J Cyst Fibros. 2022 Sep 13:S1569-1993(22)00655-5. doi: 10.1016/j.jcf.2022.08.018. Online ahead of print.

ABSTRACT

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) heterozygous for F508del and a minimal function mutation (F/MF) or homozygous for F508del (F/F) in two pivotal Phase 3 trials, significantly improving percentage predicted forced expiratory volume in 1 second, Cystic Fibrosis Questionnaire-Revised, Respiratory Domain (CFQ-R RD) scores, and sweat chloride concentration. Here, we analyzed the 11 non-respiratory domains (non-RDs) of the CFQ-R, which assess general health-related quality of life (i.e., Physical Functioning, Role Functioning, Vitality, Health Perceptions, Emotional Functioning, and Social Functioning) and quality of life impacted by CF (i.e., Body Image, Eating Problems, Treatment Burden, Weight, and Digestive Symptoms), for participants in these two Phase 3 trials. ELX/TEZ/IVA treatment led to higher scores in all CFQ-R non-RDs, with improvements in most domains compared with control treatments. These findings demonstrate that ELX/TEZ/IVA improves a range of CF-specific symptoms and general functioning and well-being.

PMID:36114142 | DOI:10.1016/j.jcf.2022.08.018

Haemophilia. 2022 Sep 16. doi: 10.1111/hae.14658. Online ahead of print.

ABSTRACT

INTRODUCTION: Elevated markers of endothelial dysfunction and inflammation indicate worse endothelial function in the aging haemophilia population. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally. Several miRNAs have been shown to be involved in the process of endothelial dysfunction and atherosclerosis.

AIM: The aim of this study was to determine the underlying molecular pathways of endothelial dysfunction and inflammation in haemophilia patients.

METHODS: A total of 25 patients with severe or moderate haemophilia A (20 patients) or B (5 patients), 14 controls and 18 patients with coronary artery disease (CAD) after myocardial infarction were included in this study. Expression of miRNA-126, -155, -222, -1, -let7a, -21 and -197 were analysed using a real time polymerase chain reaction. Network-based visualisation and analysis of the miRNA-target interactions were performed using the MicroRNA ENrichment TURned NETwork (MIENTURNET).

RESULTS: Expression of miRNA-126 (p < .05) and miRNA-let7a (p < .05) were significantly higher in CAD patients compared to haemophilia patients and controls. MiRNA-21 (p < .05) was significantly elevated in CAD patients compared to controls. MiRNA-155 (p < .05), miRNA-1 (p < .05) and miRNA-197 (p < .05) were significantly higher expressed in CAD and haemophilia patients compared to controls and showed a strong correlation with increased levels of interleukin-6 (IL-6) and soluble intercellular adhesion molecule-1 (sICAM-1). The network analysis revealed interactions in the cytokine signalling, focal adhesion and VEGFA-VEGFR2 pathway (Vascular endothelial growth factor, -receptor).

CONCLUSION: This study characterises miRNA expression in haemophilia patients in comparison to CAD patients and healthy controls. The results imply comparable biological processes in CAD and haemophilia patients.

PMID:36112753 | DOI:10.1111/hae.14658

Front Cell Dev Biol. 2022 Aug 30;10:781762. doi: 10.3389/fcell.2022.781762. eCollection 2022.

ABSTRACT

The regulatory interaction between two typical epithelial ion channels, cystic fibrosis transmembrane conductance regulator (CFTR) and the epithelial sodium channel (ENaC), for epithelial homeostasis has been noted, although the underlying mechanisms remain unclear. Here, we report that in a human endometrial epithelial cell line (ISK), shRNA-based stable knockdown of ENaC produced a biphasic effect: a low (∼23%) degree of ENaC knockdown resulted in significant increases in CFTR mRNA and protein levels, CFTR-mediated Cl- transport activity as well as intracellular cAMP concentration, while a higher degree (∼50%) of ENaC knockdown did not further increase but restored CFTR expression and cAMP levels. The basal intracellular Ca2+ level of ISK cells was lowered by ENaC knockdown or inhibition in a degree-dependent manner. BAPTA-AM, an intracellular Ca2+ chelator that lowers free Ca2+ concentration, elevated cAMP level and CFTR mRNA expression at a low (5 µM) but not a high (50 µM) dose, mimicking the biphasic effect of ENaC knockdown. Moreover, KH-7, a selective inhibitor of soluble adenylyl cyclase (sAC), abolished the CFTR upregulation induced by low-degree ENaC knockdown or Ca2+ chelation, suggesting the involvement of sAC-driven cAMP production in the positive regulation. A luciferase reporter to indicate CFTR transcription revealed that all tested degrees of ENaC knockdown/inhibition stimulated CFTR transcription in ISK cells, suggesting that the negative regulation on CFTR expression by the high-degree ENaC deficiency might occur at post-transcription stages. Additionally, similar biphasic effect of ENaC knockdown on CFTR expression was observed in a human bronchial epithelial cell line. Taken together, these results have revealed a previously unidentified biphasic regulatory role of ENaC in tuning CFTR expression involving Ca2+-modulated cAMP production, which may provide an efficient mechanism for dynamics and plasticity of the epithelial tissues in various physiological or pathological contexts.

