Positive epistasis between disease-causing missense mutations and silent polymorphism with effect on mRNA translation velocity.

Proc Natl Acad Sci U S A. 2021 Jan 26;118(4):

Authors: Rauscher R, Bampi GB, Guevara-Ferrer M, Santos LA, Joshi D, Mark D, Strug LJ, Rommens JM, Ballmann M, Sorscher EJ, Oliver KE, Ignatova Z

Abstract
Epistasis refers to the dependence of a mutation on other mutation(s) and the genetic context in general. In the context of human disorders, epistasis complicates the spectrum of disease symptoms and has been proposed as a major contributor to variations in disease outcome. The nonadditive relationship between mutations and the lack of complete understanding of the underlying physiological effects limit our ability to predict phenotypic outcome. Here, we report positive epistasis between intragenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)-the gene responsible for cystic fibrosis (CF) pathology. We identified a synonymous single-nucleotide polymorphism (sSNP) that is invariant for the CFTR amino acid sequence but inverts translation speed at the affected codon. This sSNP in cis exhibits positive epistatic effects on some CF disease-causing missense mutations. Individually, both mutations alter CFTR structure and function, yet when combined, they lead to enhanced protein expression and activity. The most robust effect was observed when the sSNP was present in combination with missense mutations that, along with the primary amino acid change, also alter the speed of translation at the affected codon. Functional studies revealed that synergistic alteration in ribosomal velocity is the underlying mechanism; alteration of translation speed likely increases the time window for establishing crucial domain-domain interactions that are otherwise perturbed by each individual mutation.

PMID: 33468668 [PubMed - in process]

Ultra-low-dose thoracic CT with model-based iterative reconstruction (MBIR) in cystic fibrosis patients undergoing treatment with cystic fibrosis transmembrane conductance regulators (CFTR).

Clin Radiol. 2021 Jan 16;:

Authors: Moloney F, Kavanagh RG, Ronan NJ, Grey TM, Joyce S, Ryan DJ, Moore N, O'Connor OJ, Plant BJ, Maher MM

Abstract
AIM: To assess the utility of a volumetric low-dose computed tomography (CT) thorax (LDCTT) protocol at a dose equivalent to a posteroanterior (PA) and lateral chest radiograph for surveillance of cystic fibrosis (CF) patients.
MATERIALS AND METHODS: A prospective study was undertaken of 19 adult patients with CF that proceeded to LDCTT at 12 and 24 months following initiation of ivacaftor. A previously validated seven-section, low-dose axial CT protocol was used for the 12-month study. A volumetric LDCTT protocol was developed for the 24-month study and reconstructed with hybrid iterative reconstruction (LD-ASIR) and pure iterative reconstruction (model-based IR [LD-MBIR]). Radiation dose was recorded for each scan. Image quality was assessed quantitatively and qualitatively, and disease severity was assessed using a modified Bhalla score. Statistical analysis was performed and p-values of <0.05 were considered statistically significant.
RESULTS: Volumetric LD-MBIR studies were acquired at a lower radiation dose than the seven-section studies (0.08 ± 0.01 versus 0.10 ± 0.02 mSv; p=0.02). LD-MBIR and seven-section ASIR images had significantly lower levels of image noise compared with LD-ASIR images (p<0.0001). Diagnostic acceptability scores and depiction of bronchovascular structures were found to be acceptable for axial and coronal LD-MBIR images. LD-MBIR images were superior to LD-ASIR images for all qualitative parameters assessed (p<0.0001). No significant change was observed in mean Bhalla score between 1-year and 2-year studies (p=0.84).
CONCLUSIONS: The use of a volumetric LDCTT protocol (reconstructed with pure IR) enabled acquisition of diagnostic quality CT images, which were considered extremely useful for surveillance of CF patients, at a dose equivalent to a PA and lateral chest radiograph.

PMID: 33468311 [PubMed - as supplied by publisher]

Contemporary analysis of ETEST for antibiotic susceptibility and minimum inhibitory concentration agreement against Pseudomonas aeruginosa from patients with cystic fibrosis.

