Suppressing "nonsense" in cystic fibrosis.

J Physiol. 2019 Dec 23;:

Authors: Hinzpeter A, Sermet-Gaudelus I, Sheppard DN

PMID: 31869855 [PubMed - as supplied by publisher]

Advances in understanding and managing Scedosporium respiratory infections in patients with cystic fibrosis.

Expert Rev Respir Med. 2019 Dec 23;:1-15

Authors: Bouchara JP, Le Govic Y, Kabbara S, Cimon B, Zouhair R, Hamze M, Papon N, Nevez G

Abstract
Introduction: Considered for a long time to be exclusively responsible for chronic localized infections, fungi of the genus Scedosporium have recently received a renewed interest because of their recognition as common colonizing agents of the respiratory tract of patients with cystic fibrosis, and of the description of severe disseminated infections in patients undergoing lung transplantation. Recently, several studies have been carried out on these opportunistic pathogens, which led to some advances in the understanding of their pathogenic mechanisms and in the biological diagnosis of the airway colonization/respiratory infections caused by these fungi.Areas covered: From a bibliographic search on the Pubmed database, we summarize the current knowledge about the taxonomy of Scedosporium species, the epidemiology of these fungi and their pathogenic mechanisms, and present the improvements in the detection of the airway colonization and diagnosis of Scedosporium respiratory infections, the difficulties in their therapeutic management, and the antifungal drugs in development.Expert opinion: As described in this review, many advances have been made regarding the taxonomy and ecology of Scedosporium species or the molecular determinants of their pathogenicity, but also in the management of Scedosporium infections, particularly by improving the biological diagnostic and publishing evidence for the efficacy of combined therapy.

PMID: 31868041 [PubMed - as supplied by publisher]

To Be or Not to Be a Pathogen: Candida albicans and Celiac Disease.

Front Immunol. 2019;10:2844

Authors: Renga G, Bellet MM, Stincardini C, Pariano M, Oikonomou V, Villella VR, Brancorsini S, Clerici C, Romani L, Costantini C

Abstract
Celiac disease (CD) is an immune-mediated disorder triggered by the ingestion of gluten and characterized by reversible small-bowel mucosal atrophy in genetically predisposed subjects. Although the prevalence of CD has increased, many aspects of this pathology are still unrecognized. Candida albicans, a commensal of the human gastrointestinal tract, has been linked to CD for a long time based, among others, upon the observation of similarity between the fungal wall component, hyphal wall protein 1, and CD-related gliadin T-cell epitopes. We have recently demonstrated that Candida may switch from commensal to pathogen contingent upon several players, including mast cells, key sentinels of the immune system at the interface between the environment and the host, and the pleiotropic cytokine IL-9. However, other factors are likely to play a role by altering the balance between inflammation and tolerance. In this regard, tryptophan and its metabolites are increasingly being recognized in promoting mucosal homeostasis by balancing the immune response to external cues. Based on these premises, we will discuss how the output of Candida colonization in the gut is highly contextual, being determined at the intersection of many immunological (IL-9/mast cells) and metabolic (tryptophan) pathways that ultimately dictate the Candida commensalism vs. pathogenicity in CD, thus paving the way for novel therapeutic opportunities in CD.

PMID: 31867008 [PubMed - in process]

StatPearls

Book. 2019 01

Authors:

Abstract
Vitamin K is a fat-soluble vitamin that affects coagulation pathways within the body. Vitamin K is found in foods and can be a dietary supplement. Vitamin K is essential for the synthesis of coagulation proteins. It is a co-factor for vitamin K dependent carboxylation, which includes various enzymes. The process of vitamin K carboxylation allows the coagulation factors to bind calcium ions, which further facilitates the cascade pathways. Vitamin K deficiency impairs the coagulation process leading to issues with bleeding. Recent research has linked vitamin K deficiency to issues with osteoporosis and cystic fibrosis.[1][2]

PMID: 31869059

Carbohydrate counting accuracy in adults with cystic fibrosis related diabetes.

