Prenatal genetic testing for cystic fibrosis: a systematic review of clinical effectiveness and an ethics review.

Genet Med. 2019 Aug 30;:

Authors: Kessels SJM, Carter D, Ellery B, Newton S, Merlin TL

Abstract
PURPOSE: We aimed to assess the clinical value of prenatal testing for cystic fibrosis (CF) and whether ethical considerations would affect endpoint selection.
METHODS: To determine effectiveness, we conducted a systematic literature review whose protocol outlined search strategies across eight databases, study inclusion criteria, and prespecified literature screening, data extraction, and synthesis processes. We conducted a scoping search on ethical considerations.
RESULTS: The genetic test showed good diagnostic performance. A change in clinical management was observed: termination of pregnancy (TOP) occurred in most cases where two pathogenic variants were identified in a fetus of carrier parents (158/167; 94.6%). The TOP rate was lower in pregnancies where CF was diagnosed after fetal echogenic bowel detection (~65%). TOP and caring for a child with CF were both associated with poor short-term parental psychological outcomes. Ethical analyses indicated that informed decisions should have been the main endpoint, rather than CF-affected births prevented.
CONCLUSION: CF testing leads to fewer CF-affected births. It is difficult to assess whether this means the test is valuable, since patients may not value TOP primarily in terms of maternal or fetal health outcomes, psychological or otherwise. The value of testing should arguably be measured in terms of improving patient autonomy rather than health.

PMID: 31467445 [PubMed - as supplied by publisher]

Re-visiting the HLA dogma.

Eur Respir J. 2019 Aug;54(2):

Authors: Roux A, Verleden SE

PMID: 31467186 [PubMed - in process]

Current status of fertility and family formation in men with cystic fibrosis.

Hum Fertil (Camb). 2019 Aug 29;:1-6

Authors: Bourke SJ, Anderson A, Briggs J, Doe S, Echevarria C, Choudhary M, McEleny K, Stewart J

Abstract
Men with cystic fibrosis are nearly always infertile due to congenital bilateral absence of the vas deferens, but can undergo assisted reproduction. Ill health may influence reproductive choices. This paper reports data on fertility and family formation in CF including the use of assisted reproduction in a total cohort of 205 men (mean age 30.9, range 16.6-64.3 years) studied over a 10-year period. Overall 102 (49.5%) were single, 52 (25.7%) were married, 48 (23.3%) were in long-term heterosexual relationships, and 3 (1.5%) were in same-sex relationships. One (0.5%) was fertile naturally. In total, 30 children were born to 23 (11%) men by assisted reproduction: 4 used donor sperm and 19 had sperm retrieval and intracytoplasmic sperm injection (ICSI). Two men each adopted two children; 15 (7.3%) men were acting as step-fathers to 20 children from their partners' previous relationships. Overall 41 (20%) men had fatherhood roles. ICSI was unsuccessful in 4 men. A further 16 men were referred for fertility treatment but did not proceed. Of the 19 men having children by ICSI, 3 died leaving 4 children. Men with CF face complex decisions when considering their relationships, fertility and fatherhood.

PMID: 31466486 [PubMed - as supplied by publisher]

Animal Models of Pneumococcal pneumonia.

Int J Mol Sci. 2019 Aug 28;20(17):

Authors: Borsa N, Pasquale MD, Restrepo MI

Abstract
Streptococcus pneumoniae remains the most common bacterial pathogen causing lower respiratory tract infections and is a leading cause of morbidity and mortality worldwide, especially in children and the elderly. Another important aspect related to pneumococcal infections is the persistent rate of penicillin and macrolide resistance. Therefore, animal models have been developed to better understand the pathogenesis of pneumococcal disease and test new therapeutic agents and vaccines. This narrative review will focus on the characteristics of the different animal pneumococcal pneumonia models. The assessment of the different animal models will include considerations regarding pneumococcal strains, microbiology properties, procedures used for bacterial inoculation, pathogenesis, clinical characteristics, diagnosis, treatment, and preventive approaches.

PMID: 31466400 [PubMed - in process]

A comorbidity of CF in need of our attention and activity: Attention Deficit Hyperactivity Disorder!