Ann Clin Microbiol Antimicrob. 2021 Jan 19;20(1):9

Authors: Lasko MJ, Huse HK, Nicolau DP, Kuti JL

Abstract
OBJECTIVES: Cystic fibrosis (CF) acute pulmonary exacerbations are often caused by Pseudomonas aeruginosa, including multi-drug resistant strains. Optimal antibiotic therapy is required to return lung function and should be guided by in vitro susceptibility results. There are sparse data describing ETEST performance for CF isolates using contemporary isolates, methods and interpretation, as well as novel antibiotics, such as ceftazidime-avibactam and ceftolozane-tazobactam.
METHODS: Pseudomonas aeruginosa (n = 105) isolated during pulmonary exacerbation from patients with CF were acquired from 3 US hospitals. Minimum inhibitory concentrations (MICs) were assessed by reference broth microdilution (BMD) and ETEST for aztreonam, cefepime, ceftazidime, ceftazidime-avibactam, ceftolozane-tazobactam, ciprofloxacin, levofloxacin, meropenem, piperacillin-tazobactam, and tobramycin. Broth microdilution was conducted in concordance with the Clinical and Laboratory Standards Institute M100. ETEST methodology reflected package insert recommendations. Performance of ETEST strips was evaluated using the Food and Drug Administration (FDA) and Susceptibility Testing Manufacturers Association (STMA) guidance.
RESULTS: Of the 105 P. aeruginosa included, 46% had a mucoid phenotype. ETEST MICs typically read 0-1 dilution higher than BMD for all drugs. Categorical agreement and essential agreement ranged from 64 to 93% and 63 to 86%, respectively. The majority of observed errors were minor. A single very major error occurred with ceftazidime (4.2%). For ceftazidime-vibactam, 2 very major errors were observed and both were within essential agreement. Major errors occurred for aztreonam (3.3%), cefepime (9.4%), ceftazidime-avibactam (5.3%, adjusted 2.1%), ceftolozane-tazobactam (1%), meropenem (3.3%), piperacillin-tazobactam (2.9%), and tobramycin (1.5%).
CONCLUSIONS: ETEST methods performed conservatively for most antibiotics against this challenging collection of P. aeruginosa from patients with CF.

PMID: 33468149 [PubMed - in process]

Role of Collagen in Airway Mechanics.

Bioengineering (Basel). 2021 Jan 16;8(1):

Authors: Liu L, Stephens B, Bergman M, May A, Chiang T

Abstract
Collagen is the most abundant airway extracellular matrix component and is the primary determinant of mechanical airway properties. Abnormal airway collagen deposition is associated with the pathogenesis and progression of airway disease. Thus, understanding how collagen affects healthy airway tissue mechanics is essential. The impact of abnormal collagen deposition and tissue stiffness has been an area of interest in pulmonary diseases such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease. In this review, we discuss (1) the role of collagen in airway mechanics, (2) macro- and micro-scale approaches to quantify airway mechanics, and (3) pathologic changes associated with collagen deposition in airway diseases. These studies provide important insights into the role of collagen in airway mechanics. We summarize their achievements and seek to provide biomechanical clues for targeted therapies and regenerative medicine to treat airway pathology and address airway defects.

PMID: 33467161 [PubMed]

A Case of Phage Therapy against Pandrug-Resistant Achromobacter xylosoxidans in a 12-Year-Old Lung-Transplanted Cystic Fibrosis Patient.

Viruses. 2021 Jan 05;13(1):

Authors: Lebeaux D, Merabishvili M, Caudron E, Lannoy D, Van Simaey L, Duyvejonck H, Guillemain R, Thumerelle C, Podglajen I, Compain F, Kassis N, Mainardi JL, Wittmann J, Rohde C, Pirnay JP, Dufour N, Vermeulen S, Gansemans Y, Van Nieuwerburgh F, Vaneechoutte M

Abstract
Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans. A 12-year-old lung-transplanted cystic fibrosis patient received two rounds of phage therapy because of persistent lung infection with pandrug-resistant A. xylosoxidans. Clinical tolerance was perfect, but initial bronchoalveolar lavage (BAL) still grew A. xylosoxidans. The patient's respiratory condition slowly improved and oxygen therapy was stopped. Low-grade airway colonization by A. xylosoxidans persisted for months before samples turned negative. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. Whole genome sequencing indicated that the eight A. xylosoxidans isolates, collected during phage therapy, belonged to four delineated strains, whereby one had a stop mutation in a gene for a phage receptor. The dynamics of lung colonisation were documented by means of strain-specific qPCRs on different BALs. We report the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. The dynamics of airway colonization was more complex than deduced from bacterial culture, involving phage susceptible as well as phage resistant strains.