Nutr Diet. 2019 Dec 22;:

Authors: Stonestreet J, Ar A, Herd K, Matson A, Bell J

Abstract
AIM: Poorly controlled Cystic Fibrosis-Related Diabetes (CFRD) is associated with adverse impacts on lung function and nutritional status. Insulin therapy is the only recommended medical treatment. Carbohydrate Counting (CC) is used to guide insulin doses and can assist in achieving optimal postprandial blood glucose levels. This study aimed to determine the prevalence of individuals with CFRD who carbohydrate count, explore barriers to its use and assess the accuracy of CC in hospitalised patients.
METHODS: A cross-sectional, mixed-methods, descriptive study recruited individuals with CFRD hospitalised at an Australian tertiary hospital. Consenting patients completed a questionnaire. Patients were asked to estimate the carbohydrate content of their ordered meals provided by hospital foodservices. The study dietitian assessed each meal's estimation against the actual content.
RESULTS: 17 individuals were recruited to this study and five declined. Seven had a fixed insulin regimen, and ten had a flexible insulin regimen and used CC. Patients in the fixed insulin group reported lower levels of confidence in their ability to carbohydrate count (P < .001) and placed less importance on CC (P < .001). 53% of the fixed insulin group's and 41.7% of the flexible insulin group's estimations of the carbohydrate content of the hospital food items were accurate.
CONCLUSION: Of those patients recruited to this study, 59% used CC as a tool to guide insulin dosing, and patients estimated accurate carbohydrate values in only 46% of meals. Further research is warranted to investigate the most suitable method to assist accurate carbohydrate content estimations in a hospital setting.

PMID: 31865636 [PubMed - as supplied by publisher]

Candida albicans enhances meropenem tolerance of Pseudomonas aeruginosa in a dual-species biofilm.

J Antimicrob Chemother. 2019 Dec 22;:

Authors: Alam F, Catlow D, Di Maio A, Blair JMA, Hall RA

Abstract
BACKGROUND: Pseudomonas aeruginosa is an opportunistic bacterium that infects the airways of cystic fibrosis patients, surfaces of surgical and burn wounds, and indwelling medical devices. Patients are prone to secondary fungal infections, with Candida albicans being commonly co-isolated with P. aeruginosa. Both P. aeruginosa and C. albicans are able to form extensive biofilms on the surfaces of mucosa and medical devices.
OBJECTIVES: To determine whether the presence of C. albicans enhances antibiotic tolerance of P. aeruginosa in a dual-species biofilm.
METHODS: Single- and dual-species biofilms were established in microtitre plates and the survival of each species was measured following treatment with clinically relevant antibiotics. Scanning electron microscopy and confocal microscopy were used to visualize biofilm structure.
RESULTS: C. albicans enhances P. aeruginosa biofilm tolerance to meropenem at the clinically relevant concentration of 5 mg/L. This effect is specific to biofilm cultures and is dependent upon C. albicans extracellular matrix polysaccharides, mannan and glucan, with C. albicans cells deficient in glycosylation structures not enhancing P. aeruginosa tolerance to meropenem.
CONCLUSIONS: We propose that fungal mannan and glucan secreted into the extracellular matrix of P. aeruginosa/C. albicans dual-species biofilms play a central role in enhancing P. aeruginosa tolerance to meropenem, which has direct implications for the treatment of coinfected patients.

PMID: 31865379 [PubMed - as supplied by publisher]

Gene therapy-emulating small molecule treatments in cystic fibrosis airway epithelial cells and patients.