J Cyst Fibros. 2018 03;17(2):135-136

Authors: Lemiere J, Havermans T

PMID: 29454878 [PubMed - indexed for MEDLINE]

Loss of incretin effect contributes to postprandial hyperglycaemia in cystic fibrosis-related diabetes.

Diabet Med. 2019 Aug 29;:

Authors: Frost F, Jones GH, Dyce P, Jackson V, Nazareth D, Walshaw MJ

Abstract
AIM: To investigate the incretin axis in people with cystic fibrosis.
METHODS: Adults with cystic fibrosis-related diabetes, cystic fibrosis without diabetes, and controls (adults without cystic fibrosis and without diabetes) underwent an oral glucose tolerance test and then a closely matched isoglycaemic i.v. glucose infusion. On each occasion, glucose, insulin, C-peptide, total and active glucagon-like peptide-1 and gastric inhibitory polypeptide responses were recorded and incremental areas under curves were calculated for 60 and 240 min.
RESULTS: Five adults with cystic fibrosis-related diabetes, six with cystic fibrosis without diabetes and six controls, matched for age and BMI, completed the study. Glucose during oral glucose tolerance test closely matched those during isoglycaemic i.v. glucose infusion. The calculated incretin effect was similar in the control group and the cystic fibrosis without diabetes group (28% and 29%, respectively), but was lost in the cystic fibrosis-related diabetes group (cystic fibrosis-related diabetes vs control group: -6% vs 28%; p=0.03). No hyposecretion of glucagon-like peptide-1 or gastric inhibitory polypeptide was observed; conversely, 60-min incremental area under the curve for total glucagon-like peptide-1 was significantly higher in the cystic fibrosis-related diabetes group than in the control group [1070.4 (254.7) vs 694.97 (308.1); p=0.03].
CONCLUSIONS: The incretin effect was lost in cystic fibrosis-related diabetes despite adequate secretion of the incretin hormones. These data support the concept that reduced incretin hormone insulinotropic activity contributes significantly to postprandial hyperglycaemia in cystic fibrosis-related diabetes.

PMID: 31466128 [PubMed - as supplied by publisher]

New insights into the immunoproteome of B. cenocepacia J2315 using serum samples from cystic fibrosis patients.

N Biotechnol. 2019 Aug 26;:

Authors: Sousa SA, Soares-Castro P, Seixas AMM, Feliciano JR, Balugas B, Barreto C, Pereira L, Santos PM, Leitão JH

Abstract
Bacteria of the Burkholderia cepacia complex (Bcc) are ubiquitous multidrug resistant organisms and opportunistic pathogens capable of causing life threatening lung infections among cystic fibrosis (CF) patients. No effective therapies are currently available to eradicate Bcc bacteria from CF patients, as these organisms are inherently resistant to the majority of clinically available antimicrobials. An immunoproteomics approach was used to identify Bcc proteins that stimulate the humoral immune response of the CF host, using bacterial cells grown under conditions mimicking the CF lung environment and serum samples from CF patients with a clinical record of Bcc infection. 24 proteins of the Bcc strain B. cenocepacia J2315 were identified as immunoreactive, 19 here reported as immunogenic for the first time. Ten proteins were predicted as extracytoplasmic, 9 of them being conserved in Bcc genomes. The immunogenic Bcc extracytoplasmic proteins are potential targets for development of novel therapeutic strategies and diagnostic tools to protect patients against the onset of chronic Bcc lung infections.

PMID: 31465856 [PubMed - as supplied by publisher]

Impact of clonally-related Burkholderia contaminans strains in two patients attending an Italian cystic fibrosis centre: a case report.