PMID:36111343 | PMC:PMC9469783 | DOI:10.3389/fcell.2022.781762

Front Oncol. 2022 Aug 30;12:849895. doi: 10.3389/fonc.2022.849895. eCollection 2022.

ABSTRACT

Defective silencing of tumor suppressor genes through epigenetic alterations contributes to oncogenesis by perturbing cell cycle regulation, DNA repair or cell death mechanisms. Reversal of such epigenetic changes including DNA hypermethylation provides a promising anticancer strategy. Until now, the nucleoside derivatives 5-azacytidine and decitabine are the sole DNA methyltransferase (DNMT) inhibitors approved by the FDA for the treatment of specific hematological cancers. Nevertheless, due to their nucleoside structure, these inhibitors directly incorporate into DNA, which leads to severe side effects and compromises genomic stability. Much emphasis has been placed on the development of less toxic epigenetic modifiers. Recently, several preclinical studies demonstrated the potent epigenetic effects of local anesthetics, which are routinely used during primary tumor resection to relief surgical pain. These non-nucleoside molecules inhibit DNMT activity, affect the expression of micro-RNAs and repress histone acetylation, thus exerting cytotoxic effects on malignant cells. The in-depth mechanistic comprehension of these epigenetic effects might promote the use of local anesthetics as anticancer drugs.

PMID:36110954 | PMC:PMC9468863 | DOI:10.3389/fonc.2022.849895

J Clin Transl Endocrinol. 2022 Sep 3;30:100304. doi: 10.1016/j.jcte.2022.100304. eCollection 2022 Dec.

ABSTRACT

BACKGROUND: Gut-derived incretin hormones, including glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), regulate post-prandial glucose metabolism by promoting insulin production. GIP, GLP-1, and insulin contribute to the acute bone anti-resorptive effect of macronutrient ingestion by modifying bone turnover. Cystic fibrosis (CF) is associated with exocrine pancreatic insufficiency (PI), which perturbs the incretin response. Cross-talk between the gut and bone ("gut-bone axis") has not yet been studied in PI-CF. The objectives of this study were to assess changes in biomarkers of bone metabolism during oral glucose tolerance testing (OGTT) and to test associations between incretins and biomarkers of bone metabolism in individuals with PI-CF.

METHODS: We performed a secondary analysis of previously acquired blood specimens from multi-sample OGTT from individuals with PI-CF ages 14-30 years (n = 23). Changes in insulin, incretins, and biomarkers of bone resorption (C-terminal telopeptide of type 1 collagen [CTX]) and formation (procollagen type I N-terminal propeptide [P1NP]) during OGTT were computed.

RESULTS: CTX decreased by 32% by min 120 of OGTT (P < 0.001), but P1NP was unchanged. Increases in GIP from 0 to 30 mins (rho = -0.48, P = 0.03) and decreases in GIP from 30 to 120 mins (rho = 0.62, P = 0.002) correlated with decreases in CTX from mins 0-120. Changes in GLP-1 and insulin were not correlated with changes in CTX, and changes in incretins and insulin were not correlated with changes in P1NP.

CONCLUSIONS: Intact GIP response was correlated with the bone anti-resorptive effect of glucose ingestion, represented by a decrease in CTX. Since incretin hormones might contribute to development of diabetes and bone disease in CF, the "gut-bone axis" warrants further attention in CF during the years surrounding peak bone mass attainment.

