BMJ Case Rep. 2024 Oct 15;17(10):e262156. doi: 10.1136/bcr-2024-262156.

ABSTRACT

Central venous catheters including totally implantable venous access devices (TIVADs) have revolutionised the management of pulmonary infections and exacerbations in patients with cystic fibrosis (CF). While being better tolerated by the patient, these have allowed aggressive intravenous antibiotic therapies during recurrent hospitalisations. Given improvement in procedural strategies and operator experience, many patients with CF undergo lung transplants in the course of their disease nowadays. TIVADs can be associated with thrombosis leading to superior vena cava (SVC) obstruction and SVC syndrome which can pose a challenge, especially during the transplant surgery. We describe a case of successful management of SVC syndrome in a patient with CF undergoing a lung transplant, highlighting the strategies used to minimise risks associated with such a procedure.

PMID:39414317 | DOI:10.1136/bcr-2024-262156

Sci Total Environ. 2024 Oct 14:176938. doi: 10.1016/j.scitotenv.2024.176938. Online ahead of print.

ABSTRACT

As revealed by culture-independent methodologies, disruption of the normal lung microbiota (LM) configuration (LM dysbiosis) is a potential mediator of adverse effects from inhaled chemicals. LM, which consists of microbiota in the upper and lower respiratory tract, is influenced by various factors, including inter alia environmental exposures. LM dysbiosis has been associated with multiple respiratory pathologies such as asthma, lung cancer, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Chemically-induced LM dysbiosis appears to play significant roles in human respiratory diseases, as has been shown for some air pollutants, cigarette smoke and some inhalable chemical antibiotics. Lung microbiota are also linked with the central nervous system (CNS) in the so-called lung-brain axis. Inhaled chemicals that undergo mucociliary clearance may be linked to respiratory conditions through gut microbiota (GM) dysbiosis in the so-called Gut-Lung axis. However, current linkages of various disease states to LM appears to be associative, with causal linkages requiring further studies using more robust approaches, methods and techniques that are different from those applied in studies involving (GM). Most importantly, the sampling techniques determine the level of risk of cross contamination. Furthermore, the development of continuous or semi-continuous systems designed to replicate the lung microbiome will go a long way to further LM dysbiosis studies. These challenges notwithstanding, the preponderance of evidence points to the significant role of LM-mediated chemical toxicity in human disease and conditions.

PMID:39414049 | DOI:10.1016/j.scitotenv.2024.176938

Microb Pathog. 2024 Oct 14:107016. doi: 10.1016/j.micpath.2024.107016. Online ahead of print.

ABSTRACT

PURPOSE: Staphylococcus aureus is one of the most prevalent pathogens in cystic fibrosis (CF), being of special relevance those methicillin-resistant (MRSA). The livestock-associated (LA)-MRSA lineage CC398 is an emerging problem, specially related to pig-farming (PF) environments. The objective was to characterize the S. aureus isolates recovered from CF-patients in a Spanish hospital located in a region with high-PF activity.

METHODS: Forty-two isolates were obtained (January-November/2022) and characterized (one/patient). The antimicrobial resistance phenotype/genotype was evaluated by Microscan/PCR. The presence of virulence and Immune Evasion Cluster (IEC) genes as well as the agr type was determined by PCR. MLST and spa-typing were studied by PCR-sequencing.

RESULTS: Nine of the 42 isolates were MRSA (21.4%), and 8 of them multidrug resistant (MDR). Among MRSA, 6 spa-types were detected, assigned to CC1, CC5, CC8, CC30, and CC398. Four MRSA isolates belonged to the lineage CC398-t011-IEC negative (animal adapted-clade, LA-MRSA). The remaining 33 isolates were methicillin-susceptible (MSSA), of 26 spa-types and associated with 11 CCs (predominant: CC5, CC30, and CC398). Seven MSSA isolates were of the lineage CC398 (spa-types t034, t108, t571, t20352); four of them were IEC-positive and erm(T)-positive (t571, and t20352, human-adapted CC398 clade), being IEC-negative the remaining three. The tst and eta/etb genes were identified in 12 and 2 isolates, respectively (none CC398). Small-colony-variants were demonstrated in 9 isolates (two CC398, both MDR).