BMC Pulm Med. 2019 Aug 29;19(1):164

Authors: Savi D, Quattrucci S, Trancassini M, Dalmastri C, De Biase RV, Maggisano M, Palange P, Bevivino A

Abstract
BACKGROUND: Burkholderia contaminans is one of the 20 closely related bacterial of the Burkholderia cepacia complex, a group of bacteria that are ubiquitous in the environment and capable of infecting people with cystic fibrosis (CF). This species is an emerging pathogen and it has been widely isolated from CF patients in Argentina, Spain, Portugal, Australia, Canada, USA with a low prevalence in Ireland, France, Russia, Switzerland, Czech Republic, and Italy. This is the first report of B. contaminans affecting two Italian CF patients attending the same CF Centre. We correlate B. contaminans colonisation with lung function decline and co-infection with other clinically relevant CF pathogens.
CASE PRESENTATION: B. contaminans was identified by Multi Locus Sequence Typing in routine sputum analysis of two Caucasian CF women homozygous for Phe508del CFTR mutation. Sequence Type 102 was detected in both strains. It is known that B. contaminans ST102 was isolated both from CF and non-CF patients, with an intercontinental spread across the world. Random Amplified Polymorphic DNA analysis revealed the genetic relatedness between the two strains. We examined their susceptibility to antimicrobial agents, comparing the latter with that recorded for other B. contaminans isolated from different countries. We also described key virulence factors possibly linked with a clinical outcome. Specifically, we attempted to correlate colonization with the incidence of acute exacerbation of symptoms and lung function decline.
CONCLUSIONS: This case presentation suggests that acquisition of B. contaminans ST102 is not directly associated with a lung function decline. We retain that the presence of other CF pathogens (i.e. MRSA and Trichosporon) along with B. contaminans ST102 might have contributed to the worsening of clinical conditions in our CF patients. The circumstances leading to the establishment of B. contaminans ST102 infections are still unknown. We highlight the importance to proper detect and typing bacteria implicated in CF infection by using molecular techniques.

PMID: 31464603 [PubMed - in process]

Associations between circulating inflammatory markers, diabetes type and complications in youth.

Pediatr Diabetes. 2019 Aug 28;:

Authors: Aulich J, Cho YH, Januszewski AS, Craig ME, Selvadurai H, Wiegand S, Jenkins AJ, Donaghue KC

Abstract
BACKGROUND: Inflammation is implicated in the pathogenesis of diabetes and its complications in adults. Little is known about the relative contribution of inflammation in common types of diabetes in youth: Type 1 diabetes (T1D), Type 2 diabetes (T2D) and cystic fibrosis-related diabetes (CFRD). This study investigates inflammatory markers by diabetes type and complication status, and assesses indicators of inflammation and complications.
METHODS: A cross-sectional study of 134 T1D, 32 T2D, 32 CFRD and 48 subjects without diabetes (including 11 with CF and normal glucose tolerance) was undertaken. Inflammation was assessed by sE-selectin by ELISA, hsCRP by turbidometry, WCC and ESR. Nephropathy was defined by albuminuria, autonomic neuropathy by heart rate variability, and peripheral neuropathy by vibration and thermal threshold testing and retinopathy by seven-field stereoscopic fundus photography. Descriptive statistics, parametric and non-parametric ANOVA and regression analyses were performed, with significance at p<0.05.
RESULTS: Of 198 diabetic participants; 49% female, mean (SD) age, median diabetes duration and median HbA1c were 16(2.5) and 6(3-9) years and 8.1(6.9-9.3)%, respectively. All inflammatory markers were lower in T1D than in other diabetes groups (p<0.05) but higher than in non-diabetic controls. T2D (n=32) and CFRD (n=32) subjects had comparable elevated levels of inflammation. BMI was a strong independent explanatory variable of inflammation. In multivariate analysis, hsCRP and ESR were associated with complications in addition to HbA1c, BMI and diastolic BP.
CONCLUSIONS: Circulating inflammatory markers are elevated in adolescents with diabetes, being higher and comparable in T2D and CFRD than in T1D. Inflammation is independently associated with diabetes complications, consistent with inflammation driving vascular pathology in diabetes. This article is protected by copyright. All rights reserved.

PMID: 31464058 [PubMed - as supplied by publisher]

Elevated risk of invasive group A streptococcal disease and host genetic variation in the human leucocyte antigen locus.

