Indian J Clin Biochem. 2023 Oct;38(4):550-552. doi: 10.1007/s12291-021-01010-y. Epub 2021 Oct 7.

ABSTRACT

Pseudo-Bartter's (PB) syndrome is characterized by hypokalemic metabolic alkalosis and failure to thrive which constitutes a rare but typical presentation of cystic fibrosis (CF) in children. The most common mutation of CF is F508del, due to loss of 3 base pairs, causing deletion of phenylalanine, at position 508. We present a case of CF presenting with failure to thrive, dehydration, PB syndrome associated with urosepsis and primo-colonization with Escherichia coli suggesting the role of epigenetic factors. The heterozygous state for Phe508del mutation in Exon 11 combination with Glu92Ala in Exon 4 resulted in epigenetic effect on atypical phenotype as PBS, a novel mutation identified in our case.

PMID:37746536 | PMC:PMC10516826 | DOI:10.1007/s12291-021-01010-y

bioRxiv. 2023 Sep 16:2023.09.15.556420. doi: 10.1101/2023.09.15.556420. Preprint.

ABSTRACT

Over 80% of people with cystic fibrosis (CF) carry the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel at the apical plasma membrane (PM) of epithelial cells. F508del impairs CFTR folding causing it to be destroyed by endoplasmic reticulum associated degradation (ERAD). Small molecule correctors, which act as pharmacological chaperones to divert CFTR-F508del from ERAD, are the primary strategy for treating CF, yet corrector development continues with only a rudimentary understanding of how ERAD targets CFTR-F508del. We conducted genome-wide CRISPR/Cas9 knockout screens to systematically identify the molecular machinery that underlies CFTR-F508del ERAD. Although the ER-resident ubiquitin ligase, RNF5 was the top E3 hit, knocking out RNF5 only modestly reduced CFTR-F508del degradation. Sublibrary screens in an RNF5 knockout background identified RNF185 as a redundant ligase, demonstrating that CFTR-F508del ERAD is highly buffered. Gene-drug interaction experiments demonstrated that correctors tezacaftor (VX-661) and elexacaftor (VX-445) stabilize sequential, RNF5-resistant folding states. We propose that binding of correctors to nascent CFTR-F508del alters its folding landscape by stabilizing folding states that are not substrates for RNF5-mediated ubiquitylation.

SIGNIFICANCE STATEMENT: Clinically effective small molecule cystic fibrosis (CF) correctors divert mutant CFTR molecules from ER-associated degradation (ERAD). However, the mechanisms underlying CFTR ERAD are not well-understood.The authors used CRISPR knockout screens to identify ERAD machinery targeting CFTR-F508del and found that the pathway is highly buffered, with RNF185 serving as a redundant ubiquitin ligase for RNF5. Gene-drug interaction experiments demonstrated that correctors act synergistically by stabilizing sequential RNF5-resistant folding states.Inhibiting proteostasis machinery is a complementary approach for enhancing current CF corrector therapies.

PMID:37745470 | PMC:PMC10515913 | DOI:10.1101/2023.09.15.556420

bioRxiv. 2023 Sep 12:2023.09.09.557002. doi: 10.1101/2023.09.09.557002. Preprint.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify novel CFTR modulators. We docked ∼155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered novel mid-nanomolar potentiators as well as inhibitors that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.

PMID:37745391 | PMC:PMC10515777 | DOI:10.1101/2023.09.09.557002

Ann Epidemiol. 2023 Sep 22:S1047-2797(23)00180-1. doi: 10.1016/j.annepidem.2023.09.006. Online ahead of print.

ABSTRACT

PURPOSE: To assess the distribution and clustering of COVID-19 testing and incidence over space and time, U.S. Department of Veteran's Affairs (VA) data were used to describe where and when Veterans experienced highest proportions of test positivity.

METHODS: Data for 6,342,455 Veterans who utilized VA services between January 1, 2018 and September 30, 2021 were assessed for COVID-19 testing and test positivity. Testing and positivity proportions by county were mapped and focused-cluster tests identified significant clustering aroung VA facilities. Spatial cluster analysis also identified where and when Veterans experienced highest proportions of test positivity.