CONCLUSION: The lineage CC398 was very frequent among CF-patients (26.2%), both among MSSA and MRSA. The emergence of LA-MRSA-CC398 in CF-patients requires monitorization, especially in hospitals of high-PF-regions.

PMID:39413853 | DOI:10.1016/j.micpath.2024.107016

Hypertension. 2024 Nov;81(11):2248-2250. doi: 10.1161/HYPERTENSIONAHA.124.23716. Epub 2024 Oct 16.

NO ABSTRACT

PMID:39413203 | DOI:10.1161/HYPERTENSIONAHA.124.23716

Nucleic Acids Res. 2024 Oct 16:gkae889. doi: 10.1093/nar/gkae889. Online ahead of print.

ABSTRACT

The opportunistic pathogen Pseudomonas aeruginosa infects the airways of people with cystic fibrosis (CF) and produces a virulence factor Cif that is associated with worse outcomes. Cif is an epoxide hydrolase that reduces cell-surface abundance of the cystic fibrosis transmembrane conductance regulator (CFTR) and sabotages pro-resolving signals. Its expression is regulated by a divergently transcribed TetR family transcriptional repressor. CifR represents the first reported epoxide-sensing bacterial transcriptional regulator, but neither its interaction with cognate operator sequences nor the mechanism of activation has been investigated. Using biochemical and structural approaches, we uncovered the molecular mechanisms controlling this complex virulence operon. We present here the first molecular structures of CifR alone and in complex with operator DNA, resolved in a single crystal lattice. Significant conformational changes between these two structures suggest how CifR regulates the expression of the virulence gene cif. Interactions between the N-terminal extension of CifR with the DNA minor groove of the operator play a significant role in the operator recognition of CifR. We also determined that cysteine residue Cys107 is critical for epoxide sensing and DNA release. These results offer new insights into the stereochemical regulation of an epoxide-based virulence circuit in a critically important clinical pathogen.

PMID:39413156 | DOI:10.1093/nar/gkae889

PLoS One. 2024 Oct 16;19(10):e0308299. doi: 10.1371/journal.pone.0308299. eCollection 2024.

ABSTRACT

In cystic fibrosis (CF), there is abnormal translocation and function of the cystic fibrosis transmembrane conductance regulator (CFTR) and an upregulation of the epithelial sodium channel (ENaC). This leads to hyperabsorption of sodium and fluid from the airway, dehydrated mucus, and an increased risk of respiratory infections. In this study, we performed a proteomic assessment of differentially regulated proteins from CF and non-CF small airway epithelial cells (SAEC) that are sensitive to Mycobacterium avium. CF SAEC and normal non-CF SAEC were infected with M. avium before the cells were harvested for protein. Protein kinase C (PKC) activity was greater in the CF cells compared to the non-CF cells, but the activity was significantly attenuated in both cell types after infection with M. avium compared to vehicle. Western blot and densitometric analysis showed a significant increase in cathepsin B protein expression in M. avium infected CF cells. Myristoylated alanine rich C-kinase substrate (MARCKS) protein was one of several differentially expressed proteins between the groups that was identified by mass spectrometry-based proteomics. Total MARCKS protein expression was greater in CF cells compared to non-CF cells. Phosphorylation of MARCKS at serine 163 was also greater in CF cells compared to non-CF cells after treating both groups of cells with M. avium. Taken together, MARCKS protein is upregulated in CF cells and there is decreased phosphorylation of the protein due to a decrease in PKC activity and presumably increased cathepsin B mediated proteolysis of the protein after M. avium infection.

PMID:39413095 | DOI:10.1371/journal.pone.0308299

Pediatr Pulmonol. 2024 Oct 16. doi: 10.1002/ppul.27330. Online ahead of print.

NO ABSTRACT

PMID:39412420 | DOI:10.1002/ppul.27330

J Pediatr Pharmacol Ther. 2024 Oct;29(5):539-543. doi: 10.5863/1551-6776-29.5.539. Epub 2024 Oct 14.

