A novel mutation in the SMPX gene associated with X-linked nonsyndromic sensorineural hearing loss in a Chinese family.

J Hum Genet. 2018 Mar 20;:

Authors: Deng Y, Niu Z, Fan L, Ling J, Chen H, Cai X, Mei L, He C, Zhang X, Wen J, Li M, Li W, Li T, Sang S, Liu Y, Feng Y

Abstract
X-linked inheritance is very rare and is estimated to account for only 1-5% of all nonsyndromic hearing loss cases. We found a multiplex family from China segregating with X-linked nonsyndromic hearing loss. After exclusive analysis of 10 common variations of three hearing loss-related genes, GJB2, mtDNA12srRNA and SLC26A4, a novel truncated variant of SMPX, c.87dupA (p.Gly30Argfs*12) (NCBI ClinVar Submission ID: SUB3136126), was identified by whole-exome sequencing. This variant was co-segregated with hearing loss in the entire family and was absent in 576 unrelated ethnically and geographically matched controls. We also detected a single nucleotide variation in two male controls with normal hearing, SMPX c.55A>G (p.Asn19Asp), which has been annotated as a rare variant in the Single Nucleotide Polymorphism (dbSNP) (rs759552778) and Exome Aggregation Consortium (ExAC) databases. This study has enriched the mutation spectrum of the SMPX gene.

PMID: 29559740 [PubMed - as supplied by publisher]

Homozygous indel mutation in CDH11 as the probable cause of Elsahy-Waters syndrome.

Am J Med Genet A. 2017 Dec;173(12):3143-3152

Authors: Taskiran EZ, Karaosmanoglu B, Koşukcu C, Doğan ÖA, Taylan-Şekeroğlu H, Şimşek-Kiper PÖ, Utine EG, Boduroğlu K, Alikaşifoğlu M

Abstract
Two sisters from a consanguineous couple were seen in genetics department for facial dysmorphic features and glaucoma. They both had broad foreheads, hypertelorism, megalocorneas, thick eyebrows with synophrys, flat malar regions, broad and bulbous noses, and mild prognathism. Both had glaucoma, younger one also had cataracts and phthisis bulbi. Other findings included bilateral partial cutaneous syndactyly of 2nd and 3rd fingers, history of impacted teeth with dentigerous cyst in the elder one, and intellectual disability (mild and borderline). The sisters were considered to have Elsahy-Waters syndrome. In order to elucidate the underlying molecular cause, sisters and their healthy parents were genotyped by SNP arrays, followed by homozygosity mapping. Homozygous regions were further analyzed by exome sequencing in one affected individual. A homozygous indel variant segregating with the condition was detected in CDH11 (c.1116_1117delinsGATCATCAG, p.(Ile372MetfsTer9)), which was then validated by using Sanger sequencing. CDH11 encodes cadherin 11 (osteo-cadherin) that regulates cell-cell adhesion, cell polarization and migration, as well as osteogenic differentiation. Further experiments revealed that CDH11 expression was decreased in patient-derived fibroblasts as compared to the heterozygous parent and another healthy donor. Immunostaining showed absence of the protein expression in patient fibroblasts. In addition, cell proliferation rate was slow and osteogenic differentiation potential was delayed. We consider that this study reveals loss-of-function mutations in CDH11 as a probable cause of this phenotype. Next generation sequencing in further patients would both prove this gene as causative, and finely delineate this clinical spectrum further contributing in identification of other possibly involved gene(s).

PMID: 28988429 [PubMed - indexed for MEDLINE]

Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.

Hum Mol Genet. 2017 Nov 01;26(21):4301-4313

Authors: Dand N, Mucha S, Tsoi LC, Mahil SK, Stuart PE, Arnold A, Baurecht H, Burden AD, Callis Duffin K, Chandran V, Curtis CJ, Das S, Ellinghaus D, Ellinghaus E, Enerback C, Esko T, Gladman DD, Griffiths CEM, Gudjonsson JE, Hoffman P, Homuth G, Hüffmeier U, Krueger GG, Laudes M, Lee SH, Lieb W, Lim HW, Löhr S, Mrowietz U, Müller-Nurayid M, Nöthen M, Peters A, Rahman P, Reis A, Reynolds NJ, Rodriguez E, Schmidt CO, Spain SL, Strauch K, Tejasvi T, Voorhees JJ, Warren RB, Weichenthal M, Weidinger S, Zawistowski M, Nair RP, Capon F, Smith CH, Trembath RC, Abecasis GR, Elder JT, Franke A, Simpson MA, Barker JN

Abstract
Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.