RESULTS: Within the Veterans study population and our time window, 21.3% received at least one COVID-19 test, and 20.4% of those tested had at least one positive test. There was statistically significant clustering of testing around VA facilities, revealing regional variation in testing practices. Veterans experienced highest test positivity proportions between November 2020 and January 2021 in a cluster of states in the Midwest, compared to those who received testing outside of the identified cluster (RR: 3.45).

CONCLUSION: Findings reflect broad regional trends in COVID-19 positivity which can inform VA policy and resource allocation. Additional analysis is needed to understand patterns during Delta and Omicron variant periods.

PMID:37742880 | DOI:10.1016/j.annepidem.2023.09.006

Eur J Pharmacol. 2023 Sep 22:176047. doi: 10.1016/j.ejphar.2023.176047. Online ahead of print.

ABSTRACT

Uncontrolled inflammation leads to nonspecific destruction and remodeling of tissues and can contribute to many human pathologies, including pulmonary diseases. Stimulation of inflammatory resolution is considered an important process that protects against the progression of chronic inflammatory diseases. Resolvins generated from essential omega-3 polyunsaturated fatty acids have been demonstrated to be signaling molecules in inflammation with important pro-resolving and anti-inflammatory capabilities. By binding to specific receptors, resolvins can modulate inflammatory processes such as neutrophil migration, macrophage phagocytosis and the presence of pro-inflammatory mediators to reduce inflammatory pathologies. The discovery of these pro-resolving mediators has led to a shift in drug research from suppressing pro-inflammatory molecules to investigating compounds that promote resolution to treat inflammation. The exploration of inflammatory resolution also provided the opportunity to further understand the pathophysiology of pulmonary diseases. Alterations of resolution are now linked to both the development and exacerbation of diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, acute respiratory distress syndrome, cancer and COVID-19. These findings have resulted in the rise of novel design and testing of innovative resolution-based therapeutics to treat diseases. Hence, this paper reviews the generation and mechanistic actions of resolvins and investigates their role and therapeutic potential in several pulmonary diseases that may benefit from resolution-based pharmaceuticals.

PMID:37742814 | DOI:10.1016/j.ejphar.2023.176047

Life Sci. 2023 Sep 22:122121. doi: 10.1016/j.lfs.2023.122121. Online ahead of print.

ABSTRACT

Vasoactive intestinal peptide (VIP) is an abundant neurotransmitter in the lungs and other organs. Its discovery dates back to 1970. And VIP gains attention again due to the potential application in COVID-19 after a research wave in the 1980s and 1990s. The diverse biological impacts of VIP extend beyond its usage in COVID-19 treatment, encompassing its involvement in various pulmonary and systemic disorders. This review centers on the function of VIP in various lung diseases, such as pulmonary arterial hypertension, chronic obstructive pulmonary disease, asthma, cystic fibrosis, acute lung injury/acute respiratory distress syndrome, pulmonary fibrosis, and lung tumors. This review also outlines two main limitations of VIP as a potential medication and gathers information on extended-release formulations and VIP analogues.

PMID:37742737 | DOI:10.1016/j.lfs.2023.122121

Respir Res. 2023 Sep 23;24(1):228. doi: 10.1186/s12931-023-02535-x.

NO ABSTRACT

PMID:37742000 | DOI:10.1186/s12931-023-02535-x

Appl Microbiol Biotechnol. 2023 Sep 23. doi: 10.1007/s00253-023-12772-1. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an emerging threat for hospitalized and cystic fibrosis patients. Biofilm, a microbial community embedded in extracellular polymeric substance, fortifies bacteria against the immune system. In biofilms, the expression of functional amyloids is linked with highly aggregative, multi-resistant strains, and chronic infections. Serrapeptase (SPT), a protease possessing similar or superior anti-microbial properties with many antibiotics, presents anti-amyloid potential. However, studies on the employment of SPT against Pseudomonas biofilms and Fap amyloid, or the possible mechanisms of action are scarce. Here, SPT inhibited biofilm formation of P. aeruginosa ATCC 27853 on both plastic and glass surfaces, with an IC50 of 11.26 µg/mL and 0.27 µg/mL, respectively. The inhibitory effect of SPT on biofilm was also verified with optical microscopy of crystal violet-stained biofilms and with confocal microscopy. Additionally, SPT caused a dose-dependent decrease of bacterial viability (IC50 of 3.07 µg/mL) as demonstrated by MTT assay. Reduction of bacterial functional amyloids was also demonstrated, employing both fluorescence microscopy with thioflavin T and photometrical determination of Congo-red-positive compounds. Both viability and functional amyloids correlated significantly with biofilm inhibition. Finally, in silico molecular docking studies provided a mechanistic insight into the interaction of SPT with FapC or FapD, proving that both peptides are possible targets of SPT. These results offer new insights into the biofilm formation of P. aeruginosa and potentiate the involvement of SPT in the prevention and eradication of Pseudomonas biofilms. KEY POINTS: • Serrapeptase inhibits biofilm formation of P. aeruginosa on plastic and glass. • Biofilm inhibition correlated with reduced viability and functional amyloid levels. • In silico studies indicated that serrapeptase may target FapC and FapD peptides.

