Ulster Med J. 2024 Dec;93(2):67-82. Epub 2024 Dec 11.

ABSTRACT

BACKGROUND: In Northern Ireland, approximately 550 people with cystic fibrosis (PwCF) attend the regional paediatric and adult centres within the Belfast Health and Social Care Trust. This autosomal recessive chronic condition necessitates regular clinical monitoring and a high treatment burden, as well as time implications for the maintenance of respiratory devices. Development of health literacy skills at an early age and promoting children with CF (CwCF) to take an active role in their healthcare has many advantages relating to their long-term self-care in preparation for transition from paediatric to adult care, decision-making and partnership engagement with the CF-multidisciplinary team (CF-MDT).

METHODS: This study comprised of four individual components, namely (i) an analysis of responses (n=24) to an anonymous questionnaire from the Northern Ireland CF community to determine where PwCF and their carers/families seek healthcare information; (ii) to co-produce paediatric-facing healthcare educational resources, namely colouring/ storybooks and animations, relating to the importance of microbiological sampling, nebuliser hygiene and pancreatic replacement therapy (PERT) in conjunction with the CF-MDT, CwCF, parents, students and animators and (iii) assess the readability of these new materials using Flesch Reading Ease (FRE), Flesch-Kincaid Grade Level (FKGL), SMOG Index and Gunning Fog (GF) Index and compare these with paediatric and adult-facing materials available from CF charities, pharmaceutical companies and the scientific literature. The final component (iv) examined parents' and children's knowledge of PERT pre- and post-viewing the bespoke animation.

RESULTS: (i) The findings showed that the CF community relied upon the CF-MDT as their primary source of healthcare information, most frequently consulting the Doctor/CF Consultant (61.5%), the physiotherapist (61.6%), the nurse (57.7%), followed by the CF dietitian (34.6%), as well as the Cystic Fibrosis Trust (38.4%). Pharmaceutical websites were least consulted with 69.2% of respondents never consulting such resources.(ii) Reflective learning points from this co-production of resources are provided to assist other healthcare teams preparing engaging and effective healthcare information for the paediatric service user.(iii) The readability of the new paediatric-facing materials prepared by the CF-MDT was appropriate for primary school aged-children and was not statistically different from paediatric-facing information prepared by charities or pharmaceutical companies. A statistical difference was noted in relation to the prepared materials in comparison with adult-facing charity information (p=0.04; 0.02; 0.03; 0.04) and scientific abstracts (p<0.0001), which were more complex in terms of readability parameters, FRE, FKGL, SMOG and GF, respectively.(iv) Following viewing the PERT animation, both parents' and children's knowledge had improved with 50% of children's understanding determined as moderate/little understanding (pre-animation) and 50% very good/ 42 % good (post-animation).

CONCLUSIONS: Healthcare professionals are important custodians of healthcare information for their service user population. Paediatric healthcare teams have a responsibility to aid in the development of health literacy skills at an early age and promoting children to take an active role in their healthcare. The use of colouring/storybooks and animations are excellent media to initiate discussions and develop partnerships in paediatric healthcare in an engaging and informative manner. Whilst this study related to CwCF, the findings may be applicable to the health literacy of children of other disease states. For optimum impact, the healthcare team should (i) co-produce these media with the paediatric service user, their families and animation teams and (ii) ensure that the readability, legibility and formats are appropriate, informative and engaging for the target age-group.

PMID:39669952 | PMC:PMC11633313

J Cyst Fibros. 2024 Dec 11:S1569-1993(24)01846-0. doi: 10.1016/j.jcf.2024.11.008. Online ahead of print.

ABSTRACT

BACKGROUND: Despite high rates of anxiety and depression, research regarding the effect of psychological interventions on people with CF (pwCF) is limited. We evaluated the impact of UPLIFT (Using Practice and Learning to Increase Favorable Thoughts), a group telehealth intervention using mindfulness-based cognitive behavioral therapy (MBCT), on symptoms of anxiety and depression in pwCF.

