Front Physiol. 2022 Aug 5;13:912049. doi: 10.3389/fphys.2022.912049. eCollection 2022.

ABSTRACT

Background: Airway mucus provides important protective functions in health and abnormal viscoelasticity is a hallmark of muco-obstructive lung diseases such as cystic fibrosis (CF). However, previous studies of sputum macrorheology from healthy individuals and patients with CF using different experimental protocols yielded in part discrepant results and data on a systematic assessment across measurement settings and conditions remain limited. Objectives: The aim of this study was to develop an optimized and reliable protocol for standardized macrorheological measurements of airway mucus model systems and native human sputum from healthy individuals and patients with muco-obstructive lung disease. Methods: Oscillatory rheological shear measurements were performed using bovine submaxillary mucin (BSM) at different concentrations (2% and 10% solids) and sputum samples from healthy controls (n = 10) and patients with CF (n = 10). Viscoelastic properties were determined by amplitude and frequency sweeps at 25°C and 37°C with or without solvent trap using a cone-plate geometry. Results: Under saturated atmosphere, we did not observe any temperature-dependent differences in 2% and 10% BSM macrorheology, whereas in the absence of evaporation control 10% BSM demonstrated a significantly higher viscoelasticity at 37°C. Similarly, during the measurements without evaporation control at 37°C we observed a substantial increase in the storage modulus G' and the loss modulus G″ of the highly viscoelastic CF sputum but not in the healthy sputum. Conclusion: Our data show systematically higher viscoelasticity of CF compared to healthy sputum at 25°C and 37°C. For measurements at the higher temperature using a solvent trap to prevent evaporation is essential for macrorheological analysis of mucus model systems and native human sputum. Another interesting finding is that the viscoelastic properties are not much sensitive to the applied experimental deformation and yield robust results despite their delicate consistency. The optimized protocol resulting from this work will facilitate standardized quantitative assessment of abnormalities in viscoelastic properties of airway mucus and response to muco-active therapies in patients with CF and other muco-obstructive lung diseases.

PMID:35991170 | PMC:PMC9388721 | DOI:10.3389/fphys.2022.912049

Clin Microbiol Infect. 2022 Aug 18:S1198-743X(22)00419-0. doi: 10.1016/j.cmi.2022.08.003. Online ahead of print.

ABSTRACT

OBJECTIVES: Pseudomonas aeruginosa colonizes the cystic fibrosis (CF) airways causing chronic bacterial lung infections. CF patients are routinely treated with macrolides, however, P. aeruginosa is considered insusceptible as consequence of inadequate susceptibility testing leaving resistance mechanism completely overlooked. Here we investigated a new mechanism of macrolide resistance caused by ribosomal protein mutations.

METHODS: Investigating a longitudinal collection of 529 isolates from CF patients and analysing 5758 protein sequences from different sources, mutations in P. aeruginosa's ribosomal proteins connected to macrolide resistance were identified. Using a modified susceptibility testing protocol, isolates harbouring a mutated uL4 ribosomal protein were tested for resistance against macrolide antibiotics and macrolide-induced quorum sensing modulation. Proteome and ribosome profiling were applied to assess the impact of the mutations on the bacterial physiology.

RESULTS: Five uL4 mutations were identified in isolates from different CF patients. Most mapped to the conserved loop region of uL4 and resulted in increased macrolide tolerance (>10-fold relative to wt strains). Greater concentrations (>10-fold) of macrolide antibiotic were needed to inhibit the growth, reduce swimming motility, and induce redox sensitivity of the uL4 mutants. 16 proteins involved in ribosome adaptation displayed altered expression possibly to compensate for the uL4 mutations, which changed the ribosome stoichiometry without negatively affecting bacterial physiology.

CONCLUSIONS: Macrolide antibiotics should, therefore, be considered as active antimicrobial agents against P. aeruginosa and resistance development should be contemplated when patients are treated with prolonged courses of macrolides. Importantly, improved macrolide susceptibility testing is necessary for the detection of resistant bacteria.