PMID: 33466377 [PubMed - in process]

Evaluating the Impact of Stopping Chronic Therapies after Modulator Drug Therapy in Cystic Fibrosis: The SIMPLIFY Study Design.

Ann Am Thorac Soc. 2021 Jan 19;:

Authors: Mayer-Hamblett N, Nichols DP, Odem-Davis K, Riekert KA, Sawicki GS, Donaldson SH, Ratjen F, Konstan MW, Simon N, Rosenbluth DB, Retsch-Bogart G, Clancy JP, VanDalfsen JM, Buckingham R, Gifford AH, Cystic Fibrosis Therapeutics Development Network and SIMPLIFY Investigators

Abstract
The care for individuals with cystic fibrosis (CF) with at least one F508del mutation will greatly change as a result of the unparalleled clinical benefits observed with the new triple combination CF transmembrane regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI). Incorporating ETI into standard of care creates new motivation and opportunity to consider reductions in overall treatment burden and evaluate whether other chronic medications can now be safely discontinued without loss of clinical benefit. SIMPLIFY is a master protocol poised to test the impact of discontinuing versus continuing two commonly used chronic therapies in people with CF who are at least 12 and older andstable on ETI therapy. The protocol is comprised of two concurrent randomized, controlled trials designed to evaluate the independent short-term effects of discontinuing hypertonic saline or dornase alfa, enabling individuals on both therapies to participate in one or both trials. The primary objective for each trial is to determine whether discontinuing treatment is non-inferior to continuing treatment after establishment of ETI, as measured by the 6-week absolute change in forced expiratory volume in one second (FEV1) % predicted. Developing this study required a balance between ideal study design principles and feasibility. SIMPLIFY will be the largest multicenter, randomized, controlled medication withdrawal study in CF. This study is uniquely positioned to provide timely evidence on whether daily treatment burden can be reduced among individuals on CFTR modulator therapy. Clinical trial registered with www.clinical trials.gov (NCT04378153).  .

PMID: 33465316 [PubMed - as supplied by publisher]

Functional Impacts of Aminoglycoside Treatment on Speech Perception and Extended High-Frequency Hearing Loss in a Pediatric Cystic Fibrosis Cohort.

Am J Audiol. 2021 Jan 19;:1-20

Authors: Blankenship CM, Hunter LL, Feeney MP, Cox M, Bittinger L, Garinis AC, Lin L, McPhail G, Clancy JP

Abstract
Purpose The purpose of this study is to better understand the prevalence of ototoxicity-related hearing loss and its functional impact on communication in a pediatric and young adult cohort with cystic fibrosis (CF) and individuals without CF (controls). Method We did an observational, cross-sectional investigation of hearing function in children, teens, and young adults with CF (n = 57, M = 15.0 years) who received intravenous aminoglycoside antibiotics and age- and gender-matched controls (n = 61, M = 14.6 years). Participants completed standard and extended high-frequency audiometry, middle ear measures, speech perception tests, and a hearing and balance questionnaire. Results Individuals with CF were 3-4 times more likely to report issues with hearing, balance, and tinnitus and performed significantly poorer on speech perception tasks compared to controls. A higher prevalence of hearing loss was observed in individuals with CF (57%) compared to controls (37%). CF and control groups had similar proportions of slight and mild hearing losses; however, individuals with CF were 7.6 times more likely to have moderate and greater degrees of hearing loss. Older participants displayed higher average extended high-frequency thresholds, with no effect of age on average standard frequency thresholds. Although middle ear dysfunction has not previously been reported to be more prevalent in CF, this study showed that 16% had conductive or mixed hearing loss and higher rates of previous otitis media and pressure equalization tube surgeries compared to controls. Conclusions Individuals with CF have a higher prevalence of conductive, mixed, and sensorineural hearing loss; poorer speech-in-noise performance; and higher rates of multiple symptoms associated with otologic disorders (tinnitus, hearing difficulty, dizziness, imbalance, and otitis media) compared to controls. Accordingly, children with CF should be asked about these symptoms and receive baseline hearing assessment(s) prior to treatment with potentially ototoxic medications and at regular intervals thereafter in order to provide otologic and audiologic treatment for hearing- and ear-related problems to improve communication functioning.