METHODS: This multicenter randomized trial compared changes in symptoms of anxiety and/or depression in adult pwCF who participated in the 8-week UPLIFT intervention to a treatment-as-usual (TAU) group. Follow up assessments occurred immediately after and 6- and 12-months post-intervention. Primary outcome measures were change in Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) scores modeled in separate linear mixed-effects models.

RESULTS: Sixty-six pwCF participated. At baseline, 43 (65.15%) had some minimal symptoms of depression (PHQ-9≥5) and 44 (66.67%) had some minimal symptoms of anxiety (GAD-7≥5). During the 12 month follow up period, the overall change in PHQ-9 was greater in the UPLIFT group compared to TAU (p = .049). Analysis of individual time points showed a statistically significant difference between groups in change from baseline immediately post-treatment (-2.321, SD 0.684 vs 0.362, SD 0.656, p = .005); differences persisted but were not statistically significant at 6 and 12 months. Similar trends for changes in GAD-7 were non-significant.

CONCLUSIONS: Participation in UPLIFT, a group telehealth intervention using MBCT, provides short-term improvement in symptoms of depression, as measured by changes in PHQ9. Improvement in symptoms of anxiety were suggested but could not be statistically confirmed.

PMID:39668003 | DOI:10.1016/j.jcf.2024.11.008

Eur Respir J. 2024 Dec 12;64(6):2401888. doi: 10.1183/13993003.01888-2024. Print 2024 Dec.

NO ABSTRACT

PMID:39667783 | DOI:10.1183/13993003.01888-2024

Int Immunopharmacol. 2024 Dec 11;145:113754. doi: 10.1016/j.intimp.2024.113754. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Multiple studies have shown that hepatic fibrosis, a progressive condition that represents the endpoint of various chronic liver diseases, is primarily marked by the extensive activation of hepatic stellate cells (HSCs). However, the exact impact of cystic fibrosis transmembrane conductance regulator (CFTR) on HSCs during the development of hepatic fibrosis remains unclear.

METHODS: In our study, we measured CFTR levels in tissue samples and in HSCs activated by TGF-β stimulation. We established mouse models of liver fibrosis using carbon tetrachloride (CCl4) and bile duct ligation (BDL). In vitro, we investigated the specific mechanisms of CFTR action in HSCs by exploring aggrephagy. We employed co-immunoprecipitation (co-IP) experiments to identify potential downstream targets of CFTR. Finally, through rescue experiments, we examined the impact of GTPase-activating protein - binding protein 1 (G3BP1) on CFTR-mediated activation of hepatic stellate cells.

RESULT: In activated HSCs induced by TGF-β, the reduction of CFTR, various liver fibrosis models, and fibrotic tissue samples were identified. In vitro functional experiments confirmed that CFTR promoted the expression of fibrosis-related markers and aggrephagy in HSCs. Mechanistically, we found that CFTR directly interacts with G3BP1, thereby further promoting the TGF-β/Smad2/3 pathway. The inhibition of G3BP1 caused by CFTR knockdown reduced extracellular matrix deposition, contributing to alleviating liver fibrosis.

CONCLUSION: We emphasize that CFTR activates aggrephagy and promotes HSC activation and hepatic fibrosis by targeting G3BP1, participating in the TGF-β/Smad2/3 signaling pathway. Overall, CFTR has been identified as a potential therapeutic target for liver fibrosis.

PMID:39667045 | DOI:10.1016/j.intimp.2024.113754

Obstet Gynecol. 2025 Jan 1;145(1):47-54. doi: 10.1097/AOG.0000000000005732. Epub 2024 Sep 19.

ABSTRACT

With improvements in overall health attributable to newly available medications called highly effective modulator therapy, an increasing number of people with cystic fibrosis (CF) are pursuing pregnancy. However, the safety of these medications for pregnant people with CF and the fetus remains largely unknown. Limited data demonstrate a decline in patients' health and well-being after withdrawal of highly effective modulator therapy during pregnancy; however, both animal and human studies suggest an association between highly effective modulator therapy and cataracts in the offspring that requires further investigation. Use of highly effective modulator therapy can also affect the results of newborn screening and may influence fetal outcomes among fetuses affected by CF as a result of transplacental passage of highly effective modulator therapy. An ongoing prospective cohort study will likely provide more information for pregnant people with CF. Until then, multidisciplinary counseling continues to be critical for people with CF who are of reproductive age.