PMID: 28973304 [PubMed - indexed for MEDLINE]

FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability?

Am J Med Genet A. 2017 Dec;173(12):3172-3181

Authors: Myers A, du Souich C, Yang CL, Borovik L, Mwenifumbo J, Rupps R, Study C, Lehman A, Boerkoel CF

Abstract
The forkhead box (FOX) transcription factors have roles in development, carcinogenesis, metabolism, and immunity. In humans FOXP1 mutations have been associated with language and speech defects, intellectual disability, autism spectrum disorder, facial dysmorphisms, and congenital anomalies of the kidney and urinary tract. In mice, Foxp1 plays critical roles in development of the spinal motor neurons, lymphocytes, cardiomyocytes, foregut, and skeleton. We hypothesized therefore that mutations of FOXP1 affect additional tissues in some humans. Supporting this hypothesis, we describe two individuals with novel variants of FOXP1 (NM_032682.5:c.975-2A>C and NM_032682.5:c.1574G>A) and additional features. One had a lung disease resembling neuroendocrine cell hyperplasia of infancy (NEHI), and the second had a skeletal disorder with undertubulation of the long bones and relapsing-remitting fevers associated with flushing and edema. Although attribution of these traits to mutation of FOXP1 requires ascertainment of additional patients, we hypothesize that the variable expression of these additional features might arise by means of stochastic developmental variation.

PMID: 28884888 [PubMed - indexed for MEDLINE]

Large-scale computational drug repositioning to find treatments for rare diseases.

NPJ Syst Biol Appl. 2018;4:13

Authors: Govindaraj RG, Naderi M, Singha M, Lemoine J, Brylinski M

Abstract
Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning. In order to find new targets for known drugs ultimately leading to drug repositioning, we recently developed eMatchSite, a new computer program to compare drug-binding sites. In this study, eMatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases. The effectiveness of this integrated approach is demonstrated for a kinase inhibitor, which is a confirmed candidate for repositioning to synapsin Ia. The resulting dataset comprises 31,142 putative drug-target complexes linked to 980 orphan diseases. The modeling accuracy is evaluated against the structural data recently released for tyrosine-protein kinase HCK. To illustrate how potential therapeutics for rare diseases can be identified, we discuss a possibility to repurpose a steroidal aromatase inhibitor to treat Niemann-Pick disease type C. Overall, the exhaustive exploration of the drug repositioning space exposes new opportunities to combat orphan diseases with existing drugs. DrugBank/Orphanet repositioning data are freely available to research community at https://osf.io/qdjup/.

PMID: 29560273 [PubMed]

Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome.

Ann Clin Transl Neurol. 2018 Mar;5(3):323-332

Authors: O'Leary HM, Kaufmann WE, Barnes KV, Rakesh K, Kapur K, Tarquinio DC, Cantwell NG, Roche KJ, Rose SA, Walco AC, Bruck NM, Bazin GA, Holm IA, Alexander ME, Swanson LC, Baczewski LM, Mayor Torres JM, Nelson CA, Sahin M

Abstract
Objective: To measure the efficacy of mecasermin (recombinant human insulin-like growth factor 1, rhIGF-1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double-blind crossover study design.
Methods: Thirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF-1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28-week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory- and electroencephalography (EEG)-based biomarkers were also analyzed.
Results: There were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication.
Interpretation: As in the phase 1 trial, rhIGF-1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

PMID: 29560377 [PubMed]

Deciding on cystic fibrosis carrier screening: three citizens' juries and an online survey.

