Microbiol Spectr. 2024 Dec 23:e0241524. doi: 10.1128/spectrum.02415-24. Online ahead of print.

ABSTRACT

Mycobacterium abscessus (Mabs) is commonly found in the cystic fibrosis (CF) lung. During infection, Mabs can form biofilms in the lung which reduce both the ability of the immune response to clear infection and the effectiveness of antibiotic therapy. In the CF lung, heme and hemoglobin levels are increased and may provide both iron and heme to Mabs cells. In this work, we show that exogenous heme altered Mabs biofilm formation and measured the effects of exogenous heme on protein level and metabolism in Mabs. Our findings suggest that heme impacts iron homeostasis in Mabs and affects other aspects of its metabolism, highlighting the potential role of heme as a critical nutrient for Mabs growth and biofilm formation.IMPORTANCEMycobacterium abscessus (Mabs) is commonly found in the cystic fibrosis (CF) lung, where Mabs can form biofilms that can reduce the efficacy of antibiotics. During infection, the CF lung can have more than 10 times the extracellular heme than that of a healthy lung. We have found that extracellular heme can change the way Mabs cells grow and form biofilms, which may have implications for pathogenesis.

PMID:39705014 | DOI:10.1128/spectrum.02415-24

Microbiol Resour Announc. 2024 Dec 20:e0103024. doi: 10.1128/mra.01030-24. Online ahead of print.

ABSTRACT

We present lung virome data recovered through shotgun metagenomics in bronchoalveolar lavage fluid from an infant with cystic fibrosis, who tested positive for Stenotrophomonas maltophilia infection. Using a bioinformatic pipeline for virus characterization in shotgun metagenomic data, we identified five viral contigs representing Pseudomonas phages classified as Caudoviricetes.

PMID:39704517 | DOI:10.1128/mra.01030-24

Pediatr Pulmonol. 2024 Dec 20:e27449. doi: 10.1002/ppul.27449. Online ahead of print.

ABSTRACT

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) was universally implemented in the United States in 2010 to improve disease outcomes. Despite universal screening, disparities in outcomes currently exist between people with CF (PwCF) with Black/African, Asian, Indigenous, and Latino/Hispanic ancestry in comparison to PwCF of European ancestry. This is in part because CFTR panels used for newborn screening are often based on variants common in European ancestries leading to higher rates of false negatives for PwCF from minoritized racial and ethnic groups.

METHODS: This study investigated how states evaluate and update their CFNBS algorithms through semi-structured interviews with professionals from four states with ethnically diverse populations and one national consultant. Interviews were transcribed verbatim and analyzed through inductive thematic analysis.

RESULTS: Five themes were identified encompassing facilitators, barriers, and motivations for evaluating and updating CF NBS algorithms. Facilitators of effective evaluation and updating of algorithms included effective communication with CF clinical centers and extensive support for CF as compared to other conditions. Although participants stated that their respective NBS programs were aware of the disparate impact of their CF panels on PwCF from minoritized racial and ethnic groups, motivations to decrease this disparity were hampered by a range of funding and logistical barriers, such as limited information about false negative cases and difficulties incorporating next generation sequencing technology.

CONCLUSIONS: This study shed light on the experiences of states considering alterations to their CFNBS panels, revealing several key barriers and facilitators to implementing equitable CFNBS algorithms.

PMID:39704065 | DOI:10.1002/ppul.27449

Pediatr Pulmonol. 2024 Dec 20:e27455. doi: 10.1002/ppul.27455. Online ahead of print.

ABSTRACT

Following the approval of elexacaftor/tezacaftor/ivacaftor (ETI), there have been post-marketing reports and published cases of papilledema and intracranial hypertension in children with cystic fibrosis (CF) taking ETI. In those reports, the patients often presented with marked symptoms and concomitant hypervitaminosis A. In this multicenter case series, we report eight cases of papilledema in children with CF taking ETI that were diagnosed via routine eye exam, the majority of whom presented with minimal to no symptoms and all had normal serum Vitamin A levels.

