J Leukoc Biol. 2023 Nov 6:qiad139. doi: 10.1093/jleuko/qiad139. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a life-shortening genetic disorder, caused by mutations in the gene that encodes Cystic Fibrosis Transmembrane-conductance Regulator (CFTR), a cAMP-activated chloride and bicarbonate channel. Persistent neutrophilic inflammation is a major contributor to CF lung disease. However, how CFTR loss-of-function leads to excessive inflammation and its clinical sequela remains incompletely understood. In this study, neutrophils from F508del-CF and healthy control (HC) participants were compared for gene transcription. We found that CF circulating neutrophils have a prematurely-primed basal state with significantly higher scores for activation, chemotaxis, immune signaling, and pattern recognition. Such an irregular basal state appeared not related to the blood environment, and was also observed in neutrophils derived from F508del-CF HL-60 cell line, indicating an innate characteristic of the phenotype. LPS stimulation drastically shifted the transcriptional landscape of HC neutrophils towards a robust immune response; however, CF neutrophils were immune-exhausted, reflected by abnormal cell aging and fate determination in gene programming. Moreover, CF sputum neutrophils differed significantly from CF circulating neutrophils in gene transcription with increased inflammatory response, aging, apoptosis and necrosis, suggesting additional environmental influences on the neutrophils in CF lungs. Taken together, our data indicate that loss of CFTR function has intrinsic effects on neutrophil immune programming, leading to premature priming and dysregulated response to challenge.

PMID:37939820 | DOI:10.1093/jleuko/qiad139

Diabetes Metab Syndr. 2023 Nov 2;17(11):102899. doi: 10.1016/j.dsx.2023.102899. Online ahead of print.

ABSTRACT

AIMS: The aim of this review is to give an update of the recent advances in the pathophysiology, prognosis, diagnosis and treatments of cystic fibrosis-related diabetes (CFRD).

METHODS: The literature survey focuses on original and review articles dealing with CFRD between 2006 and 2023, and in particular with: pathophysiology, risk and predictive factors, screening, chronic complications of CFRD, management and the effects of CFTR channel modulator therapies on glucose homeostasis, using PubMed®.

RESULTS: The rising prevalence of CFRD is due to prolonged life survival among patients with cystic fibrosis (CF). Advances in the understanding of the pathophysiology highlight the singularity of CFRD. Adherence to diagnostic guidelines remains challenging. Besides the classical OGTT, alternative diagnostic tests are being considered: HbA1c measurement, continuous glucose monitoring (CGM), intermediate measurements of alternative glucose tolerance stages through OGTT and homeostatic model assessment (HOMA). Early treatment of (pre)diabetes in CF patients is mandatory. The advent of CFTR channel modulator therapies have created a paradigm shift in the management of CF: they seem to improve glucose homeostasis, but the mechanism remains unclear.

CONCLUSION: CFRD management is an ongoing concern. Optimal care has reduced the negative impact of CFRD on lung function, nutrition, and survival. Increasing prevalence of CFRD and prolonged lifespan lead to more microvascular complications. New screening tools (Hba1c, CGM, HOMA) show potential for better classification of patients. The effect of CFTR modulators on glucose metabolism warrants further research.

PMID:37939435 | DOI:10.1016/j.dsx.2023.102899

J Clin Sleep Med. 2023 Nov 8. doi: 10.5664/jcsm.10914. Online ahead of print.

ABSTRACT

Obstructive sleep apnea (OSA) is common in children with Down syndrome (DS), with reported prevalence rates as high as 69-76%. Multiple factors predispose children with DS for OSA including craniofacial hypoplasia (maxillary and mandibular), airway abnormalities, macroglossia, generalized hypotonia, airway hypotonia, adenotonsillar hypertrophy, and obesity. Despite the pathophysiology for OSA in children with DS being multifactorial in nature, treatment methods have focused on soft tissue in the upper airway using adenotonsillectomy and/or continuous positive airway pressure therapy (CPAP). Here we present a case of a patient with DS whose severe OSA was approached in a multisystem manner including upper airway soft tissue, orthognathic, maxillofacial, and bariatric surgery, resulting in resolution of the OSA without reliance on a continuous positive airway pressure (CPAP) device.

