J Cyst Fibros. 2023 Sep 14:S1569-1993(23)00905-0. doi: 10.1016/j.jcf.2023.09.001. Online ahead of print.

ABSTRACT

BACKGROUND: Dutch newborn screening (NBS) for Cystic Fibrosis (CF) introduced in 2011 showed a sensitivity of 90% and a positive predictive value (PPV) of 63%. We describe a study including an optimization phase and evaluation of the modified protocol.

METHODS: Dutch protocol consists of four steps: determination of immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP), DNA analysis by INNO-LiPA and extended gene analysis (EGA). For the optimization phase we used results of 556,952 newborns screened between April 2011 and June 2014 to calculate effects of 13 alternative protocols on sensitivity, specificity, PPV, ratios of CF to other diagnoses, and costs. One alternative protocol was selected based on calculated sensitivity, PPV and costs and was implemented on 1st July 2016. In this modified protocol DNA analysis is performed in samples with a combination of IRT ≥60 µg/l and PAP ≥3.0 µg/l, IRT ≥100 µg/l and PAP ≥1.2 µg/l or IRT ≥124 µg/l and PAP not relevant. Results of 599,137 newborns screened between 1st July 2016 and 31st December 2019 were similarly evaluated as in the optimization phase.

RESULTS: The modified protocol showed a sensitivity of 95%, PPV of 76%, CF to CF transmembrane conductance regulator-related metabolic syndrome/CF screen positive, inconclusive diagnoses (CRMS/CFSPID) ratio 12/1, CF/CF carrier ratio 4/1. Costs per screened newborn were slightly higher. Eleven children, of whom five with classic CF, would not have been referred with the previous protocol.

CONCLUSIONS: The modified protocol results in acceptable sensitivity (95%) and good PPV of 76% with minimal increase in costs.

PMID:37716879 | DOI:10.1016/j.jcf.2023.09.001

Urology. 2023 Sep 14:S0090-4295(23)00796-3. doi: 10.1016/j.urology.2023.08.039. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the prevalence and treatment rates of low testosterone (T) in men with Cystic Fibrosis (CF). CF is a genetic disease with highly variable presentation that results from a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Phenotypic manifestations of CF include alterations in function of the lungs, liver, pancreas, and reproductive system. Despite the well-described association between CF and infertility secondary to congenital bilateral absence of the vas deferens (CBAVD), men with CF report further sexual and reproductive health concerns, many of which are often associated with low testosterone.

METHODS: We queried the TrinetX database for men over 18 years old with CF or CBAVD to assess what percentage of men had a T level measured, and if hypogonadal (below 300 ng/dL), what percentage received T therapy (TT). We hypothesized that low T would be under-evaluated in the CF population.

RESULTS: Serum T levels were measured in 10.1% of men with CF and 8.9% of men with CBAVD. Within each group, 464 men with CF (32.7%) and 132 with CBAVD (43.0%) demonstrated low T. The majority of men with T<300 ng/dL went on to appropriately receive TT: 59.3% of men with CF and 78% with CBAVD.

CONCLUSION: Our data suggests that hypogonadism is highly prevalent in men with CF and CBAVD. Investigation and appropriate treatment of testosterone deficiency may significantly improve quality of life.

PMID:37716455 | DOI:10.1016/j.urology.2023.08.039

Acta Biochim Biophys Sin (Shanghai). 2023 Sep 15. doi: 10.3724/abbs.2023152. Online ahead of print.

ABSTRACT

The downregulation of adhesion molecule catenin alpha-like 1 (CTNNAL1) in airway epithelial cells of asthma patients and house dust mite (HDM)-induced asthma animal models was illustrated in our previous study. It is assumed to contribute to airway inflammation and mucus hypersecretion. In this work, we further explore the underlying mechanism of CTNNAL1 in asthma. CTNNAL1-silenced female mice exhibit a decreased level of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated and ATP-gated Cl - channel that correlates with mucus hypersecretion. Our previous study demonstrated that ROCK1 expression decreases but ROCK2 expression increases in the lungs of a CTNNAL1-silenced mouse model. Inhibition of ROCK1 leads to a reduction in CFTR expression in CTNNAL1-overexpressing and CTNNAL1-silenced human bronchial epithelial (HBE) cells. It has been reported that ROCK1 is a downstream target of RhoA and that activation of RhoA increases CFTR expression after CTNNAL1 deficiency in vitro and in vivo. The above results indicate that CTNNAL1 regulates CFTR expression through the ROCK1 pathway. In addition, the expression of CFTR-associated ligand (CAL) is increased after CTNNAL1 silencing, and immunoprecipitation results confirm the interaction between ROCK1 and CAL. Inhibition of CAL does not influence ROCK1 expression but increases CFTR expression in CTNNAL1-silenced HBE cells. These data suggest that CTNNAL1 deficiency decreases CFTR expression in the HDM-induced asthma mouse model through the ROCK1-CAL signaling pathway.