PMID: 33465313 [PubMed - as supplied by publisher]

A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Escalation Study to Evaluate the Safety and Pharmacokinetics of ELX-02 in Healthy Subjects.

Clin Pharmacol Drug Dev. 2021 Jan 19;:

Authors: Leubitz A, Vanhoutte F, Hu MY, Porter K, Gordon E, Tencer K, Campbell K, Banks K, Haverty T

Abstract
ELX-02 is an investigational compound being developed as a therapy for genetic diseases caused by nonsense mutations such as cystic fibrosis. Structurally, ELX-02 is an aminoglycoside analogue that induces read-through of nonsense mutations through interaction with the ribosome, resulting in the production of full-length functional proteins. This phase 1 multiple-ascending-dose trial evaluated the safety and pharmacokinetics of ELX-02 in 62 healthy volunteers. ELX-02 plasma exposure was dose proportional, with no apparent accumulation, and followed by renal elimination. The most reported adverse event was injection site reactions that were mild to moderate in severity. At the top dose of 5.0 mg/kg, 1 of 6 subjects experienced auditory threshold changes in which ototoxicity could not be clearly ruled out, and 2 of 6 had hearing threshold changes consistent with possible ototoxicity. Two of 3 subjects receiving placebo in the 5.0 mg/kg group also had significant hearing threshold changes. All observed hearing threshold changes resolved or were trending toward resolution after withdrawal of the study drug. No severe or serious adverse events were reported.The results of this study support the evaluation of ELX-02 in phase 2 clinical trials with patients that have genetic diseases caused by nonsense mutations.

PMID: 33465285 [PubMed - as supplied by publisher]

The Risks of Complications During Endoscopic Sinus Surgery in Cystic Fibrosis Patients: An Anatomical and Endoscopic Study.

Laryngoscope. 2021 Jan 19;:

Authors: Maggiore G, Pietragalla M, De Amicis C, Nardi C, Bruno C, Gallo O, Bonasera L, Perrone A, Cavallo A, Colagrande S, Taccetti G, Locatello LG

Abstract
OBJECTIVE/HYPOTHESIS: An increasing proportion of adult cystic fibrosis (CF) patients is being referred to endoscopic sinus surgery (ESS) in order to relieve the symptoms of chronic rhinosinusitis (CRS). Given that CFTR mutations profoundly alter sinonasal development, we want to explore the relationship between their peculiar surgical anatomy and the risk of postoperative complications.
STUDY DESIGN: Retrospective case-control study.
METHODS: Paranasal sinuses CT scans of 103 CF adult patients with CRS were compared to those belonging to a cohort of 100 non-CF adult patients to explore their anatomical differences. Secondly, CF and non-CF patients who received primary/revision ESS were analyzed in order to assess their preoperative CT scan in terms of surgically relevant variants, and according to the CLOSE checklist. Surgical outcomes were statistically compared in order to explore the differences between groups.
RESULTS: CF group presented more frequently with smaller and less pneumatized paranasal sinuses and a higher Lund-Mckay score compared with controls. No anatomical differences emerged in terms of genotype stratification. Non-CF CRS patients undergoing ESS showed a significantly deeper olfactory fossa and a more frequent supraorbital pneumatization compared to CF patients (P < .001 and P = .031, respectively). Whereas this latter group underwent more often aggressive surgical procedures (P = .001), no difference in terms of postoperative adverse events was found (P = .620).
CONCLUSIONS: Despite receiving more often aggressive ESS procedures, adult CF patients do not show an increased risk of postoperative complication and this may be linked to a different proportion of anatomical and surgically-relevant variants.
LEVEL OF EVIDENCE: 4 Laryngoscope, 2021.

PMID: 33464574 [PubMed - as supplied by publisher]

Sharing Patient-Controlled Real-World Data Through the Application of the Theory of Commons: Action Research Case Study.