PMID:39704064 | DOI:10.1002/ppul.27455

Prenat Diagn. 2024 Dec 19. doi: 10.1002/pd.6719. Online ahead of print.

ABSTRACT

OBJECTIVE: To describe postnatal outcome following the prenatal diagnosis of an abnormal fetal gallbladder.

METHODS: We conducted a systematic review of studies from January 1980 to January 2023 that described FGB abnormalities, which included agenesis or non-visualisation, abnormal content presence of sludge, abnormal shape or size and abnormal position, and postnatal outcome to determine the association with pathology.

RESULTS: In 51 studies, 842 fetuses had abnormal FGB. Non-visualisation of the FGB was the most common diagnosis (521 fetuses, mean gestational age 21.6 weeks, range 14-29). The FGB was subsequently visualised prenatally in 128 out of 521 cases (24.6%; 95% CI, 20.9%-28.3%). Of the 393 cases with persistent FGB non-visualisation (75.4%; 95% CI, 71.7-79.1), 48 cases (12.2%; 95% CI, 9.0-15.5) underwent termination of pregnancy (TOP) with FGB agenesis confirmed in 16 out of 26 fetuses that had a postmortem examination (61.5%; 95% CI, 42.8-80.2). After excluding cases with missing outcomes (n = 121), postnatal ultrasound was performed in 82.4% of cases with persistent non-visualised FGB (224/272; 95% CI, 77.8%-86.9%). The gallbladder was not visualised in 63.4% (142/224; 95% CI, 57.1-69.7), confirming GB agenesis. This was an isolated finding in 41.1% of cases (92/224; 95% CI, 34.6-47.5). Of 272 known outcomes, biliary atresia, cystic fibrosis, and structural or chromosomal abnormalities were diagnosed in 8.5% (n = 23), 12.5% (n = 34), 18.0% (n = 49) and 6.3% (n = 17) cases, respectively. The sensitivity (true positive rate) of ultrasound for GB agenesis in fetuses with persistently non-visualised FGB was 58.1% (158/272; 95% CI, 52.2%-64.0%). Fetal gallbladder stones/sludge were described in 100 fetuses mainly in the third trimester of pregnancy (mean gestational age 33.8 weeks). Resolution of postnatally followed up cases occurred in around one-third of the cases (37.3%) within 1 month after birth. There was a low reported association with severe conditions (2%).

CONCLUSIONS: This systematic review and meta-analysis found that when the fetal gallbladder was absent in mid-trimester, it was visualised in subsequent fetal ultrasound examinations in around 25% of cases. If persistently absent on prenatal ultrasound, the confirmed rate of GB agenesis was around 50%, with the neonates having biliary atresia, cystic fibrosis, or structural abnormalities. Because of the association with severe conditions, if persistent FGB agenesis is suspected, prenatal diagnosis should be offered. FGB abnormalities such as stones/sludge tended to resolve by 1 year of age with around half of all cases resolving by 1 month postnatal.

PMID:39702857 | DOI:10.1002/pd.6719

AAPS PharmSciTech. 2024 Dec 19;26(1):17. doi: 10.1208/s12249-024-03010-6.

ABSTRACT

Over the past years, many significant advances have been made in the field of gene therapy and shown promising results in clinical trials conducted. Gene therapy aims at modifying or replacing a defective, inefficient, or nonfunctional gene with a healthy, functional gene by administration of genome material into the cell to cure genetic diseases. Various methods have been devised to do this by using several viral and non-viral vectors which are either administered by in vivo or ex vivo technique. Viral vectors are best suitable for this therapy due to their potential to invade cells and deliver their genetic material whereas non-viral vectors are less efficient than viral vectors but possess some advantages such as less immunogenic response and large gene carrying capacity. Recent advances in biotechnology such as CRISPR-Cas9 mediated genome engineering and Cancer treatment with Chimeric antigen receptor (CAR) T-cell therapy are addressed in this review. This review article also delves into some recent research studies, gene therapy trials, and its applications, laying out future hopes for gene therapy in the treatment of various diseases namely haemophilia, Muscular dystrophy, SCID, Sickle cell disease, Familial Hypercholesterolemia, Cystic Fibrosis. Additionally, it also includes various nanoformulations and clinical trial data related to gene therapy.