PMID:36110921 | PMC:PMC9467887 | DOI:10.1016/j.jcte.2022.100304

ACS Pharmacol Transl Sci. 2022 Aug 22;5(9):692-693. doi: 10.1021/acsptsci.2c00138. eCollection 2022 Sep 9.

NO ABSTRACT

PMID:36110373 | PMC:PMC9469184 | DOI:10.1021/acsptsci.2c00138

Health Sci Rep. 2022 Sep 12;5(5):e812. doi: 10.1002/hsr2.812. eCollection 2022 Sep.

ABSTRACT

BACKGROUND AND AIMS: In cystic fibrosis (CF) airways, impaired airway mucociliary clearance and mucus accumulation due to cystic fibrosis transmembrane conductance regulator defects contribute to inflammation, progressive structural lung damage, and decline of lung function. Physiotherapy is essential to promote mucus mobilization and removal in CF and is a key element of rehabilitation measures, but conventional techniques may be suboptimal to mobilize viscous mucus. This study aimed to test the specific effects of a novel bronchial drainage device (BDD) (Simeox®; PhysioAssist) in subjects with CF and evaluate lung function, diaphragm mobility, and sputum properties.

METHODS: This prospective monocentric clinical cohort study in the setting of outpatient physiotherapy of CF patients (n = 21) with stable CF lung disease collected pulmonary lung function tests (PFT), diaphragm mobility, and sputum properties before and after two physiotherapy sessions using the novel BDD. PFT was assessed using spirometry and diaphragm mobility using m-mode ultrasound analysis. Spontaneous sputum samples were collected before and after using the BDD and analyzed for microstructure and DNA concentrations.

RESULTS: PFT parameters (FEV1, FVC, MEF25/50/75) were not affected by the use of the BDD. Ultrasound analysis of diaphragm mobility revealed an increase in maximum diaphragm excursion upon the intervention. Mucus analysis demonstrated altered microstructure and higher DNA concentrations collected after using the BDD compared to samples collected before. Pearson correlation analysis showed significant correlations between changes in mucus properties and DNA levels in respective mucus samples.

CONCLUSION: Our results demonstrate that the novel BDD improves diaphragm mobility and alters sputum properties in subjects with CF. The novel BDD with unique properties may be further studied as a device in CF-specific physiotherapy to facilitate sputum mobilization of CF patients.

PMID:36110342 | PMC:PMC9466653 | DOI:10.1002/hsr2.812

Arch Pediatr. 2022 Sep 12:S0929-693X(22)00186-5. doi: 10.1016/j.arcped.2022.06.006. Online ahead of print.

ABSTRACT

INTRODUCTION: Pediatric chronic pain can lead to serious consequences in terms of daily functioning and global quality of life. Mindfulness-based intervention (MBI) approaches that emphasize accepting rather than controlling pain have gained increasing attention in adults with chronic pain. The effectiveness of MBIs for chronic pain in the pediatric population remains unknown. The aim of the Peacefull program was to study the feasibility in France of a mindfulness program for adolescents with chronic pain, based on a program especially developed in Canada and Belgium.

METHOD: An MBI for adolescents consisting of eight 90-min sessions was provided. It focused on building skills and incorporated mindfulness meditation, exercises, and activities especially adapted to teenagers with chronic pain.

RESULTS: A total of 27 adolescents aged 12-17 years who were diagnosed with a chronic pain condition were enrolled in five cohorts from April 2018 to June 2021. The completion rate of the Peacefull program was 88.89 with no dropouts and good completion of outcome measures. Secondary outcomes were assessed before the program, at the end, and 3 months later. A trend toward an improvement was observed on the mean average score for the Visual Analog Scale (VAS), but it was not statistically significant. Scores increased significantly over time on the Functional Disability Inventory (FDI), and pain catastrophizing also improved.

CONCLUSIONS: Although the findings regarding the effectiveness of Peacefull programs were inconsistent and insufficient, they can be indicative of the benefits of mindfulness as an adjuvant treatment for adolescents with chronic pain.

PMID:36109288 | DOI:10.1016/j.arcped.2022.06.006

Thorax. 2022 Sep 15:thoraxjnl-2022-219086. doi: 10.1136/thorax-2022-219086. Online ahead of print.

ABSTRACT

BACKGROUND: Life expectancy for people with cystic fibrosis (CF) varies considerably both within and between countries. The objective of this study was to compare survival among countries with single-payer healthcare systems while accounting for markers of disease severity.