J Med Internet Res. 2021 Jan 19;23(1):e16842

Authors: Hager A, Lindblad S, Brommels M, Salomonsson S, Wannheden C

Abstract
BACKGROUND: Technological advances have radically changed the opportunities for individuals with chronic conditions to practice self-care and to coproduce health care and research. Digital technologies enable patients to perform tasks traditionally carried out by health care professionals in a more convenient way, at lower costs, and without compromising quality. Patients may also share real-world data with other stakeholders to promote individual and population health. However, there is a need for legal frameworks that enable patient privacy and control in such sharing of real-world data. We believe that this need could be met by the conceptualization of patient-controlled real-world data as knowledge commons, which is a resource shared by a group of people.
OBJECTIVE: This study aimed to propose a conceptual model that describes how patient-controlled real-world data can be shared effectively in chronic care management, in a way that supports individual and population health, while respecting personal data privacy and control.
METHODS: An action research approach was used to develop a solution to enable patients, in a self-determined way, to share patient-controlled data to other settings. We chose the context of cystic fibrosis (CF) care in Sweden, where coproduction between patients, their families, and health care professionals is critical in the introduction of new drugs. The first author, who is a lawyer and parent of children with CF, was a driver in the change process. All coauthors collaborated in the analysis. We collected primary and secondary data reflecting changes during the time period from 2012 to 2020, and performed a qualitative content analysis guided by the knowledge commons framework.
RESULTS: Through a series of changes, a national system for enabling patients to share patient-controlled real-world data to different stakeholders in CF care was implemented. The case analysis resulted in a conceptual model consisting of the following three knowledge commons arenas that contributed to patient-controlled real-world data collection, use, and sharing: (1) patient world arena involving the private sphere of patients and families; (2) clinical microsystem arena involving the professional sphere at frontline health care clinics; and (3) round table arena involving multiple stakeholders from different settings. Based on the specification of property rights, as presented in our model, the patient can keep control over personal health information and may grant use rights to other stakeholders.
CONCLUSIONS: Health information exchanges for sharing patient-controlled real-world data are pivotal to enable patients, health care professionals, health care funders, researchers, authorities, and the industry to coproduce high-quality care and to introduce and follow-up novel health technologies. Our model proposes how technical and legal structures that protect the integrity and self-determination of patients can be implemented, which may be applicable in other chronic care settings as well.

PMID: 33464212 [PubMed - as supplied by publisher]

Neonatal screening program for five conditions in Honduras.

J Community Genet. 2021 Jan 18;:

Authors: Buckley MMM, Aguilar LB, Lainez RC, Valenzuela HJA, Ponce F, Melo DG

Abstract
We present the initial results of a neonatal screening program in part of the public health system in Honduras, that is, the Honduran Social Security Institute. The program design includes steps from neonatal bloodspot in the first newborn days to evaluation and treatment when necessary. In 2018 and 2019, 19,911 newborns were tested for hypothyroidism, cystic fibrosis, galactosemia, phenylketonuria, and adrenal hyperplasia. Abnormalities were identified in 18 newborns, corresponding to a prevalence of 9:10,000. Considering all births in Honduras, the estimated coverage of screening ranged between 4.4 and 5.7%. These results reinforce the need to expand and consolidate neonatal screening.

PMID: 33462772 [PubMed - as supplied by publisher]

Lower third chest wall reconstruction in a bilateral sequential lung transplant recipient.

BMJ Case Rep. 2021 Jan 18;14(1):

Authors: Hever P, Singh P, Nikkhah D, Anikin V

Abstract
Reconstruction of the sternum following deep sternal wound infection (DSWI) can be challenging, and despite advances in reconstructive surgery, DSWI remains a significant cause of morbidity and mortality in cardiothoracic patients. Transplantation patients present an additional, unique challenge for the reconstructive surgeon. These patients are often on immunosuppressant therapy, with multiple comorbidities, and cannot tolerate prolonged operations for reconstruction. They often have a prior extensive surgical history, which may limit donor options; and their wounds are often in the lower third of the sternum, which is a challenging location to reconstruct with locoregional tissues.We report a case of successful lower third chest wall reconstruction in a bilateral lung transplant recipient with a combination of bilateral pectoralis advancement flaps and omentoplasty.