PMID:37937612 | DOI:10.5664/jcsm.10914

Recent Pat Biotechnol. 2023 Nov 3. doi: 10.2174/0118722083255081231020055309. Online ahead of print.

ABSTRACT

DNA is a remarkably precise medium for copying and storing biological information. It serves as a design for cellular machinery that permits cells, organs, and even whole organisms to work. The fidelity of DNA replication results from the action of hundreds of genes involved in proofreading and damage repair. All human cells can acquire genetic changes in their DNA all over life. Genetic mutations are changes to the DNA sequence that happen during cell division when the cells make copies of themselves. Mutations in the DNA can cause genetic illnesses such as cancer, or they could help humans better adapt to their environment over time. The endogenous reactive metabolites, therapeutic medicines, and an excess of environmental mutagens, such as UV rays all continuously damage DNA, compromising its integrity. One or more chromosomal alterations and point mutations at a single site (monogenic mutation) including deletions, duplications, and inversions illustrate such DNA mutations. Genetic conditions can occur when an altered gene is inherited from parents, which increases the risk of developing that particular condition, or some gene alterations can happen randomly. Moreover, symptoms of genetic conditions depend on which gene has a mutation. There are many different diseases and conditions caused by mutations. Some of the most common genetic conditions are Alzheimer's disease, some cancers, cystic fibrosis, Down syndrome, and sickle cell disease. Interestingly, scientists find that DNA mutations are more common than formerly thought. This review outlines the main DNA mutations that occur along the human genome and their influence on human health.

PMID:37936448 | DOI:10.2174/0118722083255081231020055309

Hepatology. 2023 Oct 26. doi: 10.1097/HEP.0000000000000646. Online ahead of print.

ABSTRACT

Background and Aims Cystic fibrosis (CF) may cause a spectrum of hepatobiliary complications, including portal hypertension, multilobular cirrhosis, and liver failure. Current guidelines on the detection and monitoring of hepatobiliary complications in CF were published in 1999. The CF Foundation assembled a committee to evaluate research advances and formulate revised guidelines for CF-associated liver disease. Approach A committee of hepatologists, gastroenterologists, pulmonologists, pharmacist, nurse, dietitian, individual with CF, and parent of a child with CF devised "population, intervention, comparison, and outcome" (PICO) questions regarding hepatobiliary disease in CF. PubMed literature searches were performed for each PICO question. Recommendations were voted on with 80% agreement required to approve a recommendation. Public comment on initial recommendations was solicited prior to formulation of final recommendations. Results 31 PICO questions were assembled, 6,401 manuscripts were title screened for relevance, with 1,053 manuscripts undergoing detailed full text review. Seven recommendations were approved for screening, 13 for monitoring of existing disease, and 14 for treatment of CF-associated hepatobiliary involvement or advanced liver disease. One recommendation on liver biopsy did not meet the 80% threshold. One recommendation on screening ultrasound was revised and re-voted on. Conclusions Through a multidisciplinary committee and public engagement, we have assembled updated recommendations and guidance on screening, monitoring and treatment of CF-associated hepatobiliary involvement and advanced liver disease. While research gaps remain, we anticipate that these recommendations will lead to improvements in CF outcomes through earlier detection and increased evidence-based approaches to monitoring and treatment.

PMID:37934656 | DOI:10.1097/HEP.0000000000000646

Mol Biol Rep. 2023 Nov 7. doi: 10.1007/s11033-023-08880-w. Online ahead of print.