Respir Res. 2019 Dec 21;20(1):290

Authors: Yang Q, Soltis AR, Sukumar G, Zhang X, Caohuy H, Freedy J, Dalgard CL, Wilkerson MD, Pollard HB, Pollard BS

Abstract
BACKGROUND: Several small molecule corrector and potentiator drugs have recently been licensed for Cystic Fibrosis (CF) therapy. However, other aspects of the disease, especially inflammation, are less effectively treated by these drugs. We hypothesized that small molecule drugs could function either alone or as an adjuvant to licensed therapies to treat these aspects of the disease, perhaps emulating the effects of gene therapy in CF cells. The cardiac glycoside digitoxin, which has been shown to inhibit TNFα/NFκB signaling in CF lung epithelial cells, may serve as such a therapy.
METHODS: IB3-1 CF lung epithelial cells were treated with different Vertex (VX) drugs, digitoxin, and various drug mixtures, and ELISA assays were used to assess suppression of baseline and TNFα-activated secretion of cytokines and chemokines. Transcriptional responses to these drugs were assessed by RNA-seq and compared with gene expression in AAV-[wildtype]CFTR-treated IB3-1 (S9) cells. We also compared in vitro gene expression signatures with in vivo data from biopsied nasal epithelial cells from digitoxin-treated CF patients.
RESULTS: CF cells exposed to digitoxin exhibited significant suppression of both TNFα/NFκB signaling and downstream secretion of IL-8, IL-6 and GM-CSF, with or without co-treatment with VX drugs. No evidence of drug-drug interference was observed. RNA-seq analysis showed that gene therapy-treated CF lung cells induced changes in 3134 genes. Among these, 32.6% were altered by digitoxin treatment in the same direction. Shared functional gene ontology themes for genes suppressed by both digitoxin and gene therapy included inflammation (84 gene signature), and cell-cell interactions and fibrosis (49 gene signature), while genes elevated by both were enriched for epithelial differentiation (82 gene signature). A new analysis of mRNA data from digitoxin-treated CF patients showed consistent trends in expression for genes in these signatures.
CONCLUSIONS: Adjuvant gene therapy-emulating activities of digitoxin may contribute to enhancing the efficacy of currently licensed correctors and potentiators in CF patients.

PMID: 31864360 [PubMed - in process]

The Role of Pseudomonas aeruginosa Lipopolysaccharide in Bacterial Pathogenesis and Physiology.

Pathogens. 2019 Dec 19;9(1):

Authors: Huszczynski SM, Lam JS, Khursigara CM

Abstract
The major constituent of the outer membrane of Gram-negative bacteria is lipopolysaccharide (LPS), which is comprised of lipid A, core oligosaccharide, and O antigen, which is a long polysaccharide chain extending into the extracellular environment. Due to the localization of LPS, it is a key molecule on the bacterial cell wall that is recognized by the host to deploy an immune defence in order to neutralize invading pathogens. However, LPS also promotes bacterial survival in a host environment by protecting the bacteria from these threats. This review explores the relationship between the different LPS glycoforms of the opportunistic pathogen Pseudomonas aeruginosa and the ability of this organism to cause persistent infections, especially in the genetic disease cystic fibrosis. We also discuss the role of LPS in facilitating biofilm formation, antibiotic resistance, and how LPS may be targeted by new antimicrobial therapies.

PMID: 31861540 [PubMed]

Presentation of an H-type tracheoesophageal fistula in an adolescent male with cystic fibrosis: A case report and review of literature.

Clin Imaging. 2019 Nov 30;60(1):38-47

Authors: Klouda TM, Lindholm E, Poletto E, Rani S, Varlotta L, Velasco J

Abstract
Congenital TEFs without esophageal atresia are rare but may occur more frequently than previously documented in literature. Careful history is required to suspect the diagnoses, as most patients will present with coughing associated with solid or liquids, recurrent unexplained pulmonary infections and complaints with eating. Some patients may show signs of chronic airway changes from recurrent aspiration pneumonia at the time of presentation. Diagnosis is challenging, with multiple imaging modalities including x ray, CT scan and esophogram able to identify a fistula. Surgery is required to improve quality of life and prevent chronic airway changes, and most cases repaired have no complications.