METHODS: This cohort study used data from established national CF registries in Australia, Canada, France and New Zealand from 2015 to 2019. Median age of survival for each of the four countries was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to compare risk of death between Canada, France and Australia after adjusting for prognostic factors. Due to low number of deaths, New Zealand was not included in final adjusted models.

RESULTS: Between 2015 and 2019, a total of 14 842 people (3537 Australia, 4434 Canada, 6411 France and 460 New Zealand) were included. The median age of survival was highest in France 65.9 years (95% CI: 59.8 to 76.0) versus 53.3 years (95% CI: 48.9 to 59.8) for Australia, 55.4 years (95% CI: 51.3 to 59.2) for Canada and 54.8 years (95% CI: 40.7 to not available) for New Zealand. After adjusting for individual-level factors, the risk of death was significantly higher in Canada (HR 1.85, 95% CI: 1.48 to 2.32; p<0.001) and Australia (HR 2.08, 95% CI: 1.64 to 2.64; p<0.001) versus France.

INTERPRETATION: We observed significantly higher survival in France compared with countries with single-payer healthcare systems. The median age of survival in France exceeded 60 years of age despite having the highest proportion of underweight patients which may be due to differences in availability of transplant.

PMID:36109163 | DOI:10.1136/thorax-2022-219086

Dev Cell. 2022 Sep 8:S1534-5807(22)00596-2. doi: 10.1016/j.devcel.2022.08.010. Online ahead of print.

ABSTRACT

Pulmonary neuroendocrine cells (PNECs) are rare airway cells with potential sensory capacity linked to vagal neurons and immune cells. How PNECs sense and respond to external stimuli remains poorly understood. We discovered PNECs located within pig and human submucosal glands, a tissue that produces much of the mucus that defends the lung. These PNECs sense succinate, an inflammatory molecule in liquid lining the airway surface. The results indicate that succinate migrates down the submucosal gland duct to the acinus, where it triggers apical succinate receptors, causing PNECs to release ATP. The short-range ATP signal stimulates the contraction of myoepithelial cells wrapped tightly around the submucosal glands. Succinate-triggered gland contraction may complement the action of neurotransmitters that induce mucus release but not gland contraction to promote mucus ejection onto the airway surface. These findings identify a local circuit in which rare PNECs within submucosal glands sense an environmental cue to orchestrate the function of airway glands.

PMID:36108628 | DOI:10.1016/j.devcel.2022.08.010

ACS Infect Dis. 2022 Sep 15. doi: 10.1021/acsinfecdis.2c00314. Online ahead of print.

ABSTRACT

There is an unmet medical need for effective treatments against Mycobacterium abscessus pulmonary infections, to which cystic fibrosis (CF) patients are particularly vulnerable. Recent studies showed that the antitubercular drug isoniazid is inactive against M. abscessus due to the incapacity of the catalase-peroxidase to convert the pro-drug into a reactive metabolite that inhibits the enoyl-ACP reductase InhA. To validate InhAMAB as a druggable target in M. abscessus, we assayed the activity of NITD-916, a 4-hydroxy-2-pyridone lead candidate initially described as a direct inhibitor of InhA that bypasses KatG bioactivation in Mycobacterium tuberculosis. The compound displayed low MIC values against rough and smooth clinical isolates in vitro and significantly reduced the bacterial burden inside human macrophages. Moreover, treatment with NITD-916 reduced the number and size of intracellular mycobacterial cords, regarded as markers of the severity of the infection. Importantly, NITD-916 significantly lowered the M. abscessus burden in CF-derived lung airway organoids. From a mechanistic perspective, NITD-916 abrogated de novo synthesis of mycolic acids and NITD-916-resistant spontaneous mutants harbored point mutations in InhAMAB at residue 96. That NITD-916 targets InhAMAB directly without activation requirements was confirmed genetically and by resolving the crystal structure of the protein in complex with NADH and NITD-916. These findings collectively indicate that InhAMAB is an attractive target to be exploited for future chemotherapeutic developments against this difficult-to-treat mycobacterium and highlight the potential of NITD-916 derivatives for further evaluation in preclinical settings.

PMID:36107992 | DOI:10.1021/acsinfecdis.2c00314

mSystems. 2022 Sep 15:e0043422. doi: 10.1128/msystems.00434-22. Online ahead of print.