PMID:39666984 | DOI:10.1097/AOG.0000000000005732

Proc Natl Acad Sci U S A. 2024 Dec 17;121(51):e2406331121. doi: 10.1073/pnas.2406331121. Epub 2024 Dec 12.

ABSTRACT

Delivering medical agents to diseased tissues has been challenging, leading researchers to study the in vivo transport process in the body for improving delivery. Many imaging techniques exist for mapping the distribution of medical agent-carrying nanoparticles in tissues, but they cannot capture the three-dimensional context of tissues with single nanoparticle resolution. Here, we developed 3DEM-NPD, a three-dimensional electron microscopy (3D EM) machine learning strategy to image and map single nanoparticle distributions (NPD) in tissues. 3DEM-NPD provides unbiased visualization and quantification of individual nanoparticles within organs. We applied this technique to quantify nanoparticle transport through tumor blood vessel endothelial cells. We measured the cell diameter, surface area, and volume and found that traditional 2D EM cannot accurately measure these features. We used machine learning to locate over 550,000 nanoparticles in less than 3 h with an accuracy of over 82%. The 3DEM-NPD method allowed us to establish a metric to quantify nanoparticle transport at the single nanoparticle level and to quantify the morphological features of ~2,800 vesicles. We find that on average there are only 2.4 nanoparticles per vesicle with a theoretical maximum of 158 nanoparticles per vesicle (~66x increase). These surprising results suggest the need to increase vesicle encapsulation efficiency for improved transport and they provide a benchmark for increasing nanoparticle transport and delivery. This technique may provide unique insights into the interactions between medical agents, drug carriers, emerging materials, and cells at the single-nanoparticle level throughout tissues.

PMID:39665759 | DOI:10.1073/pnas.2406331121

J Bras Pneumol. 2024 Dec 6;50(5):e20230403. doi: 10.36416/1806-3756/e20230403.

NO ABSTRACT

PMID:39661831 | DOI:10.36416/1806-3756/e20230403

Allergy. 2024 Dec 11. doi: 10.1111/all.16427. Online ahead of print.

NO ABSTRACT

PMID:39660917 | DOI:10.1111/all.16427

J Bacteriol. 2024 Dec 11:e0042924. doi: 10.1128/jb.00429-24. Online ahead of print.

ABSTRACT

Bacterial aggregates are observed in both natural and artificial environments. In the context of disease, aggregates have been isolated from chronic and acute infections. Pseudomonas aeruginosa (Pa) aggregates contribute significantly to chronic infections, particularly in the lungs of people with cystic fibrosis (CF). Unlike the large biofilm structures observed in vitro, Pa in CF sputum forms smaller aggregates (~10-1,000 cells), and the mechanisms behind their formation remain underexplored. This study aims to identify genes essential and unique to Pa aggregate formation in a synthetic CF sputum media (SCFM2). We cultured Pa strain PAO1 in SCFM2 and LB, both with and without mucin, and used RNA sequencing (RNA-seq) to identify differentially expressed genes. The presence of mucin revealed 13 significantly differentially expressed (DE) genes, predominantly downregulated, with 40% encoding hypothetical proteins unique to aggregates. Using high-resolution microscopy, we assessed the ability of mutants to form aggregates. Notably, no mutant exhibited a completely planktonic phenotype. Instead, we identified multiple spatial phenotypes described as "normal," "entropic," or "impaired." Entropic mutants displayed tightly packed, raft-like structures, while impaired mutants had loosely packed cells. Predictive modeling linked the prioritized genes to metabolic shifts, iron acquisition, surface modification, and quorum sensing. Co-culture experiments with wild-type PAO1 revealed further spatial heterogeneity and the ability to "rescue" some mutant phenotypes, suggesting cooperative interactions during growth. This study enhances our understanding of Pa aggregate biology, specifically the genes and pathways unique to aggregation in CF-like environments. Importantly, it provides insights for developing therapeutic strategies targeting aggregate-specific pathways.