PMID: 31864198 [PubMed - as supplied by publisher]

Focal adhesion kinase and osmotic responses in ionocytes of Fundulus heteroclitus, a euryhaline teleost fish.

Comp Biochem Physiol A Mol Integr Physiol. 2019 Dec 18;:110639

Authors: Fougere B, Barnes KR, Francis ME, Claus LN, Cozzi RRF, Marshall WS

Abstract
Cystic Fibrosis Transmembrane conductance regulator (CFTR) anion channels are the regulated exit pathway in Cl- secretion by teleost salt secreting ionocytes of the gill and opercular epithelia of euryhaline teleosts. By confocal light immunocytochemistry using regular and phospho-antibodies directed against conserved sites, we found that killifish CFTR (kfCFTR) and the tyrosine kinase Focal Adhesion Kinase (FAK) phosphorylated at Y407 (FAKpY407) and FAKpY397 are colocalized at the apical membrane and in subjacent membrane vesicles of ionocytes. Hypotonic shock and the α-2 adrenergic agonist clonidine rapidly and reversibly inhibit Cl- secretion by isolated opercular epithelia, simultaneous with dephosphorylation of FAKpY407 and increased FAKpY397, located in the apical membrane of ionocytes in the opercular epithelium. FAKpY407 is re-phosphorylated at the apical membrane of ionocytes and Cl- secretion rapidly restored by hypertonic shock, detectable at 2 min., maximum at 5 min and still elevated at 30 min. In isolated opercular epithelia, the FAK phosphorylation inhibitor Y15 and p38MAP kinase inhibitor SB203580 significantly blunted the recovery of short-circuit current (Isc, equal to Cl- secretion rate) after hypertonic shock. The cSRC inhibitor saracatinib dephosphorylated FAKpY861 seen near tight junctions of pavement cells, and reduced the increase in epithelial resistance normally seen with clonidine inhibition of ion transport, while FAKpY397 was unaffected. The results show rapid osmosensitive responses in teleost fish ionocytes involve phosphorylation of CFTR by FAKpY407, an opposing role for FAKpY397 and a possible role for FAKpY861 in tight junction dynamics. 239 words.

PMID: 31863842 [PubMed - as supplied by publisher]

Normative data for multiple breath washout outcomes in school-aged Caucasian children.

Eur Respir J. 2019 Dec 20;:

Authors: Anagnostopoulou P, Latzin P, Jensen R, Stahl M, Harper A, Yammine S, Usemann J, Foong RE, Spycher B, Hall GL, Singer F, Stanojevic S, Mall M, Ratjen F, Ramsey KA

Abstract
BACKGROUND: The nitrogen multiple breath washout (N2MBW) technique is increasingly used to assess the degree of ventilation inhomogeneity in school-aged children with lung disease. However, reference values for healthy children are currently not available. The aim of this study was to generate reference values for N2MBW outcomes in a cohort of healthy Caucasian school-aged children.
METHODS: N2MBW data from healthy Caucasian school-age children between 6 and 18 years were collected from four experienced centers. Measurements were performed using an ultrasonic flowmeter (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and were analyzed with commercial software (Spiroware, 3.2.1, Eco Medics AG). Normative values and upper limits of normal were generated for lung clearance index at 2.5% (LCI2.5%) and at 5% (LCI5%), moment ratios (M1/M0 and M2/M0), and a prediction equation generated for functional residual capacity (FRC).
RESULTS: Four hundred and eighty five trials from 180 healthy Caucasian children aged from 6 to 18 years were used for analysis. While LCI increased with age, this increase was negligible (0.04 units/year for LCI2.5%) and therefore fixed upper limits of normal were defined for this age group. These limits were 7.91 for LCI2.5%, 5.73 for LCI5%, 1.75 for M1/M0, and 6.15 for M2/M0 respectively. Height and weight were found to be independent predictors of FRC.
CONCLUSION: We report reference values for N2MBW outcomes measured on a commercially available ultrasonic flowmeter device (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) in healthy school-aged children to allow accurate interpretation of ventilation distribution outcomes and FRC in children with lung disease.

