J Microbiol. 2024 Nov 18. doi: 10.1007/s12275-024-00185-2. Online ahead of print.

ABSTRACT

The increasing prevalence of multidrug-resistant bacteria imminently threatens public health and jeopardizes nearly all aspects of modern medicine. The Burkholderia cepacia complex (Bcc) comprises Burkholderia cepacia and the related species of Gram-negative bacteria. Members of the Bcc group are opportunistic pathogens responsible for various chronic illnesses, including cystic fibrosis and chronic granulomatous disease. Phage therapy is emerging as a potential solution to combat the antimicrobial resistance crisis. In this study, a temperate phage vB_BceM_CEP1 was isolated from sewage and fully characterized. Transmission electron microscopy indicated that vB_BceM_CEP1 belongs to the family Peduoviridae. The isolated phage demonstrated enhanced environmental stability and antibiofilm potential. One-step growth analysis revealed a latent period of 30 min and an average burst size of 139 plaque-forming units per cell. The genome of vB_BceM_CEP1 consists of 32,486 bp with a GC content of 62.05%. A total of 40 open reading frames were annotated in the phage genome, and none of the predicted genes was annotated as tRNA. Notably, genes associated with antibiotic resistance, host virulence factors, and toxins were absent from the vB_BceM_CEP1 genome. Based on its unique phenotype and phylogeny, the isolated phage vB_BceM_CEP1 is classified as a new temperate phage with lytic activity. The findings of this study enhance our understanding of the diversity of Bcc phages.

PMID:39557803 | DOI:10.1007/s12275-024-00185-2

Contemp Clin Trials. 2024 Nov 16:107752. doi: 10.1016/j.cct.2024.107752. Online ahead of print.

ABSTRACT

BACKGROUND: As people with cystic fibrosis (pwCF) live longer due to the breakthrough drug elexacaftor-tezacaftor-ivacaftor (ETI), they have questioned whether other CF therapies could be safely discontinued. SIMPLIFY was the first prospective, randomized trial to evaluate non-inferiority of discontinuing versus continuing two therapies. The QUEST (Qualitative Understanding of Experiences in the SIMPLIFY Trial) study was conducted to understand experiences of pwCF enrolled in SIMPLIFY, including why they joined, perceptions of randomization, decision-making around study withdrawal, and considerations for future discontinuation studies.

METHODS: QUEST enrolled SIMPLIFY participants 14 years or older stable on ETI and caregivers of the 14-17 year-olds. Interviews were audio-recorded, transcribed, and coded. A phenomenological approach was used to inductively develop codes with no a priori hypotheses; identified themes were then organized around current research and recruitment literature.

RESULTS: 114 interviews were completed (68 adults, 23 teenagers, and 23 caregivers). Among pwCF, median age was 27.8 years, 49 % were female and 80 % had participated in research before SIMPLIFY. Five themes were identified: ((Gul and Ali, 2010 [1]) Experience with SIMPLIFY randomization, CFF Patient Registry Annual Data Report [Internet] (2017) [2] Trust, CFF Patient Registry Annual Data Report [Internet] (2022) [3] Altruism, Goss et al. (2008) [4] Perceived personal benefits, and (Goss et al., 2002 [5]) Perceived risks and protocol burden.

CONCLUSION: QUEST findings highlight how a long-standing culture of research and thoughtful protocol design contributed to SIMPLIFY's successful recruitment and retention. This included understanding the importance of remaining in the trial despite not being randomized to their preferred treatment assignment. Using patient-centered approaches to select research questions, design a protocol to minimize participant barriers, and frame recruitment materials messaging contribute to successful research participation.