PMID:37715489 | DOI:10.3724/abbs.2023152

J Cyst Fibros. 2023 Sep 13:S1569-1993(23)00882-2. doi: 10.1016/j.jcf.2023.08.011. Online ahead of print.

ABSTRACT

BACKGROUND: Mucus stasis, a hallmark of muco-obstructive disease, results from impaired mucociliary transport and leads to lung function decline and chronic infection. Although therapeutics that target mucus stasis in the airway, such as hypertonic saline or rhDNAse, show some therapeutic benefit, they do not address the underlying electrostatic defect apparent in mucins in CF and related conditions. We have previously shown poly (acetyl, arginyl) glucosamine (PAAG, developed as SNSP113), a soluble, cationic polymer, significantly improves mucociliary transport in a rat model of CF by normalizing the charge defects of CF mucin. Here, we report efficacy in the CFTR-sufficient, ENaC hyperactive, Scnn1b-Tg mouse model that develops airway muco-obstruction due to sodium hyperabsorption and airway dehydration.

METHODS: Scnn1b-Tg mice were treated with either 250 µg/mL SNSP113 or vehicle control (1.38% glycerol in PBS) via nebulization once daily for 7 days and then euthanized for analysis. Micro-Optical Coherence Tomography-based evaluation of excised mouse trachea was used to determine the effect on the functional microanatomy. Tissue analysis was performed by routine histopathology.

RESULTS: Nebulized treatment of SNSP113 significantly improved mucociliary transport in the airways of Scnn1b-Tg mice, without altering the airway surface or periciliary liquid layer. In addition, SNSP113 significantly reversed epithelial hypertrophy and goblet cell metaplasia. Finally, SNSP113 significantly ameliorated eosinophilic crystalline pneumonia and lung consolidation in addition to inflammatory macrophage influx in this model.

CONCLUSION: Overall, this study extends the efficacy of SNSP113 as a potential therapeutic to alleviate mucus stasis in muco-obstructive diseases in CF and potentially in related conditions.

PMID:37714777 | DOI:10.1016/j.jcf.2023.08.011

Pediatr Pulmonol. 2023 Sep 15. doi: 10.1002/ppul.26690. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is the most frequent recessive autosomal disorder in the Caucasian population. It is caused by mutations that result in a deficient or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Among CFTR modulators, potentiator compounds increase channel opening, whereas corrector compounds increase CFTR quantity in the cell surface.

OBJECTIVE: To report real-life effects of a generic formulation of lumacaftor-ivacaftor use in patients with CF homozygous for the Phe508del CFTR mutation.

PATIENTS AND METHODS: Clinical variables (body mass index [BMI], pulmonary exacerbations, sweat test, and pulmonary function) were analyzed in 30 CF patients homozygous for the Phe508del CFTR mutation, treated with lumacaftor-ivacaftor for 12 months, at the Respiratory Center of Hospital de Niños Ricardo Gutiérrez. These clinical variables were compared with those before the use of modulators.

RESULTS: A total of 30 patients with CF homozygous for the Phe508del CFTR mutation receiving lumacaftor-ivacaftor therapy were included in this study. The median (interquartile range [IQR]) age at the start of treatment was 10.79 (7.08-14.05) years. Nineteen patients were male. Before treatment, median (IQR) sweat chloride concentration was 80 (72-92) mEq/L, and it had decreased to 74 (68-78) mEq/L (p = .05) 12 months after treatment. Median (IQR) BMI z-score improved from -0.33 (-0.86 to 0.21) to -0.13 (-0.66 to 0.54) (p = .003). A spirometry was performed in 28 of 30 patients. Median (IQR) ppFEV1 was 83.5 (71-91) before treatment and 86.5 (67-103) after treatment (p = .38), 73.3% of patients referred decreased sputum production and 40% reported improvement in their dyspnea at 12 months. Severe pulmonary exacerbations significantly decreased from 60% in the year before treatment, to 30% at 12 months after treatment (p = .037); 13 patients showed an improvement in their exacerbation rates, 2 showed an increased rate, and 15 showed no change.