PMID:35988850 | DOI:10.1016/j.cmi.2022.08.003

Curr Opin Pharmacol. 2022 Aug 18;66:102271. doi: 10.1016/j.coph.2022.102271. Online ahead of print.

ABSTRACT

In the clinically successful era of CFTR modulators and Theratyping, 10-20% of individuals with cystic fibrosis (CF) may develop disease due to CFTR mutations that remain undruggable. These individuals produce low levels of CFTR mRNA and/or not enough protein to be rescued with modulator drugs. Alternative therapeutic approaches to correct the CFTR defect at the mRNA level using nucleic acid technologies are currently feasible; e.g., oligonucleotides platforms, which are being rapidly developed to correct genetic disorders. Drug-like properties, great specificity, and predictable off-target effects by design make oligonucleotides a valuable approach with fewer clinical and ethical challenges than genomic editing strategies. Together with personalized and precision medicine approaches, oligonucleotides are ideal therapeutics to target CF-causing mutations that affect only a few individuals resilient to modulator therapies.

PMID:35988291 | DOI:10.1016/j.coph.2022.102271

Cell Mol Biol (Noisy-le-grand). 2022 Apr 30;68(4):52-59. doi: 10.14715/cmb/2022.68.4.7.

ABSTRACT

Cystic Fibrosis (CF) in Arab Mediterranean countries has a different CFTR mutational profile if compared either to Caucasians or in the Arabian Peninsula. The c.3909C>G (N1303K, p.Asn1303Lys) mutation of the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR). This mutation represents a higher frequency in the Mediterranean countries in association with different polymorphisms or mutations in cis position constituting various complex alleles. N1303K mutation induces many phenotypes, especially pancreatic insufficiency from mild to severe and it is associated in cis with other polymorphisms. The aim of this investigation is therefore to screen complex alleles carrying N1303K mutation among Lebanese, Egyptian and French patients. All exons of the CFTR and their flanking regions were performed by PCR amplification, followed by automated direct DNA sequencing. Two complex alleles are more frequent corresponding to Wild Type and mutated haplotype. Besides that two other very rare complex alleles have been detected, one in Egyptian and French samples, and then another one in Lebanon samples. We have studied their impact on the CFTR mRNA splicing using a minigene strategy. Constructs containing wild-type and mutant CFTR cloned into the pTBNdeI hybride minigene have been expressed in HeLa, HT29 and HEK293 cells. RT-PCR analysis of mRNA using β-globin-specific primers revealed that N1303K and the polymorphisms associated with cis induce weak abnormal splicing and a modification of the quality and the quantity of CFTR protein. These different associations of identified polymorphisms with N1303K in cis could have an impact on the severity of the disease.

PMID:35988290 | DOI:10.14715/cmb/2022.68.4.7

Am J Transplant. 2022 Aug 21. doi: 10.1111/ajt.17177. Online ahead of print.

ABSTRACT

In patients with interstitial lung disease (ILD) complicating classical or amyopathic idiopathic inflammatory myopathy (IIM), lung transplantation outcomes might be affected by the disease and treatments. Here, our objective was to assess survival and prognostic factors in lung transplant recipients with IIM-ILD. We retrospectively reviewed data for 64 patients who underwent lung transplantation between 2009 and 2021 at 19 European centers. Patient survival was the primary outcome. At transplantation, median age was 53 [46-59] years, 35 (55%) patients were male, 31 (48%) had classical IIM, 25 (39%) had rapidly progressive ILD, and 21 (33%) were in a high-priority transplant allocation program. Survival rates after 1, 3, and 5 years were 78%, 73%, and 70%, respectively. During follow-up (median, 33 [7-63] months), 23% of patients developed chronic lung allograft dysfunction. Compared to amyopathic IIM, classical IIM was characterized by longer disease duration, higher-intensity immunosuppression before transplantation, and significantly worse posttransplantation survival. Five (8%) patients had a clinical IIM relapse, with mild manifestations. No patient experienced ILD recurrence in the allograft. Posttransplantation survival in IIM-ILD was similar to that in international all-cause-transplantation registries. The main factor associated with worse survival was a history of muscle involvement (classical IIM).