ABSTRACT

The increase in bacterial resistance generated by the indiscriminate use of antibiotics in medical practice set new challenges for discovering bioactive natural products as alternatives for therapeutics. Lanthipeptides are an attractive natural product group that has been only partially explored and shows engaging biological activities. These molecules are small peptides with potential application as therapeutic agents. Some members show antibiotic activity against problematic drug-resistant pathogens and against a wide variety of viruses. Nevertheless, their biological activities are not restricted to antimicrobials, as their contribution to the treatment of cystic fibrosis, cancer, pain symptoms, control of inflammation, and blood pressure has been demonstrated. The study of biosynthetic gene clusters through genome mining has contributed to accelerating the discovery, enlargement, and diversification of this group of natural products. In this review, we provide insight into the recent advances in the development and research of actinobacterial lanthipeptides that hold great potential as therapeutics.

PMID:37934370 | DOI:10.1007/s11033-023-08880-w

Microbiol Spectr. 2023 Nov 7:e0229923. doi: 10.1128/spectrum.02299-23. Online ahead of print.

ABSTRACT

Diabetes is associated with several health consequences, including increased susceptibility to more frequent and severe infections. Bacterial infections associated with diabetes are typically polymicrobial, with Staphylococcus aureus and Pseudomonas aeruginosa frequently isolated from the same infection site. S. aureus and P. aeruginosa are frequently found in diabetic skin and soft tissue infections, in the lungs of people with cystic fibrosis, and in indwelling device infections. Numerous studies have investigated interactions between these two pathogens primarily using in vitro systems. These models have several limitations as they do not accurately reflect the complexities of an immune response nor the nutrient dynamics in a diabetic infection microenvironment. Here, we describe a novel murine indwelling device co-infection model that allows us to study the interactions between S. aureus and P. aeruginosa within the context of an immune response during both normal and diabetic infections. Our data shows that P. aeruginosa significantly inhibits S. aureus growth during co-infection in a normal mouse and that inhibition is not dependent on the P. aeruginosa PQS quorum sensing system. Conversely, in a diabetic co-infection, S. aureus overcomes inhibition by P. aeruginosa and this phenotype is reliant on S. aureus glycolysis. We also demonstrate that both organisms display increased virulence potential in a diabetic co-infection as we observe increased dissemination to peripheral tissues. This study revealed novel in vivo interactions between S. aureus and P. aeruginosa and advances our understanding of the complex interactions between microorganisms in polymicrobial infections in clinically relevant infection microenvironments.IMPORTANCEIndividuals with diabetes are prone to more frequent and severe infections, with many of these infections being polymicrobial. Polymicrobial infections are frequently observed in skin infections and in individuals with cystic fibrosis, as well as in indwelling device infections. Two bacteria frequently co-isolated from infections are Staphylococcus aureus and Pseudomonas aeruginosa. Several studies have examined the interactions between these microorganisms. The majority of these studies use in vitro model systems that cannot accurately replicate the microenvironment of diabetic infections. We employed a novel murine indwelling device model to examine interactions between S. aureus and P. aeruginosa. Our data show that competition between these bacteria results in reduced growth in a normal infection. In a diabetic infection, we observe increased growth of both microbes and more severe infection as both bacteria invade surrounding tissues. Our results demonstrate that diabetes changes the interaction between bacteria resulting in poor infection outcomes.