CONCLUSIONS: The use of a generic formulation of lumacaftor-ivacaftor in patients homozygous for the Phe508del CFTR mutation was associated with improvement in nutritional status and respiratory symptoms, and a significant reduction in severe pulmonary exacerbations.

PMID:37712606 | DOI:10.1002/ppul.26690

Pediatr Pulmonol. 2023 Sep 15. doi: 10.1002/ppul.26678. Online ahead of print.

ABSTRACT

INTRODUCTION: The Cystic Fibrosis Foundation (CF Foundation) recommends the provision of genetic counseling (GC) to help educate families and decrease anxiety around the cystic fibrosis (CF) newborn screening process. Unfortunately, access to genetic counselors is limited, especially for CF trained genetic counselors. We hypothesized that the GC process for families could be improved by utilizing telemedicine to leverage the availability of two dedicated, CF trained genetic counselors to provide access to GC for several CF centers. In addition, we hoped to demonstrate that use of trained CF genetic counselors, delivering GC via telemedicine at the time of sweat testing, would provide families with understanding of CF genetics as well as result in high satisfaction with the newborn screening process.

METHODS: GC was provided by CF trained genetic counselors via telemedicine at the time of sweat testing. Following the counseling session, families were administered an anonymous written survey to evaluate their impression of the services provided. A subset of 50 families was recruited for an assessment of gained knowledge regarding CF genetics using the Ciske knowledge inventory. Using χ2 analysis, Ciske knowledge inventory data from our telemedicine GC families was compared to counseled and uncounseled Ciske historical controls. Lastly, in-depth interviews about the newborn screening process for CF were performed with 10 families and interviews were coded for emerging themes.

RESULTS: During the 4 years of the study, 250 patients received GC. Overall comfort with the counseling rated 4.77 out of 5 using a Likert scale. After counseling by telemedicine, parents demonstrated improved understanding of the genetic implications of an abnormal CF newborn screen for their family, with 100% of families understanding that their child was a carrier for CF as compared to 97.2% of counseled (p = .023) and 78.5% of uncounseled (p = .0007) from Ciske historical controls. The study group also showed improvement in understanding of both parents possibly being carriers, with an 87.7% correct response rate compared to a 37.0% correct response rate in the counseled group (p < .0001) and a 35.4% correct response rate in the non-counseled group (p < .0001) from Ciske historical controls. Subgroup analysis at one site showed a significant increase in the number of infants with completed sweat tests from previous years (49% in 2013 vs. 80% in 2017 during the study, p < .0001).

CONCLUSIONS: GC by telemedicine was well received by families and demonstrated improved family knowledge acquisition and understanding of CF as it related to risks for their child as well as identification of risks for other family members. Furthermore, in addition to an increase is those receiving GC, a subgroup analysis demonstrated a significant increase in the number of infants receiving sweat tests. This study demonstrates that GC via telemedicine for CF is feasible and demonstrates improvement in parent understanding of CF genetics. Furthermore, this method can be implemented effectively across a wide geographical area with a limited number of CF trained genetic counselors to improve access to care for patients and families.

PMID:37712603 | DOI:10.1002/ppul.26678

Front Endocrinol (Lausanne). 2023 Aug 29;14:1244127. doi: 10.3389/fendo.2023.1244127. eCollection 2023.