PMID:35988032 | DOI:10.1111/ajt.17177

Nitric Oxide. 2022 Aug 17:S1089-8603(22)00084-2. doi: 10.1016/j.niox.2022.08.001. Online ahead of print.

ABSTRACT

In the process of chronic cystic fibrosis (CF) infection, Pseudomonas aeruginosa (PA) is converted into a mucoid phenotype characterized by an overproduction of exopolysaccharide alginate. The alginate forms a thick mucus that causes difficulty in patient's breathing, drug resistance and contributes to both the morbidity and mortality of the patient. AlgU of PA, an extracytoplasmic function sigma factor, is responsible for the alginate overproduction and leads to mucoidy and chronic infection of CF patients. In this report, we found that endogenous and exogenous nitric oxide (NO) can significantly reduce algU expression, leading to down-regulation of a series of alginate synthesis-related genes (algD, alg8, algX, and algK), eventually down-regulated alginate synthesis. A fluorescent reporter strain was constructed to clarify the inhibitory effect of alginate synthesis through real-time monitoring in different conditions. The results showed that NO presented inhibitory effect on alginate synthesis in nine clinical PA isolates as in the model strain, and the reduction of alginate was more significant in three mucoid strains (by about 51%, 70% and 61%, respectively, while 47% for the model strain). In the co-culture system, effect of NO on PA fluorescence intensity is similar to that in monocultures, with the best effect at 10 μM NO donor sodium nitroprusside (SNP). Finally, we examined the changes in the antibiotic susceptibility of PA under NO-inhibited alginate conditions. In the presence of 10 μM SNP, the number of planktonic cells increased, and both adherent and planktonic PA cells showed increased susceptibility to tobramycin. We thus suggest that NO can potentially be employed as a therapeutic strategy to prevent cystic fibrosis lungs from PA infection.

PMID:35987450 | DOI:10.1016/j.niox.2022.08.001

J Hepatol. 2022 Aug 17:S0168-8278(22)02999-3. doi: 10.1016/j.jhep.2022.07.034. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is characterized by ductopenia, ductular reaction, impairment of anion exchanger 2 (AE2) and the 'bicarbonate umbrella'. Ductulo-canalicular junction (DCJ) derangement is hypothesized to promote PBC progression. The secretin (Sct)/secretin receptor (SR) axis regulates cystic fibrosis transmembrane receptor (CFTR) and AE2 thus promoting choleresis. We evaluated the role of Sct/SR signaling on biliary secretory processes and subsequent injury in late-stage PBC mouse model and human samples.

METHODS: Female and male wildtype (WT) and dominant-negative transforming growth factor beta receptor II (dnTGFβRII, late-stage PBC model) at 32 wks of age were treated with Sct for 1 wk or 8 wk. Bulk RNA-seq was performed in isolated cholangiocytes from mouse models.

RESULTS: Biliary Sct/SR/CFTR/AE2 expression and bile bicarbonate levels were reduced in late-stage PBC mouse models and human samples. Sct treatment decreased bile duct loss, ductular reaction, inflammation and fibrosis in late-stage PBC models. Sct reduced hepatic bile acid levels, modified bile acid composition, and restored the DCJ and 'bicarbonate umbrella.' RNA-seq identified that Sct promoted mature epithelial marker expression, specifically anterior grade 2 (Agr2). Late-stage PBC models and human samples had reduced biliary MUC1, which was enhanced with Sct treatment.

CONCLUSION: Loss of Sct/SR signaling in late-stage PBC results in a faulty 'bicarbonate umbrella' and reduced Agr2-mediated mucin production. Sct restores cholangiocyte secretory processes and DCJ formation through enhanced mature cholangiocyte phenotypes and bile duct growth. Sct treatment may be therapeutic for late-stage PBC patients.

