskinesia (PCD) is a rare inherited disease that affects the movement of the respiratory cilia. The main clinical manifestations are chronic upper and lower respiratory symptoms and recurrent lung infections, particularly bacterial and viral infections. Fungal infections are not usually associated with PCD. Allergic bronchopulmonary aspergillosis (ABPA) is a rare complex immune hypersensitivity reaction to Aspergillus fumigatus reported in patients with asthma and cystic fibrosis. Only three cases of ABPA associated with adult PCD have been described in the literature. Herein, we reported on two cases of ABPA in two boys aged 10 and 13 years with PCD. Both had severe lung disease and chronic Pseudomonas aeruginosa infections. One patient was diagnosed according to the typical clinical features of ABPA, while the other was diagnosed during a scheduled visit with no clinical changes but worsening pulmonary function and radiologic anomalies. The diagnosis of ABPA was confirmed in the two patients who then improved after receiving specific treatment. These two cases were the first to describe the occurrence of ABPA in children with PCD. We recommend that physicians involved in the management of children with PCD be aware of this potential complication. This article is protected by copyright. All rights reserved.

PMID:35475304 | DOI:10.1002/ppul.25945

J Cyst Fibros. 2022 Apr 23:S1569-1993(22)00098-4. doi: 10.1016/j.jcf.2022.04.009. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) lung transplant (LT) recipients may warrant treatment with elexacaftor/tezacaftor/ivacaftor (ETI) to improve extrapulmonary manifestations of CF. Our objectives were to identify reasons for prescribing ETI after LT and evaluate changes in body mass index (BMI), hemoglobin A1c, hemoglobin, and liver enzymes.

METHODS: This was an electronic health record-based cohort study, October 2019-September 2020, at 14 CF LT Consortium sites in North America. The study included CF LT recipients prescribed ETI after transplant. Differences in BMI, A1c, and hemoglobin were assessed with paired t-tests.

RESULTS: There were 94 patients prescribed ETI; indications included sinus disease (68%), GI symptoms (39%), or low BMI (19%). Prescriptions were written by CF physicians (34%), LT physicians (27%), or physicians who practice both CF and LT (39%). Forty patients (42%) stopped ETI at a median of 56 days [IQR 26, 139] after start/prescription date. ETI was not associated with a significant change in BMI (0.2 kg/m2, 95% CI [-0.1, 0.6], p = 0.150), but was associated with decreased A1c (0.4%, 95% CI 0.2, 0.7, p = 0.003), and increased hemoglobin for patients with anemia (0.6 g/dL, 95% CI 0.2, 1.0, p = 0.007). Three people (3%) stopped ETI due to elevated transaminases.

CONCLUSIONS: ETI is rarely prescribed for non-pulmonary indications after LT for CF. Further study is needed to determine the risks and benefits of ETI in the CF lung transplant population given the potential for drug interactions, side effects leading to discontinuation of ETI, and the possible mechanisms for ETI to positively impact long-term post-transplant outcomes.

PMID:35474016 | DOI:10.1016/j.jcf.2022.04.009

Am J Respir Cell Mol Biol. 2022 Apr 26. doi: 10.1165/rcmb.2021-0337OC. Online ahead of print.

ABSTRACT

A significant challenge to making targeted CFTR modulator therapies accessible to all individuals with cystic fibrosis (CF) are many mutations in the CFTR gene that can cause CF, most of which remain uncharacterized. Here, we characterized the structural and functional defects of the rare CFTR mutation R352Q - with potential role contributing to intrapore chloride ion permeation - in patient-derived cell models of the airway and gut. CFTR function in differentiated nasal epithelial cultures and matched intestinal organoids was assessed using ion transport assay and forskolin-induced swelling (FIS) assay respectively. CFTR potentiators (VX-770, GLPG1837 and VX-445) and correctors (VX-809, VX-445 +/- VX-661) were tested. Data from R352Q-CFTR were compared to that of twenty participants with mutations with known impact on CFTR function. R352Q-CFTR has residual CFTR function which was restored to functional CFTR activity by CFTR potentiators but not the corrector. Molecular dynamics (MD) simulations of R352Q-CFTR were carried out which indicated the presence of a chloride conductance defect, with little evidence supporting a gating defect. The combination approach of in vitro patient-derived cell models and in silico MD simulations to characterize rare CFTR mutations can improve the specificity and sensitivity of modulator response predictions and aid in their translational use for CF precision medicine. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:35471184 | DOI:10.1165/rcmb.2021-0337OC

mSystems. 2022 Apr 26;7(2):e0011322. doi: 10.1128/msystems.00113-22. Epub 2022 Apr 11.