ABSTRACT

Cystic fibrosis (CF) is a life-threatening inherited disease related to a mutation in the CFTR gene, that leads to serious health complications such as chronic pulmonary infections, pancreatic insufficiency, dysfunction of the sweat glands and reproductive system. For the first time, we have described the profile of corticosterone and androgen metabolites in urine, as well as the activity of enzymes involved in steroid genesis and metabolism in people with CF, using gas chromatography/mass spectrometry. A significant reduction in the excretion of most of the measured metabolites in CF was found. These differences were observed in the group of progestagen metabolites, as well as among metabolites of corticosterone and androgens. We revealed higher activities of 17β-hydroxysteroid dehydrogenase and 17,20-lyase in the Δ4 pathway compared with controls, what can promote the androgen synthesis through the backdoor androgen pathway. We have also found the increased conversion activity of 11-oxyganated steroids by 5a-reductase in backdoor pathway. Levels of the most potent and vital androgens (testosterone and dihydrotestosterone) are comparable in both groups. However, the excretion of dehydroepiandrosterone was lower in CF. Decreased cholesterol lipoprotein levels may contribute to limited intracellular cholesterol supply and reduced adrenal steroidogenesis in CF individuals. Changes in the activity of some steroidogenesis enzymes may suggest the presence of some peripheral adaptive mechanisms in CF to maintain androgen balance in the body despite the limited sufficiency of secretion by the adrenal cortex.

PMID:37711888 | PMC:PMC10497873 | DOI:10.3389/fendo.2023.1244127

Respirol Case Rep. 2023 Sep 13;11(10):e01221. doi: 10.1002/rcr2.1221. eCollection 2023 Oct.

ABSTRACT

Six years ago, a 60-year-old man presented to our hospital with a cough and sputum. Upon suspicion of nontuberculous mycobacterial (NTM) infection, he was followed up at our hospital. Because the abnormal shadows in the bilateral lung fields deteriorated slightly over 6 years, bronchoscopy was performed. Exophiala dermatitidis and Mycobacterium intracellulare were detected in the bronchial lavage fluid. The patient underwent follow-up examinations without drug administration. Currently, the patient's condition remains stable. E. dermatitidis is regulatory found in the lungs of patients with cystic fibrosis, but only rarely is it found in respiratory samples from patients without cystic fibrosis. However, NTM complications have been reported more frequently in recent years. Due to the increasing number of NTM patients, E. dermatitidis pulmonary infections may also increase. Additional research is required to develop strategies for treating this infection.

PMID:37711651 | PMC:PMC10498155 | DOI:10.1002/rcr2.1221

Biofilm. 2023 Sep 4;6:100153. doi: 10.1016/j.bioflm.2023.100153. eCollection 2023 Dec 15.

ABSTRACT

Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia are notorious pathogens known for their ability to form resilient biofilms, particularly within the lung environment of cystic fibrosis (CF) patients. The heightened concentration of NaCl, prevalent in the airway liquid of CF patients' lungs, has been identified as a factor that promotes the growth of osmotolerant bacteria like S. aureus and dampens host antibacterial defenses, thereby fostering favorable conditions for infections. In this study, we aimed to investigate how increased NaCl concentrations impact the development of multi-species biofilms in vitro, using both laboratory strains and clinical isolates of P. aeruginosa, S. aureus, and B. cepacia co-cultures. Employing a low-nutrient culture medium that fosters biofilm growth of the selected species, we quantified biofilm formation through a combination of adherent CFU counts, qPCR analysis, and confocal microscopy observations. Our findings reaffirmed the challenges faced by S. aureus in establishing growth within 1:1 mixed biofilms with P. aeruginosa when cultivated in a minimal medium. Intriguingly, at an elevated NaCl concentration of 145 mM, a symbiotic relationship emerged between S. aureus and P. aeruginosa, enabling their co-existence. Notably, this hyperosmotic environment also exerted an influence on the interplay of these two bacteria with B. cepacia. We demonstrated that elevated NaCl concentrations play a pivotal role in orchestrating the distribution of these three species within the biofilm matrix. Furthermore, our study unveiled the beneficial impact of NaCl on the biofilm growth of clinically relevant mucoid P. aeruginosa strains, as well as two strains of methicillin-sensitive and methicillin-resistant S. aureus. This underscores the crucial role of the microenvironment during the colonization and infection processes. The results suggest that hyperosmotic conditions could hold the key to unlocking a deeper understanding of the genesis and behavior of CF multi-species biofilms.

PMID:37711514 | PMC:PMC10497989 | DOI:10.1016/j.bioflm.2023.100153

J Clin Res Pediatr Endocrinol. 2023 Sep 15. doi: 10.4274/jcrpe.galenos.2023.2023-2-12. Online ahead of print.