PMID:39702810 | DOI:10.1208/s12249-024-03010-6

Eur J Clin Microbiol Infect Dis. 2024 Dec 20. doi: 10.1007/s10096-024-05017-0. Online ahead of print.

ABSTRACT

PURPOSE: Achromobacter spp. may form biofilm in patients' respiratory tracts and cause serious infections. This research examined the bactericidal and synergistic effects of ceftazidime/avibactam (CZA) alone and in combination with different antibiotics against Achromobacter spp.

METHODS: MICs of 52 Achromobacter spp. were determined by broth microdilution. In-vitro time-kill curve experiments assessed CZA's bactericidal and synergistic properties alone and in combination with other antibiotics. Moreover, the antibiofilm activity of CZA alone or in combination with the antibiotics was assessed with using microplate method.

RESULTS: Based on MIC90 values, CZA exhibited four times greater in-vitro activity against tested strains than ceftazidime. The most effective agent was meropenem, with a 92% susceptibility level on the tested strains. On the other hand, ciprofloxacin was found to be bactericidal at both 1 × and 4xMIC concentrations. CZA, chloramphenicol and meropenem were observed to have bactericidal effects alone at 4xMIC concentrations against the tested isolates. CZA + CS and CZA + MEM showed synergy in three out of five and two out of five strains tested at 1xMIC, respectively. Furthermore, the pairing of CZA with colistin, CZA with meropenem and CZA with ciprofloxacin exhibited a synergistic impact at 4xMIC. Moreover, combination therapy CZA with the tested antibiotics showed reduced biofilm formation in a concentration-dependent manner at 24 h.

CONCLUSION: The outcomes of this research also suggest that CZA plus colistin, meropenem, or ciprofloxacin were more productive against Achromobacter strains. To our knowledge, this is the first article to evaluate the synergistic and antibiofilm activities of CZA alone or in combination with different agents against Achromobacter species.

PMID:39702543 | DOI:10.1007/s10096-024-05017-0

Respir Res. 2024 Dec 19;25(1):436. doi: 10.1186/s12931-024-03059-8.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) channel. For people with CF (pwCF) affected by the most common pathogenic variant F508del, a tritherapy, named Trikafta/Kaftrio (ETI: elexacaftor (VX-445) /tezacaftor (VX-661) / ivacaftor (VX-770)) was successfully developed. However, in CF airway epithelial cells the calcium homeostasis is also disturbed; it is observed an increased calcium mobilization in CF cells compared to non-CF cells. Here, we studied the effects of ETI on intracellular calcium levels in F508del-CFTR airway epithelial cells to determine whether these compounds, individually or collectively, could normalize intracellular calcium levels.

METHODS: We measured intracellular calcium variations using human airway epithelial cells (hAEC) from pwCF, human bronchial epithelial CFBE41o- F508del-CFTR cells and Chinese Hamster Ovary (CHO) cells using the fluorescent probe Fluo4-AM, in the presence or absence of extracellular calcium. The rescue to the plasma membrane of F508del-CFTR protein by ETI was determined by western blot. The SarcoEndoplasmic Reticulum Calcium ATPase (SERCA), was also analysed by western blotting and by interference assay.

RESULTS: We show that ETI normalizes calcium homeostasis in our cellular models. However, we also found that (1) each ETI-corrector compound is capable of mobilizing calcium acutely in the absence of CFTR, and (2) tezacaftor mobilizes calcium from the endoplasmic reticulum (ER) probably via inhibition of the SERCA pump.