PMID: 31862765 [PubMed - as supplied by publisher]

Structured surveillance of Achromobacter, Pandoraea and Ralstonia species from patients in England with cystic fibrosis.

J Cyst Fibros. 2019 Dec 17;:

Authors: Coward A, Kenna DTD, Woodford N, Turton JF,  and members of the UK CF Surveillance Working Group., The UK CF Surveillance Working Group comprised

Abstract
A structured survey of the cystic fibrosis pathogens Achromobacter, Pandoraea and Ralstonia species from thirteen sentinel hospitals throughout England was undertaken by Public Health England. One isolate per patient of these genera collected from CF patients during the seven-month survey period in 2015 was requested from participating hospitals. Species-level identification was performed using nrdA/gyrB sequence cluster analysis, and genotyping by pulsed-field gel electrophoresis. In total, 176 isolates were included in the survey; 138 Achromobacter spp. (78.4%), 29 Pandoraea spp. (16.5%) and 9 Ralstonia spp. (5.1%). Novel Achromobacter and Pandoraea clusters were identified. High levels of antimicrobial resistance were found, particularly among Pandoraea isolates. Genotyping analysis revealed considerable diversity, however one geographically-widespread cluster of A. xylosoxidans isolates from six hospitals was found, in addition to two other clusters, both comprising isolates from two hospitals, either derived from the same region (A. xylosoxidans), or from hospitals within the same city (P. apista).

PMID: 31862307 [PubMed - as supplied by publisher]

Prevalence of unmet palliative care needs in adults with cystic fibrosis.

J Cyst Fibros. 2019 Dec 17;:

Authors: Trandel ET, Pilewski JM, Dellon EP, Jeong K, Yabes JG, Moreines LT, Arnold RM, Hoydich ZP, Kavalieratos D

Abstract
BACKGROUND: Physical and emotional burdens impair quality of life (QoL) in many adults with cystic fibrosis (CF). Palliative care (PC) improves QoL in other serious illnesses, yet the full array of palliative needs amenable to PC are unknown in CF.
METHODS: We surveyed 164 adults with CF using the Supportive Care Needs Survey 34 (SCNS-34) to assess unmet PC needs across five domains, the Edmonton Symptom Assessment System (ESAS) to assess symptom burden, and the Cystic Fibrosis Questionnaire-Revised (CFQ-R) to assess CF-specific QoL. We assessed associations between SCNS-34 domain scores and respondent characteristics, including symptom burden and FEV1.
RESULTS: Median age was 29 years; 56% of respondents were male. Median FEV1 was 57% predicted. 78% of respondents reported ≥1 unmet PC need; physical and daily living (72%) and psychological (66%) needs were most prevalent. Symptom burden was correlated with all SCNS-34 domains scores, and strongly correlated with the physical (r = 0.79) and psychological (r = 0.72) domain scores. FEV1 was moderately inversely correlated with the physical domain score (r = -0.41). Forty-four of the 45 inverse correlations between SCNS-34 domain scores and CFQ-R domain scores were significant. Patient-reported depressive and anxiety symptoms were significantly associated with higher scores in five and four SCNS-34 domains, respectively.
CONCLUSIONS: Adults with CF have substantial unmet PC needs. Patient-reported symptom burden is more strongly associated with reporting unmet PC needs than FEV1. Routine screening of unmet PC needs, using tools such as the SCNS-34, may enable CF care teams to optimize the provision of primary and specialist PC.

PMID: 31862306 [PubMed - as supplied by publisher]

Lights and Shadows in the Use of Mesenchymal Stem Cells in Lung Inflammation, a Poorly Investigated Topic in Cystic Fibrosis.