Genes Immun. 2019 Aug 29;:

Authors: Parks T, Elliott K, Lamagni T, Auckland K, Mentzer AJ, Guy R, Cartledge D, Strakova L, Connor DO, Pollard AJ, Neville MJ, Mahajan A, Ashrafian H, Chapman SJ, Hill AVS, Sriskandan S, Knight JC

Abstract
Invasive group A streptococcal (GAS) disease is uncommon but carries a high case-fatality rate relative to other infectious diseases. Given the ubiquity of mild GAS infections, it remains unclear why healthy individuals will occasionally develop life-threatening infections, raising the possibility of host genetic predisposition. Here, we present the results of a case-control study including 43 invasive GAS cases and 1540 controls. Using HLA imputation and linear mixed models, we find each copy of the HLA-DQA1*01:03 allele associates with a twofold increased risk of disease (odds ratio 2.3, 95% confidence interval 1.3-4.4, P = 0.009), an association which persists with classical HLA typing of a subset of cases and analysis with an alternative large control dataset with validated HLA data. Moreover, we propose the association is driven by the allele itself rather than the background haplotype. Overall this finding provides impetus for further investigation of the immunogenetic basis of this devastating bacterial disease.

PMID: 31462703 [PubMed - as supplied by publisher]

GH-IGF1 Axis in Children with Cystic Fibrosis.

Clin Med Res. 2019 Aug 28;:

Authors: Pagani S, Bozzola E, Acquafredda G, Terlizzi V, Raia V, Maio F, Villani A, Bozzola M

Abstract
OBJECTIVE: To verify whether growth hormone receptor gene expression plays a role in Cystic fibrosis (CF)children's growth, as a consequence of the chronic inflammatory condition and malnutrition.
DESIGN: We enrolled forty-nine prepubertal patients (24 males and 25 females) affected by CF in a stable clinical condition, 19 of whom had been diagnosed through newborn screening and 30 following presentation of symptoms. Patients had no significant comorbidity affecting growth or CFTR (Cystic Fibrosis Transmembrane conductance Regulator)-related diabetes requiring insulin therapy. Blood was collected during two follow-up visits to measure IGF-I, GHBP and GH-R gene expression. Fifty-two healthy children, sex- and age-matched, were recruited as a control group.
METHODS: In this study we compared BMI, height, weight, IGF-I, GHBP and GHR gene expression values (evaluated by Chemiluminescent Immunometric assay; ELISA and Real time PCR respectively) in CF patients diagnosed through NBS (New born screening), or by symptoms (Late Diagnosis (LD)) and in healthy controls.
RESULTS: BMI increased significantly in patients between the time of diagnosis and check-ups (p<0.001) and particularly in the LD group, the median value was lower at diagnosis and significantly higher (p<0.001) at follow up visits compared to controls. At the initial evaluation, higher levels of IGF-I (not statistically significant) were found in both the NBS group and in the LD group compared to the control group. At the second evaluation, significantly higher levels of IGF-I (p=0.003) were found in both the NBS and LD groups compared to controls; GHR mRNA expression had significantly increased (p=0.013) in LD patients in comparison with the first evaluation and was significantly higher in the NBS and LD groups than in controls. GHBP values had significantly increased (p=0.047) in the NBS group after one year of therapy compared to first visit levels and were significantly higher (p<0,0001) in the NBS and LD groups compared to controls.
CONCLUSION: In our LD patients during childhood, we observed good auxological values and a GH/IGF-I axis function within normal range for the factor evaluated. However, earlier diagnosis through NBS might further minimize and prevent growth retardation, by reducing the duration of symptoms before treatment.

PMID: 31462537 [PubMed - as supplied by publisher]

A Case Report of Intraoperative Coagulopathy Secondary to Chronic Vitamin K Deficiency.

