BMJ Sex Reprod Health. 2024 Dec 31:bmjsrh-2024-202564. doi: 10.1136/bmjsrh-2024-202564. Online ahead of print.

NO ABSTRACT

PMID:39740981 | DOI:10.1136/bmjsrh-2024-202564

BMJ Support Palliat Care. 2024 Dec 31:spcare-2024-005318. doi: 10.1136/spcare-2024-005318. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is an incurable, progressive disease that affects multiple organs, causing burdensome symptoms. This study aimed to explore the palliative care needs in patients with CF, focusing on health-related quality of life (HRQOL), fatigue, anxiety and depression.

METHODS: From October 2019 to March 2020, a cross-sectional questionnaire survey was conducted with outpatients with CF at the Infectious Medicine Clinic in a Danish University Hospital.

RESULTS: 130 patients completed at least one questionnaire. Mean age was 35.5 years (SD 11.5), with 51.7% males. Charlson's comorbidity index mean score was 1.3 (SD 1.6). Patients with CF had significantly lower scores in general health, vitality, social functioning, role emotional and mental health compared with the Danish population. Mean fatigue score of patients was 50.9 (SD 16.2), with the highest scores in general fatigue, physical fatigue and reduced activity. Additionally, 33% indicated anxiety and 19.5% depression. 51.6% were treated with Tezacaftor/Ivacaftor or Lumacaftor/Ivacaftor.

CONCLUSION: This study found poor HRQOL and burdensome symptoms of fatigue, anxiety and depression in patients with CF compared with the general Danish population. The results suggest that systematic assessments and palliative care interventions should be integrated into routine CF care.

PMID:39740962 | DOI:10.1136/spcare-2024-005318

J Med Genet. 2024 Dec 31:jmg-2024-110365. doi: 10.1136/jmg-2024-110365. Online ahead of print.

ABSTRACT

BACKGROUND: Targeted cystic fibrosis (CF) carrier screening panels may lack sensitivity in non-European ancestry groups. This study aims to evaluate the sensitivity of various panels in Australian CF carriers identified through sequencing.

METHODS: The following panels were evaluated in 869 CF carriers: Asuragen, Elucigene, Devyser, American College of Medical Genetics and Genomics and Victorian Clinical Genetics Services. Ancestry-specific CF carrier frequencies from population databases and Bayesian analysis were used to estimate post-test residual carrier risks.

RESULTS: When variants with varying clinical consequences (VCC) were not considered, mean test sensitivity was highest in the Northern Europe group (95.6%) and lowest in the Southern Asia group (64.0%). The post-test residual carrier risk in the Northern Europe group was approximately 1 in 546, with only the Southern Asia group having a higher residual carrier risk of 1 in 179.

CONCLUSION: The Southern Asia group exhibited the lowest test sensitivity and the highest post-test residual carrier risk, surpassing that of the Northern Europe group. The inclusion or exclusion of VCC significantly impacted the calculated test sensitivities. Further research is suggested to better characterise CFTR variants in non-European ancestry groups and to determine which VCC, if any, should be included in carrier screening reports.

PMID:39740802 | DOI:10.1136/jmg-2024-110365

Pediatr Pulmonol. 2024 Dec 31. doi: 10.1002/ppul.27251. Online ahead of print.

NO ABSTRACT

PMID:39739449 | DOI:10.1002/ppul.27251

Pediatr Pulmonol. 2024 Dec 31. doi: 10.1002/ppul.27255. Online ahead of print.

NO ABSTRACT

PMID:39739446 | DOI:10.1002/ppul.27255

Acta Paediatr. 2024 Dec 31. doi: 10.1111/apa.17544. Online ahead of print.

ABSTRACT

AIM: Knowledge about the clinical role that respiratory viruses play in infants and toddlers with cystic fibrosis (CF) remains limited. We determined the prevalence of respiratory viruses in routine respiratory secretion samples in children aged 0-3 years with CF. Associations with bacterial infections, respiratory tract symptoms and lung function were also explored.

METHODS: This prospective, longitudinal, single-centre study added viral polymerase chain reaction detection to the routine monitoring of CF lung disease at Copenhagen University Hospital, Denmark, from 1 July 2019 to 31 August 2020. The existing programme included monthly clinical assessments with endo-laryngeal suction for bacterial culturing and quarterly lung function testing.