ABSTRACT

Opportunistic pathogens such as Pseudomonas aeruginosa adapt their genomes rapidly during chronic infections. Understanding their epigenetic regulation may provide biomarkers for diagnosis and reveal novel regulatory mechanisms. We performed single-molecule real-time sequencing (SMRT-seq) to characterize the methylome of a chronically adapted P. aeruginosa clinical strain, TBCF10839. Two N6-methyladenine (6mA) methylation recognition motifs (RCCANNNNNNNTGAR and TRGANNNNNNTGC [modification sites are in bold]) were identified and predicted as new type I methylation sites using REBASE analysis. We confirmed that the motif TRGANNNNNNTGC was methylated by the methyltransferase (MTase) M.PaeTBCFII, according to methylation sensitivity assays in vivo and vitro. Transcriptomic analysis showed that a ΔpaeTBCFIIM knockout mutant significantly downregulated nitric oxide reductase (NOR) regulation and expression of coding genes such as nosR and norB, which contain methylated motifs in their promoters or coding regions. The ΔpaeTBCFIIM strain exhibited reduced intercellular survival capacity in NO-producing RAW264.7 macrophages and attenuated virulence in a Galleria mellonella infection model; the complemented strain recovered these defective phenotypes. Further phylogenetic analysis demonstrated that homologs of M.PaeTBCFII occur frequently in P. aeruginosa as well as other bacterial species. Our work therefore provided new insights into the relationship between DNA methylation, NO detoxification, and bacterial virulence, laying a foundation for further exploring the molecular mechanism of DNA methyltransferase in regulating the pathogenicity of P. aeruginosa. IMPORTANCE Pseudomonas aeruginosa is an opportunistic pathogen which causes acute and chronic infections that are difficult to treat. Comparative genomic analysis has showed broad genome diversity among P. aeruginosa clinical strains and revealed their different regulatory traits compared to the laboratory strains. While current investigation of the epigenetics of P. aeruginosa is still lacking, understanding epigenetic regulation may provide biomarkers for diagnosis and facilitate development of novel therapies. Denitrification capability is critical for microbial versatility in response to different environmental stress conditions, including the bacterial infection process, where nitric oxide (NO) can be generated by phagocytic cells. The denitrification regulation mechanisms have been studied intensively at genetic and biochemical levels. However, there is very little evidence about the epigenetic regulation of bacterial denitrification mechanism. P. aeruginosa TBCF10839 is a chronically host-adapted strain isolated from a cystic fibrosis (CF) patient with special antiphagocytosis characteristics. Here, we investigated the regulatory effect of an orphan DNA MTase, M.PaeTBCFII, in P. aeruginosa TBCF10839. We demonstrated that the DNA MTase regulates the transcription of denitrification genes represented by NOR and affects antiphagocytic ability in bacteria. In silico analysis suggested that DNA methylation modification may enhance gene expression by affecting the binding of transacting factors such as DNR and RpoN. Our findings not only deepen the understanding of the role of DNA MTase in transcriptional regulation in P. aeruginosa but also provide a theoretical foundation for the in-depth study of the molecular mechanism of the epigenetic regulation on denitrification, virulence, and host-pathogen interaction.

PMID:36106744 | DOI:10.1128/msystems.00434-22

Mater Today Bio. 2022 Sep 6;16:100419. doi: 10.1016/j.mtbio.2022.100419. eCollection 2022 Dec.

ABSTRACT

Bacterial infections can compromise the physical and biological functionalities of humans and pose a huge economical and psychological burden on infected patients. Nitric oxide (NO) is a broad-spectrum antimicrobial agent, whose mechanism of action is not affected by bacterial resistance. S-nitrosoglutathione (GSNO), an endogenous donor and carrier of NO, has gained increasing attention because of its potent antibacterial activity and efficient biocompatibility. Significant breakthroughs have been made in the application of GSNO in biomaterials. This review is based on the existing evidence that comprehensively summarizes the progress of antimicrobial GSNO applications focusing on their anti-infective performance, underlying antibacterial mechanisms, and application in anti-infective biomaterials. We provide an accurate overview of the roles and applications of GSNO in antibacterial biomaterials and shed new light on the avenues for future studies.

PMID:36105674 | PMC:PMC9465324 | DOI:10.1016/j.mtbio.2022.100419

J Toxicol Sci. 2022;47(10):389-407. doi: 10.2131/jts.47.389.