PMID: 33462038 [PubMed - in process]

Changes in airway inflammation with pseudomonas eradication in early cystic fibrosis.

J Cyst Fibros. 2021 Jan 15;:

Authors: Garratt LW, Breuer O, Schofield CJ, McLean SA, Laucirica DR, Tirouvanziam R, Clements BS, Kicic A, Ranganathan S, Stick SM, Cf OBOA

Abstract
BACKGROUND: Neutrophil elastase is a significant risk factor for structural lung disease in cystic fibrosis, and Pseudomonas aeruginosa airway infection is linked with neutrophilic inflammation and substantial respiratory morbidity. We aimed to evaluate how neutrophil elastase (NE) activity changes after P. aeruginosa eradication and influences early disease outcomes.
METHODS: We assessed participants in the AREST CF cohort between 2000 and 2018 who had P. aeruginosa cultured from their routine annual bronchoalveolar lavage (BAL) fluid and who underwent eradication treatment and a post eradication BAL. Factors associated with persistent P. aeruginosa infection, persistent neutrophilic inflammation following eradication and worse structural lung disease one year post-eradication were evaluated.
RESULTS: Eighty-eight episodes (3 months to 6 years old) of P. aeruginosa infection were studied. Eradication was successful in 84.1% of episodes. Median activity of NE was significantly reduced post-eradication from 9.15 to 3.4 nM (p = 0.008) but persisted in 33 subjects. High post-eradication NE levels were associated with an increased risk for P. aeruginosa infection in the next annual visit (odds ratio=1.7, 95% confidence interval 1.1-2.7, p = 0.014). Post-eradication NE levels (difference, 0.8; 95% confidence interval, 0.1-1.5) and baseline bronchiectasis computed tomography (CT) score (difference, 0.4; 95% confidence interval, 0.1-0.8) were the best predictors of bronchiectasis progression within 1 year (backward stepwise linear regression model, R2= 0.608, P<0.001), independent of eradication.
CONCLUSION: In children with CF, NE activity may persist following successful P. aeruginosa eradication and is significantly associated with bronchiectasis progression. Evaluating strategies to diminish neutrophilic inflammation is essential for improving long-term outcomes.

PMID: 33461938 [PubMed - as supplied by publisher]

COVID-19 lockdown beneficial effects on lung function in a cohort of cystic fibrosis patients.

Ital J Pediatr. 2021 Jan 18;47(1):12

Authors: Servidio AG, Capata G, Levantino L, Riccio G, Contorno S, Barbi E, Maschio M

PMID: 33461569 [PubMed - in process]

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Pancreatic Cancer-Associated Diabetes is Clinically Distinguishable From Conventional Diabetes.

J Surg Res. 2021 Jan 13;261:215-225

Authors: Yoon BH, Ang SM, Alabd A, Furlong K, Yeo CJ, Lavu H, Winter JM

Abstract
BACKGROUND: Type 3c diabetes mellitus (T3cDM) is diabetes secondary to other pancreatic diseases such as chronic pancreatitis, pancreatic resection, cystic fibrosis, and pancreatic ductal adenocarcinoma (PDA). Clinically, it may easily be confused with conventional type 2 diabetes mellitus (T2DM). A delay in pancreatic cancer diagnosis and treatment leads to a worse outcome. Therefore, early recognition of PDA-associated T3cDM and distinction from conventional T2DM represents an opportunity improve survival in patients with PDA.
METHODS: Six hundred and sixty four patients with PDA underwent pancreatic resection. Patients were classified as per whether or not they had diabetes. The specific type of diabetes was determined. T3cDM surgical patients (n = 127) were compared with a control group of medical patients with T2DM who did not have PDA (n = 127).
RESULTS: Patients with T3cDM were older (66 versus 61 y, P < 0.001), had lower body mass indices (25.9 versus 32.1, P < 0.001), more favorable hemoglobin A1c levels (7.0 versus 8.8, P < 0.001), higher alanine aminotransferase levels (39 versus 20, P < 0.001), and lower creatinine levels (0.8 versus 0.9 mg/dL, P < 0.001). In addition, they were more likely to be insulin dependent. In a subgroup analysis of surgical patients, T3cDM (versus surgical patients with T2DM and no diabetes) was not associated with surrogate markers of main pancreatic duct obstruction and glandular atrophy.
CONCLUSIONS: PDA-associated T3cDM has a distinctive presenting phenotype compared with medical patients with conventional T2DM. Greater attention to associated signs, symptoms, and biochemical data could identify patients at risk for harboring an underlying pancreatic malignancy and trigger diagnostic pathways leading to earlier PDA diagnosis and treatment.