IMPORTANCE: This study identifies genes essential for the formation of Pseudomonas aeruginosa (Pa) aggregates in cystic fibrosis (CF) sputum, filling a critical gap in understanding their specific biology. Using a synthetic CF sputum model (SCFM2) and RNA sequencing, 13 key genes were identified, whose disruption led to distinct spatial phenotypes observed through high-resolution microscopy. The addition of wild-type cells either rescued the mutant phenotype or increased spatial heterogeneity, suggesting cooperative interactions are involved in aggregate formation. This research advances our knowledge of Pa aggregate biology, particularly the unique genes and pathways involved in CF-like environments, offering valuable insights for developing targeted therapeutic strategies against aggregate-specific pathways.

PMID:39660900 | DOI:10.1128/jb.00429-24

Respirol Case Rep. 2024 Dec 10;12(12):e70087. doi: 10.1002/rcr2.70087. eCollection 2024 Dec.

ABSTRACT

Totally implantable venous access devices (TIVADs) are frequently used in people with cystic fibrosis as a means of securing consistent vascular access, particularly in the context of severe disease and microbial colonization. Infection of TIVADs is not uncommon and typically associated with coagulase negative staphylococci, though infection with other organisms does occur too. We report on the first case of a TIVAD infection caused by Achromobacter xylosoxidans in person with cystic fibrosis. The TIVAD infection was complicated by a bacteraemia and an associated intracardiac infected thrombus at the superior atriocaval junction. We explore the complex management decisions surrounding the removal of the TIVAD and prolonged antibiotic treatment, with treatment ultimately resulting in a good outcome and full recovery. The case helps to serve as a timely reminder of requirement to review the necessity to retain TIVAD in the era of CFTR modulator therapy and associated improved health outcomes being experienced.

PMID:39659805 | PMC:PMC11631499 | DOI:10.1002/rcr2.70087

Afr J Thorac Crit Care Med. 2024 Oct 14;30(3):e1128. doi: 10.7196/AJTCCM.2024.v30i3.1128. eCollection 2024.

ABSTRACT

BACKGROUND: Bronchiectasis (BE) in children living with HIV (CLWH) remains a significant cause of morbidity and mortality, especially in tuberculosis (TB)-endemic low- and middle-income countries. Treatment modalities for BE in CLWH currently focus mainly on prevention of infections and management of symptoms, while surgical management is indicated for a select group. In contrast, surgical management in non-cystic fibrosis BE is well established.

OBJECTIVES: To describe the indications for and complications of surgical resection for BE in CLWH, and to identify variables influencing outcome.

METHODS: A retrospective medical records review was conducted of all CLWH aged ≤14 years who underwent surgical resection for BE at Tygerberg Hospital, Cape Town, South Africa, between 1 January 2007 and 30 September 2014. The variables collected included immune status, antiretroviral treatment (ART), previous treatment for TB, operative and postoperative complications, and postoperative symptom relief.

RESULTS: Twelve CLWH on ART with symptomatic BE underwent surgical resection. The mean age was 7 years and the mean CD4 count 970 cells/µL. Indications for surgery included recurrent infections, chronic cough and persistent lobar collapse. The most common procedures were left lower lobe lobectomy (42%), left pneumonectomy (17%) and right bilobectomy (17%). Complications were limited to persistent pneumothorax after surgery in one child. There were no deaths. Ten children (83%) showed significant improvement of symptoms at follow-up.

CONCLUSION: Surgical resection for BE in CLWH can be performed safely with a low complication rate, resulting in significant improvement of symptoms postoperatively.

STUDY SYNOPSIS: What the study adds. Bronchiectasis (BE) in children living with HIV (CLWH) is a significant cause of morbidity and mortality. Current treatment focuses on preventing infections and managing symptoms, while surgical management is rarely considered. A retrospective medical records review of 12 children aged ≤14 years in South Africa found that surgical resection for BE can be performed with a low complication rate, resulting in significant improvement of symptoms postoperatively. Variables influencing outcome include immune status, antiretroviral treatment and previous treatment for tuberculosis.Implications of the findings. This study demonstrates that surgery for BE can be performed safely in CLWH, with significant improvement of respiratory symptoms postoperatively.