LAY SUMMARY: Primary biliary cholangitis (PBC) causes inflammation and scarring of the bile ducts, leading to cholestasis and injury to the biliary epithelial cells (i.e., cholangiocytes) due to toxic bile buildup. The secretin/secretin receptor pathway promotes cholangiocyte secretion of bicarbonate and mucin, which is protective from toxic bile, but these characteristics are lost in late-stage PBC. Secretin administration activates this pathway and reduces damage by restoring the protective 'bicarbonate umbrella,' mucin production and expression of mature cholangiocyte markers in a model of late-stage PBC.

PMID:35987275 | DOI:10.1016/j.jhep.2022.07.034

J Cyst Fibros. 2022 Aug 16:S1569-1993(22)00635-X. doi: 10.1016/j.jcf.2022.07.017. Online ahead of print.

ABSTRACT

BACKGROUND: Nodular liver (NOD) in cystic fibrosis (CF) suggests advanced CF liver disease (aCFLD); little is known about progression of liver disease (LD) after detection of sonographic NOD.

METHODS: Clinical, laboratory, and ultrasound (US) data from Prediction by Ultrasound of the Risk of Hepatic Cirrhosis in CFLD Study participants with NOD at screening or follow-up were compared with normal (NL). Linear mixed effects models were used for risk factors for LD progression and Kaplan-Meier estimator for time-to-event.

RESULTS: 54 children with NOD (22 screening, 32 follow-up) and 112 NL were evaluated. Baseline (BL) and trajectory of forced expiratory volume, forced vital capacity, height/BMI z-scores were similar in NOD vs NL. Platelets were lower in NOD at BL (250 vs 331×103/microL; p < 0.001) and decreased by 8600/year vs 2500 in NL. Mean AST to Platelet Ratio Index (1.1 vs 0.4; p < 0.001), Fibrosis-4 Index (0.4 vs 0.2, p < 0.001), and spleen size z-score (SSZ) [1.5 vs 0.02; p < 0.001] were higher in NOD at BL; SSZ increased by 0.5 unit/year in NOD vs 0.1 unit/year in NL. Median liver stiffness (LSM) by transient elastography was higher in NOD (8.2 kPa, IQR 6-11.8) vs NL (5.3, 4.2-7, p < 0.0001). Over 6.3 years follow-up (1.3-10.3), 6 NOD had esophageal varices (cumulative incidence in 10 years: 20%; 95% CI: 0.0%, 40.0%), 2 had variceal bleeding, and 2 underwent liver transplantation; none had ascites or hepatic encephalopathy. No NL experienced liver-related events.

CONCLUSIONS: NOD developed clinically evident portal hypertension faster than NL without worse growth or lung disease.

PMID:35985930 | DOI:10.1016/j.jcf.2022.07.017

Biochemistry. 2022 Aug 19. doi: 10.1021/acs.biochem.2c00334. Online ahead of print.

ABSTRACT

The opportunistic pathogen Pseudomonas aeruginosa causes antibiotic-resistant, nosocomial infections in immuno-compromised individuals and is a high priority for antimicrobial development. Key to pathogenicity in P. aeruginosa are biofilm formation and virulence factor production. Both traits are controlled by the cell-to-cell communication process called quorum sensing (QS). QS involves the synthesis, release, and population-wide detection of signal molecules called autoinducers. We previously reported that the activity of the RhlR QS transcription factor depends on a protein-protein interaction with the hydrolase, PqsE, and PqsE catalytic activity is dispensable for this interaction. Nonetheless, the PqsE-RhlR interaction could be disrupted by the substitution of an active site glutamate residue with tryptophan [PqsE(E182W)]. Here, we show that disruption of the PqsE-RhlR interaction via either the E182W change or alteration of PqsE surface residues that are essential for the interaction with RhlR attenuates P. aeruginosa infection in a murine host. We use crystallography to characterize the conformational changes induced by the PqsE(E182W) substitution to define the mechanism underlying disruption of the PqsE-RhlR interaction. A loop rearrangement that repositions the E280 residue in PqsE(E182W) is responsible for the loss of interaction. We verify the implications garnered from the PqsE(E182W) structure using mutagenic, biochemical, and additional structural analyses. We present the next generation of molecules targeting the PqsE active site, including a structure of the tightest binding of these compounds, BB584, in complex with PqsE. The findings presented here provide insights into drug discovery against P. aeruginosa with PqsE as the target.