Cells. 2019 Dec 19;9(1):

Authors: Caretti A, Peli V, Colombo M, Zulueta A

Abstract
Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic stem cells residing in many tissues, including the lung. MSCs have long been regarded as a promising tool for cell-based therapy because of their ability to replace damaged tissue by differentiating into the resident cell and repopulating the injured area. Their ability to release soluble factors and extracellular vesicles has emerged as crucial in the resolution of inflammation and injury. There is a growing literature on the use of MSCs and MSC secretome to hamper inflammation in different lung pathologies, including: asthma, pneumonia, acute lung injury (ALI), pulmonary hypertension, and chronic obstructive pulmonary disease (COPD). However, their potential therapeutic role in the context of Cystic Fibrosis (CF) lung inflammation is still not fully characterized. CF morbidity and mortality are mainly due to progressive lung dysfunction. Lung inflammation is a chronic and unresolved condition that triggers progressive tissue damage. Thus, it becomes even more important to develop innovative immunomodulatory therapies aside from classic anti-inflammatory agents. Here, we address the main features of CF and the implications in lung inflammation. We then review how MSCs and MSC secretome participate in attenuating inflammation in pulmonary pathologies, emphasizing the significant potential of MSCs as new therapeutic approach in CF.

PMID: 31861724 [PubMed - in process]

Smoking Cessation and Vaping Cessation Attempts among Cigarette Smokers and E-Cigarette Users in Central and Eastern Europe.

Int J Environ Res Public Health. 2019 Dec 18;17(1):

Authors: Jankowski M, Lawson JA, Shpakou A, Poznański M, Zielonka TM, Klimatckaia L, Loginovich Y, Rachel M, Gereová J, Minarowski Ł, Naumau I, Kornicki K, Pepłowska P, Kovalevskiy V, Raskiliene A, Bielewicz K, Krištúfková Z, Mróz R, Majek P, Skoczyński S, Zejda JE, Brożek GM

Abstract
Our aim is to assess the smoking cessation and vaping cessation activity, including quit attempts and willingness to quit among university students in Central and Eastern Europe, as well as to investigate personal characteristics associated with smoking cessation and vaping cessation attempts. Data were collected by questionnaire which included 46 questions on cigarette and e-cigarette use. Questionnaires were obtained from 14,352 university students (aged 20.9 ± 2.4 years; cooperation rate of 72.2%). For the purposes of this analysis, only data from exclusive cigarette smokers (n = 1716), exclusive e-cigarette users (n = 129), and dual users (216) were included. Of all cigarette smokers, 51.6% had previously tried to quit smoking and 51.5% declared a willingness to quit cigarette smoking in the near future. Among all e-cigarette users only 13.9% had ever tried to quit using the e-cigarette and 25.2% declared a willingness to give up using e-cigarette in the near future. The majority of the group did not use pharmacotherapy to quit cigarette (87.5%) or e-cigarette (88.9%) use. Our results indicate that while most university students have some desire to quit conventional smoking, those who use e-cigarettes do not have the same desire.

PMID: 31861455 [PubMed - in process]

Assessing gastro-intestinal related quality of life in cystic fibrosis: Validation of PedsQL GI in children and their parents.

PLoS One. 2019;14(12):e0225004

Authors: Boon M, Claes I, Havermans T, Fornés-Ferrer V, Calvo-Lerma J, Asseiceira I, Bulfamante A, Garriga M, Masip E, Woodcock S, Walet S, Barreto C, Colombo C, Crespo P, Van der Wiel E, Hulst J, Martinez-Barona S, Nobili R, Pereira L, Ruperto M, Vicente S, De Boeck K, Ribes-Koninckx C, MyCyFAPP consortium