PMID:37741938 | DOI:10.1007/s00253-023-12772-1

Prostaglandins Leukot Essent Fatty Acids. 2023 Sep 16;197:102590. doi: 10.1016/j.plefa.2023.102590. Online ahead of print.

ABSTRACT

BACKGROUND: Sphingolipid species in the lung epithelium have a critical role for continuity of membrane structure, vesicular transport, and cell survival. Sphingolipid species were reported to have a role in the inflammatory etiology of cystic fibrosis by previous work. The aim of the study was to investigate the levels of plasma sphingomyelin and ceramide in adult cystic fibrosis (CF) patients and compared with healthy controls.

MATERIALS AND METHODS: Blood samples were obtained from CF patients at exacerbation (n = 15), discharge (n = 13) and stable periods (n = 11). Healthy individuals (n = 15) of similar age served as control. Levels of C16-C24 sphingomyelin and C16-C24 ceramide were measured in the plasma by LC-MS/MS. Also, cholesterol and triglyceride levels were determined in plasma samples of the patients at stable period.

RESULTS: All measured sphingomyelin and ceramide levels in all periods of CF patients were significantly lower than healthy controls except C16 sphingomyelin level in the stable period. However, plasma Cer and SM levels among exacerbation, discharge, and stable periods of CF were not different. CF patients had significantly lower cholesterol levels compared to healthy individuals. We found significant correlation of cholesterol with C16 sphingomyelin.

CONCLUSION: We observed lower plasma Cer and SM levels in adult CF patients at exacerbation, discharge, and stable periods compared to healthy controls. We didn't find any significant difference between patient Cer and SM levels among these three periods. Our limited number of patients might have resulted with this statistical insignificance. However, percentage of SM16 levels were increased at discharge compared to exacerbation levels, while percentage of Cer16 and Cer 20 decreased at stable compared to exacerbation. Inclusion of a larger number of CF patients in such a follow up study may better demonstrate any possible difference between exacerbation, discharge, and stable periods.

PMID:37741047 | DOI:10.1016/j.plefa.2023.102590

J Dent Educ. 2023 Sep 22. doi: 10.1002/jdd.13376. Online ahead of print.

ABSTRACT

PURPOSE: To improve health equity, dental and medical students must have a firm grasp of the proper use of race as a social construct. The purpose of this study was to determine the degree to which an innovative learning event affected students' understanding of race as a social construct. It also sought to examine the effects that personally experienced and/or witnessed racism and previous education had on students' responses to the learning event.

METHODS: In 2022, all incoming first-year dental (N = 48) and medical (N = 114) students completed an online pre-matriculation assignment about the use of race in healthcare. Students initially completed an anonymous 14-item pre-survey and then read assigned publications, followed by answering questions about a real-life vignette concerning the topic of race as a social construct. Students finished the assignment by completing an anonymous seven-item post-survey. Data from the pre- and post-surveys were collected and analyzed to assess if differences existed among students and between the two surveys.

RESULTS: Dental and medical students were significantly more likely to endorse race as a social construct after the learning experience (p < 0.001). Students who had experienced discrimination or obtained training were more likely to define race as a social construct before and after the learning event.

CONCLUSION: Dental and medical schools can increase students' understanding of race as a social construct, rather than a biological construct, with educational interventions.

PMID:37740558 | DOI:10.1002/jdd.13376

BMJ Case Rep. 2023 Sep 22;16(9):e255502. doi: 10.1136/bcr-2023-255502.