ABSTRACT

Early detection of glycemic dysregulation and optimization of glycemic control at cystic fibrosis related diabetes (CFRD) is associated with improved pulmonary function and decreased mortality. The standard 2-hour oral glucose tolerance test (OGTT) is the current routine screening test for CFRD. However, hyperglycemia can be detected by continuous glucose monitoring systems (CGMS) in patients with normal OGTT evaluation. High-dose acarbose is an important alternative, in the treatment of glycemic dysregulation especially accompanied by hypoglycemia. A 7-year-old boy with cystic fibrosis (CF) presented with hyperglycemia. Hypoglycemia (29 mg/dL) and hyperglycemia (400 mg/dL) were demonstrated by OGTT and intermittent CGM (iCGMS). Thickener was added to nutritional solutions and acarbose was initiated as 3x12.5 mg /dose and increased to 6x25 mg without any side effects. On the 20th day of treatment, glycemic dysregulation was resolved. In the early detection of CFRD, screening with OGTT after the age of 10 is insufficient; therefore, routine use of continous or intermittent glucose monitoring systems should be considered. In addition, in CFRDs with severe hypoglycemia, acarbose is an important alternative in the high and increased dose range.

PMID:37710956 | DOI:10.4274/jcrpe.galenos.2023.2023-2-12

Nature. 2023 Sep 14. doi: 10.1038/d41586-023-02890-1. Online ahead of print.

NO ABSTRACT

PMID:37709973 | DOI:10.1038/d41586-023-02890-1

Sci Rep. 2023 Sep 14;13(1):15236. doi: 10.1038/s41598-023-42198-8.

ABSTRACT

Modification of proteins with a broad range of chemical functionalities enables the investigation of protein structure and activity by manipulating polypeptides at single amino acid resolution. Indeed, various functional groups including bulky non-canonical amino acids like strained cyclooctenes could be introduced by the unique features of the binding pocket of the double mutant pyrrolysyl-tRNA synthetase (Y306A, Y384F), but the instable nature of the enzyme limits its application in vivo. Here, we constructed a cell-free protein production system, which increased the overall enzyme stability by combining different reaction compartments. Moreover, a co-expression approach in a one-pot reaction allowed straightforward site-specific fluorescent labeling of the functional complex membrane protein cystic fibrosis transmembrane conductance regulator. Our work provides a versatile platform for introducing various non-canonical amino acids into difficult-to-express proteins for structural and fluorescence based investigation of proteins activity.

PMID:37709815 | DOI:10.1038/s41598-023-42198-8

J Cyst Fibros. 2023 Sep 12:S1569-1993(23)00881-0. doi: 10.1016/j.jcf.2023.08.012. Online ahead of print.

ABSTRACT

Cystic fibrosis arthropathy (CFA) is a transient, intermittent form of arthritis that cannot be associated with any other disease other than CF thus making CFA a diagnosis of exclusion. NSAIDs, short-term intermittent splinting, glucocorticoids, and disease-modifying anti-rheumatic drugs are treatment options for CFA. Currently, there is no consensus on how to best treat CFA. Diagnosis and treatment of CFA remain a challenge for physicians and people with CF. The newest CFTR modulator therapy, elexacaftor/tezacaftor/ivacaftor (ETI), was approved by the FDA recently for children over the age of 6 with at least one Phe508del allele in the CFTR gene. Multiple clinical benefits of ETI in pulmonary functions and overall disease burden have been reported since its approval, however, the data on the musculoskeletal therapeutic benefits of ETI has been limited. In this report, we present a 7-year-old female with CF whose CFA symptoms resolved after starting ETI therapy.

PMID:37709627 | DOI:10.1016/j.jcf.2023.08.012

Int J Chron Obstruct Pulmon Dis. 2023 Sep 8;18:1959-1964. doi: 10.2147/COPD.S428391. eCollection 2023.