Am J Med Case Rep. 2019;7(8):167-169

Authors: Haddadin M, Al-Sadawi M, Madanat S, McKenzie DS, Lewis R, McFarlane SI

Abstract
Dietary Vitamin K is a well-known anti-hemorrhagic agent that plays an integral role in the coagulation pathway. Vitamin K is involved in synthesis of coagulation factors; II, VII, IX and factor X. Vitamin K deficiency leads to bleeding diathesis. Hemorrhages usually present in deep soft tissue, rather than mucosal or epithelial membranes, bleeding that is generally caused by disorders of platelets. Major causes of vitamin K deficiency include; medications and diseases involving fat metabolism with a resultant fat malabsorption. Warfarin and Cephalosporins are one of the commonly prescribed medications that lead to vitamin K deficiency. Disease affecting fat metabolism pathway, such as; diseases of the pancreas (cystic fibrosis), short gut syndrome and certain pathologies of the biliary tree. Vitamin K deficiency is more common in newborns. In adults it is uncommon because of its ubiquitous nature and the abundance of its sources. Hemorrhagic disorders in adults due to Vitamin K deficiency are not commonly encountered in practice. We are presenting a case of an adult who presented with a compartment syndrome secondary to a traumatic intramuscular bleeding. Our case highlights the importance of considering vitamin K deficiency in the differential diagnosis of unexplained hemorrhages resulting from a coagulopathy.

PMID: 31457073 [PubMed]

Cystic Fibrosis Transmembrane Conductance Regulator: A Possible New Target for Photodynamic Therapy Enhances Wound Healing.

Adv Wound Care (New Rochelle). 2019 Oct 01;8(10):476-486

Authors: Chiu WT, Tran TV, Pan SC, Huang HK, Chen YC, Wong TW

Abstract
Objective: Cell migration is an essential process in skin wound healing. Photodynamic therapy (PDT) enhances wound healing by photoactivating a photosensitizer with a specific wavelength of light. Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel expressed in multiple layers of keratinocytes. Recent studies showed that the activation of CFTR-related downstream signaling affects skin wound healing. We examined whether indocyanine green (ICG)-mediated PDT-enhanced cell migration is related to CFTR activation. Approach: The spatial and temporal expression levels of CFTR and proteins involved in focal adhesion, including focal adhesion kinase (FAK) and paxillin, were evaluated during cell migration in vitro and in vivo for wound healing. Results: ICG-PDT-conditioned medium collected from cells exposed to 5 J/cm2 near-infrared light in the presence of 100 μg/mL ICG activated CFTR and enhanced HaCaT cell migration. The expression of phosphorylated FAK Tyr861 and phosphorylated paxillin in focal adhesions was spatially and temporally regulated in parallel by ICG-PDT-conditioned medium. Curcumin, a nonspecific activator of CFTR, further increased PDT-enhanced cell migration, whereas inhibition of CFTR and FAK delayed cell migration. The involvement of CFTR in ICG-PDT-enhanced skin wound healing was confirmed in a mouse back skin wound model. Innovation: CFTR is a potential new therapeutic target in ICG-PDT to enhance wound healing. Conclusion: ICG-PDT-enhanced cell migration may be related to activation of the CFTR and FAK pathway. Conditioned medium collected from ICG-PDT may be useful for treating patients with chronic skin ulcer by regulating CFTR expression in keratinocytes.

PMID: 31456905 [PubMed]

A Metabolome- and Metagenome-Wide Association Network Reveals Microbial Natural Products and Microbial Biotransformation Products from the Human Microbiota.

mSystems. 2019 Aug 27;4(4):

Authors: Cao L, Shcherbin E, Mohimani H

Abstract
The human microbiome consists of thousands of different microbial species, and tens of thousands of bioactive small molecules are associated with them. These associated molecules include the biosynthetic products of microbiota and the products of microbial transformation of host molecules, dietary components, and pharmaceuticals. The existing methods for characterization of these small molecules are currently time consuming and expensive, and they are limited to the cultivable bacteria. Here, we propose a method for detecting microbiota-associated small molecules based on the patterns of cooccurrence of molecular and microbial features across multiple microbiomes. We further map each molecule to the clade in a phylogenetic tree that is responsible for its production/transformation. We applied our proposed method to the tandem mass spectrometry and metagenomics data sets collected by the American Gut Project and to microbiome isolates from cystic fibrosis patients and discovered the genes in the human microbiome responsible for the production of corynomycolenic acid, which serves as a ligand for human T cells and induces a specific immune response against infection. Moreover, our method correctly associated pseudomonas quinolone signals, tyrvalin, and phevalin with their known biosynthetic gene clusters.IMPORTANCE Experimental advances have enabled the acquisition of tandem mass spectrometry and metagenomics sequencing data from tens of thousands of environmental/host-oriented microbial communities. Each of these communities contains hundreds of microbial features (corresponding to microbial species) and thousands of molecular features (corresponding to microbial natural products). However, with the current technology, it is very difficult to identify the microbial species responsible for the production/biotransformation of each molecular feature. Here, we develop association networks, a new approach for identifying the microbial producer/biotransformer of natural products through cooccurrence analysis of metagenomics and mass spectrometry data collected on multiple microbiomes.