PMID:35985643 | DOI:10.1021/acs.biochem.2c00334

Stem Cell Reports. 2022 Aug 11:S2213-6711(22)00373-3. doi: 10.1016/j.stemcr.2022.07.013. Online ahead of print.

ABSTRACT

Human macrophages are a natural host of many mycobacterium species, including Mycobacterium abscessus (M. abscessus), an emerging pathogen affecting immunocompromised and cystic fibrosis patients with few available treatments. The search for an effective treatment is hindered by the lack of a tractable in vitro intracellular infection model. Here, we established a reliable model for M. abscessus infection using human pluripotent stem cell-derived macrophages (hPSC-macrophages). hPSC differentiation permitted reproducible generation of functional macrophages that were highly susceptible to M. abscessus infection. Electron microscopy demonstrated that M. abscessus was present in the hPSC-macrophage vacuoles. RNA sequencing analysis revealed a time-dependent host cell response, with differing gene and protein expression patterns post-infection. Engineered tdTOMATO-expressing hPSC-macrophages with GFP-expressing mycobacteria enabled rapid image-based high-throughput analysis of intracellular infection and quantitative assessment of antibiotic efficacy. Our study describes the first to our knowledge hPSC-based model for M. abscessus infection, representing a novel and accessible system for studying pathogen-host interaction and drug discovery.

PMID:35985333 | DOI:10.1016/j.stemcr.2022.07.013

ERJ Open Res. 2022 Aug 15;8(3):00139-2022. doi: 10.1183/23120541.00139-2022. eCollection 2022 Jul.

ABSTRACT

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients.

PMID:35983540 | PMC:PMC9379353 | DOI:10.1183/23120541.00139-2022

Microbiome. 2022 Aug 19;10(1):129. doi: 10.1186/s40168-022-01315-x.

ABSTRACT

BACKGROUND: The increasing prevalence of resistance against the last-resort antibiotic colistin is a significant threat to global public health. Here, we discovered a novel colistin resistance mechanism via enzymatic inactivation of the drug and proposed its clinical importance in microbial communities during polymicrobial infections.

RESULTS: A bacterial strain of the Gram-negative opportunistic pathogen Stenotrophomonas maltophilia capable of degrading colistin and exhibiting a high-level colistin resistance was isolated from the soil environment. A colistin-degrading protease (Cdp) was identified in this strain, and its contribution to colistin resistance was demonstrated by growth inhibition experiments using knock-out (Δcdp) and complemented (Δcdp::cdp) mutants. Coculture and coinfection experiments revealed that S. maltophilia carrying the cdp gene could inactivate colistin and protect otherwise susceptible Pseudomonas aeruginosa, which may seriously affect the clinical efficacy of the drug for the treatment of cystic fibrosis patients with polymicrobial infection.

CONCLUSIONS: Our results suggest that Cdp should be recognized as a colistin resistance determinant that confers collective resistance at the microbial community level. Our study will provide vital information for successful clinical outcomes during the treatment of complex polymicrobial infections, particularly including S. maltophilia and other colistin-susceptible Gram-negative pathogens such as P. aeruginosa. Video abstract.

PMID:35982474 | DOI:10.1186/s40168-022-01315-x

Respirology. 2022 Sep;27(9):688-719. doi: 10.1111/resp.14340. Epub 2022 Aug 10.