PMID:39557157 | DOI:10.1016/j.cct.2024.107752

Crit Rev Microbiol. 2024 Nov 18:1-19. doi: 10.1080/1040841X.2024.2429599. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa, able to survive on the surfaces of medical devices, is a life-threatening pathogen that mainly leads to nosocomial infection especially in immunodeficient and cystic fibrosis (CF) patients. The antibiotic resistance in P. aeruginosa has become a world-concerning problem, which results in reduced and ineffective therapy efficacy. Besides intrinsic properties to decrease the intracellular content and activity of antibiotics, P. aeruginosa develops acquired resistance by gene mutation and acquisition, as well as adaptive resistance under specific situations. With in-depth research on drug resistance mechanisms and the development of biotechnology, innovative strategies have emerged and yielded benefits such as screening for new antibiotics based on artificial intelligence technology, utilizing drugs synergistically, optimizing administration, and developing biological therapy. This review summarizes the recent advances in the mechanisms of antibiotic resistance and emerging treatments for combating resistance, aiming to provide a reference for the development of therapy against drug-resistant P. aeruginosa.

PMID:39556143 | DOI:10.1080/1040841X.2024.2429599

Pediatr Pulmonol. 2024 Nov 18. doi: 10.1002/ppul.27400. Online ahead of print.

ABSTRACT

OBJECTIVE: This retrospective study aimed to analyze the clinical characteristics, ventilatory strategies, and effectiveness of ventilation in pediatric patients with central apneas treated at the Sleep Medicine and Long-Term Ventilation Unit of the Bambino Gesù Children's Hospital in Rome from 2012 to 2022.

METHODS: Among all ventilated patients at our Center from January 2012 to December 2022, we retrospectively included children with a cAHI ≥ 1 events/h on baseline poly(somno)graphic study. Additional parameters assessed included the underlying disease, type of ventilation (non-invasive vs. invasive), age at ventilation onset, ventilation mode, and transcutaneous capnometry parameters. To assess the effectiveness of ventilation on central apneas, we compared the cAHI at baseline and on ventilation.

RESULTS: Sixty-seven patients met the inclusion criteria for central apnea (cAHI > 1 events/h). Diagnoses included hypoxic-ischemic encephalopathy, 15 (22.4%); Ondine syndrome, 14 (20.9%); polymalformative syndrome, 10 (14.9%); Prader-Willi syndrome, 8 (11.9%); brain tumor, 6 (9.0%); Down syndrome, 4 (6.0%); ROHHAD syndrome, 2 (3.0%); other infrequent pathologies were, Arnold-Chiari II, primary central apnea, epilepsy, lisosomal diseases, hydrocephalus, myopathy, obesity, Rett Syndrome. Pressure-supported ventilation (PSV) was the most common mode used (45 out 67 patients, 67.2%), followed by pressure-controlled ventilation (PCV) (15 out 67 patients, 22.4%) and continuous positive airway pressure (CPAP) (7 out 67 patients, 10.4%). Statistically significant improvement (p < 0.05) in cAHI was observed in patients with polymalformative syndrome (3.5 vs. 0.3, p = 0.01), hypoxic-ischemic encephalopathy (3.1 vs. 0.1, p = < 0.01), and Prader-Willi syndrome (3.5 vs. 0.1, p = 0.03), while there was no significant improvementn in children with brain tumor (6.2 vs. 1.5, p = 0.21).

CONCLUSION: Central apneas are present in children with various underlying pathologies. Ventilatory strategies tailored to the specific diagnosis and severity of central apneas yield significant improvements in cAHI. PSV was the preferred ventilation mode in this study and there was notable effectiveness across different diagnostic categories. PCV was employed in most severe cases. CPAP was exclusively used in patients with predominantly obstructive sleep apneas.

PMID:39555711 | DOI:10.1002/ppul.27400

J Surg Case Rep. 2024 Nov 15;2024(11):rjae690. doi: 10.1093/jscr/rjae690. eCollection 2024 Nov.