Eur J Public Health. 2018 Mar 19;:

Authors: Mosconi P, Colombo C, Roberto A, Candiani G, Greco MT, Satolli R, Castellani C

Abstract
Background: Health technology assessment and ethical issues have to be dealt with in deciding on national carrier screening for cystic fibrosis (CF)-the most frequent severe autosomal recessive disease in Caucasian populations and several stakeholders need to be involved. A citizens' jury is one way to ask citizens to deliberate on controversial topics in the interests of a society. The aims of this project were to gather opinions about CF carrier screening through citizens' jury deliberations and to match them with the findings of a large online consultation survey open to the general population, people with CF and families and health professionals.
Methods: Three citizens' juries and an online survey were asked: 'Should the Health Service organize screening of the population with the aim of identifying healthy people who may have children with CF?' The jurors had no medical background and no personal or family CF history. The survey was open to people with CF, families, and healthcare professionals.
Results: Jurors and survey respondents were in favour of CF carrier screening, mainly considering the severity of CF, the value of informed reproductive choices and the equality of the screening. All the citizens' juries felt positively about the health service actively offer CF carrier screening to provide women and couples of reproductive age equal access and standardized information on the pros and cons.
Conclusion: Considering the favourable attitude towards CF screening, the feasibility of CF screening, in terms of best setting, target age and healthcare professionals providing it, should be tested in a clinical trial.

PMID: 29562330 [PubMed - as supplied by publisher]

Meconium Ileus in a Neonate with Cystic Fibrosis.

N Engl J Med. 2018 Mar 22;378(12):1142

Authors: Wood KE

PMID: 29562160 [PubMed - in process]

The presence of Interleukin-13 in nasal lavage may be a predictor of nasal polyposis in pediatric patients with cystic fibrosis.

Rhinology. 2018 Mar 21;:

Authors: Manji J, Thamboo A, Tacey M, Garnis C, Chadha NK

Abstract
BACKGROUND: Sinonasal disease is a common feature of cystic fibrosis (CF) and can cause significant morbidity in these patients. Our objective was to determine if CF individuals with concomitant nasal polyposis (NP) express a unique profile of inflammation and if so, whether these inflammatory cytokine mediators have predictive value in identifying these individuals for prompt management by an Otolaryngologist.
METHODOLOGY: Nasal lavage samples and clinical outcomes of disease severity were obtained from thirty-eight pediatric CF individuals. Participants were subdivided based on the presence or absence of NP. Nasal lavage samples were analyzed on a panel of seventeen cytokine targets using a Bio-Plex Luminex assay. A Perl Permutation test with correction for multiple hypotheses was performed to identify uniquely expressed cytokines between CF individuals with NP (CFwNP) and those without (CFsNP).
RESULTS: Thirty-five patients were included in the analysis. Cytokines IL-13 and GM-CSF were uniquely expressed in the CFwNP group when compared to the CFsNP group. Logistic regression analysis demonstrated a significant association of IL-13 with NP.
CONCLUSION: In children diagnosed with CF, the level of IL-13 in nasal lavage samples could potentially serve as a non-invasive clinical tool in predicting NP in this population, and a target for future immunotherapy.

PMID: 29561922 [PubMed - as supplied by publisher]

Dextran Sulfate Sodium (DSS)-induced Chronic Colitis Attenuates Ca2+-activated Cl- Secretion in Murine Colon by Down-regulating TMEM16A.

Am J Physiol Cell Physiol. 2018 Mar 21;:

Authors: Rottgen TS, Nickerson AJ, Minor EA, Stewart AB, Harold AD, Rajendran VM

Abstract
Attenuated Ca2+-activated Cl- secretion has previously been observed in the model of dextran-sulfate-sodium (DSS)-induced colitis. Prior studies have implicated dysfunctional muscarinic signaling from basolateral membranes as the potential perpetrator leading to decreased Ca2+-activated Cl- secretion. However, in our chronic model of DSS-colitis, Chrm3 transcript (1.028 {plus minus} 0.12 vs. 1.029 {plus minus} 0.27, p > 0.05) and CHRM3 protein expression (1.021 {plus minus} .24 vs. .928 {plus minus} .09, p > 0.05) were unchanged. Therefore, we hypothesized that decreased CCH-stimulated Cl- secretion in DSS-induced colitis can be attributed to a loss of Ca2+-activated Cl- channels (CaCC) in apical membranes of colonic epithelium. To establish this chemically-induced colitis, Balb/C mice were exposed to 4% DSS for 5 alternating weeks to stimulate a more moderate, chronic colitis. Upon completion of the 10-week protocol, whole thickness sections of colon were mounted in the Ussing chamber under voltage-clamp conditions. DSS-induced colitis demonstrated a complete inhibition of basolateral administration of CCH-stimulated Cl- secretion that actually displayed a reversal in polarity (15.40 {plus minus} 2.22 μA/cm2 vs. -2.47{plus minus}0.25 μA/cm2). Western blot of potential CaCCs, quantified by densitometric analysis, demonstrated no change in bestrophin-2 (BEST2) and cystic fibrosis transmembrane regulator (CFTR), while Anoctamin-1 (ANO1, TMEM16A) was significantly down-regulated (1.001 {plus minus} 0.13 vs. 0.510 {plus minus} 0.12, p < 0.05). Our findings indicate that decreased expression of TMEM16A in DSS-induced colitis contributes to the decreased Ca2+-activated Cl- secretion in murine colon.

PMID: 29561662 [PubMed - as supplied by publisher]

Intrapulmonary percussive ventilation improves lung function in cystic fibrosis patients chronically colonized with Pseudomonas aeruginosa: a pilot cross-over study.

Eur J Clin Microbiol Infect Dis. 2018 Mar 20;:

Authors: Dingemans J, Eyns H, Willekens J, Monsieurs P, Van Houdt R, Cornelis P, Malfroot A, Crabbé A

Abstract
High levels of shear stress can prevent and disrupt Pseudomonas aeruginosa biofilm formation in vitro. Intrapulmonary percussive ventilation (IPV) could be used to introduce shear stress into the lungs of cystic fibrosis (CF) patients to disrupt biofilms in vivo. We performed a first-of-its-kind pilot clinical study to evaluate short-term IPV therapy at medium (200 bursts per minute, bpm) and high frequency (400 bpm) as compared to autogenic drainage (AD) on lung function and the behavior of P. aeruginosa in the CF lung in four patients who are chronically colonized by P. aeruginosa. A significant difference between the three treatment groups was observed for both the forced expiratory volume in 1 s (FEV1) and the forced vital capacity (FVC) (p < 0.05). More specifically, IPV at high frequency significantly increased FEV1 and FVC compared to AD (p < 0.05) and IPV at medium frequency (p < 0.001). IPV at high frequency enhanced the expression levels of P. aeruginosa planktonic marker genes, which was less pronounced with IPV at medium frequency or AD. In conclusion, IPV at high frequency could potentially alter the behavior of P. aeruginosa in the CF lung and improve lung function.
TRIAL REGISTRATION: The trail was retrospectively registered at the ISRCTN registry on 6 June 2013, under trial registration number ISRCTN75391385.

PMID: 29560543 [PubMed - as supplied by publisher]

Combination antibiotics against Pseudomonas aeruginosa, representing common and rare cystic fibrosis strains from different Irish clinics.

Heliyon. 2018 Mar;4(3):e00562

Authors: Kapoor P, Murphy P

Abstract
Objectives: To evaluate the effect of antibiotic combination therapy versus single therapy against cystic fibrosis strains of Pseudomonas aeruginosa identified as common and rare among patient groups in different Irish hospitals.
Methods: This study compares the susceptibility profiles of P. aeruginosa isolates from different cystic fibrosis (CF) clinics in Ireland, collected from 2004-2005. Strains were recovered in small numbers and typed by pulsed-field gel electrophoresis. Five common clonal variants were identified in five different hospitals, described as 'common strains'. A number of 'rare strains' associated with any single patient were also included in the study. Certain virulence factors were determined and in vitro assays such as minimum inhibitory concentrations (MIC) and biofilm inhibitory concentrations (BIC) were employed to assess potential synergistic effects of antipseudomonal antibiotic combination therapy.
Results: There was no distinct virulence factors associated with clinical strains that were common in comparison to those that were rare. Antibiotic combination testing revealed the majority of combinations were similar to the activity of either antibiotic used as single agents. Tobramycin-ceftazidime was the most effective combination exhibiting synergistic interactions (FIC ≤ 0.5) against certain clinical isolates of P. aeruginosa.
Conclusion: The efficacy of single antibiotics and synergistic interactions of antibiotic combinations were strain specific, irrespective of virulence characteristics of P. aeruginosa. Common clonal P. aeruginosa strains do not have distinct characteristics that possibly influence persistence in the chronic CF lung. Tobramycin-ceftazidime may be successful for controlling specific P. aeruginosa strains. Further studies on representative isolates are needed to support these results.