PMID: 31455639 [PubMed]

Effect of Lumacaftor/Ivacaftor on Pulmonary Exacerbation Rates in Members with Cystic Fibrosis in a Medicaid Population.

J Manag Care Spec Pharm. 2019 Sep;25(9):1021-1025

Authors: Tesell MA, Alper CJ, Bacon R, Greenwood BC, Lenz K, Jeffrey PL, Stevens K

Abstract
BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) is indicated for patients with cystic fibrosis (CF) homozygous for the F508del mutation in the CFTR gene. In clinical trials, LUM/IVA decreased pulmonary exacerbation rates. To our knowledge, there is no published data evaluating real-world outcomes for Medicaid patients receiving LUM/IVA.
OBJECTIVE: To compare CF pulmonary exacerbation rates before and after initiation of LUM/IVA in 1 state's Medicaid program.
METHODS: This pre-post claims analysis screened fee-for-service and managed Medicaid members who had ≥ 1 pharmacy claim for LUM/IVA between July 2, 2015, and September 30, 2016. Members were included if they were aged ≥ 6 years with a CF diagnosis and homozygous for the F508del mutation, consistent with the indication at study initiation. Exclusion criteria included Medicaid as a secondary payer or any break in coverage during the study. The index date was defined as the first claim for LUM/IVA. Demographics and outcomes were derived from pharmacy and medical claims. Outcomes included overall rate of pulmonary exacerbations (reported as the total events for the study population 6 months before and after the index date and average annualized rate). Pulmonary exacerbation was defined as any combination of medical claims for an emergency room (ER) visit or inpatient hospitalization with a CF pulmonary exacerbation or respiratory infection (ICD-9/10-CM codes) or pharmacy claims for an oral or intravenous antibiotic (excluding macrolides). A gap of > 7 days was considered a new pulmonary exacerbation. Paired t-test was used to test significance.
RESULTS: 21 patients met inclusion criteria with an average age at treatment initiation of 20.1 years. Average proportion of days covered (SD) was 0.62 (0.29). The number of pulmonary exacerbations increased from 45 to 48 during the 6 months before and after the index date, respectively, and the annualized rate increased from 4.37 to 4.66 (P = 0.69). While the number of pulmonary exacerbations associated with antibiotics alone increased (23 to 33; P = 0.08), those associated with at least 1 ER visit or inpatient hospitalization decreased (22 to 15; P = 0.08).
CONCLUSIONS: This analysis did not find a decrease in pulmonary exacerbation rate for Medicaid members receiving LUM/IVA; however, adherence was low. Further study of similar populations is needed to better understand the long-term effect of treatment.
DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. A poster of this project was presented at the Academy of Managed Care Pharmacy Managed Care & Specialty Pharmacy Annual Meeting 2018 in Boston, MA, on April 23-26, 2018.

PMID: 31456498 [PubMed - in process]

Major depression and psychiatric comorbidity in Turkish children and adolescents with cystic fibrosis.