PMID:39659748 | PMC:PMC11629482 | DOI:10.7196/AJTCCM.2024.v30i3.1128

JAC Antimicrob Resist. 2024 Nov 20;6(6):dlae185. doi: 10.1093/jacamr/dlae185. eCollection 2024 Dec.

ABSTRACT

BACKGROUND: Ivacaftor exhibits anti-staphylococcal properties but does not clear Staphylococcus aureus from the lungs of people with cystic fibrosis (pwCF). We assessed whether exposure to therapeutic concentrations of ivacaftor could allow S. aureus to form small colony variants (SCVs), a phenotype commonly associated with bacterial persistence.

METHODS: Humanized G551D-CFTR (hG551D) rats were treated with ivacaftor for 7 days. Concentrations in the plasma, epithelial lining fluid and lung tissue lysate were measured using LC-MS/MS. Survival of S. aureus during ivacaftor treatment was assessed in an hG551D rat model of lung infection. S. aureus adaptation to therapeutic concentrations of ivacaftor was investigated in vitro by serial passage in the presence of 10 µM ivacaftor. Bacterial survival in the presence of antimicrobials was evaluated using growth curves and density assays.

RESULTS: Ivacaftor plasma concentrations of treated hG551D rats reached 3.488 ± 1.118 µM, with more variable concentrations in the epithelial lining fluid and lung tissue lysate. During S. aureus infection, ivacaftor-treated hG551D rats returned similar numbers of bacteria from the lung, compared with vehicle-treated controls. Exposure of S. aureus to ivacaftor in vitro led to the formation of ivacaftor-tolerant SCVs with an unstable phenotype and increased antibiotic tolerance.

CONCLUSIONS: Treatment with ivacaftor did not alter S. aureus burden in the cystic fibrosis rat and led to the formation of tolerant SCVs in vitro, suggesting that development of an SCV phenotype may allow S. aureus to persist in the cystic fibrosis lung during ivacaftor therapy.

PMID:39659642 | PMC:PMC11630538 | DOI:10.1093/jacamr/dlae185

Nat Biotechnol. 2024 Dec 10. doi: 10.1038/s41587-024-02490-y. Online ahead of print.

ABSTRACT

Ionizable lipids are a key component of lipid nanoparticles, the leading nonviral messenger RNA delivery technology. Here, to advance the identification of ionizable lipids beyond current methods, which rely on experimental screening and/or rational design, we introduce lipid optimization using neural networks, a deep-learning strategy for ionizable lipid design. We created a dataset of >9,000 lipid nanoparticle activity measurements and used it to train a directed message-passing neural network for prediction of nucleic acid delivery with diverse lipid structures. Lipid optimization using neural networks predicted RNA delivery in vitro and in vivo and extrapolated to structures divergent from the training set. We evaluated 1.6 million lipids in silico and identified two structures, FO-32 and FO-35, with local mRNA delivery to the mouse muscle and nasal mucosa. FO-32 matched the state of the art for nebulized mRNA delivery to the mouse lung, and both FO-32 and FO-35 efficiently delivered mRNA to ferret lungs. Overall, this work shows the utility of deep learning for improving nanoparticle delivery.

PMID:39658727 | DOI:10.1038/s41587-024-02490-y

Eur J Pediatr. 2024 Dec 10;184(1):74. doi: 10.1007/s00431-024-05829-4.