CONCLUSIONS: We show that ETI not only corrects the abnormal trafficking and function of F508del-CFTR but also normalizes calcium homeostasis in our cellular models. Finally, we identified SERCA as a potential intracellular target for tezacaftor.

PMID:39702307 | DOI:10.1186/s12931-024-03059-8

Mol Cancer. 2024 Dec 20;23(1):275. doi: 10.1186/s12943-024-02189-3.

ABSTRACT

BACKGROUND: Immunogenic cell death (ICD) inducers are often identified in phenotypic screening campaigns by the release or surface exposure of various danger-associated molecular patterns (DAMPs) from malignant cells. This study aimed to streamline the identification of ICD inducers by leveraging cellular morphological correlates of ICD, specifically the condensation of nucleoli (CON).

METHODS: We applied artificial intelligence (AI)-based imaging analyses to Cell Paint-stained cells exposed to drug libraries, identifying CON as a marker for ICD. CON was characterized using SYTO 14 fluorescent staining and holotomographic microscopy, and visualized by AI-deconvoluted transmitted light microscopy. A neural network-based quantitative structure-activity relationship (QSAR) model was trained to link molecular descriptors of compounds to the CON phenotype, and the classifier was validated using an independent dataset from the NCI-curated mechanistic collection of anticancer agents.

RESULTS: CON strongly correlated with the inhibition of DNA-to-RNA transcription. Cytotoxic drugs that inhibit RNA synthesis without causing DNA damage were as effective as conventional cytotoxicants in inducing ICD, as demonstrated by DAMPs release/exposure and vaccination efficacy in mice. The QSAR classifier successfully predicted drugs with a high likelihood of inducing CON.

CONCLUSIONS: We developed AI-based algorithms for predicting CON-inducing drugs based on molecular descriptors and their validation using automated micrographs analysis, offering a new approach for screening ICD inducers with minimized adverse effects in cancer therapy.

PMID:39702289 | DOI:10.1186/s12943-024-02189-3

J Cyst Fibros. 2024 Dec 18:S1569-1993(24)01853-8. doi: 10.1016/j.jcf.2024.12.002. Online ahead of print.

NO ABSTRACT

PMID:39701903 | DOI:10.1016/j.jcf.2024.12.002

Ann Am Thorac Soc. 2024 Dec 19. doi: 10.1513/AnnalsATS.202404-446OC. Online ahead of print.

ABSTRACT

RATIONALE+OBJECTIVE/ Cystic fibrosis (CF) is characterized by bronchiectasis on imaging, while functionally evolving towards obstructive impairment. Despite its assumed importance in CF, small airway remodeling and its relation to bronchiectasis, is still poorly understood. METHOD/ On high-resolution computed tomography (HRCT, 600µm, CF=21, control=6) and micro-computed tomography (µCT, 150µm, CF=3, control=1) scans of inflated explant lungs, AV% (airway/total lung volume) was calculated as marker for bronchiectasis, while airway segmentation was used for generation analysis. Clinical data was retrospectively collected. On µCT (8.5µm) images of lung cores (±2.8cm³), extracted randomly from each lobe (3/lobe), distal airway (DA) diameter, number of airway collapses and open terminal bronchioles (oTB)/mL were analyzed. Morphometric analysis was supplemented with histological analysis of DA collapse. RESULTS/ AV% on HRCT was heterogeneous amongst CF lungs (0.7-4.6%), overlapping with controls (0.4-1.2%). However, the pattern of airway loss on µCT was homogeneous amongst CF lungs and most pronounced from generation 9-16. AV% did not correlate with the number of oTB/mL or FEV1%, which correlated with eachother. Open DA in CF were narrowed compared to DA in controls. On the other hand, collapsed DA in CF showed a varying degree of proximal dilation, with DA diameter correlating with AV%. On histology, collapsed CF DA showed constrictive bronchiolitis. CONCLUSION/ Airway remodeling in end-stage CF is heterogeneous, ranging from minimal bronchiectasis, overlapping with controls, to extensive bronchiectasis with small airway dilation. However, the degree of bronchiectasis is unrelated to functional impairment or amount of small airway loss, underscoring the importance of small airway disease.