ABSTRACT

The Thoracic Society of Australia and New Zealand (TSANZ) and the Australian and New Zealand Society of Respiratory Science (ANZSRS) commissioned a joint position paper on pulmonary function testing during coronavirus disease 2019 (COVID-19) in July 2021. A working group was formed via an expression of interest to members of both organizations and commenced work in September 2021. A rapid review of the literature was undertaken, with a 'best evidence synthesis' approach taken to answer the research questions formed. This allowed the working group to accept findings of prior relevant reviews or societal document where appropriate. The advice provided is for providers of pulmonary function tests across all settings. The advice is intended to supplement local infection prevention and state, territory or national directives. The working group's key messages reflect a precautionary approach to protect the safety of both healthcare workers (HCWs) and patients in a rapidly changing environment. The decision on strategies employed may vary depending on local transmission and practice environment. The advice is likely to require review as evidence grows and the COVID-19 pandemic evolves. While this position statement was contextualized specifically to the COVID-19 pandemic, the working group strongly advocates that any changes to clinical/laboratory practice, made in the interest of optimizing the safety and well-being of HCWs and patients involved in pulmonary function testing, are carefully considered in light of their potential for ongoing use to reduce transmission of other droplet and/or aerosol borne diseases.

PMID:35981737 | DOI:10.1111/resp.14340

Eur J Epidemiol. 2022 Aug 18. doi: 10.1007/s10654-022-00889-y. Online ahead of print.

ABSTRACT

Children with a chronic condition face more obstacles than their healthy peers, which may impact their physical, social-emotional, and cognitive development. The PROactive cohort study identifies children with a chronic disease at high risk of debilitating fatigue, decreased daily life participation and psychosocial problems, as well as children who are resilient and thrive despite the challenges of growing up with a chronic condition. Both groups will teach us how we can best support children, adolescents and parents to adapt to and manage a disease, as well as tailor interventions to their specific needs.This cohort follows a continuous longitudinal design. It is based at the Wilhelmina Children's Hospital (WKZ) in the Netherlands and has been running since December 2016. Children with a chronic condition (e.g. cystic fibrosis, juvenile idiopathic arthritis, chronic kidney disease, or congenital heart disease) as well children with medically unexplained fatigue or pain in a broad age range (2-18 years) are included, as well as their parent(s). Data are collected from parents (of children between 2 and 18 years) and children (8-18 years), as well as data from their electronic health record (EHR). Primary outcome measures are fatigue, daily life participation, and psychosocial well-being, all assessed via patient- and proxy-reported outcome measures. Generic biological/lifestyle, psychological, and social factors were assessed using clinical assessment tools and questionnaires. In the PROactive cohort study the research assessment is an integrated part of clinical care. Children are included when they visit the outpatient clinic and are followed up annually.

PMID:35980506 | DOI:10.1007/s10654-022-00889-y

World J Gastroenterol. 2022 Jun 28;28(24):2680-2688. doi: 10.3748/wjg.v28.i24.2680.

ABSTRACT

Celiac disease (CD) is well recognized as a systemic, chronic autoimmune disease mainly characterized by gluten-sensitive enteropathy in genetically predisposed individuals but with various extraintestinal features. One of the affected organs in CD is the pancreas, consisting of both endocrine and exocrine alterations. Over the last decades there has been increasing interest in the pancreatic changes in CD, and this has been reflected by a great number of publications looking at this extraintestinal involvement during the course of CD. While pancreatic endocrine changes in CD, focusing on type 1 diabetes mellitus, are well documented in the literature, the relationship with the exocrine pancreas has been less studied. This review summarizes currently available evidence with regard to pancreatic exocrine alterations in CD, focusing on risk of pancreatitis in CD patients, association with autoimmune pancreatitis, prevalence and outcomes of pancreatic exocrine insufficiency in newly diagnosed and gluten-free diet treated CD patients, and the link with cystic fibrosis. In addition, we discuss mechanisms behind the associated pancreatic exocrine impairment in CD and highlight the recommendations for clinical practice.

PMID:35979168 | PMC:PMC9260863 | DOI:10.3748/wjg.v28.i24.2680

Clin Pharmacokinet. 2022 Jul 25. doi: 10.1007/s40262-022-01147-w. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Brensocatib is an investigational, first-in-class, selective, and reversible dipeptidyl peptidase 1 inhibitor that blocks activation of neutrophil serine proteases (NSPs). The NSPs neutrophil elastase, cathepsin G, and proteinase 3 are believed to be central to the pathogenesis of several chronic inflammatory diseases, including bronchiectasis. In a phase II study, oral brensocatib 10 mg and 25 mg reduced sputum neutrophil elastase activity and prolonged the time to pulmonary exacerbation in patients with non-cystic fibrosis bronchiectasis (NCFBE). A population pharmacokinetic (PPK) model was developed to characterize brensocatib exposure, determine potential relationships between brensocatib exposure and efficacy and safety measures, and inform dose selection in clinical studies.