ABSTRACT

The complexity of COPD implies the need to identify groups of patients with similar clinical characteristics and prognosis or treatment requirements. This is why much attention has been paid to identifying the different clinical phenotypes by investigating the clinical expression of the disease, and endotypes by studying the biological networks that enable and limit reactions. However, this approach is complicated because one endotype gives rise to one or more clinical characteristics, and clinical phenotypes can be derived from several endotypes. To simplify the approach, a new taxonomic classification of COPD based on the different causes (or etiotypes) has been proposed, but these etiotypes have not yet been validated. A simpler method is the so-called tractable traits approach, which is free from any designation of the disorder to be treated and does not present the criticality of using etiotypes. A large randomised controlled trial on using the treatable traits approach in COPD is still lacking. Nevertheless, this approach is already applied by following the GOLD strategy. However, its application is complicated because several potentially treatable traits have been identified within the pulmonary domain, the extrapulmonary domain, and the behavioural/risk factor domain. In addition, the hierarchy of the dominant treatable traits has not yet been established, and they change over time both spontaneously and because of treatment. This means that the patients being treated according to the tractable traits approach must be constantly followed over time so that the therapy is focused on their temporal needs.

PMID:37705673 | PMC:PMC10497043 | DOI:10.2147/COPD.S428391

J Clin Transl Endocrinol. 2023 Aug 25;33:100323. doi: 10.1016/j.jcte.2023.100323. eCollection 2023 Sep.

ABSTRACT

BACKGROUND: Cystic fibrosis related diabetes (CFRD) is associated with insulin-remediable pulmonary decline, so early detection is critical. Continuous glucose monitors (CGM) have shown promise in screening but are not recommended by clinical practice guidelines. Little is known about the reproducibility of CGM results for a given patient.

METHODS: Twenty non-insulin treated adults and adolescents with CF placed an in-home CGM and wore it for two 14-day periods. Participants underwent a mixed meal tolerance test (MMTT) on day 5 of each 14-day period. Glycemic data from CGM 1 and CGM 2 were compared regarding published thresholds to define abnormality: percent time >140 mg/dL of ≥4.5%, percent time >140 mg/dL of >17.5%, and percent time >180 mg/dL of >3.4%. Results of the repeat MMTT were compared for peak glucose and 2-hour glucose thresholds: >140 mg/dL, >180 mg/dL, and >200 mg/dL.

RESULTS: For percent time >140 mg/dL of ≥ 4.5%, five of 20 subjects had conflicting results between CGM 1 and CGM 2. For percent time >140 mg/dL of >17.5% and >180 mg/dL of >3.4%, only one of 20 subjects had conflicting results between CGM 1 and CGM 2. On the MMTT, few participants had a 2-hour glucose >140 mg/dL. Peak glucose >140 mg/dL, 180 mg/dL, and 200 mg/dL were more common, with 10-37% of participants demonstrating disagreement between CGM 1 and CGM 2.

CONCLUSIONS: Repeated in-home CGM acquisitions show reasonable reproducibility regarding the more stringent thresholds for time >140 mg/dL and >180 mg/dL. More data is needed to determine thresholds for abnormal mixed meal tolerance tests in CFRD screening.

PMID:37705602 | PMC:PMC10495624 | DOI:10.1016/j.jcte.2023.100323

J Pediatr Gastroenterol Nutr. 2023 Sep 14. doi: 10.1097/MPG.0000000000003945. Online ahead of print.

ABSTRACT

Refeeding syndrome (RS) is characterized by electrolyte imbalances that can occur in malnourished and abruptly refed patients. Typical features of RS are hypophosphatemia, hypokalemia, hypomagnesemia and thiamine deficiency. It is a potentially life-threatening condition that can affect both adults and children, although there is scarce evidence in the pediatric literature. The sudden increase in food intake causes a shift in the body's metabolism and electrolyte balance, leading to symptoms such as weakness, seizures, and even heart failure. A proper management with progressive increase in nutrients is essential to prevent the onset of this condition and ensure the best possible outcomes. Moreover, an estimated incidence of up to 7.4% has been observed in pediatric intensive care unit patients receiving nutritional support, alone or as an adjunct. To prevent RS, it is important to carefully monitor feeding resumption, particularly in severely malnourished individuals. A proper strategy should start with small amounts of low-calorie fluids and gradually increasing the calorie content and amount of food over several days. Close monitoring of electrolyte levels is critical and prophylactic use of dietary supplements such as thiamine may be required to correct any imbalances that may occur. In this narrative review, we aim to provide a comprehensive understanding of RS in pediatric clinical practice and provide a possible management algorithm.

PMID:37705405 | DOI:10.1097/MPG.0000000000003945

J Biol Chem. 2023 Sep 11:105247. doi: 10.1016/j.jbc.2023.105247. Online ahead of print.