PMID:37933971 | DOI:10.1128/spectrum.02299-23

Am J Physiol Lung Cell Mol Physiol. 2023 Nov 7. doi: 10.1152/ajplung.00045.2023. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is marked by unremitting matrix deposition and architectural distortion. Multiple pro-fibrotic pathways contribute to the persistent activation of mesenchymal cells (MCs) in fibrosis, highlighting the need to identify and target common signaling pathways. The transcription factor NFAT1 (nuclear factor of activated T cells 1) lies downstream of second messenger calcium signaling and has been recently shown to regulate key pro-fibrotic mediator autotaxin (ATX) in lung MCs. Herein, we investigate the role of NFAT1 in regulating fibroproliferative responses during the development of lung fibrosis. Nfat1-/- deficient mice subjected to bleomycin injury demonstrated improved survival, and protection from lung fibrosis and collagen deposition as compared to bleomycin-injured wildtype (WT) mice. Chimera mice, generated by reconstituting bone marrow cells from WT or Nfat1-/- mice into irradiated WT mice (WTàWT and Nfat1-/-àWT), demonstrated no difference in bleomycin-induced fibrosis, suggesting immune influx-independent fibro-protection in Nfat1-/- mice. Examination of lung tissue and flow sorted lineageneg/PDGFRαpos MCs demonstrated decreased MC numbers, proliferation (cyclin D1 and EdU incorporation), myofibroblast differentiation (αSMA), and survival (Birc5) in Nfat1-/- mice. Nfat1 deficiency abrogated ATX expression in response to bleomycin in vivo and MCs derived from Nfat1-/- mice demonstrated decreased ATX expression and migration in vitro. Human IPF MCs demonstrated constitutive NFAT1 activation, and regulation of ATX in these cells by NFAT1 was confirmed utilizing pharmacologic and genetic inhibition. Our findings identify NFAT1 as a critical mediator of pro-fibrotic processes contributing to dysregulated lung remodeling and suggest its targeting in MCs as a potential therapeutic strategy in IPF.

PMID:37933452 | DOI:10.1152/ajplung.00045.2023

Clin Otolaryngol. 2023 Nov 6. doi: 10.1111/coa.14122. Online ahead of print.

NO ABSTRACT

PMID:37933411 | DOI:10.1111/coa.14122

Clin Infect Dis. 2023 Nov 2;77(Supplement_5):S416-S422. doi: 10.1093/cid/ciad528.

ABSTRACT

Patients with chronic lung disease and lung transplantation have high rates of colonization and infection from multidrug-resistant (MDR) organisms. This article summarizes the current state of knowledge regarding phage therapy in the setting of lung transplantation. Phage therapy has been used in several lung transplant candidates and recipients on a compassionate use basis targeting mostly MDR gram-negative infections and atypical mycobacterial infections with demonstrated clinical safety. Phage biodistribution given intravenously or via nebulization has not been extensively studied, though preliminary data are presented. Phage interacts with both the innate and adaptive immune system; current literature demonstrates the development of serum neutralization in some cases of phage therapy, although the clinical impact seems variable. A summary of current clinical trials involving patients with chronic lung disease is presented, though none are specifically targeting lung transplant candidates or recipients. In addition to treatment of active infections, a variety of clinical scenarios may benefit from phage therapy, and well-designed clinical trials involving this vulnerable patient population are needed: pre- or peritransplantation use of phage in the setting of MDR organism colonization may lead to waitlisting of candidates currently declined by many centers, along with potential reduction of waitlist mortality rates and posttransplant infections; phage may be used for biofilm-related bronchial stent infections; and, finally, there is a possibility that phage use can affect allograft function and chronic rejection.

PMID:37932113 | DOI:10.1093/cid/ciad528

Med Ultrason. 2023 Oct 26. doi: 10.11152/mu-4297. Online ahead of print.

ABSTRACT

In this series of articles with comments and illustrations on the World Federation for Medicine and Biology (WFUMB) guidelines on contrast-enhanced ultrasound (CEUS) the topics of very rare focal liver lesions (FLL) are discussed. Improving the detection and characterization of the most common FLL are the main topics of these guidelines. The focus of this review is on the many manifestations of cystic fibrosis-related liver disease (CFLD). These include focal biliary fibrosis, liver cirrhosis, vascular manifestations with nodular regenerative hyperplasia and portal hypertension with or without cirrhosis. This article describes the diverse changes of liver involvement in cystic fibrosis and their appearance on ultrasound, duplex sonography, and contrast enhanced ultrasonography. This knowledge and the imaging should help to recognize liver manifestations in time and enable a correct interpretation of ultrasound images in CF in the corresponding clinical situation.

PMID:37931013 | DOI:10.11152/mu-4297

Front Microbiol. 2023 Oct 20;14:1245755. doi: 10.3389/fmicb.2023.1245755. eCollection 2023.