Pediatr Pulmonol. 2019 Aug 27;:

Authors: Gundogdu U, Fis NP, Eralp EE, Karadag BT

Abstract
BACKGROUND: Many psychological factors contribute to an increased risk of depression in children and adolescents with cystic fibrosis (CF). This study aims to evaluate coexisting psychiatric disorders, perceived social support, and quality of life (QoL) in Turkish children with CF and compare these factors with those of a control group.
METHODS: The study group consisted of 32 children (8-16 years of age) with CF and a group of 33 age- and sex-matched control children. All subjects completed the Children's Depression Inventory (CDI), Screen for Child Anxiety and Related Disorders (SCARED), Social Support Appraisals Scale, and Pediatric Quality of Life Questionnaire. Psychiatric diagnoses were established using the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version.
RESULTS: Of the children with CF, 80% of those in the 8 to 11 years age range and 50% of those in the 12 to 17 years age range had at least one psychiatric disorder, that is, 68% of the 33 children with CF had at least one psychiatric disorder. Anxiety disorder (46.8%) and attention deficit and hyperactivity disorder (21.8%) were also common among children with CF. The rates of depression in the CF group and control group were 21.9% and 6.1%, respectively (P > .05). The CF subjects with coexisting depression exhibited higher levels of disease severity, longer periods of hospitalization, and more frequent anxiety disorder. When compared with the control group, the QoL among the Turkish children with CF was lower (P < .05). The CDI and SCARED are relatively sensitive and specific screening tools for depression and anxiety in children with CF.
CONCLUSIONS: Psychiatric disorders were more frequently found in children and adolescents with CF. By examining symptoms of anxiety and depression and by using screening tools, CF patients who exhibit symptoms of psychiatric disorders can be better identified and evaluated.

PMID: 31456343 [PubMed - as supplied by publisher]

Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel.

J R Soc Interface. 2019 Aug 30;16(157):20190187

Authors: Olivença DV, Fonseca LL, Voit EO, Pinto FR

Abstract
The lung epithelium is lined with a layer of airway surface liquid (ASL) that is crucial for healthy lung function. ASL thickness is controlled by two ion channels: epithelium sodium channel (ENaC) and cystic fibrosis (CF) transmembrane conductance regulator (CFTR). Here, we present a minimal mathematical model of ENaC, CFTR and ASL regulation that sheds light on the control of ENaC by the short palate lung and nasal epithelial clone 1 (SPLUNC1) protein and by phosphatidylinositol 4,5-biphosphate (PI(4,5)P2). The model, despite its simplicity, yields a good fit to experimental observations and is an effective tool for exploring the interplay between ENaC, CFTR and ASL. Steady-state data and dynamic information constrain the model's parameters without ambiguities. Testing the hypothesis that PI(4,5)P2 protects ENaC from ubiquitination suggests that this protection does not improve the model results and that the control of the ENaC opening probability by PI(4,5)P2 is sufficient to explain all available data. The model analysis further demonstrates that ASL at the steady state is sensitive to small changes in PI(4,5)P2 abundance, particularly in CF conditions, which suggests that manipulation of phosphoinositide metabolism may promote therapeutic benefits for CF patients.

PMID: 31455163 [PubMed - in process]

Combined Thoracic and Abdominal Organ Transplantation: Special Considerations.

Semin Cardiothorac Vasc Anesth. 2019 Aug 27;:1089253219870631

Authors: Yager A, Khorsand S, Chokshi R, Cheruku S

Abstract
Combined thoracic-abdominal organ transplants are infrequently performed procedures indicated for patients with failure of two or more transplantable organs. In this review, we discuss recipient selection, surgical considerations, anesthetic management, and outcomes associated with common combinations of thoracic-abdominal transplant operations. General principles regarding the postoperative care of these patients are also discussed. These procedures present a unique challenge requiring specialized knowledge, technical expertise, and leadership from the anesthesiology team throughout the perioperative period.

PMID: 31455153 [PubMed - as supplied by publisher]

Specific Inhibition of the NLRP3 Inflammasome as an Anti-Inflammatory Strategy in Cystic Fibrosis.