ABSTRACT

A boy presented with cough, breathlessness for 1 month, fever for 1 week with similar previous episodes without hospitalisation. He had generalised muscle wasting, acute chronic malnutrition and required immediate ventilation. Provisional diagnosis of recurrent pneumonia with failure to thrive was made. As serial chest X-rays showed recurrent lung collapse, congenital lung anomalies were ruled out. 2D-echocardiography showed pulmonary arterial hypertension. Workup for congenital immunodeficiency and cystic fibrosis was negative. There was no improvement in muscle mass despite total parenteral nutrition. He was noticed to have myopathic facies. History was reviewed when the mother reported reduced fetal movements in this pregnancy. The patient had low voice amplitude. Creatine kinase levels were normal. Muscle biopsy followed by whole exome sequencing identified frameshift duplication NM_020451.3(SELENON):c.249_250dupGG (p.Asp84Glyfs*17), thus, confirming diagnosis of SEPN1-related congenital myopathy (CM) with fibre-type disproportion. Respiratory system involvement was distracter, emphasising consideration of CM while evaluating persistent lung collapse with muscle wasting.

PMID:37739444 | DOI:10.1136/bcr-2023-255502

Gastroenterology. 2023 Sep 20:S0016-5085(23)04780-7. doi: 10.1053/j.gastro.2023.07.007. Online ahead of print.

ABSTRACT

DESCRIPTION: Exocrine pancreatic insufficiency (EPI) is a disorder caused by the failure of the pancreas to deliver a minimum/threshold level of specific pancreatic digestive enzymes to the intestine, leading to the maldigestion of nutrients and macronutrients, resulting in their variable deficiencies. EPI is frequently underdiagnosed and, as a result, patients are often not treated appropriately. There is an urgent need to increase awareness of and treatment for this condition. The aim of this American Gastroenterological Association (AGA) Clinical Practice Update Expert Review was to provide Best Practice Advice on the epidemiology, evaluation, and management of EPI.

METHODS: This Expert Review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: EPI should be suspected in patients with high-risk clinical conditions, such as chronic pancreatitis, relapsing acute pancreatitis, pancreatic ductal adenocarcinoma, cystic fibrosis, and previous pancreatic surgery. BEST PRACTICE ADVICE 2: EPI should be considered in patients with moderate-risk clinical conditions, such as duodenal diseases, including celiac and Crohn's disease; previous intestinal surgery; longstanding diabetes mellitus; and hypersecretory states (eg, Zollinger-Ellison syndrome). BEST PRACTICE ADVICE 3: Clinical features of EPI include steatorrhea with or without diarrhea, weight loss, bloating, excessive flatulence, fat-soluble vitamin deficiencies, and protein-calorie malnutrition. BEST PRACTICE ADVICE 4: Fecal elastase test is the most appropriate initial test and must be performed on a semi-solid or solid stool specimen. A fecal elastase level <100 μg/g of stool provides good evidence of EPI, and levels of 100-200 μg/g are indeterminate for EPI. BEST PRACTICE ADVICE 5: Fecal elastase testing can be performed while on pancreatic enzyme replacement therapy. BEST PRACTICE ADVICE 6: Fecal fat testing is rarely needed and must be performed when on a high-fat diet. Quantitative testing is generally not practical for routine clinical use. BEST PRACTICE ADVICE 7: Response to a therapeutic trial of pancreatic enzymes is unreliable for EPI diagnosis. BEST PRACTICE ADVICE 8: Cross-sectional imaging methods (computed tomography scan, magnetic resonance imaging, and endoscopic ultrasound) cannot identify EPI, although they play an important role in the diagnosis of benign and malignant pancreatic disease. BEST PRACTICE ADVICE 9: Breath tests and direct pancreatic function tests hold promise, but are not widely available in the United States. BEST PRACTICE ADVICE 10: Once EPI is diagnosed, treatment with pancreatic enzyme replacement therapy (PERT) is required. If EPI is left untreated, it will result in complications related to fat malabsorption and malnutrition, having a negative impact on quality of life. BEST PRACTICE ADVICE 11: PERT formulations are all derived from porcine sources and are equally effective at equivalent doses. There is a need for H2 or proton pump inhibitor therapy with non-enteric-coated preparations. BEST PRACTICE ADVICE 12: PERT should be taken during the meal, with the initial treatment of at least 40,000 USP units of lipase during each meal in adults and one-half of that with snacks. The subsequent dosage can be adjusted based on the meal size and fat content. BEST PRACTICE ADVICE 13: Routine supplementation and monitoring of fat-soluble vitamin levels are appropriate. Dietary modifications include a low-moderate fat diet with frequent smaller meals and avoiding very-low-fat diets. BEST PRACTICE ADVICE 14: Measures of successful treatment with PERT include reduction in steatorrhea and associated gastrointestinal symptoms; a gain of weight, muscle mass, and muscle function; and improvement in fat-soluble vitamin levels. BEST PRACTICE ADVICE 15: EPI should be monitored and baseline measurements of nutritional status should be obtained (body mass index, quality-of-life measure, and fat-soluble vitamin levels). A baseline dual-energy x-ray absorptiometry scan should be obtained and repeated every 1-2 years.