ABSTRACT

Trimeresurus stejnegeri is one of the top ten venomous snakes in China, and its bite causes acute and severe diseases. Elucidating the metabolic changes of the body caused by Trimeresurus stejnegeri bite will be beneficial to the diagnosis and treatment of snakebite. Thus, an animal pig model of Trimeresurus stejnegeri bite was established, and then the metabolites of serum and urine were subsequently screened and identified in both ESI+ and ESI- modes identified by ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS) methods. There are 9 differential metabolites in serum, including Oleic acid, Lithocholic acid, Deoxycholic acid, Hypoxanthine, etc. There are 11 differential metabolites in urine, including Dopamine, Thiocysteine, Arginine, Indoleacetaldehyde, etc. Serum enrichment pathway analysis showed that 5 metabolic pathways, including Tryptophanuria, Liver disease due to cystic fibrosis, Hartnup disease, Hyperbaric oxygen exposure and Biliary cirrhosis, the core metabolites in these pathways, including deoxycholic acid, lithocholic acid, tryptophan and hypoxanthine, changed significantly. Urine enrichment pathway analysis showed that 4 metabolic pathways, including Aromatic L-Amino Acid Decarboxylase, Vitiligo, Blue Diaper Syndrome and Hyperargininemia, the core metabolites in these pathways including dopamine, 5-hydroxyindole acetic acid and arginine. Taken together, the current study has successfully established an animal model of Trimeresurus stejnegeri bite, and identified the metabolic markers and metabolic pathways of Trimeresurus stejnegeri bite. These metabolites and pathways may have potential application value and provide a therapeutic basis for the treatment of Trimeresurus stejnegeri bite.

PMID:36104186 | DOI:10.2131/jts.47.389

Pediatr Phys Ther. 2022 Sep 10. doi: 10.1097/PEP.0000000000000967. Online ahead of print.

ABSTRACT

PURPOSE: To explore the association between cardiorespiratory fitness and other physical literacy domains in children with cystic fibrosis (CF) or congenital heart disease (CHD).

METHODS: In 28 children with CF (n = 10) or CHD (n = 18), aged 7 to 11 years, cardiorespiratory fitness and the following physical literacy domains were measured: (a) physical competence, (b) motivation and confidence, (c) knowledge and understanding, and (d) daily behavior (ie, self-perceived moderate-to-vigorous physical activity [MVPA]).

RESULTS: Cardiorespiratory fitness was significantly associated with motivation and confidence and self-perceived MVPA. There were no other significant associations.

CONCLUSIONS: Cardiorespiratory fitness is associated with self-perceived MVPA, motivation, and confidence in children with CF or CHD.

PMID:36103630 | DOI:10.1097/PEP.0000000000000967

J Bacteriol. 2022 Sep 14:e0018522. doi: 10.1128/jb.00185-22. Online ahead of print.

ABSTRACT

A subpopulation of small-colony variants (SCVs) is a frequently observed feature of Pseudomonas aeruginosa isolates obtained from colonized cystic fibrosis lungs. Since most SCVs have until now been isolated from clinical samples, it remains unclear how widespread the ability of P. aeruginosa strains to develop this phenotype is and what the genetic mechanism(s) behind the emergence of SCVs are according to the origin of the isolate. In the present work, we investigated the ability of 22 P. aeruginosa isolates from various environmental origins to spontaneously adopt an SCV-like smaller alternative morphotype distinguishable from that of the ancestral parent strain under laboratory culture conditions. We found that all the P. aeruginosa strains tested could adopt an SCV phenotype, regardless of their origin. Whole-genome sequencing of SCVs obtained from clinical and environmental sources revealed single mutations exclusively in two distinct c-di-GMP signaling pathways, the Wsp and YfiBNR pathways. We conclude that the ability to switch to an SCV phenotype is a conserved feature of P. aeruginosa and results from the acquisition of a stable genetic mutation, regardless of the origin of the strain. IMPORTANCE P. aeruginosa is an opportunistic pathogen that thrives in many environments. It poses a significant health concern, notably because this bacterium is the most prevalent pathogen found in the lungs of people with cystic fibrosis. In infected hosts, its persistence is considered related to the emergence of an alternative small-colony-variant (SCV) phenotype. By reporting the distribution of P. aeruginosa SCVs in various nonclinical environments and the involvement of c-di-GMP in SCV emergence from both clinical and environmental strains, this work contributes to understanding a conserved adaptation mechanism used by P. aeruginosa to adapt readily in all environments. Hindering this adaptation strategy could help control persistent infection by P. aeruginosa.