RESULTS: We studied 19 children (11 males) with a median age of 1.8 (range 0.11-2.99) years. Viruses were detected in 86/193 (45%) samples. Rhinoviruses and enteroviruses were the most common (88%), followed by adenoviruses (9%), parainfluenza 1-3 (6%) and the respiratory syncytial virus (5%). A positive association was found between the annual incidence of viruses and bacteria, but there was no correlation with respiratory tract symptoms or lung function.

CONCLUSIONS: Respiratory viruses were commonly detected in routine respiratory secretion samples. However, the results from this small study did not justify specific conclusions.

PMID:39739363 | DOI:10.1111/apa.17544

Sci Rep. 2024 Dec 30;14(1):31790. doi: 10.1038/s41598-024-82840-7.

ABSTRACT

The aetiology of Alzheimer's disease (AD) and Parkinson's disease (PD) are unknown and tend to manifest at a late stage in life; even though these neurodegenerative diseases are caused by different affected proteins, they are both characterized by neuroinflammation. Links between bacterial and viral infection and AD/PD has been suggested in several studies, however, few have attempted to establish a link between fungal infection and AD/PD. In this study we adopted a nanopore-based sequencing approach to characterise the presence or absence of fungal genera in both human brain tissue and cerebrospinal fluid (CSF). We observed the presence of small fungal burden DNA in two AD brains and a control case (extensive amyloid angiopathy). This approach would be well-placed to investigate potential links between microbial infection and neurodegenerative disease.

PMID:39738312 | DOI:10.1038/s41598-024-82840-7

Dig Liver Dis. 2024 Dec 28:S1590-8658(24)01129-0. doi: 10.1016/j.dld.2024.12.010. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: The aim of the present study was to assess prevalence and disease outcomes of arthritis in a nationwide cohort of pediatric patients with inflammatory bowel disease (IBD).

METHODS: We collected data of pediatric IBD patients experiencing arthritis from the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition IBD registry. We gathered baseline and one-year follow-up data on concomitant IBD and arthritis diagnosis.

RESULTS: 150 patients [(99 Crohn's Disease (CD), 51 Ulcerative Colitis (UC) and Unclassified IBD (IBDU)] with arthritis out of 3061 (1301 CD and 1760 UC) patients were identified, with an overall prevalence of 4.9 %. Arthritis was more frequent in CD than in UC (7.6 % vs 2.9 %, p < 0.01). Peripheral arthritis was more frequently diagnosed in patients with active IBD than in those with quiescent disease (94.6 % vs 67.3 %, p < 0.01). At one-year follow-up, clinically active IBD was independently associated with lower peripheral arthritis remission rates, whereas it did not impact axial arthritis remission. The presence of additional EIMs was associated with lower IBD clinical remission rates.

DISCUSSION: Clinically active IBD impacts peripheral arthritis but not axial one, whose activity appeared to be independent by intestinal disease. The presence of additional EIMs has a negative prognostic impact on IBD course.

PMID:39734162 | DOI:10.1016/j.dld.2024.12.010

Pediatr Infect Dis J. 2024 Oct 4. doi: 10.1097/INF.0000000000004580. Online ahead of print.

ABSTRACT

fibrosis is a genetic disease characterized by chronic lung infection, often with Pseudomonas aeruginosa, requiring repeated antibiotic treatment for pulmonary exacerbations. In the era of cystic fibrosis transmembrane conductance regulator modulator therapy, we assessed susceptibility to antipseudomonal antibiotics in modulator-eligible and modulator-ineligible children over 3 years and found that P. aeruginosa isolates largely remained susceptible to standard parenteral but not oral antimicrobial agents.

PMID:39733270 | DOI:10.1097/INF.0000000000004580

Sci Rep. 2024 Dec 28;14(1):31237. doi: 10.1038/s41598-024-82535-z.

ABSTRACT

The lungs of people with cystic fibrosis (PwCF) are characterized by recurrent bacterial infections and inflammation. Infections in cystic fibrosis (CF) are left unresolved despite excessive neutrophil infiltration. The role of CFTR in neutrophils is not fully understood. In this study, we aimed to assess which antimicrobial functions are directly impaired by loss of CFTR function in neutrophils. In order to do so, we used a specific inhibitor of CFTR ion channel activity, inh-172. CF neutrophils from PwCF harboring severe CFTR mutations were additionally isolated to further discern CFTR-specific functional defects. We evaluated phagocytosis, reactive oxygen species (ROS) production, neutrophil elastase (NE) and myeloperoxidase (MPO) exocytosis and bacterial killing. The inh-172 model identified decreased acidification of the phagosome, increased bacterial survival and decreased ROS production upon stimulation. In PwCF neutrophils, we observed reduced degranulation of both NE and MPO. When co-culturing neutrophils with CF sputum supernatant and airway epithelial cells, the extent of phagocytosis was reduced, underscoring the importance of recreating an inflammatory environment as seen in PwCF lungs to model immune responses in vitro. Despite low CFTR expression in blood neutrophils, functional defects were found in inh-172-treated and CF neutrophils. The inh-172 model disregards donor variability and allows pinpointing neutrophil functions directly impaired by dysfunctional CFTR.