ABSTRACT

Discrimination is a social construct that discredits individuals based on attributes deemed socially undesirable. Adolescence is a period of transition where individuals acquire skills, values, and experiences that prepare them for adulthood. Adverse experiences during adolescence could particularly affect these acquisitions. For adolescents, discrimination is an experience that can lead to social and health consequences. Our hypothesis is that adolescents with chronic disease are more likely to be exposed to discrimination than their healthy peers. This systematic review aimed to study the prevalence, nature, and the additional risk of discrimination in adolescents with chronic disease compared to their healthy peers. A systematic review was conducted following PRISMA guidelines, including both quantitative and qualitative studies, published between January 2000 and December 2022. Searches were conducted using several electronic databases, including PubMed, COCHRANE, PsycINFO, EMBASE, CAIRN, and CINAHL. Included articles studied adolescents between 12 and 18 years old affected by one of the most prevalent chronic diseases (obesity, epilepsy, diabetes, respiratory diseases including asthma and cystic fibrosis, cancer, and cardiovascular disease). Those articles reported discrimination from the adolescents' perspective and studied the association between discrimination and disease. We identified 27 studies conducted across almost all continents, including a total of 3,290,446 adolescents. Most of the studies are cross-sectional and recent (published after 2017). They are mainly focused on obesity and epilepsy. All types of discrimination were studied, although cyberbullying was explored in only one study. The prevalence of discrimination was reported in 11 studies and varies depending on the type of chronic disease and contexts (from 14% in adolescents with cystic fibrosis to 99% in adolescents with diabetes). Discrimination was mostly self-reported by the adolescents and it came from multiple sources: peers, parents, or educational and healthcare professionals. It seems that the presence of a chronic disease exposes individuals to an additional risk of discrimination, even though quantifying this risk was not possible due to the diversity of methods.

CONCLUSION: Discrimination against adolescents with chronic diseases has received poorly studied in literature even though they appear to be more vulnerable than their peers. The phenomenon is complex since discrimination occurs through several forms and originates from diverse sources. Given the multiple repercussions of discrimination on all aspects of adolescents' life and development, it is essential to study it further. Awareness of discrimination's diversity will allow to establish preventing actions. Early screening could help limit discrimination's prejudice on adolescents' quality of life.

WHAT IS KNOWN: • Discrimination has a significant impact on the life of individuals who experienced it. • Some risk factors of discrimination are already known, e.g., age, gender, disability, ethnic origin. • There is no strong evidence that having a chronic disease at adolescence increases the risk of discrimination.

WHAT IS NEW: • Adolescents with chronic disease have an additional risk of discrimination coming from their peers, their parents, and professionals. • The discrimination could be explained by the permanent physical difference, the occasional visibility of the symptoms or physical limitations, and the sociocultural constructs of the disease.

PMID:39658646 | DOI:10.1007/s00431-024-05829-4

J Antimicrob Chemother. 2024 Dec 10:dkae445. doi: 10.1093/jac/dkae445. Online ahead of print.

NO ABSTRACT

PMID:39658091 | DOI:10.1093/jac/dkae445

Nucleic Acids Res. 2024 Dec 10:gkae1180. doi: 10.1093/nar/gkae1180. Online ahead of print.

ABSTRACT

Several studies have now described instances where G-rich sequences in promoters and enhancers regulate gene expression through forming G-quadruplex (G4) structures. Relatedly, our group recently identified 301 long genomic stretches significantly enriched for minimal G4 motifs (LG4s) in humans and found the majority of these overlap annotated enhancers, and furthermore, that the promoters regulated by these LG4 enhancers are similarly enriched with G4-capable sequences. While the generally accepted model for enhancer:promoter specificity maintains that interactions are dictated by enhancer- and promoter-bound transcriptional activator proteins, the current study tested an alternative hypothesis: that LG4 enhancers interact with cognate promoters via a direct G4:G4 DNA-based mechanism. This work establishes the nuclear proximity of LG4 enhancer:promoter pairs, biochemically demonstrates the ability of individual LG4 single-stranded DNAs (ssDNAs) to directly interact target promoter ssDNAs, and confirms that these interactions, as well as the ability of LG4 enhancers to activate target promoters in culture, are mediated by G4 DNA.

PMID:39658038 | DOI:10.1093/nar/gkae1180

J Clin Endocrinol Metab. 2024 Dec 9:dgae857. doi: 10.1210/clinem/dgae857. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective therapy that improves lung disease in people with cystic fibrosis (pwCF), but its effect on glucose tolerance and insulin secretion is unclear.

METHODS: PROMISE is a multicenter prospective, observational study of ETI in pwCF ≥12 years and at least one F508del allele. The PROMISE Endocrine sub-study (PROMISE-ENDO) enrolled participants at 10 CF Centers where hemoglobin A1c (HbA1c) was collected and 3-hour oral glucose tolerance tests (OGTT) conducted to examine glucose tolerance, glucose excursions, insulin secretory rates (deconvolution of C-peptide) and sensitivity (oral minimal model) prior to ETI and 12-18 months (mos) and 24-30 mos following ETI initiation. Longitudinal mixed effects models were used to test within-subject ETI effects.