ABSTRACT

This case report presents the treatment of a 36-year-old male patient with massive anal condyloma lata following lung transplantation due to cystic fibrosis. The patient, under long-term immunosuppressive therapy, developed extensive wart-like lesions around the anal canal. A modified circular hemorrhoidectomy with mucosal bridges was performed to excise the affected tissue while preserving functional integrity. The surgery, conducted under general anesthesia, successfully removed all lesions without complications. Postoperatively, the patient experienced no pain, bleeding, incontinence, or recurrence during follow-up. The preservation of mucosal bridges helped prevent common complications such as anal stenosis and mucosal ectropion. Histology confirmed the diagnosis of condyloma lata. This case underscores the effectiveness of circular hemorrhoidectomy, particularly in patients with circular anal canal lesions, and highlights the role of mucosal bridges in minimizing postoperative complications while ensuring complete lesion excision. This technique should be considered in similar cases of extensive anal lesions.

PMID:39554384 | PMC:PMC11567738 | DOI:10.1093/jscr/rjae690

Heliyon. 2024 Oct 29;10(21):e39935. doi: 10.1016/j.heliyon.2024.e39935. eCollection 2024 Nov 15.

ABSTRACT

BACKGROUND: Cystic fibrosis transmembrane conductance regulator metabolic syndrome/cystic fibrosis screen-positive, inconclusive diagnosis (CRMS/CFSPID) is a designation given following a positive newborn screen for cystic fibrosis (CF) when CF is not excluded but cannot be confirmed. We describe the long-term clinical outcomes of a CRMS/CFSPID cohort.

METHODS: A retrospective, single centre study of children with a current or previous diagnosis of CRMS/CFSPID. Study period extended from February 1, 2007 to August 1, 2022. Baseline and longitudinal data were assessed.

RESULTS: 30 children were designated as CRMS/CFSPID between 2007 and 2021. At baseline, 13 CFTR variants were identified, of which F508del and R117H 7T/9T were most common (occurring in 25 and 20 children respectively). Initial mean immunoreactive trypsinogen and sweat chloride were 82.8 mmol/L and 34.3 mmol/L respectively. During longitudinal assessment (n = 27), occurring over a mean duration of 8.5 years, five children progressed to CF at a mean age of 9.5 years. All children were pancreatic sufficient except one who reclassified to CF. Four isolated Pseudomonas aeruginosa and 12 isolated Staphylococcus aureus, of which one and two progressed to CF respectively. All recent Z-scores for weight and spirometry were above -2. Initial mean sweat chloride was higher in those who progressed to CF versus those who did not, although this did not reach statistical significance (38.4 mmol/L versus 32.0 mmol/L respectively, p = 0.105).

CONCLUSIONS: Most children with CRMS/CFSPID remained well with a low progression rate to CF. This supports a less intensive medical surveillance approach. Our results highlight the importance of assessment in a dedicated CRMS/CFSPID clinic during adolescence to detect progression to CF after 6 years of age.

PMID:39553608 | PMC:PMC11566679 | DOI:10.1016/j.heliyon.2024.e39935

J Thorac Dis. 2024 Oct 31;16(10):7155-7164. doi: 10.21037/jtd-24-832. Epub 2024 Oct 30.

ABSTRACT

BACKGROUND: The presence of free air in the pleural space of lungs is termed pneumothorax and in individuals with underlying lung disease, it is known as secondary spontaneous pneumothorax. The incidence of spontaneous pneumothorax is 16 to 18 per lakh population. The most common causes for secondary spontaneous pneumothorax are chronic obstructive pulmonary disease (COPD), tuberculosis (TB), human immunodeficiency virus (HIV), cystic fibrosis of lung, and history of smoking. The clinical signs and symptoms include acute dyspnea, thoracic pain and cough. Persistent air leaks are frequently seen in secondary spontaneous pneumothorax. The incidence of persistent air leaks in post-surgical patients varies from 8% to 43%. The aim of the study is to compare the efficacy of doxycycline, tetracycline, and minocycline to other pleurodesis agents in the cessation of air leaks and reducing the recurrence of pneumothorax in adults with persistent air leaks following secondary spontaneous pneumothorax.

METHODS: A systematic search from PubMed, Cochrane, Embase, Web of Science, and clinical trials.gov was performed. After screening, three studies were selected which includes 2 randomized controlled trials (RCTs) and 1 prospective study with a pooled sample size of 168.