PMID:39700513 | DOI:10.1513/AnnalsATS.202404-446OC

Ann Am Thorac Soc. 2024 Dec 19. doi: 10.1513/AnnalsATS.202407-771OC. Online ahead of print.

ABSTRACT

RATIONALE: Patients with Primary Ciliary Dyskinesia (PCD) experience acute pulmonary exacerbations (PEx). In Cystic Fibrosis (CF), PEx treated with oral antibiotics (oPEx) were found to be related to short and long-term lung function deficits, however the impact oPEx on lung function in patients with PCD has not yet been assessed.

OBJECTIVE: To assess the impact of oPEx on lung function recovery in PCD and determine the factors associated with poorer response.

METHODS: This was a retrospective study of pediatric patients with PCD followed between 2000 to 2022 at SickKids (Toronto, Canada). PEx were defined as an increase in baseline symptoms with a physician decision to treat with systemic (intravenous (IV) or oral antibiotics. Lung function recovery was defined as a forced expiratory volume in 1 second (FEV1) measurement ≥90% of a stable baseline within 12 months before the PEx. Univariate and multivariate analyses were completed to identify risk factors for nonresponse.

RESULTS: 337 PEx events in 85 patients were included in this analysis, of which 297 (88%) were treated with oral antibiotics. The mean (SD) follow up time for patients was 6.7 years (3.5) and the mean age of oPEx was 12.5 years (3.2). Patients with oPEx had a significant drop from baseline in mean FEV1 values at time of PEx (85.1% to 69.5%) with absolute and relative changes of -10.4% and -12.9%, respectively. At follow up (3 months post PEx) and up to 12 months post PEx, the mean FEV1 was 79.6% and 84.1%, respectively. 73.2% of the patients had lung function recovery at follow up visit which increased to 84.2% within one year post event. We identified two risk factors for nonresponse: being a non responder on the last PEx and younger age at time of oPEx. Conclusions oPEx in PCD show a similar pattern previously seen in CF patients with a decrease in FEV1 during exacerbation and an improvement post therapy. Most oPEx events recover to baseline FEV1 within the year post-exacerbation, with younger age and being non responder in the last PEx identified as risk factors for nonresponse.

PMID:39700507 | DOI:10.1513/AnnalsATS.202407-771OC

Eur Respir Rev. 2024 Dec 18;33(174):240142. doi: 10.1183/16000617.0142-2024. Print 2024 Oct.

ABSTRACT

OBJECTIVES: Accurate measurement of exercise capacity is an important prognostic indicator for people with cystic fibrosis (pwCF); however, gold-standard, cardiopulmonary exercise tests are commonly unavailable. This review systematically describes the clinimetric properties of field exercise tests for pwCF.

METHODS: A systematic review was undertaken for studies reporting field exercise tests in pwCF. Four electronic databases were searched for studies published from 1990 to January 2024. Where available, clinimetric properties reported included reliability, validity, responsiveness and interpretability.

RESULTS: 4041 studies were identified with 153 eligible for inclusion. 10 different field exercise tests were described, including six walk/run tests (incremental shuttle walk test (ISWT), modified shuttle test-15 levels (MST-15), MST-25 levels (MST-25), 20-m shuttle test, 6-min walk test (6MWT) and 12-min walk test (12MWT)), three step tests (3-min step test (3MST), incremental step test and Alfred step test (A-STEP)) and the 1-min sit-to-stand test (1STS). Reliability was found for the ISWT, MST-15, 6MWT, 1STS and 3MST (intraclass correlation coefficients >0.80). The ISWT, MST-15 and 6MWT were found to be valid (concurrent and discriminate). Responsiveness was supported for the 6MWT only. Four tests (MST-15, 6MWT, 3MST and 1STS) demonstrated ceiling effects.