ABSTRACT

Pseudomonas aeruginosa thrives in the airways of individuals with cystic fibrosis, in part by forming robust biofilms that are resistant to immune clearance or antibiotic treatment. In the cystic fibrosis lung, the thickened mucus layers create an oxygen gradient, often culminating with the formation of anoxic pockets. In this environment, P. aeruginosa can use nitrate instead of oxygen to grow. Current fluorescent reporters for studying P. aeruginosa are limited to the GFP and related analogs. However, these reporters require oxygen for the maturation of their chromophore, making them unsuitable for the study of anaerobically grown P. aeruginosa. To overcome this limitation, we evaluated seven alternative fluorescent proteins, including iLOV, phiLOV2.1, evoglow-Bs2, LucY, UnaG, Fluorescence-Activating and Absorption-Shifting Tag (FAST), and iRFP670, which have been reported to emit light under oxygen-limiting conditions. We generated a series of plasmids encoding these proteins and validated their fluorescence using plate reader assays and confocal microscopy. Six of these proteins successfully labeled P. aeruginosa in anoxia. In particular, phiLOV2.1 and FAST provided superior fluorescence stability and enabled dual-color imaging of both planktonic and biofilm cultures. This study provides a set of fluorescent reporters for monitoring P. aeruginosa under low-oxygen conditions. These reporters will facilitate studies of P. aeruginosa in biofilms or other contexts relevant to its pathogenesis, such as those found in cystic fibrosis airways. Due to the broad host range of our expression vector, the phiLOV2.1 and FAST-based reporters may be applicable to the study of other Gram-negative bacteria that inhabit similar low-oxygen niches.

PMID:37928662 | PMC:PMC10623331 | DOI:10.3389/fmicb.2023.1245755

Can J Respir Ther. 2023 Oct 31;59:214-222. doi: 10.29390/001c.89093. eCollection 2023.

ABSTRACT

BACKGROUND: Inhaled hypertonic saline (HS) is an effective mucolytic agent in patients with cystic fibrosis (CF). However, adverse events can impair the clinical utility of hypertonic saline (HS) in this patient population. In this study, we aimed to investigate the effectiveness of hyaluronic acid (HA) in reducing these adverse events.

METHODS: A literature search was conducted across three electronic databases (Medline, Cochrane Central, and EMBASE) from inception through February 2023. Randomized controlled trials (RCTs) assessing the impact of hyaluronic acid (HA) in reducing adverse events in patients taking hypertonic saline (HS) for CF were included in the analysis. Outcomes of interest included cough, throat irritation, unpleasant taste, and FEV1. Evaluations were reported as risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CI). The Cochrane Risk of Bias Tool (CRBT) was employed to assess the quality of RCTs. The New Castle Ottawa Scale was used to assess the quality of observational studies.

RESULTS: From the 1960 articles retrieved from the initial search, five relevant studies (n=236 patients) were included in the final analysis. Compared with patients only on HS, patients with HS and HA were significantly less likely to experience cough (RR: 0.45; 95% CI, 0.28-0.72, p=0.001), throat irritation (RR: 0.43; 95% CI, 0.22-0.81, p= 0.009), and unpleasant smell (RR: 0.43; 95% CI, 0.23 - 0.80, p=0.09). In addition, patients with HS with HA had significantly less forced expiratory volume (FEV1) (MD: -2.97; 95% CI, -3.79-2.15, p=0.52) compared to patients only on HS.

DISCUSSION: The addition of HA to HS was linked to a better tolerability profile. When HS was coupled with HA, there was a reduction in all side effects. This may permit tolerance of the medication in otherwise difficult patients, improve adherence to patients receiving frequent inhalations, and improve therapeutic outcomes.

CONCLUSION: The addition of HA is advantageous in CF patients who require continuous HS therapy and have previously shown poor tolerance to therapy.