RESULTS: The mean age and standard deviation of the study participants was 50.57±13.23 years. The success rate of autologous blood patch pleurodesis (ABPP) was reported as 94.70% followed by doxycycline with 84.20%, talc with 84% and tetracycline 63%. The mean time of cessation of air leaks was lowest with doxycycline (11 and 36 hours) and ABPP (24 and 27 hours). Furthermore, ABPP is reported having fewer complications when compared with other agents.

CONCLUSIONS: Among chemical pleurodesis agents, doxycycline is reported to be having higher success rate and less recurrences. However, it is found to be inferior when compared directly to ABPP.

PMID:39552893 | PMC:PMC11565308 | DOI:10.21037/jtd-24-832

Med J Aust. 2024 Nov 18. doi: 10.5694/mja2.52527. Online ahead of print.

NO ABSTRACT

PMID:39552247 | DOI:10.5694/mja2.52527

Magn Reson Med. 2024 Nov 17. doi: 10.1002/mrm.30367. Online ahead of print.

ABSTRACT

PURPOSE: To implement and validate an algorithm to determine the statistical errors in self-gated non-contrast-enhanced functional lung imaging.

METHODS: A bootstrapping residuals approach to determine the error in quantitative functional lung imaging is proposed. Precision and accuracy of the median error over the lungs, as well as reproducibility of the approach were investigated in 7 volunteers. The algorithm was additionally applied to data acquired in a patient with cystic fibrosis.

RESULTS: The obtained bootstrapping error maps appear comparable to the error maps determined from repeated measurements, and median absolute error values for both methods show comparable median errors when reducing the number of averages. In a volunteer in whom 10 consecutive measurements were carried out, the median functional parameters were ventilation = 0.22 mL gas/mL lung tissue, perfusion amplitude = 0.028, perfusion timing = -82 ms, whereas precision and accuracy of the median error were below 3.2 × 10-3 mL gas/mL lung for ventilation tissue, 4.4 × 10-4 for perfusion amplitude, and 11 ms for perfusion timing. In the measurement of the patient, low errors in areas with reduced ventilation support the assessment as real defects.

CONCLUSION: Using a bootstrapping residuals method, the error of functional lung MRI could be determined without the need for repeated measurements. The error values can be determined reproducibly and can be used as a future means of quality control for functional lung MRI.

PMID:39552181 | DOI:10.1002/mrm.30367

Cell Death Differ. 2024 Nov 16. doi: 10.1038/s41418-024-01410-6. Online ahead of print.

ABSTRACT

Acyl-CoA binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular checkpoint of autophagy. Here, we report that patients with histologically confirmed metabolic-associated steatohepatitis (MASH) or liver fibrosis exhibit elevated levels of circulating ACBP/DBI protein as compared to non-affected controls. Plasma ACBP/DBI strongly correlated with the NAFLD and FIB4 scores in patients, and these correlations were independent of age and body mass index. We studied the capacity of a monoclonal antibody (mAb) neutralizing mouse ACBP/DBI to combat active liver disease in several mouse models, in which steatohepatitis had been induced by four different protocols, namely, (i) methionine/choline-deficient diet, (ii) Western style diet (WD) alone, (iii) WD combined with the hepatotoxic agent CCl4, and (iv) a combination of CCl4 injections and oral ethanol challenge. Injections of anti-ACBP/DBI mAb attenuated histological, enzymological, metabolomic and transcriptomic signs of liver damage in these four models, hence halting or reducing the progression of non-alcoholic and alcoholic liver disease. Steatosis, inflammation, ballooning and fibrosis responded to ACBP/DBI inhibition at the preclinical level. Altogether, these findings support a causal role of ACBP/DBI in MASH and liver fibrosis, as well as the possibility to therapeutically target ACBP/DBI.

PMID:39550516 | DOI:10.1038/s41418-024-01410-6

Lancet Digit Health. 2024 Nov 14:S2589-7500(24)00198-5. doi: 10.1016/S2589-7500(24)00198-5. Online ahead of print.