CONCLUSION: This review supports the reliability, validity and responsiveness of the 6MWT in pwCF. The ISWT and MST-15 were found to be valid. The 1STS is reliable and feasible, but its utility is limited by ceiling effects. The 3MST, MST-25, 20-m shuttle test, incremental step test, A-STEP and 12MWT require further investigations of their clinimetric properties.

PMID:39694588 | DOI:10.1183/16000617.0142-2024

Aust J Gen Pract. 2024 Dec-Supplement;53(12 Suppl):S78-S84. doi: 10.31128/AJGP-10-23-6989.

ABSTRACT

BACKGROUND AND OBJECTIVES: The Royal Australian College of General Practice recommends that all women contemplating pregnancy or in early pregnancy should be offered reproductive genetic carrier screening (RGCS). In November 2023, a new Medicare item number was introduced for RGCS to detect cystic fibrosis (CF), spinal muscular atrophy (SMA) and fragile X syndrome (FXS) carrier status. The role of general practice in offering RGCS is recognised as being of crucial importance, but only a minority of general practitioners (GPs) are offering such screening. This study investigates the facilitators and barriers to offering RGCS in general practice.

METHOD: Fifteen Victorian GPs who had offered RGCS for CF, SMA and FXS participated in semi-structured telephone interviews. A behavioural change framework was used for this study.

RESULTS: Barriers to offering screening (eg out-of-pocket costs, low frequency of preconception care and lack of GP education) mapped predominantly onto the 'opportunity' domain of the behaviour change framework.

DISCUSSION: Reducing out-of-pocket costs and increasing the provision of preconception care and GP education will provide more people with the opportunity to make informed choices about participation in RGCS.

PMID:39693757 | DOI:10.31128/AJGP-10-23-6989

J Headache Pain. 2024 Dec 18;25(1):220. doi: 10.1186/s10194-024-01927-8.

ABSTRACT

BACKGROUND: The total burden of migraine includes not only the episodes with headache pain but extends throughout the interictal periods. Interictal symptoms and associated psychological responses may profoundly impact well-being and drive treatment-seeking behavior.

METHODS: A cross-sectional online survey was conducted with participants aged ≥ 18 years, 250 with episodic migraine (EM) and 250 with chronic migraine (CM), having ≥ 4 monthly migraine headache days. All were naïve to galcanezumab or began ≤ 6 months before survey completion. The study evaluated factors associated with the Migraine Interictal Burden Scale (MIBS-4), including social determinants of health and well-being. Multiple linear regression, logistic regression, and random forests (RF) were used to explore predictors of MIBS-4.

RESULTS: The majority of participants (90%) were female with a mean (standard deviation) age of 40.6 (± 12.0) years and 18.1 (± 12.7) years since the first migraine episode. Sociodemographically, the EM and CM groups were similar. Common comorbidities were anxiety disorder (45%) and depression (44%). Migraine family history was reported in 59% of participants. MIBS-4 was correlated with a number of diverse variables, including well-being, anxiety sensitivity, income, aura symptoms, and the worst migraine pain in the year before starting galcanezumab. Linear and logistic regression identified years since the first symptom, worst migraine attack pain, premonitory symptoms, and income as significant predictors. RF explained more of the variance than multiple linear regression and introduced additional concepts to the prediction of MIBS, identifying well-being (WHO-5 total score), the WHO-5 item "cheerful and in good spirits," worry about exercise, and fear of missing social obligations as significant predictors. Socioeconomic status and income were also critical explanatory variables for interictal burden (IIB) based on regression modeling and RF. Still, income was the only variable significantly associated with IIB across regression and RF methods.

CONCLUSIONS: Interictal burden should be considered in the medical care of people with migraine. This additional burden is holistic, with psychosocial and socioeconomic elements in addition to residual symptoms. It is essential to consider this when assessing the impact of IIB.