PMID: 33453685 [PubMed - as supplied by publisher]

Commentary for the article: MicroRNA-1246 regulates proliferation, invasion and differentiation in human vascular smooth muscle cell by targeting cystic fibrosis transmembrane conductance regulator (CFTR).

Pflugers Arch. 2021 Jan 16;:

Authors: Choi MR

PMID: 33452915 [PubMed - as supplied by publisher]

Phenotype and Natural History of Children With Coexistent Inflammatory Bowel Disease and Celiac Disease.

Inflamm Bowel Dis. 2021 Jan 16;:

Authors: Bramuzzo M, Lionetti P, Miele E, Romano C, Arrigo S, Cardile S, Di Nardo G, Illiceto MT, Pastore M, Felici E, Fuoti M, Banzato C, Citrano M, Congia M, Norsa L, Pozzi E, Zuin G, Agrusti A, Bianconi M, Grieco C, Giudici F, Aloi M, Alvisi P

Abstract
BACKGROUND: Adult patients with both inflammatory bowel disease (IBD) and celiac disease (CeD) have peculiar phenotypic features. This study aimed at describing the characteristics and natural history of children with both IBD and CeD.
METHODS: This was a case-control study based on a national registry. Cases included children diagnosed with both IBD and CeD. Two matched IBD controls without CeD, and 2 matched CeD controls were selected for each case. Inflammatory bowel disease phenotype and natural history, comprising growth and pubertal development, were compared between groups.
RESULTS: Forty-nine (1.75%) patients with IBD and CeD were identified out of 2800 patients with IBD. Compared with patients with IBD alone, patients with IBD and CeD presented more frequently with autoimmune diseases (odds ratio, 2.81; 95% CI, 0.97-8.37; P = 0.04). Ileocolonic localization (46.1% vs 73.1%), treatment with azathioprine (46.2% vs 71.2%), and anti-TNF biologics (46.2% vs 69.2%) were less common in patients with Crohn's disease and CeD than in patients with Crohn's disease alone. Patients with ulcerative colitis and CeD had an increased risk of colectomy despite similar medical treatments compared with patients with ulcerative colitis alone (13.0% vs 0%). Pubertal delay was more common in patients with IBD and CeD compared with patients with IBD alone (14.9% vs 3.2%; odds artio, 5.24; 95% CI, 1.13-33.0; P = 0.02) and CeD alone (14.9% vs 1.1%; P = 0.002).
CONCLUSIONS: Children with IBD and CeD may have peculiar features with a higher risk for autoimmune diseases, colectomy, and pubertal delay compared with IBD alone.

PMID: 33452803 [PubMed - as supplied by publisher]

Diagnosis of cystic fibrosis in adulthood and eligibility for novel CFTR modulator therapy.

Postgrad Med J. 2021 Jan 15;:

Authors: Farley H, Poole S, Chapman S, Flight W

Abstract
BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive condition that primarily manifests as a chronic respiratory disease. CF is usually diagnosed in early childhood or through newborn screening although in a small but important group, diagnosis is not made until adulthood. Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are now available for most genetic causes of CF highlighting the importance of identifying people with late presentations of CF.
AIM: We aimed to identify the clinical characteristics of people diagnosed with CF in adulthood and their resulting eligibility for novel CFTR modulator therapies.
DESIGN: Retrospective single-centre cohort study.
METHODS: Patients diagnosed with CF at age 18 years or older were identified from a patient database. Paper and electronic medical records were reviewed and clinical, microbiological and radiological data at diagnosis were recorded.
RESULTS: Nineteen patients were identified. Median age at diagnosis was 38 years (range: 19-71) and 9 (47%) were female. All patients had a history of chronic respiratory symptoms and 18/19 (94%) had radiological evidence of bronchiectasis. All patients had two pathogenic CFTR mutations identified with 16/19 (84%) compound heterozygotes for the F508del mutation. The majority of patients had a CFTR genotype considered eligible for CFTR modulator therapy (84% and 89% according to European and US licences, respectively).
CONCLUSIONS: Adult patients with unexplained chronic bronchiectasis should be thoroughly investigated for CF. A low index of suspicion will help to identify adults with undiagnosed CF who are likely to benefit from CFTR modulator therapy.