PMID:39732786 | DOI:10.1038/s41598-024-82535-z

Can J Diabetes. 2024 Dec 26:S1499-2671(24)00413-1. doi: 10.1016/j.jcjd.2024.12.003. Online ahead of print.

NO ABSTRACT

PMID:39732285 | DOI:10.1016/j.jcjd.2024.12.003

J Biol Chem. 2024 Dec 26:108145. doi: 10.1016/j.jbc.2024.108145. Online ahead of print.

ABSTRACT

The chloride transporter-channel SLC26A9 is mediated by a reciprocal regulatory mechanism through the interaction between its cytoplasmic STAS domain and the R domain of CFTR. In vertebrate Slc26a9s, the STAS domain structures are interrupted by a disordered loop which is conserved in mammals but is variable in non-mammals. Despite the numerous studies involving the STAS domains in SLC26 proteins, the role of the disordered loop region has not been identified. Deletion of the entire Slc26a9-STAS domain results in loss of Cl- channel function. Surprisingly, we found that partial or full deletion of the STAS-disordered loop substantially increases the SLC26A9 chloride transport-channel activity. Bioinformatics analysis reveals that the disordered loop there are three subregions: a K/R-rich region, a "middle" region, and an ordered S/T-rich motif. In this study, the role of this STAS-disordered loop is investigated by using serial deletions and the ordered S/T-rich motif is examined by serial alanine substitution. Substitutions of alanine for serine or threonine in the 620-628 S/T-rich motif decrease SLC26A9 chloride channel activity. These experiments parse the functional roles of SLC26A9-STAS disordered loop and its subdivisions modifying overall SLC26A9 activities. Recently, SLC26A9 has emerged as one of the potential substitutes for abnormal CFTR in cystic fibrosis. Our findings suggest that deletion of variable loop of human SLC26A9 may provide a new gene therapy strategy in the treatment of CF disease.

PMID:39732169 | DOI:10.1016/j.jbc.2024.108145

Iran Biomed J. 2024 Dec 1;28(7):173.

NO ABSTRACT

PMID:39731435

Sci Rep. 2024 Dec 28;14(1):30899. doi: 10.1038/s41598-024-81276-3.

ABSTRACT

Mesenchymal stromal cells (MSCs) are multipotent adult stem cells which possess immunomodulatory and repair capabilities. In this study, we investigated whether MSC therapy could modulate inflammation and lung damage in the lungs of Scnn1b-transgenic mice overexpressing the β-subunit of the epithelial sodium channel (β-ENaC), a model with features of Cystic Fibrosis lung disease. Human bone marrow derived MSC cells were intravenously delivered to mice, prior to collection of bronchoalveolar lavage (BALF) and tissue. BALF analysis revealed a significant reduction in inflammatory cells after MSC administration, with both monocytic cells and neutrophils significantly reduced. Pro-inflammatory cytokines keratinocyte-derived chemokine (KC) and osteopontin were also significantly reduced. Histological tissue analysis revealed a reduction in emphysema in Scnn1b-TG mice treated with MSCs and consistent with these findings, improvements in lung function after MSC therapy were observed. Furthermore, MSCs enhanced Ki67 staining in alveolar cells, which may indicate regeneration of the destroyed parenchyma. Mechanistically, restoration of peroxisome proliferator-activated receptor-γ (PPARγ) expression and its transcriptional program were identified after MSC treatment. Our data demonstrate that MSC therapy can reduce inflammation, damage, and lung function decline in the chronically inflamed lung of Scnn1b-Tg mice, suggesting that MSCs may provide an effective tool in the treatment of muco-obstructive diseases such as cystic fibrosis.

PMID:39730509 | DOI:10.1038/s41598-024-81276-3

Sci Rep. 2024 Dec 28;14(1):30775. doi: 10.1038/s41598-024-80994-y.