Am J Respir Crit Care Med. 2019 Aug 27;:

Authors: McElvaney OJ, Zaslona Z, Becker-Flegler K, Palsson-McDermott EM, Boland F, Gunaratnam C, Gulbins E, O'Neill LA, Reeves EP, McElvaney NG

Abstract
RATIONALE: Cystic fibrosis (CF) pulmonary disease is characterized by chronic infection with Pseudomonas aeruginosa and sustained neutrophil-dominant inflammation. The lack of effective anti-inflammatory therapies for people with CF (PWCF) represents a significant challenge.
OBJECTIVES: To identify altered immunometabolism in the CF neutrophil, and investigate the feasibility of specific inhibition of the NLR family, pyrin domain-containing protein 3 (NLRP3) inflammasome as a CF anti-inflammatory strategy in vivo.
METHODS: Key markers of increased aerobic glycolysis, known as a Warburg effect, including cytosolic pyruvate kinase M2 (PKM2), phosphorylated PKM2, succinate, HIF-1α, lactate and the interleukin (IL)-1β precursor pro-IL-1β, as well as caspase-1 activity and processing of pro-IL-1β to IL-1β by the NLRP3 inflammasome, were measured in neutrophils from blood and airway secretions from healthy controls (n=12), PWCF (n=16) and PWCF post-double-lung transplant (n=6). The effects of specific inhibition of NLRP3 on airway inflammation and bacterial clearance in a murine CF model were subsequently assessed in vivo.
MAIN RESULTS: CF neutrophils display increased aerobic glycolysis in the systemic circulation. This effect is driven by low-level endotoxemia, unaffected by CFTR modulation, and resolves post-transplant. The increased pro-IL-1β produced is processed to its mature active form in the lipopolysaccharide-rich CF lung by the NLRP3 inflammasome via caspase-1. Specific NLRP3 inhibition in vivo with MCC950 inhibited IL-1β in the lungs of CF mice (P<0.0001), resulting in significantly reduced airway inflammation and improved Pseudomonas clearance (P<0.0001).
CONCLUSIONS: CF neutrophil immunometabolism is altered in response to inflammation. NLRP3 inflammasome inhibition may have an anti-inflammatory and anti-infective role in CF.

PMID: 31454256 [PubMed - as supplied by publisher]

Prevalence and Antibiotic Resistance of Stenotrophomonas maltophilia in Respiratory Tract Samples: A 10-Year Epidemiological Snapshot.

Health Serv Res Manag Epidemiol. 2019 Jan-Dec;6:2333392819870774

Authors: Gajdács M, Urbán E

Abstract
Background: Since the 1980s, Stenotrophomonas maltophilia has emerged as an important pathogen associated with significant mortality in pneumonia and bacteremia of severely immunocompromised, hospitalized patients. The drug of choice in S maltophilia infections is sulfamethoxazole-trimethoprim (SMX/TMP); SMX/TMP resistance is a serious concern in clinical practice. The aim of this study was to assess the prevalence of S maltophilia in lower respiratory tract (LRTI) samples at a tertiary-care university hospital.
Methods: This retrospective cohort study was carried out using microbiological data collected between January 2008 and December 2017. Routine antimicrobial susceptibility testing was performed for SMX/TMP and levofloxacin; in case of resistance, susceptibility testing for additional antibiotics (tigecycline, amikacin, and colistin) was also performed.
Results: A total of 579 individual S maltophilia isolates were identified (2008-2012: n = 160, 2013-2017: n = 419; P = .0008). In all, 78.46% of patients were younger than 5 or older than 50 years of age and had recent trauma, surgery, or underlying conditions (malignancies, respiratory distress syndrome, congenital disorders, and cystic fibrosis). In 28.16% of samples, more than 1 pathogen was identified, and 5.35% of coisolated pathogens were multidrug resistant (MDR). In all, 12.1% of isolates were SMX/TMP-resistant (2008-2012: 6.12%, 2013-2017: 18.06%; P = .034), while 8.99% were resistant to levofloxacin (2008-2012: 7.86%, 2013-2017: 10.12%; P > .05). SMX/TMP resistance was detected more frequently in samples originating from inpatients (n = 2.50 ± 2.39 vs n = 11.50 ± 3.76; P = .0002).
Conclusions: In all, 5.87% of isolates were extensively drug resistant (XDR), that is, in addition to SMX/TMP, they were resistant to levofloxacin, amikacin, colistin, and tigecycline. The results of our study correspond to the findings in the literature.

PMID: 31453265 [PubMed]