PMID:37927455 | PMC:PMC10621800 | DOI:10.29390/001c.89093

Respir Med. 2023 Nov 3:107455. doi: 10.1016/j.rmed.2023.107455. Online ahead of print.

ABSTRACT

BACKGROUND: The advent of elexacaftor/tezacaftor/ivacaftor (ETI) resulted in unprecedented clinical benefits for eligible adults with CF. As a result, the question of whether chronic treatments can be safely stopped or adapted to this new situation has become a matter of great interest. Our objective was to derive a consensus among Italian experts on the impact of ETI on the current clinical management of CF lung disease.

METHODS: From December 2021 to April 2022 a panel of Italian experts endorsed by the national CF scientific society derived and graded a set of statements on the pulmonary management of adults with cystic fibrosis through a modified Delphi methodology.

RESULTS: The panel produced 13 statements exploring possible modifications in the fields of inhaled antibiotics and mucoactives; airway clearance and physical activity; chronic macrolides and bronchodilators; and lung transplant referral. The areas that the experts considered most urgent to explore were the impact of ETI on the role of inhaled antibiotics and lung transplant.

CONCLUSIONS: The list of priorities that emerged from this study could be useful to guide and inform clinical research on the most urgent area of impact of ETI on CF lung disease and its clinical management.

PMID:37926181 | DOI:10.1016/j.rmed.2023.107455

J Cyst Fibros. 2023 Nov 3:S1569-1993(23)01661-2. doi: 10.1016/j.jcf.2023.10.013. Online ahead of print.

ABSTRACT

BACKGROUND: For children with cystic fibrosis (CF), achieving and maintaining optimal growth by the age of 2 years is critical for future health outcomes. A standardized nutrition screening is needed to identify growth problems, enable timely interventions, and improve nutritional outcomes for children (0 to 2 years) with CF. The purpose of this study was to develop a nutrition screening tool for children (0 to 2 years) with CF to identify nutrition risk at every clinical encounter.

METHODS: A retrospective cross-sectional study was used to develop a nutrition screening tool to determine if nutrition interventions needed to change (at-risk) or continue (not at-risk). Retrospective data for pertinent nutrition factors were collected for 99 children attending an accredited CF clinic. The nutrition factors were compared to a dietitian assessment. A stepwise discriminant analysis determined weight-for-age (WFA) and weight-for-length (WFL) z-scores were significant. Then anthropometric data and corresponding dietitian assessment results were collected for children with CF attending two other accredited CF clinics (n = 29, n = 30). Discriminant analysis was used to determine sensitivity and specificity of the nutrition factors and to create a nutrition screening tool equation.

RESULTS: The nutrition screening model that included WFA z-score, LFA z-score, WFL z-score, and weight change velocity adequacy determined nutrition risk the best. The sensitivity was 89.7 %, specificity 83.2 %, NPV 93.3 %, and PPV 75.4 % for this model.

CONCLUSION: The nutrition screening tool equation developed in this study standardizes the process to identify children (0 to 2 years) with CF at nutrition risk. Further validation is needed.

PMID:37926667 | DOI:10.1016/j.jcf.2023.10.013

Nat Commun. 2023 Nov 4;14(1):7091. doi: 10.1038/s41467-023-42916-w.

ABSTRACT

As observed in cancers, individual mutagens and defects in DNA repair create distinctive mutational signatures that combine to form context-specific spectra within cells. We reasoned that similar processes must occur in bacterial lineages, potentially allowing decomposition analysis to detect both disruption of DNA repair processes and exposure to niche-specific mutagens. Here we reconstruct mutational spectra for 84 clades from 31 diverse bacterial species and find distinct mutational patterns. We extract signatures driven by specific DNA repair defects using hypermutator lineages, and further deconvolute the spectra into multiple signatures operating within different clades. We show that these signatures are explained by both bacterial phylogeny and replication niche. By comparing mutational spectra of clades from different environmental and biological locations, we identify niche-associated mutational signatures, and then employ these signatures to infer the predominant replication niches for several clades where this was previously obscure. Our results show that mutational spectra may be associated with sites of bacterial replication when mutagen exposures differ, and can be used in these cases to infer transmission routes for established and emergent human bacterial pathogens.