PMID: 29560472 [PubMed]

The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites.

ERJ Open Res. 2018 Jan;4(1):

Authors: Schneider EK, McQuade RM, Carbone VC, Reyes-Ortega F, Wilson JW, Button B, Saito A, Poole DP, Hoyer D, Li J, Velkov T

Abstract
Ivacaftor-lumacaftor and ivacaftor are two new breakthrough cystic fibrosis transmembrane conductance modulators. The interactions of ivacaftor and its two metabolites hydroxymethylivacaftor (iva-M1) and ivacaftorcarboxylate (iva-M6) with neurotransmitter receptors were investigated in radioligand binding assays. Ivacaftor displayed significant affinity to the 5-hydroxytryptamine (5-HT; serotonin) 5-HT2C receptor (pKi=6.06±0.03), β3-adrenergic receptor (pKi=5.71±0.07), δ-opioid receptor (pKi=5.59±0.06) and the dopamine transporter (pKi=5.50±0.20); iva-M1 displayed significant affinity to the 5-HT2C receptor (pKi=5.81±0.04) and the muscarinic M3 receptor (pKi=5.70±0.10); iva-M6 displayed significant affinity to the 5-HT2A receptor (pKi=7.33±0.05). The in vivo central nervous system activity of ivacaftor (40 mg·kg-1 intraperitoneally for 21 days) was assessed in a chronic mouse model of depression. In the forced swim test, the ivacaftor-treated group displayed decreased immobility (52.8±7.6 s), similarly to fluoxetine (33.8±11.0 s), and increased climbing/swimming activity (181.5±9.2 s). In the open field test, ivacaftor produced higher locomotor activity than the fluoxetine group, measured both as mean number of paw touches (ivacaftor 81.1±9.6 versus fluoxetine 57.9±9.5) and total distance travelled (ivacaftor 120.6±16.8 cm versus fluoxetine 84.5±16.0 cm) in 600 s. Treatment of 23 cystic fibrosis patients with ivacaftor-lumacaftor resulted in significant improvements in quality of life (including anxiety) in all five domains of the AweScoreCF questionnaire (p=0.092-0.096). Our findings suggest ivacaftor displays potential clinical anxiolytic and stimulating properties, and may have beneficial effects on mood.

PMID: 29560360 [PubMed]

Case Report: Dual nebulised antibiotics among adults with cystic fibrosis and chronic Pseudomonas infection.

F1000Res. 2017;6:2079

Authors: Mann N, Murray S, Hoo ZH, Curley R, Wildman MJ

Abstract
Pulmonary exacerbations in adults with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa (Psae) infection are usually treated with dual intravenous antibiotics for 14 days, despite the lack of evidence for best practice. Intravenous antibiotics are commonly associated with various systemic adverse effects, including renal failure and ototoxicity. Inhaled antibiotics are less likely to cause systematic adverse effects, yet can achieve airway concentrations well above conventional minimum inhibitory concentrations. Typically one inhaled antibiotic is used at a time, but dual inhaled antibiotics (i.e. concomitant use of two different inhaled antibiotics) may have synergistic effect and achieve better results in the treatment of exacerbations. We presented anecdotal evidence for the use of dual inhaled antibiotics as an acute treatment for exacerbations, in the form of a case report. A female in her early thirties with CF and chronic Psae infection improved her FEV 1 by 5% and 2% with two courses of dual inhaled antibiotics to treat exacerbations in 2016. In contrast, her FEV 1 changed by 2%, -2%, 0% and 2%, respectively, with four courses of dual intravenous antibiotics in 2016. Baseline FEV 1 was similar prior to all six courses of treatments. The greater FEV 1 improvements with dual inhaled antibiotics compared to dual intravenous antibiotics suggest the potential role of using dual inhaled antibiotics to treat exacerbations among adults with CF and chronic Psae infection, especially since a greater choice of inhaled anti-pseudomonal antibiotics is now available. A previous study in 1985 has looked at the concomitant administration of inhaled tobramycin and carbenicillin, by reconstituting antibiotics designed for parenteral administration. To our knowledge, this is the first literature to describe the concomitant use of two different antibiotics specifically developed for delivery via the inhaled route.