Abstract
BACKGROUND: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency, leading to fat malabsorption, malnutrition and abdominal discomfort. Until recently, no specific tool was available for assessing gastro-intestinal related quality of life (GI QOL) in patients with CF. As the Horizon2020 project MyCyFAPP aims to improve GI QOL by using a newly designed mobile application, a sensitive and reliable outcome measure was needed. We aimed to study the applicability of the existing child-specific Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Scales and Module (PedsQL GI) in children with CF.
METHODS: A multicenter, prospective observational study was performed in 6 European centers to validate the PedsQL GI in children with CF during 3 months.
RESULTS: In total, 248 children and their parents were included. Within-patient variability of PedsQL GI was low (24.11), and there was reasonable agreement between children and parents (ICC 0.681). Nine of 14 subscales were informative (no ceiling effect). The PedsQL GI and the median scores for 4 subscales were significantly lower in patients compared to healthy controls. Positive associations were found between PedsQL GI and age (OR = 1.044, p = 0.004) and between PedsQL GI and BMI z-score (OR = 1.127, p = 0.036). PedsQL GI correlated with most CFQ-R subscales (r 0.268 to 0.623) and with a Visual Analogue Scale (r = 0.20).
CONCLUSIONS: PedsQL GI is a valid and applicable instrument to assess GI QOL in children with CF. Future research efforts should examine the responsiveness of the CF PedsQL GI to change in the context of clinical interventions and trials.

PMID: 31860639 [PubMed - in process]

Cystic Fibrosis: Emergence of Highly Effective Targeted Therapeutics and Potential Clinical Implications.

Am J Respir Crit Care Med. 2019 Dec 20;:

Authors: Mall MA, Mayer-Hamblett N, Rowe SM

Abstract
Cystic fibrosis (CF) remains the most common life-shortening hereditary disease in Caucasian populations with high morbidity and mortality related to chronic airway mucus obstruction, inflammation, infection and progressive lung damage. In 1989, the discovery that CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cAMP-dependent anion channel vital for proper Cl- and HCO3- transport across epithelial surfaces, provided a solid foundation for unraveling underlying disease mechanisms and the development of therapeutics targeting the basic defect in people with CF. In this review, we focus on recent advances in our understanding of the molecular defects caused by different classes of CFTR mutations, implications for pharmacological rescue of mutant CFTR and insights into how CFTR dysfunction impairs key host defense mechanisms such as mucociliary clearance and bacterial killing in CF airways. Further, we review the path that led to the recent breakthrough in the development of highly effective CFTR-directed therapeutics, now applicable for up to 90% of people with CF that carry responsive CFTR mutations including those with just a single copy of the most common F508del mutation. Finally, we discuss the remaining challenges and strategies to develop highly effective targeted therapies for all patients, and the unprecedented potential of these novel therapies to transform CF from a fatal to a treatable chronic condition.

PMID: 31860331 [PubMed - as supplied by publisher]

Diagnosis and Management of Chronic Pancreatitis: A Review.

JAMA. 2019 Dec 24;322(24):2422-2434

Authors: Singh VK, Yadav D, Garg PK

Abstract
Importance: Chronic pancreatitis (CP) is a chronic inflammatory and fibrotic disease of the pancreas with a prevalence of 42 to 73 per 100 000 adults in the United States.
Observations: Both genetic and environmental factors are thought to contribute to the pathogenesis of CP. Environmental factors associated with CP include alcohol abuse (odds ratio [OR], 3.1; 95% CI, 1.87-5.14) for 5 or more drinks per day vs abstainers and light drinkers as well as smoking (OR, 4.59; 95% CI, 2.91-7.25) for more than 35 pack-years in a case-control study involving 971 participants. Between 28% to 80% of patients are classified as having "idiopathic CP." Up to 50% of these individuals have mutations of the trypsin inhibitor gene (SPINK1) or the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approximately 1% of people diagnosed with CP may have hereditary pancreatitis, associated with cationic trypsinogen (PRSS1) gene mutations. Approximately 80% of people with CP present with recurrent or chronic upper abdominal pain. Long-term sequelae include diabetes in 38% to 40% and exocrine insufficiency in 30% to 48%. The diagnosis is based on pancreatic calcifications, ductal dilatation, and atrophy visualized by imaging with computed tomography, magnetic resonance imaging, or both. Endoscopic ultrasound can assist in making the diagnosis in patients with a high index of suspicion such as recurrent episodes of acute pancreatitis when imaging is normal or equivocal. The first line of therapy consists of advice to discontinue use of alcohol and smoking and taking analgesic agents (nonsteroidal anti-inflammatory drugs and weak opioids such as tramadol). A trial of pancreatic enzymes and antioxidants (a combination of multivitamins, selenium, and methionine) can control symptoms in up to 50% of patients. Patients with pancreatic ductal obstruction due to stones, stricture, or both may benefit from ductal drainage via endoscopic retrograde cholangiopancreatography (ERCP) or surgical drainage procedures, such as pancreaticojejunostomy with or without pancreatic head resection, which may provide better pain relief among people who do not respond to endoscopic therapy.
Conclusions and Relevance: Chronic pancreatitis often results in chronic abdominal pain and is most commonly caused by excessive alcohol use, smoking, or genetic mutations. Treatment consists primarily of alcohol and smoking cessation, pain control, replacement of pancreatic insufficiency, or mechanical drainage of obstructed pancreatic ducts for some patients.