PMID:36102640 | DOI:10.1128/jb.00185-22

Curr Opin Pulm Med. 2022 Sep 15. doi: 10.1097/MCP.0000000000000917. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: The introduction of highly effective cystic fibrosis transmembrane conductance regulator modulators has resulted in a paradigm shift towards treating underlying cause of cystic fibrosis (CF) rather than the ensuing complications. In this review, we will describe the impact of these small molecules on growth, nutrition, and metabolic status in people with CF (pwCF).

RECENT FINDING: Results of clinical trials and real world data demonstrate that these small molecules are having a significant impact of on augmenting body weight, improving nutritional status and reducing gastrointestinal symptom burden. Early treatment can also positively impact on pancreatic endocrine and exocrine function.

SUMMARY: Nutritional and metabolic management of pwCF needs to change in order to maximize long term health and avoid future complications relating to obesity and increased cardiovascular risk. Longitudinal registry studies will be key to improve our understanding of the longer-term outcome of these new therapies.

PMID:36102602 | DOI:10.1097/MCP.0000000000000917

Rev Paul Pediatr. 2022 Sep 9;41:e2021286. doi: 10.1590/1984-0462/2023/41/2021286. eCollection 2022.

ABSTRACT

OBJECTIVE: To analyze the association between phenotypic and genotypic characteristics and disease severity in individuals with cystic fibrosis treated at a reference center in Minas Gerais, Brazil.

METHODS: This is a retrospective study that collected clinical and laboratory data, respiratory and gastrointestinal manifestations, type of treatment, Shwachman-Kulczycki score, and mutations from the patients' medical records.

RESULTS: The sample included 50 participants aged one to 33 years, 50% of whom were female. Out of the one hundred alleles of the Cystic Fibrosis Transmembrane Conductance Regulator gene, the most prevalent mutations were DeltaF508 (45%) and S4X (18%). Mutation groups were only associated with pancreatic insufficiency (p=0.013) and not with disease severity (p=0.073). The latter presented an association with colonization by Pseudomonas aeruginosa and Staphylococcus aureus (p=0.007) and with underweight (p=0.036). Death was associated with age at diagnosis (p=0.016), respiratory symptomatology (p=0.013), colonization (p=0.024), underweight (p=0.017), and hospitalization (p=0.003).

CONCLUSIONS: We could identify the association of mutations with pancreatic insufficiency; the association of Staphylococcus aureus colonization and underweight with disease severity; and the lack of association between mutations and disease severity. Environmental factors should be investigated more thoroughly since they seem to have an important effect on disease severity.

PMID:36102402 | DOI:10.1590/1984-0462/2023/41/2021286

Epidemiol Prev. 2022 Jul-Aug;46(4 Suppl 2):1-38. doi: 10.19191/EP22.4S2.060.

ABSTRACT

INTRODUCTION: Italian cystic fibrosis registry (ICFR) collects data from cystic fibrosis (CF) patients through the collaboration with Italian CF referral and support Centres (Italian law 548/93). ICFR contributes: • to the analysis of medium and long term clinical and epidemiological trends of the disease; • to the identification of the main health care needs at regional and national level to contribute to the Health Care programmes and to the distribution of resources; • to the comparison of the Italian data with international ones. This latter is based on the collaboration with the European CF registry and, due the COVID-19 pandemic emergency, with important global projects.

OBJECTIVES: The purpose of this Report is to update the demographic and clinical data of the Italian FC population in the years 2019 and 2020, contributing to the information necessary to implement projects to improve the management of patients affected by this disease.

DESIGN: Analyses and results described in the present Report are referred to patients currently followed at the Italian National Referral and Support Centres for Cystic Fibrosis in the 2019-2020 period. Data were sent by clinical Centres through a dedicated web-based software. Data undergo a double quality control (QC): the first is automatically performed by the software (quantitative QC), the second is performed at a European level (before the inclusion of the Italian data within the European Cystic Fibrosis Registry). These QCs assure the completeness and the accuracy of data as well as their longitudinal consistency with the European core data.