ABSTRACT

Digital health technology (DHT) describes tools and devices that generate or process health data. The application of DHTs could improve the diagnosis, treatment, and surveillance of bacterial infection and the prevention of antimicrobial resistance (AMR). DHTs to optimise antimicrobial use are rapidly being developed. To support the global adoption of DHTs and the opportunities offered to optimise antimicrobial use consensus is needed on what data are required to support antimicrobial decision making. This Series paper will explore bacterial AMR in humans and the need to optimise antimicrobial use in response to this global threat. It will also describe state-of-the-art DHTs to optimise antimicrobial prescribing in high-income and low-income and middle-income countries, and consider what fundamental data are ideally required for and from such technologies to support optimised antimicrobial use.

PMID:39547912 | DOI:10.1016/S2589-7500(24)00198-5

Metabolism. 2024 Nov 13:156064. doi: 10.1016/j.metabol.2024.156064. Online ahead of print.

ABSTRACT

PCSK9 is a serine protease that regulates plasma levels of low-density lipoprotein (LDL) and cholesterol by mediating the endolysosomal degradation of LDL receptor (LDLR) in the liver. When PCSK9 functions unchecked, it leads to increased degradation of LDLR, resulting in elevated circulatory levels of LDL and cholesterol. This dysregulation contributes to lipid and cholesterol metabolism abnormalities, foam cell formation, and the development of various diseases, including cardiovascular disease (CVD), viral infections, cancer, and sepsis. Emerging clinical and experimental evidence highlights an imperative role for PCSK9 in metabolic anomalies such as hypercholesterolemia and hyperlipidemia, as well as inflammation, and disturbances in mitochondrial homeostasis. Moreover, metabolic hormones - including insulin, glucagon, adipokines, natriuretic peptides, and sex steroids - regulate the expression and circulatory levels of PCSK9, thus influencing cardiovascular and metabolic functions. In this comprehensive review, we aim to elucidate the regulatory role of PCSK9 in lipid and cholesterol metabolism, pathophysiology of diseases such as CVD, infections, cancer, and sepsis, as well as its pharmaceutical and non-pharmaceutical targeting for therapeutic management of these conditions.

PMID:39547595 | DOI:10.1016/j.metabol.2024.156064

PLoS One. 2024 Nov 15;19(11):e0309907. doi: 10.1371/journal.pone.0309907. eCollection 2024.

ABSTRACT

OBJECTIVE: Hypoglycemia is a major concern in type 2 diabetes (T2DM), but little is known about its likelihood compared across common therapies. We compared the likelihood of hypoglycemia among metformin-treated patients with T2DM randomized to the addition of one of 4 common therapies.

RESEARCH DESIGN & METHODS: Randomized, controlled trial of 5,047 participants with T2DM of <10 years' duration, hemoglobin A1c (HbA1c) 6.8-8.5% (50.8-69.4 mmol/mol). Randomization to addition of glargine U100, glimepiride, liraglutide, or sitagliptin over 5.0 ± 1.3 (mean ± SD) years. HbA1c was measured quarterly; if a level >7.5% (>58.5 mmol/mol) was confirmed, rescue glargine and/or aspart insulin was added. We conducted a per-protocol analysis of 4,830, who attended at least one post-baseline visit and took at least one dose of assigned study medication. We assessed severe hypoglycemia events reported throughout the entire study. At quarterly visits, all participants were asked about hypoglycemic symptoms within the last 30 days, and those in the glargine and glimepiride groups were asked for any measured glucose <70 mg/dL (3.9 mmol/L) within this time period.

RESULTS: While participants were taking their assigned medications, severe hypoglycemia occurred in 10 (0.8%), 16 (1.3%), 6 (0.5%), and 4 (0.3%), (p<0.05) and hypoglycemic symptoms in 659 (54.2%), 833 (68.3%), 375 (32.4%), and 361 (29.1%) of participants following randomization to glargine, glimepiride, liraglutide, and sitagliptin, respectively (p<0.001).

CONCLUSIONS: In metformin-treated patients with T2DM who add a second medication, hypoglycemia is most likely with addition of glimepiride, less with glargine, and least likely with liraglutide and sitagliptin.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01794143.