PMID: 31860051 [PubMed - in process]

Review of the sweat test indications in a Brussels' cystic fibrosis reference center.

Ann Biol Clin (Paris). 2019 Dec 01;77(6):687-692

Authors: Bensliman S, Lefevre N, Duchateau J, Hanssens L

Abstract
Sweat test is the gold standard of the diagnosis of cystic fibrosis (CF). The aim of our study was to identify the indications leading to perform a sweat test and those that led to the diagnosis of CF.
METHODOLOGY: We collected data of all sweat tests performed between 2008, 1th of March and 2015, 28th of February. They were analyzed following Rosenstein diagnosis criteria (1998): clinical manifestations suggesting CF, positive neonatal screening (≥ 1 positive assay of immunoreactive trypsin) or familial history of CF.
RESULTS: We reviewed 1,208 sweat tests over this period. Patients were aged from 13 days to 79 years. Indications were: clinical events (94.0%), a positive neonatal screening (3.7%) and a family history (2.3%). Over the 20 newly diagnosed patients, a positive neonatal screening was the main indication for the sweat test (55%). A positive neonatal screening (p<0.0001), a family history (p<0.0001) and pulmonary signs associated with digestive signs (p=0.004) were more frequently found in these patients.
CONCLUSION: Sweat test indications are mostly clinical and mainly pulmonary. This study confirms that a sweat test should be performed in case of pulmonary manifestations suggesting CF especially if these are associated with digestive manifestations.

PMID: 31859647 [PubMed - in process]

Genomic information on Stenotrophomonas maltophilia ST264 isolated from a cystic fibrosis pediatric patient in Brazil.

Braz J Microbiol. 2019 Dec 19;:

Authors: Braga FS, D'Allincourt Carvalho Assef AP, Leão RS, Albano RM, Marques EA

Abstract
Stenotrophomonas maltophilia is one of the Gram-negative bacilli most frequently found in the airways of cystic fibrosis patients. This opportunistic pathogen is intrinsically multidrug-resistant, and therefore, its treatment presents a challenge. The genetic characterization of S. maltophilia is largely unknown, especially from those strains that colonize/infect the airways of cystic fibrosis patients. This work reports the draft genome sequences of three S. maltophilia isolates recovered from the sputum of a cystic fibrosis pediatric patient in Southeast Brazil. Several resistance- and virulence-related genes were detected. Furthermore, one intact phage and one incomplete prophage region were also identified in all strains. Multilocus sequence typing showed that all strains belonged to a new sequence type (ST264). Interestingly, all S. maltophilia strains were genetically identical, showing persistence for at least 16 months. To our knowledge, this is the first report of S. maltophilia draft genome sequences obtained from a cystic fibrosis pediatric patient in Brazil.

PMID: 31858443 [PubMed - as supplied by publisher]