ABSTRACT

In people with the genetic disease cystic fibrosis (CF), bacterial infections involving the opportunistic pathogen Pseudomonas aeruginosa are a significant cause of morbidity and mortality. P. aeruginosa uses a cell-cell signaling mechanism called quorum sensing (QS) to regulate many virulence functions. One type of QS consists of acyl-homoserine lactone (AHL) signals produced by LuxI-type signal synthases, which bind a cognate LuxR-type transcription factor. In laboratory strains and conditions, P. aeruginosa employs two AHL synthase/receptor pairs arranged in a hierarchy, with the LasI/R system controlling the RhlI/R system and many downstream virulence factors. However, P. aeruginosa isolates with inactivating mutations in lasR are frequently isolated from chronic CF infections. We and others have shown that these isolates frequently use RhlR as the primary QS regulator. RhlR is rarely mutated in CF and environmental settings. We were interested in determining whether there were reproducible genetic characteristics of these isolates and whether there was a central group of genes regulated by RhlR in all isolates. We examined five isolates and found signatures of adaptation common to CF isolates. We did not identify a common genetic mechanism to explain the switch from Las- to Rhl-dominated QS. We describe a core RhlR regulon encompassing 20 genes encoding 7 products. These results suggest a key group of QS-regulated factors important for pathogenesis of chronic infections and position RhlR as a target for anti-QS therapeutics. Our work underscores the need to sample a diversity of isolates to understand QS beyond what has been described in laboratory strains. IMPORTANCE The bacterial pathogen Pseudomonas aeruginosa can cause chronic infections that are resistant to treatment in immunocompromised individuals. Over the course of these infections, the original infecting organism adapts to the host environment. P. aeruginosa uses a cell-cell signaling mechanism termed quorum sensing (QS) to regulate virulence factors and cooperative behaviors. The key QS regulator in laboratory strains, LasR, is frequently mutated in infection-adapted isolates, leaving another transcription factor, RhlR, in control of QS gene regulation. Such isolates provide an opportunity to understand Rhl-QS regulation without the confounding effects of LasR, as well as the scope of QS in the context of within-host evolution. We show that a core group of virulence genes is regulated by RhlR in a variety of infection-adapted LasR-null isolates. Our results reveal commonalities in infection-adapted QS gene regulation and key QS factors that may serve as therapeutic targets in the future.

PMID:35471121 | DOI:10.1128/msystems.00113-22

Microbiol Spectr. 2022 Apr 26:e0258221. doi: 10.1128/spectrum.02582-21. Online ahead of print.

ABSTRACT

Stenotrophomonas maltophilia is a multidrug-resistant human opportunistic pathogen. S. maltophilia contributes to disease progression in cystic fibrosis patients and is found in wounds and infected tissues and on catheter surfaces. Due to its well-known multidrug resistance, it is difficult to treat S. maltophilia infections. Strain-specific susceptibility to antimicrobials has also been reported in several studies. Recently, three fungal diorcinols and 14 rubrolides were shown to reduce S. maltophilia K279a biofilm formation. Based on these initial findings, we were interested to extend this approach by testing a larger number of diorcinols and rubrolides and to understand the molecular mechanisms behind the observed antibiofilm effects. Of 52 tested compounds, 30 were able to significantly reduce the biofilm thickness by up to 85% ± 15% and had strong effects on mature biofilms. All compounds with antibiofilm activity also significantly affected the biofilm architecture. Additional RNA-sequencing data of diorcinol- and rubrolide-treated biofilm cells of two clinical isolates (454 and K279) identified a small set of shared genes that were affected by these potent antibiofilm compounds. Among these, genes for iron transport, general metabolism, and membrane biosynthesis were most strongly and differentially regulated. A further hierarchical clustering and detailed structural inspection of the diorcinols and rubrolides implied that a prenyl group as side chain of one of the phenyl groups of the diorcinols and an increasing degree of bromination of chlorinated rubrolides were possibly the cause of the strong antibiofilm effects. This study gives a deep insight into the effects of rubrolides and diorcinols on biofilms formed by the important global pathogen S. maltophilia. IMPORTANCE Combating Stenotrophomonas maltophilia biofilms in clinical and industrial settings has proven to be challenging. S. maltophilia is multidrug resistant, and occurrence of resistance to commonly used drugs as well as to antibiotic combinations, such as trimethoprim-sulfamethoxazole, is now frequently reported. It is therefore now necessary to look beyond conventional and already existing antimicrobial drugs when battling S. maltophilia biofilms. Our study contains comprehensive and detailed data sets for diorcinol and rubrolide-treated S. maltophilia biofilms. The study defines genes and pathways affected by treatment with these different compounds. These results, together with the identified structural elements that may be crucial for their antibiofilm activity, build a strong backbone for further research on diorcinols and rubrolides as novel and potent antibiofilm compounds.

PMID:35471093 | DOI:10.1128/spectrum.02582-21

Am J Med Sci. 2022 Apr 22:S0002-9629(22)00179-3. doi: 10.1016/j.amjms.2022.04.018. Online ahead of print.

ABSTRACT

Bone disease is a known complication of cystic fibrosis (CF). To date, there have been no reports on the effectiveness of romosozumab, monoclonal antibody to sclerostin, to treat CF-related bone disease. We report a case of a 46-year-old premenopausal female with CF-related bone disease and multiple fractures who was treated with romosozumab. After one year of therapy with romosozumab, the patient tolerated therapy and bone mineral density (BMD) significantly improved. Of the currently available anti-resorptive or anabolic osteoporosis medications, only bisphosphonates have been studied in individuals with CF. This report highlights that romosozumab may be an effective alternative treatment modality in selected patients with CF at high risk for fractures. Further studies are warranted to evaluate the efficacy and safety profile of romosozumab in people with CF.

PMID:35469767 | DOI:10.1016/j.amjms.2022.04.018