ABSTRACT

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was given US Food and Drug Administration approval based on its therapeutic benefits to treat patients with cystic fibrosis (CF) who had at least 1 allele of the CF transmembrane conductance regulator (CFTR) with phenylalanine deleted at position 508 (F508del). The increase in genotyping studies has increased the frequency of use of CFTR modulators; however, severe allergic reactions to CFTR modulators have also been described. It is critical to avoid the offending medication and select alternative treatments while dealing with drug allergies. Drug desensitization may be taken into consideration in situations where there is no other option. This article describes home desensitization treatment for a patient with CF who developed a maculopapular rash following CFTR modulator medication. There are currently no alternative drugs for CFTR modulators, which are crucial for patients with CF, and limited experience is available with allergic reactions to these drugs. It is important to establish desensitization protocols in order to control drug reactions to CFTR modulators, which are vital for individuals with CF.

PMID:39411414 | PMC:PMC11472403 | DOI:10.5863/1551-6776-29.5.539

Sisli Etfal Hastan Tip Bul. 2024 Sep 30;58(3):389-394. doi: 10.14744/SEMB.2024.65983. eCollection 2024.

ABSTRACT

OBJECTIVES: Current guidelines suggest that patients with cystic fibrosis (CF), who are over the age of 10, should be annually evaluated with oral glucose tolerance test (OGTT). In this study, it was aimed to evaluate the OGTT results in patients above the age of 10, who were followed up in our center with the diagnosis of CF.

METHODS: In the study, 46 patients with CF at the age of 10 and above, who underwent OGTT were included. Data such as gender, age at diagnosis, anthropometric measurements, lung function (FEV1 %) and the OGTT results were obtained. In the analysis, the patient groups with normal glucose tolerance (NGT) and abnormal glucose tolerance(AGT) were compared.

RESULTS: NGT was found in 37(80.4%) of the patients, and AGT was found in 9(19.5%) of the patients. The median fasting glucose levels of the patients in the NGT group and the mean glucose levels measured at 120 minutes in the OGTT were found to be lower compared to the patients in the AGT group(p<0.005). Although the mean body weight, height, VKİ-SDS, FEV1in the AGT group were found to be lower than the patients in the NGT group, the difference was not statistically significant (p>0.05).

CONCLUSION: We detected AGT in approximately 1 out of 5 patients with CF who were at the age of 10 and above. Almost half (44.4%) of the patients with AGT were found to have normal fasting blood glucose levels. Therefore, cystic fibrosis-related diabetes screening should be performed with OGTT instead of fasting blood glucose in patients with CF.

PMID:39411039 | PMC:PMC11472201 | DOI:10.14744/SEMB.2024.65983

Lancet Reg Health Eur. 2024 Jul 3;44:100996. doi: 10.1016/j.lanepe.2024.100996. eCollection 2024 Sep.

ABSTRACT

BACKGROUND: COVID-19 dramatically reshaped mortality across Europe. This study aimed to assess its impact on total mortality in European countries taking into consideration the relationship with selected country-level socioeconomic indicators, non-pharmaceutical interventions, and vaccine uptake.

METHODS: We obtained weekly mortality data from 2010 to 2023 from the Short-term Mortality Fluctuations data series, the annual population data from the United Nations archives, selected sociodemographic and economic indicators from the World Bank's database, the stringency index and the percentage of the population fully vaccinated from Our World in Data. A quasi-Poisson regression model trained on pre-pandemic years was used to estimate expected number of deaths in 2020-2023 in 29 European countries. Excess mortality was estimated using three different metrics: excess deaths (number), relative excess mortality (% different from expected deaths) and age-standardized excess death rate per 10,000 population. The relationship between socioeconomic indicators and excess mortality was evaluated using linear regression models, which included both linear and quadratic terms for the predictors to account for possible non-linear relationships.