PMID:37737818 | DOI:10.1053/j.gastro.2023.07.007

Pediatr Pulmonol. 2023 Sep 22. doi: 10.1002/ppul.26694. Online ahead of print.

NO ABSTRACT

PMID:37737463 | DOI:10.1002/ppul.26694

AACE Clin Case Rep. 2023 Jul 17;9(5):170-173. doi: 10.1016/j.aace.2023.07.001. eCollection 2023 Sep-Oct.

ABSTRACT

BACKGROUND/OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) is one of the most common nonrespiratory complications of cystic fibrosis (CF). There is a lack of clinical research to provide guidance on optimal treatment regimens for various subtypes of CFRD.

CASE REPORT: This case describes an 18-year-old woman, diagnosed with CF in infancy, who presented to our clinic for evaluation of possible CFRD and episodes of hypoglycemia. Subsequent testing revealed normal fasting glucose with elevated blood glucose levels on oral glucose tolerance test, consistent with the diagnosis of CFRD without fasting hyperglycemia. She was found to have large glycemic excursions after carbohydrate-containing meals, followed by delayed postprandial hypoglycemia.

DISCUSSION: We initiated low-dose mealtime rapid-acting analog insulin and saw both a decrease in her postprandial hyperglycemia as well as resolution of her hypoglycemic episodes.

CONCLUSION: This case highlights the spectrum of pancreatic dysfunction and insulin dysregulation in CFRD as well as the benefit of prandial insulin alone as a treatment option.

PMID:37736319 | PMC:PMC10509377 | DOI:10.1016/j.aace.2023.07.001

Respir Med Res. 2023 Jul 4;84:101038. doi: 10.1016/j.resmer.2023.101038. Online ahead of print.

ABSTRACT

INTRODUCTION: Nebulization plays a key role in the treatment of cystic fibrosis. The Favorite function couple to jet nebulizers (AKITA®) emerged recently. The aim of this study was to assess the efficiency of the lung delivery by the AKITA® by comparing the urinary concentration of amikacin after nebulization with the AKITA® and the eFlow rapid®, in healthy subjects and patients with CF (PwCF).

METHOD: The two samples (healthy subjects and PwCF) were randomized (cross-over 1:1) for two nebulizations (500 mg of amikacin diluted in 4 mL of normal saline solution), with the AKITA® and with the eFlow rapid®. The primary endpoint was the amount of urinary excretion of amikacin over 24 h. The constant of elimination (Ke) was calculated based on the maximal cumulative urinary amikacin excretion plotted over time.

RESULTS: The total amount of urinary amikacin excretion was greater when AKITA® was used in PwCF (11.7 mg (8.2-14.1) vs 6.1 mg (3.7-13.3); p = 0.02) but not different in healthy subjects (14.5 mg (11.7-18.5) vs 12.4 mg (8.0-17.1); p = 0.12). The duration of the nebulization was always shorter with eFlow rapid® than with AKITA® (PwCF: 6.5 ± 0.6 min vs 9.2 ± 1.8 min; p = 0.001 - Healthy: 4.7 ± 1.3 min vs 9.7 ± 1.6 min; p = 0.03). The constant of elimination was similar between the two modalities in CF subjects (0.153 (0.071-0.205) vs 0.149 (0.041-0.182); p = 0.26) and in healthy subjects (0.166 (0.130-0.218) vs 0.167 (0.119-0.210), p = 0.25).