PMID:37925514 | DOI:10.1038/s41467-023-42916-w

BMC Pulm Med. 2023 Nov 4;23(1):429. doi: 10.1186/s12890-023-02737-5.

ABSTRACT

BACKGROUND: A heavy financial burden is imposed on patients suffering from chronic diseases due to medicine out-of-pocket payments.

OBJECTIVES: This study focuses on assessing the affordability of medications used for chronic respiratory diseases (CRDs) such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) in Iran, specifically on the category R medicines listed in the 2017 Iran drug list (IDL) that are used for the treatment of these diseases, based on the anatomical therapeutic chemical (ATC) drug code.

METHODS: The affordability of medicines in mono and combination therapy approaches was assessed in CRDs using the World Health Organization/Health Action International (WHO/HAI) methodology. Accordingly, if out-of-pocket payment for 30-days of pharmacotherapy exceeds one day for the lowest-paid unskilled government worker (LPGW), it's considered non-affordable.

RESULTS: Based on the monotherapy approach, our finding demonstrates that all generic medicines of category R were affordable. However, branded drugs such as Symbicort®, Pulmicort Respules®, Flusalmex®, Seretide®, Fluticort Plus®, Seroflo®, and Salmeflo® cost between 1.2 and 2.5 days' wage of LPGW and considered unaffordable despite 70% insurance coverage. Moreover, based on the affordability ratio in the combination therapy approach, all medicines used in asthma, COPD, and CF patients with mild respiratory problems are affordable except omalizumab (inj), which is non-affordable due to its high price and no insurance coverage.

CONCLUSION: Results showed that the existing insurance coverage does not protect households from hardship, so more considerations are needed such as different insurance schedules and patient support programs.

PMID:37925396 | DOI:10.1186/s12890-023-02737-5

J Cyst Fibros. 2023 Nov 3:S1569-1993(23)01666-1. doi: 10.1016/j.jcf.2023.10.017. Online ahead of print.

ABSTRACT

BACKGROUND: Aspergillus infection is known to be associated with worse respiratory outcomes in people with CF (pwCF) and is a well-recognised complication of severe SARS-CoV-2 infection. The aim of this observational cross-sectional study was to examine the association of pre-existing Aspergillus infection and/or allergic bronchopulmonary aspergillosis (ABPA) in pwCF and severity of COVID-19.

METHODS: Data on SARS-CoV-2 infections in pwCF from January 2020 to June 2021 were collected by the European Cystic Fibrosis Society Patient Registry. The primary outcome was COVID-19 severity measured by hospitalisation comparing those with Aspergillus infection and/or ABPA in the 12 months preceding COVID-19and those without.

RESULTS: In total, 1095 pwCF were diagnosed with SARS-CoV-2 and information on pre-existing Aspergillus/ABPA status was available from 807. PwCF and SARS-CoV-2 in the Aspergillus/ABPA group (n = 153), in comparison to the non-Aspergillus/ABPA group (n = 654), were more likely to be hospitalised (adjusted OR 1.79 (1.19 to 2.85); p = 0.005) and their disease course was more likely to be complicated by sepsis (adjusted OR 7.78 (1.78 to 49.43); p = 0.008). The association with hospital admission was no longer significant after excluding patients with ABPA. Secondary analysis comparing pwCF who received antifungal treatment (n = 18), versus those who did not (n = 474) during COVID-19, showed a higher rate of hospitalisation (p < 0.001); intensive care unit admission (p < 0.001), and requirement for invasive ventilation (p < 0.001) in the antifungal treated group.

CONCLUSION: We show that pre-existing Aspergillus/ABPAis associated with increased rates of hospitalisation and sepsis during COVID-19 in pwCF.