FINDINGS: We estimated 1,642,586 excess deaths (95% confidence interval, CI: 1,607,161-1,678,010) across all countries over the four years (+8.0% compared to the expected number of deaths). Excess mortality was mainly concentrated in 2020-2022 (0.52 million excess deaths in 2020, 0.57 million in 2021 and 0.44 million in 2022), with no substantial excess (0.11 million) estimated for 2023. Over the period 2020-23, the highest number of excess deaths was estimated for Italy (227,736 deaths, +8.7%), Poland (223,735 deaths, +13.7%), and Germany (218,111 deaths, +5.6%), while the highest excesses in relative terms were in Bulgaria (72,328 deaths, +17.2%), Lithuania (23,813 deaths, +16.1%), and Slovakia (31,984 deaths, +14.9%). The age-standardised death rates ranged from 1.8 per 10,000 population in Sweden to 24.7 in Bulgaria. The percentage of the population living below the poverty line and the Gini index were significantly associated with an increased excess death rate, with p-values for the linear and quadratic terms being 0.003 and 0.003 for the Gini index, and 0.024 and 0.017 for the population living below the poverty line. Conversely, gross domestic product per capita (p-values for the linear and quadratic terms: <0.001, 0.003), health expenditure (0.001, 0.273) and the percentage of people fully vaccinated by the end of 2021 (<0.001, 0.989) or 2022 (0.001, 0.890) were inversely associated with excess death rate. No significant association was observed with population density and stringency index.

INTERPRETATION: The observed geographic disparities in total mortality excess across Europe can be related to differences in socioeconomic contexts, as well as to suboptimal vaccine uptakes in some countries.

FUNDING: This research was supported by European Union (EU) funding within the NextGeneration EU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT). The funding source had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

PMID:39410937 | PMC:PMC11473197 | DOI:10.1016/j.lanepe.2024.100996

Int J Mol Sci. 2024 Sep 30;25(19):10551. doi: 10.3390/ijms251910551.

ABSTRACT

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective chloride ion channels. This leads to thick, dehydrated mucus that severely disrupts mucociliary clearance in the respiratory system and triggers infection that eventually is the cause of death of CF patients. Current therapeutic strategies primarily focus on restoring CFTR function, blocking epithelial sodium channels to prevent mucus dehydration, or directly targeting mucus to reduce its viscosity. Among the ion channels expressed in ciliated bronchial epithelial cells, the transient receptor potential vanilloid 4 (TRPV4) channel emerges as a significant channel in CF pathogenesis. Activation of TRPV4 channels affects the regulation of airway surface liquid by modulating sodium absorption and intracellular calcium levels, which indirectly influences CFTR activity. TRPV4 is also involved in the regulatory volume decrease (RVD) process and enhances inflammatory responses in CF patients. Here, we combine current findings on TRPV4 channel modulation as a promising therapeutic approach for CF. Although limited studies have directly explored TRPV4 in CF, emerging evidence indicates that TRPV4 activation can significantly impact key pathological processes in the disease. Further investigation into TRPV4 modulators could lead to innovative treatments that alleviate severe respiratory complications and improve outcomes for CF patients.

PMID:39408877 | DOI:10.3390/ijms251910551

Int J Mol Sci. 2024 Sep 27;25(19):10424. doi: 10.3390/ijms251910424.

ABSTRACT

Complex alleles of the CFTR gene complicate the diagnosis of cystic fibrosis (CF), the classification of its pathogenic variants, affect the clinical picture of the disease and can affect the efficiency of targeted drugs. The total frequency of complex allele [L467F;F508del] in the Russian population of patients with CF is 0.74%, and in patients with the F508del/F508del genotype, its frequency reaches 8%. This article presents multi-faceted study of the complex allele [L467F;F508del] in a cohort of patients with genotypes [L467F;F508del]/class I (c.3532_3535dup, c.1766+2T>C, W1310X, 712-1G>T), and data for a unique patient with the genotype [L467F;F508del]/[L467F;F508del]. Using the intestinal current measurement method, it was demonstrated the absence of CFTR function for [L467F;F508del]/class I and [L467F;F508del]/[L467F;F508del] genotypes. In intestinal organoids, it was shown that [L467F;F508del] in combination with class I variants and in the homozygotes abolishes the efficacy of both two-component (ivacaftor+lumacaftor; ivacaftor+tezacaftor) and three-component (ivacaftor+tezacaftor+elexacaftor) targeted drugs. When prescribing ivacaftor+tezacaftor+elexacaftor to three patients, they did not have a clinical effect after 6-12 months.

PMID:39408749 | DOI:10.3390/ijms251910424

Int J Mol Sci. 2024 Sep 26;25(19):10360. doi: 10.3390/ijms251910360.