RESULTS: At baseline, 79 participants completed OGTTs [39 (49%) male, median (IQR) age 19.6 (14.7, 27.3) years, BMI z-score 0.12 (-0.51, 0.65)]. At 12-18 mos n=68 and at 24-30 mos n=58 completed OGTTs. At 24-30 mos, fasting glucose (mg/dL) decreased [94 (92, 96) to 90 (88, 93), p=0.02] in the subset not on insulin therapy (n=61), but no differences in 1-hr or 2-hr glucose were found. HbA1c (%) decreased from 5.8 (5.6, 5.9) to 5.5 (5.4, 5.6), p<0.001 by 24-30 mos. Although insulin sensitivity (mU/L-1.min-1) decreased [8.4 (7.2, 9.5) vs. 6.8 (5.8, 7.9), p=0.03], no changes in oral disposition index were found, p=0.14.

CONCLUSIONS: After two years of ETI, fasting glucose and HbA1c showed modest decreases. Glucose tolerance varied, and overall measures of insulin secretion did not deteriorate.

PMID:39657947 | DOI:10.1210/clinem/dgae857

Klin Padiatr. 2024 Dec 10. doi: 10.1055/a-2449-3360. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease that results from mutations in the CFTR gene. It primarily affects the lungs and digestive system. Recent advancements in the treatment of CF have been driven by highly effective therapies that modulate the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which target the underlying molecular defects in CFTR function. These modulators have been demonstrated to significantly improve lung function, weight gain, and quality of life for 90% of individuals with CF, particularly those with the F508del mutation. HEMT has also demonstrated potential benefits for pancreatic and liver function, and its early use in young children may delay or prevent disease progression. However, challenges remain in optimizing biomarkers and outcome measures for younger children, addressing side effects, and developing novel therapies for mutations not responsive to current treatments. This review focuses on the efficacy, safety, and future perspectives of HEMT in children under 12 years of age, emphasizing the importance of early intervention to improve long-term outcomes in CF patients.Mukoviszidose (CF) ist die häufigste genetisch bedingte Stoffwechselerkrankung durch Mutationen im CFTR-Gen. Sie betrifft insbesondere die Lunge und das Verdauungssystem. Die jüngsten Fortschritte in der Behandlung der CF sind das Resultat von hochwirksamen Therapien (HEMT), welche die Funktion des CFTR-Proteins (Cystic Fibrosis Transmembrane Conductance Regulator) modulieren und damit eine kausale Therapie ermöglichen. Diese führt nachweislich zu einer Verbesserung der Lungenfunktion und Gewichtszunahme, sowie einer Steigerung der Lebensqualität bei 90% der Menschen mit Mukoviszidose, insbesondere bei denen, die mindestens eine F508del-Mutation aufweisen. Zusätzlich besteht ein potenzieller Nutzen für die Funktion der Bauchspeicheldrüse und der Leber. Eine frühzeitige Anwendung von HEMT bei Kleinkindern kann das Fortschreiten der Krankheit voraussichtlich weiter verzögern oder gar verhindern. Herausforderungen bestehen in der Etablierung valider Biomarker - insbesondere für jüngere Kinder, unerwünschten Arzneimittelwirkungen und der Entwicklung neuartiger Therapien für Mutationen, die auf die HEMT nicht ansprechen. Die vorliegende Übersichtsarbeit beschreibt die Effektivität und Sicherheit bei Kindern unter 12 Jahren, sowie das zukünftige therapeutische Potential der HEMT. Ein besonderes Augenmerk wird dabei auf die Notwendigkeit eines frühzeitigen Therapiebeginns zur Verbesserung des langfristigen Verlaufs gelegt.

PMID:39657774 | DOI:10.1055/a-2449-3360

Microbiol Spectr. 2024 Dec 10:e0140924. doi: 10.1128/spectrum.01409-24. Online ahead of print.