PMID: 33452147 [PubMed - as supplied by publisher]

Signal Synthase-Type versus Catabolic Monooxygenases: Retracing 3-Hydroxylation of 2-Alkylquinolones and Their N-Oxides by Pseudomonas aeruginosa and Other Pulmonary Pathogens.

Appl Environ Microbiol. 2021 Jan 15;:

Authors: Ritzmann NH, Drees SL, Fetzner S

Abstract
The multiple biological activities of 2-alkylquinolones (AQs) are crucial for virulence of Pseudomonas aeruginosa, conferring advantages during infection and in polymicrobial communities. Whereas 2-heptyl-3-hydroxyquinolin-4(1H)-one (the "Pseudomonas quinolone signal", PQS) is an important quorum sensing signal molecule, 2-heptyl-1-hydroxyquinolin-4(1H)-ones (also known as 2-alkyl-4-hydroxyquinoline-N-oxides, AQNOs) are antibiotics inhibiting respiration. Hydroxylation of the PQS precursor 2-heptylquinolin-4(1H)-one (HHQ) by the signal synthase PqsH boosts AQ quorum sensing. Remarkably, the same reaction, catalyzed by the ortholog AqdB, is used by Mycobacteroides abscessus to initiate degradation of AQs. The antibiotic 2-heptyl-1-hydroxyquinolin-4(1H)-one (HQNO) is hydroxylated by Staphylococcus aureus to the less toxic derivative PQS-N-oxide (PQS-NO), a reaction probably also catalyzed by a PqsH/AqdB ortholog. In this study, we provide a comparative analysis of four AQ 3-monooxygenases of different organisms. Due to the major impact of AQ/AQNO 3-hydroxylation on the biological activities of the compounds, we surmised adaptations on enzymatic and/or physiological level to serve either the producer or target organisms. Our results indicate that all enzymes share similar features and are incapable of discriminating between AQs and AQNOs. PQS-NO hence occurs as native metabolite of P. aeruginosa although the unfavorable AQNO 3-hydroxylation is minimized by export as shown for HQNO, involving at least one multidrug efflux pump. Moreover, M. abscessus is capable of degrading the AQNO heterocycle by concerted action of AqdB and dioxygenase AqdC. However, S. aureus and M. abscessus orthologs disfavor AQNOs despite their higher toxicity, suggesting that catalytic constraints, rather than evolutionary adaptation, lead to the preference of non-N-oxide substrates by AQ 3-monooxygenases.IMPORTANCE Pseudomonas aeruginosa, Staphylococcus aureus and Mycobacteroides abscessus are major players in bacterial chronic infections and particularly common colonizers of cystic fibrosis (CF) lung tissue. Whereas S. aureus is an early onset pathogen in CF, P. aeruginosa establishes at later stages. M. abscessus occurs at all stages but has a lower epidemiological incidence. The dynamics of how these pathogens interact can affect survival and therapeutic success.2-Alkylquinolone (AQ) and 2-alkylhydroxyquinoline N-oxide (AQNO) production is a major factor of P. aeruginosa virulence. The 3-position of the AQ scaffold is critical, both for attenuation of AQ toxicity or degradation by competitors, as well as for full unfolding of quorum sensing. Despite lacking signaling functionality, AQNOs have the strongest impact on suppression of Gram-positives. Because evidence for 3-hydroxylation of AQNOs has been reported, it is desirable to understand the extent by which AQ 3-monooxygenases contribute to manipulation of the AQ/AQNO equilibrium, resistance, and degradation.

PMID: 33452035 [PubMed - as supplied by publisher]