ABSTRACT

The triple combination therapy for cystic fibrosis (CF), including elexacaftor, tezacaftor and ivacaftor (ETI or Trikafta), has been shown to improve lung function and reduce pulmonary exacerbations, thereby enhancing the quality of life for most CF patients. Recent findings suggest that both the individual components and ETI may have potential off-target effects, highlighting the need to understand how these modulators impact cellular physiology, particularly in cells that do not express CF transmembrane conductance regulator (CFTR). We used HEK293 cells, as a cell model not expressing the CFTR protein, to evaluate the effect of ETI and each of its components on autophagic machinery and on the Rab5/7 components of the Rab pathway. We firstly demonstrate that the single modulators Teza and Iva, and the combinations ET and ETI, increased ROS production in the absence of their target while decreasing it in cells expressing the CFTR ∆F508del. This increase in cellular stress was followed by an increase in the total level of polyubiquitinated proteins as well as the p62 level and LC3II/LC3I ratio. Furthermore, we found that ETI had the opposite effect on Rabs by increasing Rab5 levels while decreasing Rab7. Interestingly, these changes were abolished by the expression of mutated CFTR. Overall, our data suggest that in the absence of their target, both the individual modulators and ETI increased ROS production and halted both autophagic flux and plasma membrane protein recycling.

PMID:39408688 | DOI:10.3390/ijms251910360

Int J Mol Sci. 2024 Sep 24;25(19):10234. doi: 10.3390/ijms251910234.

ABSTRACT

Respiratory diseases (RDs) constitute a common public health problem both in industrialized and developing countries. The comprehension of the pathophysiological mechanisms underlying these conditions and the development of new therapeutic strategies are critical for improving the quality of life of affected patients. β2-adrenergic receptor (β2AR) and transient receptor potential vanilloid 1 (TRPV1) are both involved in physiological responses in the airways. β2AR is implicated in bronchodilation, mucociliary clearance, and anti-inflammatory effects, while TRPV1 is involved in the mediation of pain and cough reflexes. In RDs, such as respiratory infections, asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, the concentration and expression of these receptors can be altered, leading to significant consequences. In this review, we provided an update on the literature about the role of β2AR and TRPV1 in these conditions. We reported how the diminished or defective expression of β2AR during viral infections or prolonged therapy with β2-agonists can increase the severity of these pathologies and impact the prognosis. Conversely, the role of TRPV1 was pivotal in neuroinflammation, and its modulation could lead to innovative treatment strategies in specific patients. We indicate future perspectives and potential personalized treatments in RDs through a comprehensive analysis of the roles of these receptors in the physiological and pathological mechanisms of these pathologies.

PMID:39408565 | DOI:10.3390/ijms251910234

Nutrients. 2024 Sep 28;16(19):3293. doi: 10.3390/nu16193293.

ABSTRACT

Background: The combination of elexacaftor-tezacaftor-ivacaftor modulators (ETI) has improved clinical outcomes for people with cystic fibrosis (pwCF). Objectives: This study aimed to evaluate changes in nutritional and morphofunctional assessments, as well as anxiety, depression symptoms, and quality of life, in pwCF after starting ETI therapy. Methods: This was a prospective observational study. We measured body composition (fat mass [FM] and fat-free mass [FFM]) using bioelectrical impedance analysis (BIA) and skinfold thickness measurements (SMs). We also assessed hand grip strength, dietary intake via surveys, blood and stool biomarkers, symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale [HADS], and quality of life through the Cystic Fibrosis Questionnaire-Revised (CFQR). Results: A total of 31 pwCF were evaluated. Significant improvements were observed in respiratory function and quality of life, alongside an average weight increase of approximately 5 kg (60% FM and 40% FFM). The prevalence of malnutrition, based on BMI and the FFM index, decreased significantly, while the rate of overweight/obesity increased. Biomarker analysis indicated better nutrient absorption and reduced intestinal inflammation, as evidenced by significant changes in faecal calprotectin, nitrogen, and fat levels, as well as blood lipid and vitamin profiles. Conclusions: Despite a reduction in caloric intake, an increase in weight was observed one year after initiating ETI. This increase was attributed to gains in both FM and FFM, suggesting improved metabolic efficiency and nutrient absorption. Both SM and BIA were found to be useful assessment tools. These findings indicate the need to modify the nutritional approach, focusing on the quality rather than the quantity of intake, and aiming for an appropriate body composition (FFM) rather than solely focusing on BMI.