ABSTRACT

Mycobacterium abscessus (Mabs), an intracellular and opportunistic pathogen, is considered the most pathogenic fast-growing mycobacterium, and causes severe pulmonary infections in patients with cystic fibrosis. While bacterial factors contributing to its pathogenicity are well studied, the host factors and responses that worsen Mabs infection are not fully understood. Here, we report that Mabs systemic infection alters Drosophila melanogaster intestinal homeostasis. Mechanistically, Mabs remotely induces a self-damaging oxidative burst, leading to excessive differentiation of intestinal stem cells into enterocytes. We demonstrated that the subsequent increased intestinal renewal is mediated by both the Notch and JAK/STAT pathways and is deleterious to Drosophila survival. In conclusion, this work highlights that the ability of Mabs to induce an exacerbated and self-damaging response in the host contributes to its pathogenesis.

PMID:39730463 | DOI:10.1038/s41598-024-80994-y

Ophthalmology. 2024 Dec 25:S0161-6420(24)00799-1. doi: 10.1016/j.ophtha.2024.12.035. Online ahead of print.

NO ABSTRACT

PMID:39730105 | DOI:10.1016/j.ophtha.2024.12.035

Int J Neonatal Screen. 2024 Dec 4;10(4):80. doi: 10.3390/ijns10040080.

ABSTRACT

Newborn screening (NBS) represents an important public health measure for the early detection of specified disorders; such screening can prevent disability and death, not only from metabolic disorders but also from endocrine, hematologic, immune, and cardiac disorders. Screening for critical congenital conditions affecting newborns' health is a great challenge, especially in developing countries such as Morocco, where NBS program infrastructure is lacking. In addition, the consanguinity rate is high in Morocco. This study aimed to demonstrate the feasibility of integrating NBS into a diagnostic laboratory for routine analysis. Six primary severe conditions were included: congenital hypothyroidism (CH), cystic fibrosis (CF), phenylketonuria (PKU), glucose-6-phosphate dehydrogenase deficiency (G6PD), congenital adrenal hyperplasia (CAH), and hemoglobinopathies.

METHODS: A retrospective investigation was carried out to examine the outcomes of NBS in Casablanca, Morocco. A total of 5511 newborn blood samples were collected via heel-prick sampling and tested for the above disorders. Most of the samples were collected within the third and sixth days of birth. The dried blood spots were analyzed via a quantitative immunofluorescence technique and isoelectric focusing.

RESULTS: A total of 72 newborns had one of the six pathological conditions. The most prevalent disorders were hemoglobinopathies, which were identified in 47 newborns (0.9%), with 29 having HbC carrier status (0.5%), 15 having Hb S carrier status (0.3%), and 3 having an Hb Bart's carrier profile (0.05%). This was followed by G6PD deficiency, which was found to affect 16 newborns (0.32% of cases). CF was found in one case (0.02%), whereas five newborns (0.09%) tested positive for CAH. Additionally, two newborns (0.04%) tested positive for CH, and one newborn tested positive for PKU (0.02%).

CONCLUSION: Our findings underscore the importance and success of NBS programs in preventing morbidity and mortality and improving the quality of life of affected neonates. The significant gap in data and research on these disorders within the Moroccan population highlights the urgent need to integrate NBS into routine practice in diagnostic laboratories across Morocco. This integration is crucial for enhancing the health and well-being of Moroccan newborns.

PMID:39728400 | DOI:10.3390/ijns10040080

J Fungi (Basel). 2024 Dec 17;10(12):875. doi: 10.3390/jof10120875.

ABSTRACT

The importance of fungal pathogens in cystic fibrosis (CF) patients and their diagnosis remains a challenge, so our aim was to analyze the influence of the detection of fungi in sputum by using conventional culture and molecular techniques, polymerase chain reaction (PCR), lateral flow devices (LFDs), and galactomannan (GM) on exacerbations in patients with cystic fibrosis. A prospective study was conducted in patients via follow-up in the CF Unit of the Central University Hospital of Asturias from January 2021 to April 2022. Adult patients with at least one documented exacerbation were included. A complete fungal analysis of sputum samples was performed both in a period of clinical stability and in the exacerbation period. The microbiological study included conventional cultures for fungi, qPCR (polymerase chain reaction), LFDs (lateral flow devices), and galactomannan (GM) in sputum. We found that there were changes in their detection according to whether the patient is in a period of clinical stability or exacerbation; the positivity of the molecular tests and biomarkers in the period of exacerbation increased by 14%, 25%, and 21% for the analysis by qPCR, GM, and LFDs for Aspergillus and by 15% for the sputum culture for Aspergillus, which may mean that fungal isolates may play a role in the exacerbations of these patients.