PMID:37925255 | DOI:10.1016/j.jcf.2023.10.017

Chest. 2023 Nov 2:S0012-3692(23)05689-1. doi: 10.1016/j.chest.2023.10.043. Online ahead of print.

ABSTRACT

BACKGROUND: Italy initiated Elexacaftor/Tezacaftor/Ivacaftor (ETI) for people with cystic fibrosis (pwCF) in July 2021. It has been led to dramatic improvements in lung function, BMI, sweat chloride, and respiratory symptoms. However, little data is available on side-effects or effects on a broad range of outcomes.

RESEARCH QUESTION: How does ETI affect mental health, cognitive processing, neuropsychological side-effects, GI symptoms, and HRQoL over time?

STUDY DESIGN: AND METHODS This was a prospective, "real world" longitudinal study. Participants were recruited consecutively and evaluated at initiation T0 and after 1-month (T1), 3-months (T2), and 6-months (T3). Assessments included depression (PHQ-9), anxiety (GAD-7), cognition (SDMT), GI Symptom Tracker, and HRQoL (CFQ-R). Based on literature, an ad-hoc questionnaire was developed to assess side-effects: insomnia, headache, memory problems, "brain fog" and concentration problems. Following descriptive analyses, longitudinal data were analyzed using mixed models for repeated measures (MMRM), controlling for age and gender when appropriate.

RESULTS: Ninety-two consecutive pwCF (F/M=46/46; age M=25.4 years) participated. FEV1 increased initially then remained stable. BMI also increased significantly from T0 to T3 (p<0.01). Depression improved from T0 to T1 (p<0.001), however no changes in anxiety were found. Cognitive processing improved from T0 to subsequent assessments. Positive changes were reported on the GI Symptom Tracker for Stools and Adherence Challenges, however, no changes were found for Abdominal Pain and Digestion. Side-effects occurred in 10%-29%, with no reduction over time; insomnia increased significantly across time. Women reported more side-effects than men (i.e., insomnia, headache, concentration problems, brain fog).

INTERPRETATION: This prospective study evaluated the effects of ETI using multiple measures. Significant improvements were found in many domains, however, side-effects were reported by a substantial proportion of pwCF, with no improvements over time. Women reported more side-effects than men. PwCF should be followed systematically to assess the frequency of side-effects after starting this new modulator.

PMID:37925143 | DOI:10.1016/j.chest.2023.10.043

Clin Chim Acta. 2023 Nov 1:117625. doi: 10.1016/j.cca.2023.117625. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis is the most common hereditary recessive disease with an incidence of about 1:2500/3000. It has long been known that the disease is caused by deleterious mutations in the CFTR gene. Conventionally, the disease is diagnosed in several phases. The analysis of all the possible disease-causing molecular alterations is time consuming and may not lead to a definitive diagnosis in several cases. Consequently, we propose, in this paper, a rapid sequencing method that, in a single procedural asset, reveals the presence of small mutations and also the copy number variants (CNVs) from the DNA extracted from the Guthrie Spot.

MATERIALS AND METHODS: We first sequenced 30 blood spots, then we validated the method on 100 spots that underwent both traditional analyses and this complete NGS sequencing, and lastly, we tested the strategy on patients who normally do not reach the molecular sequencing step because of low level of Immune-Reactive Trypsinogen.

RESULTS: Using this procedure, we identified 97 variants in the CFTR gene of our samples and 6 CNVs. Notably, the significant data were obtained in the group of patients with borderline or negative IRT who routinely would not undergo molecular testing. We also identified 6 carriers of "disease-causing" variants.

CONCLUSION: This method is very robust. Indeed, there was a 100% concordance with Sanger sequencing validation, and 6 mutation carriers were identified who normally escaped molecular testing with actual conventional procedure. There were also 3 duplications of almost the entire gene in heterozygosity, which were not seen with traditional methods. Being quick and easy to perform, we suggest that complete sequencing of the CFTR gene, as in this study be considered for all newborns.

PMID:37923102 | DOI:10.1016/j.cca.2023.117625