PMID:39408260 | DOI:10.3390/nu16193293

J Clin Med. 2024 Oct 7;13(19):5961. doi: 10.3390/jcm13195961.

ABSTRACT

Background: Cystic fibrosis bone disease (CFBD) is a common comorbidity in adult people with cystic fibrosis (pwCF), resulting in an increased risk of bone fractures. This study evaluated the capacity of artificial intelligence (AI)-assisted low-dose chest CT (LDCT) opportunistic screening for detecting low bone mineral density (BMD) in adult pwCF. Methods: In this retrospective single-center study, 65 adult pwCF (mean age 30.1 ± 7.5 years) underwent dual-energy X-ray absorptiometry (DXA) of the lumbar vertebrae L1 to L4 to determine BMD and corresponding z-scores and completed LDCTs of the chest within three months as part of routine clinical care. A fully automated CT-based AI algorithm measured the attenuation values (Hounsfield units [HU]) of the thoracic vertebrae Th9-Th12 and first lumbar vertebra L1. The ability of the algorithm to diagnose CFBD was assessed using receiver operating characteristic (ROC) curves. Results: HU values of Th9 to L1 and DXA-derived BMD and the corresponding z-scores of L1 to L4 showed a strong correlation (all p < 0.05). The area under the curve (AUC) for diagnosing low BMD was highest for L1 (0.796; p = 0.001) and Th11 (0.835; p < 0.001), resulting in a specificity of 84.9% at a sensitivity level of 75%. The HU threshold values for distinguishing normal from low BMD were <197 (L1) and <212 (Th11), respectively. Conclusions: Routine LDCT of the chest with the fully automated AI-guided determination of thoracic and lumbar vertebral attenuation values is a valuable tool for predicting low BMD in adult pwCF, with the best results for Th11 and L1. However, further studies are required to define clear threshold values.

PMID:39408020 | DOI:10.3390/jcm13195961

J Clin Med. 2024 Sep 28;13(19):5806. doi: 10.3390/jcm13195806.

ABSTRACT

The aim of this article is to identify and illustrate the most used psychological techniques in the field of cystic fibrosis (CF) and to help clinicians choose the most appropriate strategy among various possibilities. The disease and its medical treatments can be difficult to tolerate and can cause anxiety about health status or feelings of hopelessness and stress. The prevalence of depression and anxiety is 2.3 times higher in adults with CF than in community samples. A strong correlation has been identified between elevated psychological distress and unfavorable health outcomes, including, among others, impaired lung function, reduced BMI, an increased incidence of pulmonary exacerbations, and an elevated risk of transplantation. The use of psychological interventions is useful in addressing these common distresses in CF patients. Aware of the necessity of identifying efficacious interventions for all levels of depression and anxiety in CF patients, this study presents an overview of the research on psychological interventions for patients with CF, in order to complement the treatments suggested by the international guidelines on mental health in CF cases. In fact, the aim of this study is to conduct a review and quantitative synthesis of the psychological intervention techniques that are currently available for individuals with CF.

PMID:39407865 | DOI:10.3390/jcm13195806

Results Probl Cell Differ. 2024;74:239-256. doi: 10.1007/978-3-031-65944-7_9.

ABSTRACT

Our understanding of the origin, phenotype, and function of pulmonary macrophages has evolved over recent years. The use of lineage tracing and single-cell RNA sequencing has led to a greater understanding of how these cells regulate homeostasis in the lung. The primary function of alveolar macrophages is to clear any inhaled particles or pathogens and they as well as tissue-resident cells also play a role in the clearance of apoptotic cells and the resolution of inflammation. Lung diseases affect over half a billion people globally and are attributable to 7% of all deaths each year. The common diseases are chronic obstructive pulmonary disease (COPD) and asthma but others that contribute to this statistic include cystic fibrosis and idiopathic pulmonary fibrosis (IPF). Macrophages are aberrant in all these diseases with a reduced phagocytic capacity and a high proinflammatory phenotype with changes to their capacity to resolve inflammation. The pathways leading to these macrophage dysfunctions differ with disease and may relate to the specific lung environment in each condition. However, there are clear changes in metabolic profiles and mitochondrial activity in many of these conditions that contribute to a change in macrophage phenotype towards a more proinflammatory, less homeostatic cell. Understanding the mechanisms that drive these changes will allow for more targeted therapies for the treatment of these long-term and debilitating conditions.