PMID:39695402 | DOI:10.1186/s10194-024-01927-8

Respir Med. 2024 Dec 15:107913. doi: 10.1016/j.rmed.2024.107913. Online ahead of print.

ABSTRACT

BACKGROUND: Preterm birth survivors are at risk for short- and long-term respiratory morbidity. This includes increased rates of chronic obstructive pulmonary disease and infectious morbidity. Previous studies showed increased utilization of healthcare services throughout early childhood. However, only a few large-scale studies showed the effect on respiratory morbidity throughout the full spectrum of gestational age at birth. The aim of this study was to show the healthcare burden associated with prematurity, in a large nationwide cohort.

STUDY DESIGN: Data regarding gestational age at birth, month and year of birth, and infant sex were gathered for all 1 762 149 infants born in Israel between January 1, 2010, and December 31, 2019. Rates of hospitalization, length of hospitalization, and emergency department visits were calculated per 1000 live births and stratified by gestational age. Poisson regression was constructed to adjust for infant sex, year and month of birth.

RESULTS: Preterm birth occurred in 6.43% of deliveries (n=109,405). A negative association was found between gestational age at birth and respiratory morbidity. As gestational age at birth advances, rates of respiratory hospitalization decrease, and length of hospitalization shortens. This association continues even after full term is reached.

CONCLUSION: The short- and long-term effect of preterm birth poses a significant burden on healthcare systems globally, not only at birth or in infancy, but well into early childhood. These results are a call for action to stakeholders and professional organizations to increase efforts in preventing and treating preterm and early term labor.

PMID:39689734 | DOI:10.1016/j.rmed.2024.107913

JBRA Assist Reprod. 2024 Dec 17. doi: 10.5935/1518-0557.20240087. Online ahead of print.

ABSTRACT

OBJECTIVE: There is a rising demand for assisted reproductive medicine, including sperm, oocyte and embryo donation. Besides medical and legal considerations, genetic testing, including carrier screening for multiple autosomal and X-linked recessive disorders plays an essential role in evaluating hereditary risk among donors and therefore exclude them from the donation process.

METHODS: A retrospective study was conducted on oocyte donors from a private clinic of assisted reproduction who underwent genetic testing between June 2014 and September 2023. Pre and post-test procedures were performed at the private clinic while karyotyping and carrier screening for Cystic Fibrosis, Fragile X syndrome and Spinal Muscular Atrophy were performed at the Genetic Unit of Faculty of Medicine, University of Porto.

RESULTS: Among 581 donors, 81 women were excluded from the donation process since 5/563 had an alteration in karyotype, 57/581 were carriers of a Cystic Fibrosis Transmembrane conductance Regulator pathogenic variant or had a 5T allele, 11/394 had Survival of Motor Neuron 1 deletion and 8/426 had an intermediate or premutation allele in Fragile X Messenger Ribonucleoprotein gene. While recommendations from fertility societies advocate for comprehensive screening, opinions differ on the mandatory implementation of expanded carrier screening.

CONCLUSIONS: In conclusion, the genetic tests and the pre and post-test counseling is imperative to optimize reproductive outcomes in the oocyte donation process.

PMID:39688442 | DOI:10.5935/1518-0557.20240087

Tumori. 2024 Dec 17:3008916241301912. doi: 10.1177/03008916241301912. Online ahead of print.

ABSTRACT

INTRODUCTION: The association of acute lymphoblastic leukaemia (ALL) and cystic fibrosis (CF) is rare. We present the case of a paediatric patient affected by CF and refractory B-cell precursor (BCP) ALL, who was treated with combined chimeric antigen receptor T-cells (CAR-T) and allogeneic haematopoietic stem cell transplantation (HSCT).

CASE DESCRIPTION: Autologous-CD19 targeting CAR-T allowed to achieve molecular remission and spare chemo-related toxicity. As B-cell aplasia was not achieved, the patient underwent HSCT after total body irradiation (TBI)-based conditioning. The course after HSCT was complicated by veno-occlusive disease, status epileptic and pulmonary invasive fungal infection which showed progressive radiological worsening despite aggressive treatment. Five months after HSCT a left upper lobe lobectomy was successfully performed. Thirteen months after HSCT the patient is in complete disease remission with normal lung function.