PMID:39546502 | DOI:10.1371/journal.pone.0309907

Pediatr Pulmonol. 2024 Nov 15:e27406. doi: 10.1002/ppul.27406. Online ahead of print.

NO ABSTRACT

PMID:39545636 | DOI:10.1002/ppul.27406

Rev Med Liege. 2024 Nov;79(11):716-718.

ABSTRACT

The chloride (Cl-) sweat test remains the reference test in the diagnosis of cystic fibrosis, allowing direct assessment of CFTR (Cystic Fibrosis Transmembrane conductance Regulator) channel function. Under highly effective modulators such as the combination of Elexacaftor, Tezacaftor and Ivacaftor (ETI), the Cl- level in sweat significantly improves, as shown in our cohort of patients when ETI was introduced. In addition to its role in the diagnosis of the disease, the sweat test is also important for individual clinical trials (n-of-1) in patients not eligible for ETI and for newborn screening for cystic fibrosis.

PMID:39545532

J Antimicrob Chemother. 2024 Nov 15:dkae381. doi: 10.1093/jac/dkae381. Online ahead of print.

ABSTRACT

BACKGROUND: Scedosporium/Lomentospora species are ranked as the second most frequently isolated filamentous fungi from cystic fibrosis (CF) patients. Previously, we demonstrated that the minimum inhibitory concentration (MIC) for voriconazole and posaconazole increased when performed on a mucin-containing synthetic CF sputum medium (SCFM) compared to the standard medium, RPMI-1640. In this study, we have expanded the MIC comparison to four additional azoles and investigated characteristics linked to azole resistance in Scedosporium apiospermum, Scedosporium minutisporum, Scedosporium aurantiacum and Lomentospora prolificans.

METHODS: MIC was assayed by CLSI protocol, efflux pump activity was assessed by rhodamine 6G and sterols were analysed by gas chromatography-mass spectrometry (GC-MS).

RESULTS: Overall, MICs for fluconazole, itraconazole, voriconazole, posaconazole, miconazole and ketoconazole increased by least 2-fold when susceptibility tests were performed using SCFM compared to RPMI. The activity of efflux pumps was similar in both media; however, in RPMI, but not in SCFM, the activity was induced by voriconazole and fluconazole. Additionally, MICs for those antifungals decreased more noticeably in SCFM than in RPMI in the presence of the efflux pump inhibitor PaβN. The SCFM-grown cells presented fewer sterols in their composition, and consequently higher membrane fluidity, than RPMI-grown cells. GC-MS analysis demonstrated a remodulation in the sterol profile in SCFM- compared to RPMI-grown cells. Accordingly, when the MIC assay was performed in the presence of the membrane stressor NaCl (3%), the susceptibility to voriconazole and fluconazole increased more in SCFM- than RPMI-grown cells.

CONCLUSIONS: Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.

PMID:39545480 | DOI:10.1093/jac/dkae381

Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241297877. doi: 10.1177/17534666241297877.

ABSTRACT

Cystic fibrosis (CF) causes life-shortening respiratory and systemic disease due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Highly effective modulator therapies (HEMT) improve the lives of many people with cystic fibrosis (PwCF) by correcting the structure and function of the defective CFTR channel at the molecular level. Despite these advancements, a subset of patients-termed modulator-refractory CF-continues to experience two or more pulmonary exacerbations per year requiring hospitalization or intravenous antibiotics, regardless of other modulator benefits. This underrecognized group represents an emerging challenge within the CF community. We discuss the benefits and limitations of current CFTR modulator therapies and the urgent need to investigate this emerging at-risk population. While HEMT improves lung function, decreases exacerbations, reduces the need for lung transplantation, and lowers mortality, increasing evidence shows that not all patients benefit equally. At the University of Virginia, nearly 6% of adults with CF exhibit the modulator-refractory phenotype. The driving factors of modulator-refractory CF are likely multifactorial, including genetic variations, variable immune responses, preexisting bronchiectasis, microbiological colonization, preexisting comorbid conditions, and environmental and socioeconomic factors. This perspective review recognizes and defines modulator-refractory CF as a distinct emerging clinical phenotype in the post-modulator era. Understanding this phenotype is crucial for reducing morbidity and mortality, and for improving the quality of life for PwCF. Raising awareness of modulator-refractory CF will help the community address this population and perform further research to identify causes. The emergence of modulator-refractory CF highlights a significant gap in our current treatment landscape and provides an opportunity to develop innovative therapeutic strategies that may benefit the entire CF community, ensuring that no person with CF is left behind.