PMID:39406908 | DOI:10.1007/978-3-031-65944-7_9

J Cyst Fibros. 2024 Oct 14:S1569-1993(24)01788-0. doi: 10.1016/j.jcf.2024.09.020. Online ahead of print.

ABSTRACT

BACKGROUND: A highly effective therapy involving elexacaftor, tezacaftor, and ivacaftor (ETI) for cystic fibrosis (CF) patients has recently raised safety concerns regarding potential psychiatric disorders. The manuscript reports cases of suicide attempts in patients receiving ETI and investigates putative causality using the WHO spontaneous reporting database.

METHODS: First, four cases of suicide attempts/self-injury are described. Second, a disproportionality analysis was conducted using spontaneous reports collected in Vigibase through the standardised MedDRA Query (narrow version) "Suicide/Self-injury" and ETI exposure. Reporting Odds Ratio (ROR) was calculated for the main and subgroup (i/suicide attempt, ii/suicidal ideation) analyses. Sensitivity analyses were performed with variations in exposure, to ivacaftor/lumacaftor to assess the intrinsic psychiatric risk of CF patients, and paracetamol as a positive control for suicide attempt and a negative one for suicidal ideation. Exposure to reduced-dose ETI was studied to evaluate the dose-gradient effect.

RESULTS: Four cases of suicide attempt/self-injury occurred 3 to 13 months after ETI initiation in CF patients and were reported to the Bordeaux Pharmacovigilance centre. Aside, in Vigibase, ETI is associated with an increased likelihood of reporting suicidal behaviour (ROR 2.5, 95 % CI[2.1; 2.8]). A signal of disproportionate reporting was found for the subgroup of suicide attempts (1.4, 95 % CI[1.2; 1.8]), unlike ivacaftor/lumacaftor, which was associated only with the risk of reporting suicidal ideation. Significant ROR values were also found for reduced-dose ETI for all psychiatric effects studied except suicide attempt.

CONCLUSIONS: ETI exposure is related with increased reporting of suicidal behaviour. A potential dose-dependent effect merits further investigation.

PMID:39406576 | DOI:10.1016/j.jcf.2024.09.020

J Cyst Fibros. 2024 Oct 14:S1569-1993(24)01712-0. doi: 10.1016/j.jcf.2024.09.004. Online ahead of print.

ABSTRACT

BACKGROUND: It is difficult to determine CFTR activity following highly effective CFTR modulator therapies (HEMT). The sweat gland provides two biomarkers of CFTR activity: a linear readout via the β-sweat rate and a logarithmic readout via sweat chloride concentration (SCC). In prior work, different logarithmic functions were generated to calibrate SCC with the percent of healthy control CFTR activity (HCCFTR). Two functions, A and B, were fit to SCC means from healthy controls set = 100 % and CF carriers measured as 50 % HCCFTR. A and B differ in the % HCCFTR activity assigned to SCC for minimal function mutations = 0.01 % for A and 1 % for B.

METHODS: Here, the functions are evaluated based on retrospective analysis of three multi-center studies of CF subjects with one or two F508del mutations treated with Elexacaftor/Tezacaftor/Ivacaftor (ETI). Predictions of the percent HCCFTR activity for one vs two mutations were compared for the two functions. The expectation is that after ETI treatment, subjects with two responsive mutations will have 2-fold higher HCCFTR activity than subjects with only one. The hypothesis is that the SCCHCCFTR function that most closely fits that expectation provides the more accurate prediction of CFTR activity.

RESULTS: In two separate comparisons, function B most accurately predicted a 2-fold (1.9, 2.3-fold) higher level of HCCFTR activity in subjects on ETI with two vs. one responsive mutation. Function A predicted a 4, 5.5-fold higher level.

CONCLUSIONS: Function B predicts that 60 mmol/L SCC, the cutoff for a CF diagnosis, is associated with 10 % HCCFTR activity. Comparing HEMT effects on subjects with one or two mutations provides an additional tool for calibrating SCC to CFTR activity.

PMID:39406575 | DOI:10.1016/j.jcf.2024.09.004