CONCLUSION: the Favorite inhalation is better to deliver a specific amount of drug than a mesh nebulizer (eFlow rapid®) in PwCF but not in healthy subjects.

PMID:37734235 | DOI:10.1016/j.resmer.2023.101038

Respir Med Res. 2023 Jun 30;84:101040. doi: 10.1016/j.resmer.2023.101040. Online ahead of print.

ABSTRACT

BACKGROUND: Lung function in individuals with cystic fibrosis (CF) is closely monitored as an objective marker of clinical status. The COVID-19 pandemic shifted our ability to assess individuals from in-person to remote monitoring using telehealth. As part of efforts to monitor individuals remotely during this time, this study describes the process of education and implementation of home spirometry in an adolescent CF population at Nemours Children's Hospital in Wilmington, Delaware, USA. In addition, this study reviews the ability of adolescents with CF to produce reliable, consistent, and accurate results using home spirometry.

METHODS: This was a quality-improvement study over a 9-month period at a single CF center. Home spirometers were supplied by the CF Foundation to 40 adolescents with CF. An educational curriculum was used for initial training on the device by a dedicated CF respiratory therapist. After training, participants reported spirometry results weekly until reliable technique was established. Once reliable technique was achieved, participants reported results monthly. Results were retrospectively reviewed to determine accuracy and consistency. The percentages of patients who were able to achieve reliable, consistent, and accurate results were recorded as well as the need for additional training or other reasons for inability to produce ongoing results.

RESULTS: Home spirometers were distributed to 40 adolescents. Out of these 40 participants, 35 (88%) completed initial training; 29 (83%) sent at least one set of results, and 24 (60%) established reliable technique after an average of 5 weekly attempts. When home spirometer results were retrospectively reviewed, 83% (20/24) were deemed accurate in comparison to spirometry completed in clinic, and 83% (20/24) showed consistency between efforts sent.

CONCLUSION: Home spirometry, when properly implemented with structured education and active participant engagement, has potential to provide meaningful data and feedback to CF care teams. Implementation of this process requires substantial resources and active participation from an adolescent population who are at higher risk for non-adherence. Future studies are needed to determine the impact of home spirometry on clinical outcomes and reliability over time and to address barriers to consistent and enduring engagement in the adolescent population.

PMID:37734233 | DOI:10.1016/j.resmer.2023.101040

J Cyst Fibros. 2023 Sep 19:S1569-1993(23)00910-4. doi: 10.1016/j.jcf.2023.09.006. Online ahead of print.

ABSTRACT

BACKGROUND: There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after initiation of E/T/I in CF adults.

METHODS: Outcome measures of liver fibrosis, including liver stiffness measurement (LSM) using FibroScan, AST-to-platelet-ratio index (APRI) and gamma-GT-to-platelet-ratio (GPR) were available in 74 CF adults following initiation of E/T/I. This was compared to historical data collected in 2018 prior to UK availability of E/T/I.

RESULTS: The median duration of E/T/I therapy at the time liver fibrosis markers were repeated was 21 (IQR: 17-25) months. There was an increase in APRI from historical measurement to follow-up but no change in LSM or GPR. There were no differences in change in fibrosis markers according to CF liver disease (CFLD) status, although those with a raised LSM at baseline (>6.8 kPa) (n = 14) had a significant reduction in LSM from historical measurement to follow-up versus those with a normal historical value (-3.3 kPa vs 0.25 kPa, p < 0.01).

CONCLUSIONS: Apart from APRI, we found no changes in liver fibrosis outcomes after initiation of E/T/I in adults with CF. Those with a historical diagnosis of CFLD had no significant worsening or improvement of liver fibrosis markers. We did observe a reduction in LSM in those with liver nodularity, with an initial highest result suggesting a potential positive treatment effect of E/T/I in this category of those with severe CFLD.

PMID:37735009 | DOI:10.1016/j.jcf.2023.09.006

Thorax. 2023 Sep 21:thorax-2023-220021. doi: 10.1136/thorax-2023-220021. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) lung disease is characterised by progressive airway wall thickening and widening. We aimed to validate an artificial intelligence-based algorithm to assess dimensions of all visible bronchus-artery (BA) pairs on chest CT scans from patients with CF.