ABSTRACT

Dihydroxy acid leukotriene (LTB4) and cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are inflammatory mediators derived from arachidonic acid via the 5-lipoxygenase pathway. While structurally similar, these two types of leukotrienes exert their functions through interactions with two distinct G -protein-coupled receptor (GPCR) families, BLT and CysLT receptors, which share low sequence similarity and belong to phylogenetically divergent GPCR groups. Selective antagonism of leukotriene receptors has been proposed as a promising strategy for the treatment of many inflammation-related diseases including asthma and COPD, rheumatoid arthritis, cystic fibrosis, diabetes, and several types of cancer. Selective CysLT1R antagonists are currently used as anti-asthmatic drugs, however, there are no approved drugs targeting CysLT2 and BLT receptors. In this review we highlight recently published structures of BLT1R and CysLTRs revealing unique structural features of the two receptor families. X-ray and cryo-EM data shed light on their overall conformations, differences in functional motifs involved in receptor activation and details of the ligand binding pockets. An unexpected binding mode of the selective antagonist BIIL260 in the BLT1R structure makes it the first example of a compound targeting the sodium binding site of GPCRs and suggests a novel strategy for the receptor activity modulation. Taken together, these recent structural data reveal dramatic differences in the molecular architecture of the two leukotriene receptor families and pave the way to new therapeutic strategies of selective targeting individual receptors with novel tool compounds obtained by the structure-based drug design approach.

PMID:37703990 | DOI:10.1016/j.jbc.2023.105247

J Cyst Fibros. 2023 Sep 11:S1569-1993(23)00907-4. doi: 10.1016/j.jcf.2023.09.003. Online ahead of print.

ABSTRACT

BACKGROUND: Outcomes of cystic fibrosis (CF) differ between low-middle income and high-income countries, but comparative data are lacking. We compared South African (SA) and Canadian CF outcomes to explore what disparities existed prior to access of CFTR modulators in Canada.

METHODS: A cross-sectional study of SA and Canadian CF registries data for period 1 January to 31 December 2018. CF registry data were harmonised between countries to compare lung function and nutrition outcomes. Poor nutrition was defined as BMIz-score < -1 in children and < 18.5 kg/m2 in adults. Standardised mean difference (SMD) >10 was considered significant.

RESULTS: After excluding Canadians on CFTR modulators and lung transplant recipients, data on 4049 Canadian and 446 SA people was analysed. Compared to Canada, people in SA were younger (median age 15.8 years vs. 24.1 years: SMD 52) with fewer males (47.8% vs 54.2%; SMD 12.5) and White (70.9% vs. 93.3%; SMD 61.3). Class I-III CFTR mutation frequency was similar in SA (n = 384, 86.1%) and Canada (n = 3426, 84.9%). After adjusting for age, gender, diagnosis age, genotype, P.aeruginosa infection and pulmonary treatments, FEV1pp was 8.9% lower (95% CI 6.3% to 11.4%) and poor nutrition 1.7-fold more common (OR 1.70; 95% CI 1.19-2.41) in SA compared to Canada.

CONCLUSION: Lung function and nutrition was significantly lower in SA compared to Canada. Global disparities in CF outcomes between high and low-middle income countries are likely to widen as CFTR modulators are rapidly scaled up in only high-income countries.

PMID:37704465 | DOI:10.1016/j.jcf.2023.09.003

J Cyst Fibros. 2023 Sep 11:S1569-1993(23)00906-2. doi: 10.1016/j.jcf.2023.09.002. Online ahead of print.

ABSTRACT

BACKGROUND: We previously discovered that Korean red ginseng aqueous extract (RGAE) potentiates the TMEM16A channel, improved mucociliary transport (MCT) parameters in CF nasal epithelia in vitro, and thus could serve as a therapeutic strategy to rescue the MCT defect in cystic fibrosis (CF) airways. The hypothesis of this study is that RGAE can improve epithelial Cl- secretion, MCT, and histopathology in an in-vivo CF rat model.

METHODS: Seventeen 4-month old CFTR-/- rats were randomly assigned to receive daily oral control (saline, n = 9) or RGAE (Ginsenosides 0.4mg/kg/daily, n = 8) for 4 weeks. Outcomes included nasal Cl- secretion measured with the nasal potential difference (NPD), functional microanatomy of the trachea using micro-optical coherence tomography, histopathology, and immunohistochemical staining for TMEM16a.