ABSTRACT

The infectious microenvironment in chronic respiratory tract infections is characterized by substantial variability in nutrient conditions, which may impact colonization and treatment response of pathogens. Metabolic adaptation of the cystic fibrosis (CF)-associated pathogen Pseudomonas aeruginosa has been shown to lead to changes in antibiotic sensitivity. The impact of specific nutrients on the response to antibiotics is, however, poorly characterized. Here, we investigated how different carbon sources impact the antimicrobial pharmacodynamic responses in P. aeruginosa. We evaluated the effect of six antibiotics (aztreonam, ceftazidime, ciprofloxacin, colistin, imipenem, and tobramycin) on P. aeruginosa cultured in a basal medium enriched for seven different carbon sources (alanine, arginine, aspartate, glucose, glutamate, lactate, and proline). Pharmacodynamic responses were characterized by measuring time-kill profiles for a bioluminescent P. aeruginosa PAO1 Xen41 strain. We show that single-nutrient modifications minimally affected bacterial growth rate. For specific nutrient-antibiotic combinations, we find relevant alterations in antibiotic sensitivity (i.e., EC50) and the maximum drug effect (Emax), in particular for ciprofloxacin, colistin, imipenem, and tobramycin. The most pronounced effect was observed for tobramycin, where glucose was found to reduce the EC50 (0.5-fold), whereas lactate-enriched conditions led to a 4.3-fold increase in EC50. Using pharmacokinetic-pharmacodynamic simulations, we illustrate that the magnitude of the nutrient-driven pharmacodynamic changes impact treatment for clinical dosing strategies of tobramycin. In summary, this study underscores the impact of nutrient composition on antimicrobial pharmacodynamics, which could potentially contribute to observed variability of antimicrobial treatment responses in CF patients.IMPORTANCEChronic respiratory tract infections in cystic fibrosis patients present significant challenges for antibiotic treatment due to the complexity of the respiratory environment. This study investigated how variations in nutrient levels, altered during chronic infections, affect pathogen response to antibiotics in an experimental setting. By simulating different nutrient conditions, we aimed to uncover interactions between nutrient availability and antibiotic sensitivity. Our findings provide critical insights that could lead to more effective treatment strategies for managing chronic respiratory tract infections in cystic fibrosis patients while also guiding future research in improving treatment methodologies.

PMID:39656019 | DOI:10.1128/spectrum.01409-24

Microbiol Spectr. 2024 Dec 10:e0169924. doi: 10.1128/spectrum.01699-24. Online ahead of print.

ABSTRACT

Exposure of Pseudomonas aeruginosa to cinnamaldehyde (CNA), a natural electrophilic antimicrobial often used as self-medication to treat mild infections, triggers overproduction of the MexAB-OprM efflux system, leading to multidrug resistance. In this study, we demonstrate that CNA exposure induces expression of genes regulated by the two-component system AmgRS. AmgRS activates MexAB-OprM production, independent of repressors MexR and NalD. In addition to the essential role played by the NalC-ArmR pathway in this adaptive process, AmgRS is critical for the survival of P. aeruginosa challenged with CNA. Altogether, these data suggest that efflux-dependent and -independent mechanisms are activated in the early phase of CNA exposure, allowing for progressive enzymatic reduction of the biocide to non-toxic cinnamic alcohol.IMPORTANCEExposure of Pseudomonas aeruginosa to cinnamaldehyde (CNA), an antimicrobial used in self-medication, induces overproduction of the MexAB-OprM efflux system, leading to multidrug resistance. Our study demonstrates that the AmgRS two-component system aids in the survival of P. aeruginosa strain PA14 under CNA exposure through both MexAB-OprM-dependent and -independent mechanisms until the enzymatic reduction of CNA into the less toxic cinnamic alcohol. This discovery highlights the pivotal role of AmgRS in mediating defense against aldehyde biocides, emphasizing its significance in the persistence of P. aeruginosa, a pathogen associated with hospital-acquired infections and cystic fibrosis, and underscores the potential impact on clinical treatment strategies.

PMID:39656006 | DOI:10.1128/spectrum.01699-24