METHODS: The algorithm fully automatically segments the bronchial tree; identifies bronchial generations; matches bronchi with the adjacent arteries; measures for each BA-pair bronchial outer diameter (Bout), bronchial lumen diameter (Bin), bronchial wall thickness (Bwt) and adjacent artery diameter (A); and computes Bout/A, Bin/A and Bwt/A for each BA pair from the segmental bronchi to the last visible generation. Three datasets were used to validate the automatic BA analysis. First BA analysis was executed on 23 manually annotated CT scans (11 CF, 12 control subjects) to compare automatic with manual BA-analysis outcomes. Furthermore, the BA analysis was executed on two longitudinal datasets (Copenhagen 111 CTs, ataluren 347 CTs) to assess longitudinal BA changes and compare them with manual scoring results.

RESULTS: The automatic and manual BA analysis showed no significant differences in quantifying bronchi. For the longitudinal datasets the automatic BA analysis detected 247 and 347 BA pairs/CT in the Copenhagen and ataluren dataset, respectively. A significant increase of 0.02 of Bout/A and Bin/A was detected for Copenhagen dataset over an interval of 2 years, and 0.03 of Bout/A and 0.02 of Bin/A for ataluren dataset over an interval of 48 weeks (all p<0.001). The progression of 0.01 of Bwt/A was detected only in the ataluren dataset (p<0.001). BA-analysis outcomes showed weak to strong correlations (correlation coefficient from 0.29 to 0.84) with manual scoring results for airway disease.

CONCLUSION: The BA analysis can fully automatically analyse a large number of BA pairs on chest CTs to detect and monitor progression of bronchial wall thickening and bronchial widening in patients with CF.

PMID:37734952 | DOI:10.1136/thorax-2023-220021

Expert Opin Drug Deliv. 2023 Sep 21. doi: 10.1080/17425247.2023.2261369. Online ahead of print.

ABSTRACT

INTRODUCTION: Inhaled gene therapy programs targeting diseases of the lung have seen increasing interest in recent years, though as of yet no product has successfully entered the market. Preclinical research to support such programs is critically important in maximizing the chances of developing successful candidates.

AREAS COVERED: Aspects of inhalation delivery of gene therapies are reviewed, with a focus on preclinical research in animal models. Various barriers to inhalation delivery of gene therapies are discussed, including aerosolization stresses, aerosol behavior in the respiratory tract, and disposition processes post-deposition. Important aspects of animal models are considered, including determinations of biologically-relevant determinations of dose and issues related to translatability.

EXPERT OPINION: Development of clinically-efficacious inhaled gene therapies has proven difficult owing to numerous challenges. Fit-for-purpose experimental and analytical methods are necessary for determinations of biologically-relevant doses in preclinical animal models. Further developments in disease-specific animal models may aid in improving translatability of results in future work, and we expect to see accelerated interests in inhalation gene therapies for various diseases. Sponsors, researchers, and regulators are encouraged to engage in early and frequent discussion regarding candidate therapies, and additional dissemination of preclinical methodologies would be of immense value in avoiding common pitfalls.

PMID:37732957 | DOI:10.1080/17425247.2023.2261369

World J Gastroenterol. 2023 Sep 7;29(33):4920-4926. doi: 10.3748/wjg.v29.i33.4920.

ABSTRACT

Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious diagnoses such as Hirschsprung's disease (HD), meconium ileus due to Cystic Fibrosis, etc. The diagnosis of HD particularly warrants invasive testing to confirm the diagnosis, such as anorectal manometry or rectal suction biopsy. What if there was another etiology of perinatal constipation, that is far lesser known? Cow's milk protein allergy (CMPA) is often diagnosed in infants within the first few weeks of life, however, there are studies that show that the CMPA allergen can be passed from mother to an infant in-utero, therefore allowing symptoms to show as early as day one of life. The presentation is more atypical, with perinatal constipation rather than with bloody stools, diarrhea, and vomiting. The diagnosis and management would be avoidance of cow's milk protein within the diet, with results and symptom improvement in patients immediately. Therefore, we discuss whether an alternative pathway to address perinatal constipation should be further discussed and implemented to potentially avoid invasive techniques in patients. This entails first ruling out CMPA with safe, noninvasive techniques with diet modification, and if unsuccessful, then moving forward with further diagnostic modalities.

PMID:37731998 | PMC:PMC10507509 | DOI:10.3748/wjg.v29.i33.4920