RESULTS: RGAE-treated CF rats had greater mean NPD polarization with UTP (control = -5.48 +/- 2.87 mV, RGAE = -9.49 +/- 2.99 mV, p < 0.05), indicating, at least in part, potentiation of UTP-mediated Cl- secretion through TMEM16A. All measured tracheal MCT parameters (airway surface liquid, periciliary liquid, ciliary beat frequency, MCT) were significantly increased in RGAE-treated CF rats with MCT exhibiting a 3-fold increase (control, 0.45+/-0.31 vs. RGAE, 1.45+/-0.66 mm/min, p < 0.01). Maxillary mucosa histopathology was markedly improved in RGAE-treated cohort (reduced intracellular mucus, goblet cells with no distention, and shorter epithelial height). TMEM16A expression was similar between groups.

CONCLUSION: RGAE improves TMEM16A-mediated transepithelial Cl- secretion, functional microanatomy, and histopathology in CF rats. Therapeutic strategies utilizing TMEM16A potentiators to treat CF airway disease are appropriate and provide a new avenue for mutation-independent therapies.

PMID:37704464 | DOI:10.1016/j.jcf.2023.09.002

Am J Respir Crit Care Med. 2023 Sep 13. doi: 10.1164/rccm.202308-1317OC. Online ahead of print.

ABSTRACT

RATIONALE: Clinical trials have shown that use of Elexacaftor/Tezacaftor/Ivacaftor (ETI) is associated with improvements in sweat chloride, pulmonary function, nutrition and quality of life in people with CF. Little is known about the impact of ETI on ventilation inhomogeneity and lung structure.

OBJECTIVES: RECOVER is a real-world study, designed to measure the impact of ETI in people with CF. The primary endpoints were lung clearance (LCI2.5) and FEV1. Secondary endpoints included spirometry-controlled chest CT scores.

METHODS: The study was conducted in seven sites in Ireland and the UK. Participants 12 years and older homozygous for the F508del mutation (F508del/F508del)) or heterozygous for F508del and a minimum function mutation (F508del/MF) were recruited prior to starting ETI and followed up over 12 months. LCI2.5 was measured using nitrogen multiple breath washout (MBW) at baseline, 6 and 12 months. Spirometry was performed as per ERS/ATS criteria. Spirometry controlled Chest CT scans were performed at baseline and 12 months. CT scans were scored using the Perth Rotterdam Annotated Grid Morphometric Analysis (PRAGMA) system. Other outcome measures include weight, height, Cystic Fibrosis Quality of Life, Revised (CFQ-R) questionnaire and sweat chloride.

MEASUREMENTS AND MAIN RESULTS: 117 people with CF aged 12 and above were recruited to the study. Significant improvements were seen in LCI (-2.5, 95%CI -3.0, -2.0) and ppFEV1 (8.9, 95%CI 7.0 - 10.9), ppFVC (6.6, 95%CI 4.9 - 8.3) and ppFEF25-75% (12.4, 95%CI 7.8 - 17.0). Overall PRAGMA-CF scores reflecting airways disease (-3.46 , 95%CI -5.23 , -1.69). Scores for trapped air, mucus plugging and bronchial wall thickening improved significantly, but bronchiectasis scores did not. Sweat chloride levels decreased in both F508del/F508del (-43.1, 95%CI -47.4, -38.9) and F508del/MF (-42.8, 95%CI -48.5, -37.2) groups. CFQ-R Respiratory Domain (RD) scores improved by 14.2 points (95%CI 11.3, 17.2). At one year, sweat chloride levels were significantly lower in the F508del/F508del group compared to the F508del/MF group (33.93 v. 53.36, p<0.001).

CONCLUSIONS: ETI is associated with substantial improvements in LCI2.5, spirometry and PRAGMA-CF CT scores in people with CF aged 12 years and older. ETI led to improved nutrition and quality of life. People in the F508del/F508del group have significantly lower sweat chloride on ETI treatment compared to the F508del/MF group. Clinical trial registration available at www.

CLINICALTRIALS: gov, ID: NCT04602468.

PMID:37703083 | DOI:10.1164/rccm.202308-1317OC