PMID:39543951 | DOI:10.1177/17534666241297877

Expert Opin Pharmacother. 2024 Nov 14:1-10. doi: 10.1080/14656566.2024.2426677. Online ahead of print.

ABSTRACT

INTRODUCTION: Mutation-specific disease modifying drugs such as the triple combination Elexacaftor/Tezacaftor/Ivacaftor (ETI), are associated with significant improvements in physical health. Reproductive health and a pursuit of parenthood are of increased relevance; a dramatic increase in childbirth rates for females with CF has already been observed.

AREAS COVERED: Fertility in males and females with CF, and any subsequent impact of CFTR modulator therapy, is reviewed. The potential impacts of maternal use of CFTR modulator drugs on offspring health are considered, as constituent components have been found in fetal circulation in animals and humans, and the implications for maternal continuation or cessation of treatment. Clinical data are reassuring, although cases of lens opacities, and missed CF diagnoses due to false negative newborn screening results have been reported.

EXPERT OPINION: More research and high-quality evidence are needed to characterize maternal, fetal and long-term offspring outcomes following CFTR modulator therapy use during pregnancy and breastfeeding. There is a potential therapeutic impact of targeting CFTR-related organ dysfunction in CF-fetuses via maternal-administration of CFTR modulators. Additionally, any consequences of CFTR-modulation in heterozygote carrier infant warrants urgent and collective consensus regarding ethical and clinical research programs to evaluate this discrete population.

PMID:39543810 | DOI:10.1080/14656566.2024.2426677

Exp Lung Res. 2024;50(1):208-220. doi: 10.1080/01902148.2024.2424201. Epub 2024 Nov 14.

ABSTRACT

Recent advances in cystic fibrosis (CF) treatments have led to improved survival, with life expectancy for Australians living with CF at 57yo. As life expectancy improves, long-term cardiovascular disease risk factors (as for the general population) will become an issue in these patients. We hypothesized that increased leukocyte expression of vasoconstriction and pro-fibrotic mediators may contribute to CF severity in adults with CF. We recruited 13 adult and 24 pediatric healthy controls, and 53 adults and 9 children living with CF. Leukocyte expression/release of endothelin-1 (ET1) and members of the TGF-β/Smad signaling were measured by multifluorescence quantitative confocal microscopy, Western blotting, ELISA, and real-time quantitative polymerase chain reaction. The association between plasma ET1 levels and lung function was assessed. Leukocytes from adults living with CF expressed higher ET1 levels (p = 0.0033), and TGF-β (p = 0.0031); the phosphorylation ratio increased for Smad2/3 (p = 0.0136) but decreased for Smad1/5/8 (p = 0.0007), vs. control subjects. Plasma ET1 levels were significantly increased in adults with CF with FEV1<50% (p = 0.002) vs. controls, and adults with CF with normal lung function. The release of ET1 in adult plasma inversely correlated with CF severity (-0.609, p = 0.046). Our data indicates that upregulated ET1 and TGF-β/Smad signaling in leukocytes may contribute to CF severity, highlighting the need for further investigations into their impact on the clinical outcomes of people living with CF.

PMID:39543807 | DOI:10.1080/01902148.2024.2424201

Eur Respir J. 2024 Nov 14;64(5):2401898. doi: 10.1183/13993003.01898-2024. Print 2024 Nov.

NO ABSTRACT

PMID:39542511 | DOI:10.1183/13993003.01898-2024