CONCLUSIONS: CAR-T cell therapy bridge-to-HSCT may be an effective approach in paediatric refractory ALL in the context of multiple comorbidities as observed in CF.

PMID:39688204 | DOI:10.1177/03008916241301912

ERJ Open Res. 2024 Dec 16;10(6):00502-2024. doi: 10.1183/23120541.00502-2024. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Inflammation in cystic fibrosis (CF) airways is difficult to treat with well-established regimens often including azithromycin (AZ) as an immunomodulatory drug. As AZ has been reported to require CF transmembrane conductance regulator (CFTR) to be able to reduce interleukin (IL)-8 and given the emergence of highly effective CFTR "triple" modulator therapy (elexacaftor/tezacaftor/ivacaftor; ETI), the aim of this study was to investigate the effect of AZ and ETI, singly and in combination, on ion channel activity and to assess the potential anti-inflammatory effects.

METHODS: Electrophysiological assessment of ETI and AZ was performed on three-dimensional cultures of primary CF human bronchial epithelial (HBE) cells using a Multi Trans-Epithelial Current Clamp. IL-8 from NuLi-1 (non-CF) and CuFi-1 (CF) cells treated with AZ was measured by ELISA. Inflammatory mediators from primary CF HBE cells exposed to tumour necrosis factor-α in the presence of AZ, ETI and their combination, were screened using the Proteome Profiler™ Human Cytokine Array Kit, with selected targets validated by ELISA.

RESULTS: AZ did not alter CFTR chloride efflux, nor did it have any synergistic/antagonistic effect in combination with ETI. AZ reduced IL-8 in NuLi-1 but not CuFi-1 cells. The Proteome Profiler™ screen identified several disease-relevant cytokines that were modulated by treatment. Subsequent analysis by ELISA showed IL-8, IL-6, CXCL1 and granulocyte-macrophage colony-stimulating factor to be significantly reduced by treatment with ETI, but not by AZ.

CONCLUSIONS: Incorporating ETI into the standard of CF care provides an opportunity to re-evaluate therapeutic regimens to reduce treatment burden and safely discontinue chronic treatments such as AZ, without loss of clinical benefit. Identification of redundant treatments in the era of CFTR modulation may improve medication adherence and overcome potential adverse effects associated with the chronic use AZ and other drugs.

PMID:39687397 | PMC:PMC11647873 | DOI:10.1183/23120541.00502-2024

iScience. 2024 Nov 15;27(12):111393. doi: 10.1016/j.isci.2024.111393. eCollection 2024 Dec 20.

ABSTRACT

Inflammation, acinar atrophy, and ductal hyperplasia drive pancreatic remodeling in newborn cystic fibrosis (CF) ferrets lacking a functional cystic fibrosis conductance regulator (CFTR) channel. These changes are associated with a transient phase of glucose intolerance that involves islet destruction and subsequent regeneration near hyperplastic ducts. The phenotypic changes in CF ductal epithelium and their impact on islet function are unknown. Using bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on CF ferret models, we demonstrate that ductal CFTR protein constrains PDX1 expression by maintaining PTEN and GSK3β activation. In the absence of CFTR protein, centroacinar cells adopted a bipotent progenitor-like state associated with enhanced WNT/β-Catenin, transforming growth factor β (TGF-β), and AKT signaling. We show that the level of CFTR protein, not its channel function, regulates PDX1 expression. Thus, this study has discovered a cell-autonomous CFTR-dependent mechanism by which CFTR mutations that produced little to no protein could impact pancreatic exocrine/endocrine remodeling in people with CF.

PMID:39687022 | PMC:PMC11647141 | DOI:10.1016/j.isci.2024.111393