PMID: 29560254 [PubMed]

A fuzzy rule-based expert system for diagnosing cystic fibrosis.

Electron Physician. 2017 Dec;9(12):5974-5984

Authors: Hassanzad M, Orooji A, Valinejadi A, Velayati A

Abstract
Background: Finding a valid diagnosis is mostly a prolonged process. Current advances in the sector of artificial intelligence have led to the appearance of expert systems that enrich the experiences and capabilities of doctors for making decisions for their patients.
Objective: The objective of this research was developing a fuzzy expert system for diagnosing Cystic Fibrosis (CF).
Methods: Defining the risk factors and then, designing the fuzzy expert system for diagnosis of CF were carried out in this cross-sectional study. To evaluate the performance of the proposed system, a dataset that corresponded to 70 patients with respiratory disease who were serially admitted to the CF Clinic in the Pediatric Respiratory Diseases Center, Masih Daneshvari Hospital in Tehran, Iran during August 2016 to January 2017 was considered. Whole procedures of system construction were implemented in a MATLAB environment.
Results: Results showed that the suggested system can be used as a strong diagnostic tool with 93.02% precision, 89.29% specificity, 95.24% sensitivity and 92.86% accuracy for diagnosing CF. There was also a good relationship between the user and the system through the appealing user interface.
Conclusion: The system is equipped with information, knowledge, and expertise from certified specialists; hence, as a training tool it can be useful for new physicians. It is worth mentioning that the accomplishment of this project depends on advocacy of decision making in CF diagnosis. Nevertheless, it is expected that the system will reduce the number of false positives and false negatives in unusual cases.

PMID: 29560150 [PubMed]

Comparative Genomics of Environmental and Clinical Burkholderia cenocepacia Strains Closely Related to the Highly Transmissible Epidemic ET12 Lineage.

Front Microbiol. 2018;9:383

Authors: Bodilis J, Denet E, Brothier E, Graindorge A, Favre-Bonté S, Nazaret S

Abstract
The Burkholderia cenocepacia epidemic ET12 lineage belongs to the genomovar IIIA including the reference strain J2315, a highly transmissible epidemic B. cenocepacia lineage. Members of this lineage are able to cause lung infections in immunocompromised and cystic fibrosis patients. In this study, we describe the genome of F01, an environmental B. cenocepacia strain isolated from soil in Burkina Faso that is, to our knowledge, the most closely related strain to this epidemic lineage. A comparative genomic analysis was performed on this new isolate, in association with five clinical and one environmental B. cenocepacia strains whose genomes were previously sequenced. Antibiotic resistances, virulence phenotype, and genomic contents were compared and discussed with an emphasis on virulent and antibiotic determinants. Surprisingly, no significant differences in antibiotic resistance and virulence were found between clinical and environmental strains, while the most important genomic differences were related to the number of prophages identified in their genomes. The ET12 lineage strains showed a noticeable greater number of prophages (partial or full-length), especially compared to the phylogenetically related environmental F01 strain (i.e., 5-6 and 3 prophages, respectively). Data obtained suggest possible involvements of prophages in the clinical success of opportunistic pathogens.

PMID: 29559964 [PubMed]

IN VITRO ANTIMICROBIAL ACTIVITY OF CEFTOLOZANE/TAZOBACTAM AGAINST P. AERUGINOSA AND OTHER NON-FERMENTING GRAM-NEGATIVE ORGANISMS IN ADULTS WITH CYSTIC FIBROSIS.