METHODS: Pharmacokinetic (PK) data pooled from a phase I study of once-daily brensocatib (10, 25, and 40 mg) in healthy adults and a phase II study of once-daily brensocatib (10 mg and 25 mg) in adults with NCFBE were used to develop a PPK model and to evaluate potential covariate effects on brensocatib pharmacokinetics. PK-efficacy relationships for sputum neutrophil elastase below the level of quantification (BLQ) and reduction in pulmonary exacerbation and PK-safety relationships for adverse events of special interest (AESIs; periodontal disease, hyperkeratosis, and infections other than pulmonary infections) were evaluated based on model-predicted brensocatib exposure. A total of 1284 steady-state brensocatib concentrations from 225 individuals were included in the PPK data set; 241 patients with NCFBE from the phase II study were included in the pharmacodynamic (PD) population for the PK/PD analyses.

RESULTS: The PPK model that best described the observed data consisted of two distributional compartments and linear clearance. Two significant covariates were found: age on volume of distribution and renal function on apparent oral clearance. PK-efficacy analysis revealed a threshold brensocatib exposure (area under the concentration-time curve) effect for attaining sputum neutrophil elastase BLQ and a strong relationship between sputum neutrophil elastase BLQ and reduction in pulmonary exacerbations. A PK-safety evaluation showed no noticeable trends between brensocatib exposure and the incidence of AESIs. Based on the predicted likelihood of clinical outcomes for sputum neutrophil elastase BLQ and pulmonary exacerbations, brensocatib doses of 10 mg and 25 mg once daily were selected for a phase III clinical trial in patients with NCFBE (ClinicalTrials.gov identifier: NCT04594369).

CONCLUSIONS: PPK results revealed that age and renal function have a moderate effect on brensocatib exposure. However, this finding does not warrant dose adjustments based on age or in those with mild or moderate renal impairment. The PK/PD evaluation demonstrated the clinically meaningful relationship between suppression of neutrophil elastase activity and reduction in exacerbations in brensocatib-treated patients with NCFBE, supporting further development of brensocatib for bronchiectasis.

PMID:35976570 | DOI:10.1007/s40262-022-01147-w

J Pediatr Gastroenterol Nutr. 2022 Aug 17. doi: 10.1097/MPG.0000000000003590. Online ahead of print.

ABSTRACT

OBJECTIVES: To investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP).

METHODS: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP.

RESULTS: Of 689 children, 365 had ARP (53%), 324 CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP.

CONCLUSIONS: Children with family history of CP, constant pain or obstructive risk factors should raise suspicion for CP.

PMID:35976273 | DOI:10.1097/MPG.0000000000003590

JBI Evid Synth. 2022 Jul 12. doi: 10.11124/JBIES-22-00018. Online ahead of print.

ABSTRACT

OBJECTIVE: The objective of this review is to determine the incidence and prevalence, clinical features, and outcomes of COVID-19 in persons with cystic fibrosis.

INTRODUCTION: Cystic fibrosis, predominantly a chronic respiratory illness, has long been known to be fatal with concomitant bacterial or viral infections. However, the effects of COVID-19 on this protracted disease need to be understood, especially since the major manifestations affect the respiratory system. Hence, the burden, clinical features, and outcomes of COVID-19 on individuals with cystic fibrosis need to be understood.

INCLUSION CRITERIA: This review will consider studies on persons in all age groups with preexisting cystic fibrosis who are diagnosed with COVID-19 using either a polymerase chain reaction, serology, or point-of-care test for SARS-CoV-2.