SETTING AND PARTICIPANTS: A total of 29 CF Centres (referral and support centres and 'Bambino Gesù' Children's Hospital CF centre) sent to ICFR their data referred referred to years 2019-2020. CF Centres of Verona, Messina, and Palermo (this latter only for 2019) do not use the ICFR software; however, their data are firstly collected in a centralized manner, then sent to the European Registry. Data from support centres of Treviso and Rovereto are sent through the Verona CF Center. Finally, data from Sardinia Centre are still missing.

RESULTS: The present Report has been organized into 10 sections. 1. Demography: in 2019, 5,585 CF patients were registered in the ICFR and 5,801 in 2020; median age was 21.6 years in 2019 and 22.4 years in 2020. Prevalence was 9.36/100,000 and 9.79/100,000 residents in Italy in 2019 and in 2020, respectively. Male percentage was 51.5% in 2019 and 2020 and CF distribution by age range showed higher frequency in patients aged 7 to 35 years. Adult patients (aged more than 18 years) were 59.5% on average in both years. 2. Diagnoses: most of the CF patients were diagnosed before two years of age (median value 68.5%); a significant percentage of patients (12.9% in 2019 and 13.4% in 2020) was diagnosed in adult age. 3. New diagnoses: new diagnoses were 136 in 2019 and 96 in 2020. Estimated incidence was 1/5.568 living births in 2019 and 1/7.369 in 2020. 4. Genetics: 99.9% of patients underwent genetic analyses and in 98.2% of these patients a mutation in Cystic Fibrosis Transmembrane Regulator (CFTR) gene was identified. The F508del mutation was the most frequent (identified in 44.7% allele; 2019 data). Furthermore, on average 17.3% of patients had at least one ‘residual function’ mutation. At least one gating mutation is present in 3.3% of Italian patients. Finally, 20.5% of patients had at least one stop codon mutation (class 1). 5. Lung function: percent predicted FEV1 (Forced Expiratory Volume in the first second) progressively declined before adult age, in accordance with the natural history of the disease. The majority of paediatric patients (6-17 years of age), i.e., 86.7% in 2019 and 90.5% in 2020, had percent predicted FEV1 >=70%; whereas paediatric patients with a FEV1% >=40% are less than 2% in the study period. 6. Nutrition: the two most critical periods are the first 6 months of life and adolescence. Prevalence of malnourished adolescent males (12-17 years of age) is higher than the prevalence observed in females. Increasing percentages of female patients with a suboptimal BMI value (33.5% and 31.4%, respectively, in 2019 and 2020) are observed in adult age. 7. Complications: in 2019, CF-related liver disease without cirrhosis was the main complication both in patients aged less than 18 years (20.3% on average) and in adults (37.5%). CF-related diabetes was also frequent in CF adults (23.4%). 8. Transplantation: in 2019-2020, 64 patients received a double-lung transplantation. Median and range of age were 33 years (12.29-57.46) in 2017 and 32.9 (16.5-53.6) years in 2020. Median waiting times for lung transplantation in the two-year period ranged from 6 to 8 months. 9. Microbiology: percentage of adult patients with chronic Pseudomonas aeruginosa infection was 41.6% in 2019 and 38.8% in 2020 vs 14.3% in 2019 and 7.6% in 2020 in paediatric age. Staphylococcus aureus infection is present in 31.1% and 35.9% of adult patients in 2019 and in 33.5% and 34.7% of paediatric patients in 2020. 10. Mortality: a total of 51 patients died in the 2019-2020 period (28 females and 23 males); median age at death was 35.7 years in 2019 and 39 years in 2020 (transplanted patients are not included).

CONCLUSIONS: The present report shows that the Italian CF population is growing (4,159 in 2010 vs 5,801 in 2020). Median age of patients increased in the 2010-2020 period (17 years in 2010 vs 22.4 years in 2020). Prevalence of adult patients is increasing (in 2020, 60.5% of patients is more than 18 years old). About 68.5% of new patients is diagnosed within the second year of life and median age at death (transplanted patients not included) increased in 2020 up to 39 years (in 2018 this value was 35.8). Some statistical differences between 2019 and 2020 are mainly due to the absence of about 200 patients not included in 2019 data by a participating centre for a technical problem.

PMID:36102313 | DOI:10.19191/EP22.4S2.060

Indian Pediatr. 2022 Sep 15;59(9):728.

NO ABSTRACT

PMID:36101956