J Glob Antimicrob Resist. 2018 Mar 17;:

Authors: Gramegna A, Millar BC, Blasi F, Elborn JS, Downey DG, Moore JE

Abstract
INTRODUCTION: Pulmonary exacerbations in people with Cystic Fibrosis (CF), with chronic Gram-negative pathogens, are associated with reduced survival. These pathogens are usually treated with repeated courses of systemic antibiotics. However there is a linked emergence of multidrug resistant (MDR) pathogens. Ceftolozane/tazobactam is a new cephalosporin/beta-lactamase inhibitor combination that has been demonstrated to have good activity against MDR Pseudomonas aeruginosa.
MATERIAL & METHODS: In this study ceftolozane/tazobactam was compared to other commonly used intravenous antibiotics against 193 non-fermenting Gram-negative bacteria isolated from CF sputum specimens, including P. aeruginosa, Achromobacter xylosoxidans, Stenotrophomonas maltophilia and Burkholderia. MICs to ceftolozane/tazobactam were determined by standard E-test assay and interpreted according to current EUCAST guidelines.
RESULTS: Ceftolozane/tazobactam had good in vitro antimicrobial activity against CF clinical isolates of P. aeruginosa in comparison to other antimicrobials with the exception of colistin. Ceftolozane/tazobactam also had activity against S. maltophilia, but was not active against B. cenocepacia and A. xylosoxidans.
DISCUSSION: ceftolozane/tazobactam showed excellent in vitro activity against P. aeruginosa from CF clinical isolates. This antibiotic is a potential therapeutic option when presented with challenging MDR P. aeruginosa and S. maltophilia exacerbations. Further clinical experience and trials in CF are required to determine the place of this antimicrobial in clinical practice.

PMID: 29559421 [PubMed - as supplied by publisher]

Cystic fibrosis sputum rheology correlates with both acute and longitudinal changes in lung function.

Chest. 2018 Mar 17;:

Authors: Ma JT, Tang C, Kang L, Voynow JA, Rubin BK

Abstract
BACKGROUND: Cystic fibrosis (CF) airway secretions are abnormal, contributing to decreased clearance and a cycle of infection and inflammation. CF sputum properties may predict disease progression. We hypothesized that sputum viscoelasticity and clearance abnormalities would inversely correlate with pulmonary function during exacerbation and that sputum properties would return to baseline after therapy.
METHODS: We collected sputa longitudinally from 13 CF subjects with moderate to severe lung disease during both clinical stability and exacerbation. Dynamic rheology was analyzed using cone and plate rheometer. Mucociliary clearability was measured on mucus depleted frog palate, cough clearability in a simulated cough machine, and sputum hydration as percent solids was measured following lyophilization.
RESULTS: Elastic modulus G' and viscous modulus G" increased during exacerbation and returned to baseline levels with recovery (p<0.05 for both). Solid content did not change. Sputum mucociliary clearability decreased during exacerbations (p<0.01) but not cough clearance. FEV1% predicted was inversely correlated with G' and G" (p< 0.01 for both). The regression slope of the natural log transformed of G' and G" vs FEV1% predicted was statistically homogenous among subjects (estimated common slope m = -3.84, p<0.001 and m = -8.53, p<0.0001, respectively).
CONCLUSIONS: Among these subjects with CF, there is a striking identity of the slope defining the relationship between ln Gꞌ or ln G" and FEV1. There are dramatic increases in dynamic viscosity and elasticity during a pulmonary exacerbation with return to baseline at recovery. This suggests that sputum viscoelastic properties are tightly associated with lung function and disease status.

PMID: 29559310 [PubMed - as supplied by publisher]

Sweat chloride testing: controversies and issues.

Lancet Respir Med. 2016 08;4(8):605-607

Authors: Kharrazi M, Milla C, Wine J

PMID: 27511631 [PubMed - indexed for MEDLINE]

Pilot evaluation of ivacaftor for chronic bronchitis.

Lancet Respir Med. 2016 06;4(6):e32-3

Authors: Solomon GM, Hathorne H, Liu B, Raju SV, Reeves G, Acosta EP, Dransfield MT, Rowe SM

PMID: 27185048 [PubMed - indexed for MEDLINE]