PMID:39728371 | DOI:10.3390/jof10120875

Adv Respir Med. 2024 Dec 20;92(6):559-572. doi: 10.3390/arm92060049.

ABSTRACT

Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a CFTR modulator therapy approved for people with cystic fibrosis (pwCF) who have at least one phe508del mutation. However, its approval in the European Union (EU) for pwCF with non-phe508del mutations is lacking, because data on treatment response in this subgroup are scarce. Methods: This retrospective observational study evaluated six pwCF (ages 6 to 66) with responsive CFTR mutations (M1101K, R347P, 2789+5G>A, G551D) undergoing off-label ETI therapy. Evaluations were conducted at 0, 3, 6, 9, and 12 months, assessing lung function (FEV1), sweat chloride levels, body mass index (BMI), quality of life, medication satisfaction, ear, nose and throat (ENT) symptoms, and physical activity. A control group of four pwCF with classic symptoms and no ETI treatment was included. Results: FEV1 improved significantly after 3 and 6 months (p < 0.05) and stabilized by 12 months. Sweat chloride levels decreased significantly, with four pwCF achieving levels <60 mmol/L. Improvements in the upper and lower airway symptoms, medication satisfaction, and increased BMI were noted. Conclusions: ETI demonstrates high efficacy in this small group of pwCF with rare CFTR mutations, offering a treatment option that warrants further monitoring and evaluation.

PMID:39727500 | DOI:10.3390/arm92060049

BMJ Open. 2024 Dec 26;14(12):e092503. doi: 10.1136/bmjopen-2024-092503.

ABSTRACT

INTRODUCTION: People with cystic fibrosis (PwCF) are at high risk for developing cystic fibrosis (CF)-related diabetes (CFRD), which worsens morbidity and mortality. Although the pathological events leading to the development of CFRD are complex and not completely understood, dietary factors may play a role. For example, habitual intake of dietary added sugar (i.e., sugar not naturally occurring in foods) has been shown to be increased in PwCF and this excess intake of added sugar could increase the risk of CFRD.

METHODS AND ANALYSIS/DESIGN: The goal of this ongoing double-blind, randomised, parallel-group clinical trial is to recruit approximately 60 clinically stable adults with CF to determine if a low-added sugar intervention improves beta-cell responsiveness and insulin sensitivity (Aim 1), reduces visceral adipose tissue (VAT) and other ectopic fat deposition (Aim 2) and improves plasma redox status (Aim 3) over 8 weeks compared with a typical CF diet. All foods will be provided. Participant selection criteria include confirmed CF diagnosis without CFRD, ≥18 years of age, and baseline estimated daily total added sugar intake >16 tsp. Eligible participants will be randomised to one of two arms: a low-added sugar diet (<5% of kcal from added sugars) or a high-added sugar (≥13% kcal from added sugars) diet. The two diets will be isocaloric and provide 35%-40% kcal from fat. Participants will be seen in the research unit for a screening, baseline/randomisation and 4-week and 8-week follow-up visits. Major study endpoints are changes in beta-cell responsiveness determined by a glucose-potentiated arginine stimulation test (primary endpoint), VAT assessed by magnetic resonance imagin (MRI) and fasted plasma cysteine redox potential. Diet tolerance, body weight and compliance are monitored weekly by phone by an unblinded study dietitian. All analyses will be intention-to-treat. Changes in study endpoints will be assessed with repeated-measures analysis. Models will assess the effects by study arm, time on study, and the interaction between arm and time on study.

ETHICS AND DISSEMINATION: The National Institutes of Health (NIH) funds this study (R01 DK133523). The study protocol was approved by the Emory Institutional Review Board (IRB approval number: 000004517). Any protocol modifications will be reviewed and approved by the IRB prior to implementation and communicated with the study team and participants, as relevant.We will provide reports of the findings to the NIH and Emory IRB in regular progress reports and post the findings on www.

CLINICALTRIALS: gov. We will inform the findings of the study to the scientific community through presentations and peer-reviewed publications. Authorship for any resulting publications will follow the guidelines established by the International Committee of Medical Journal Editors.

TRIAL REGISTRATION NUMBER: This research study is registered at www.

CLINICALTRIALS: gov (NCT05766774).

PMID:39725418 | DOI:10.1136/bmjopen-2024-092503