METHODS: JBI methodology for systematic reviews of prevalence and incidence will be used for this review. A methodical search for eligible studies in English (as well as available translations) in MEDLINE, Embase, Scopus, and CINAHL, and unpublished literature in Google Scholar, Dissertation Abstracts International, ProQuest Dissertations and Theses, and MedNar will be conducted from the year 2020 onwards. Studies meeting the inclusion criteria will be selected for appraisal and their methodological quality will be assessed by two independent reviewers based on study titles and abstracts, followed by full-text review focusing on sampling and statistical analysis. Data extraction will be accomplished using a standardized tool. If adequate synthesized data are obtained, a meta-analysis will be conducted; otherwise, the findings will be presented in a narrative format, including tables and figures to aid in data presentation where appropriate.

SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42021237792.

PMID:35975314 | DOI:10.11124/JBIES-22-00018

Acta Endocrinol (Buchar). 2022 Jan-Mar;18(1):86-92. doi: 10.4183/aeb.2022.86.

ABSTRACT

Radioactive iodine (RAI) therapy is a mainstay adjuvant treatment for thyroid cancer. Administration of RAI therapy after total or near-total thyroidectomy has shown a survival advantage in numerous properly selected patients. However, the role of RAI therapy after reoperation for persistent or recurrent differentiated thyroid carcinomas (DTCs) is unclear. One reason may be the possible downregulation of the I- transport system after primary surgery. RAI is transported by the sodium iodide symporter (NIS), PENDRIN, anoctamin 1 (ANO1) and cystic fibrosis transmembrane conductance regulator (CFTR) and emits β particles that destroy follicular cells. The identification of pathways of iodide (I-) transport has allowed use of the transport system to render tumours susceptible to RAI treatment via gene therapy. This review focuses on the effect of RAI therapy in follicular cell-derived thyroid cancers and offers potential novel targets that enable improved radioiodine uptake and thus an improved prognosis of thyroid cancer.

PMID:35975265 | PMC:PMC9365402 | DOI:10.4183/aeb.2022.86

Hum Genomics. 2022 Aug 16;16(1):31. doi: 10.1186/s40246-022-00407-x.

ABSTRACT

BACKGROUND: The American College of Medical Genetics and Genomics (ACMG)-recommended five variant classification categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign) have been widely used in medical genetics. However, these guidelines are fundamentally constrained in practice owing to their focus upon Mendelian disease genes and their dichotomous classification of variants as being either causal or not. Herein, we attempt to expand the ACMG guidelines into a general variant classification framework that takes into account not only the continuum of clinical phenotypes, but also the continuum of the variants' genetic effects, and the different pathological roles of the implicated genes.

MAIN BODY: As a disease model, we employed chronic pancreatitis (CP), which manifests clinically as a spectrum from monogenic to multifactorial. Bearing in mind that any general conceptual proposal should be based upon sound data, we focused our analysis on the four most extensively studied CP genes, PRSS1, CFTR, SPINK1 and CTRC. Based upon several cross-gene and cross-variant comparisons, we first assigned the different genes to two distinct categories in terms of disease causation: CP-causing (PRSS1 and SPINK1) and CP-predisposing (CFTR and CTRC). We then employed two new classificatory categories, "predisposing" and "likely predisposing", to replace ACMG's "pathogenic" and "likely pathogenic" categories in the context of CP-predisposing genes, thereby classifying all pathologically relevant variants in these genes as "predisposing". In the case of CP-causing genes, the two new classificatory categories served to extend the five ACMG categories whilst two thresholds (allele frequency and functional) were introduced to discriminate "pathogenic" from "predisposing" variants.

CONCLUSION: Employing CP as a disease model, we expand ACMG guidelines into a five-category classification system (predisposing, likely predisposing, uncertain significance, likely benign, and benign) and a seven-category classification system (pathogenic, likely pathogenic, predisposing, likely predisposing, uncertain significance, likely benign, and benign) in the context of disease-predisposing and disease-causing genes, respectively. Taken together, the two systems constitute a general variant classification framework that, in principle, should span the entire spectrum of variants in any disease-related gene. The maximal compliance of our five-category and seven-category classification systems with the ACMG guidelines ought to facilitate their practical application.

PMID:35974416 | DOI:10.1186/s40246-022-00407-x