The LMTK-family of kinases: Emerging important players in cell physiology and disease pathogenesis.

Biochim Biophys Acta Mol Basis Dis. 2018 Dec 29;:

Authors: Wendler F

Abstract
Lemur Tail (former tyrosine) Kinases (LMTKs) comprise a novel family of regulated serine/threonine specific kinases with three structurally and evolutionary related members. LMTKs exercise a confusing variety of cytosolic functions in cell signalling and membrane trafficking. Moreover, LMTK2 and LMTK3 also reside in the nucleus where they participate in gene transcription/regulation. As a consequence, LMTKs impact cell proliferation and apoptosis, cell growth and differentiation, as well as cell migration. All these fundamental cell behaviours can turn awry, most prominently during neuropathologies and tumour biogenesis. In cancer cells, LMTK levels are often correlated with poor overall prognosis and therapy outcome, not least owned to acquired drug resistance. In brain tissue, LMTKs are highly expressed and have been linked to neuronal and glia cell differentiation and cell homeostasis. For one member of the LMTK-family (LMTK2) a role in cystic fibrosis has been identified. Due to their role in fundamental cell processes, altered LMTK physiology may also warrant a hitherto unappreciated role in other diseases, and expose them as potential valuable drug targets. On the backdrop of a compendium of LMTK cell functions, I hypothesize that the primary role of LMTKs may dwell within the endocytic cargo recycling and/or nuclear receptor transport pathways.

PMID: 30597196 [PubMed - as supplied by publisher]

Functional characterization reveals that zebrafish CFTR prefers to occupy closed channel conformations.

PLoS One. 2018;13(12):e0209862

Authors: Zhang J, Yu YC, Yeh JT, Hwang TC

Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR), the culprit behind the genetic disease cystic fibrosis (CF), is a phosphorylation-activated, but ATP-gated anion channel. Studies of human CFTR over the past two decades have provided an in-depth understanding of how CFTR works as an ion channel despite its structural resemblance to ABC transporters. Recently-solved cryo-EM structures of unphosphorylated human and zebrafish CFTR (hCFTR and zCFTR), as well as phosphorylated ATP-bound zebrafish and human CFTR offer an unprecedented opportunity to understand CFTR's function at a molecular level. Interestingly, despite millions of years of phylogenetic distance between human and zebrafish, the structures of zCFTR and hCFTR exhibit remarkable similarities. In the current study, we characterized biophysical and pharmacological properties of zCFTR with the patch-clamp technique, and showed surprisingly very different functional properties between these two orthologs. First, while hCFTR has a single-channel conductance of 8.4 pS with a linear I-V curve, zCFTR shows an inwardly-rectified I-V relationship with a single-channel conductance of ~3.5 pS. Second, single-channel gating behaviors of phosphorylated zCFTR are very different from those of hCFTR, featuring a very low open probability Po (0.03 ± 0.02, vs. ~0.50 for hCFTR) with exceedingly long closed events and brief openings. In addition, unlike hCFTR where each open burst is clearly defined with rare short-lived flickery closures, the open bursts of zCFTR are not easily resolved. Third, although abolishing ATP hydrolysis by replacing the catalytic glutamate with glutamine (i.e., E1372Q) drastically prolongs the open bursts defined by the macroscopic relaxation analysis in zCFTR, the Po within a "locked-open" burst of E1372Q-zCFTR is only ~ 0.35 (vs. Po > 0.94 in E1371Q-hCFTR). Collectively, our data not only provide a reasonable explanation for the unexpected closed-state structure of phosphorylated E1372Q-zCFTR with a canonical ATP-bound dimer of the nucleotide binding domains (NBDs), but also implicate significant structural and functional differences between these two evolutionarily distant orthologs.

PMID: 30596737 [PubMed - in process]

A Neutralizing Aptamer to TGFBR2 and miR-145 Antagonism Rescue Cigarette Smoke- and TGF-β-Mediated CFTR Expression.

Mol Ther. 2018 Dec 06;:

Authors: Dutta RK, Chinnapaiyan S, Rasmussen L, Raju SV, Unwalla HJ

Abstract
Transforming growth factor β (TGF-β), signaling induced by cigarette smoke (CS), plays an important role in the progression of airway diseases, like chronic bronchitis associated with chronic obstructive pulmonary disease (COPD), and in smokers. Chronic bronchitis is characterized by reduced mucociliary clearance (MCC). Cystic fibrosis transmembrane conductance regulator (CFTR) plays an important role in normal MCC. TGF-β and CS (via TGF-β) promote acquired CFTR dysfunction by suppressing CFTR biogenesis and function. Understanding the mechanism by which CS promotes CFTR dysfunction can identify therapeutic leads to reverse CFTR suppression and rescue MCC. TGF-β alters the microRNAome of primary human bronchial epithelium. TGF-β and CS upregulate miR-145-5p expression to suppress CFTR and the CFTR modifier, SLC26A9. miR-145-5p upregulation with a concomitant CFTR and SLC26A9 suppression was validated in CS-exposed mouse models. While miR-145-5p antagonism rescued the effects of TGF-β in bronchial epithelial cells following transfection, an aptamer to block TGF-β signaling rescues CS- and TGF-β-mediated suppression of CFTR biogenesis and function in the absence of any transfection reagent. These results demonstrate that miR-145-5p plays a significant role in acquired CFTR dysfunction by CS, and they validate a clinically feasible strategy for delivery by inhalation to locally modulate TGF-β signaling in the airway and rescue CFTR biogenesis and function.

PMID: 30595527 [PubMed - as supplied by publisher]

Predictive factors for lumacaftor/ivacaftor clinical response.

J Cyst Fibros. 2018 Dec 27;:

Authors: Masson A, Schneider-Futschik EK, Baatallah N, Nguyen-Khoa T, Girodon E, Hatton A, Flament T, Le Bourgeois M, Chedevergne F, Bailly C, Kyrilli S, Achimastos D, Hinzpeter A, Edelman A, Sermet-Gaudelus I

Abstract
BACKGROUND: Ivacaftor-lumacaftor combination therapy corrects the F508 del-CFTR mutated protein which causes Cystic Fibrosis. The clinical response of the patients treated with the combination therapy is highly variable. This study aimed to determine factors involved in the individual's response to lumacaftor-ivacaftor therapy.
METHODS: Sweat test was assessed at baseline and after 6 months of ivacaftor-lumacaftor treatment in 41 homozygous F508del children and young adults. β-adrenergic peak sweat secretion, nasal potential difference (NPD) and intestinal current measurements (ICM) were performed in patients accepting these tests. Seric level of lumacaftor and ivacaftor were determined and additional CFTR variant were searched.
RESULTS: Sweat chloride concentration significantly decreased after treatment, whereas the β-adrenergic peak sweat response did not vary in 9 patients who underwent these tests. The average level of F508del-CFTR activity rescue reached up to 15% of the normal level in intestinal epithelium, as studied by ICM in 12 patients (p = .03) and 20% of normal in the nasal epithelium in NPD tests performed in 21 patients (NS). There was no significant correlation between these changes and improvements in FEV1 at 6 months. Serum drug levels did not correlate with changes in FEV1, BMI-Zscore or other CFTR activity biomarkers. Additional exonic variants were identified in 4 patients. The F87L-I1027T-F508del-CFTR complex allele abolished the lumacaftor corrector effect.
CONCLUSION: This observational study investigates a number of potential factors linked to the clinical response of F508del homozygous patients treated with lumacaftor-ivacaftor combination therapy. Lumacaftor and ivacaftor blood levels are not associated with the clinical response. Additional exonic variants may influence protein correction.

PMID: 30595473 [PubMed - as supplied by publisher]

Management of Excessive Daytime Sleepiness in Narcolepsy With Baclofen.

Pediatr Neurol. 2018 Nov 22;:

Authors: Morse AM, Kelly-Pieper K, Kothare SV

Abstract
BACKGROUND: Narcolepsy is a disabling sleep-wake disorder characterized by the pentad symptoms of excessive daytime sleepiness, sleep paralysis, sleep fragmentation, sleep-related hallucinations, and cataplexy. There is no curative therapy for narcolepsy. Treatment is therefore symptom directed. Symptom management is generally directed at improving excessive daytime sleepiness, sleep fragmentation, and cataplexy. First-line treatment for excessive daytime sleepiness is typically daily use of wake-promoting agents, such as modafinil or armodafinil, or stimulant therapy, such as methylphenidate or amphetamines. Alternatively, sodium oxybate can be used nightly for improved cataplexy, sleep consolidation, and following day wakefulness. These therapies can be limited in some patients because of inadequate efficacy, poor tolerability, or side effects.
METHODS: We describe five narcolepsy patients with severe excessive daytime sleepiness who had an inadequate response or experienced side effects with the initial therapies, but had a positive response to treatment with baclofen.
RESULTS: These patients reported subjective improvement in sleep maintenance without fragmentation and daytime sleepiness. Average Epworth Sleepiness Scale assessment before treatment was 15.8 with post-treatment assessment being 10.4 (P < 0.05).
CONCLUSIONS: Baclofen may be an effective treatment for excessive daytime sleepiness and sleep fragmentation in narcolepsy and warrants further study.

PMID: 30595352 [PubMed - as supplied by publisher]

Calcium-induced chloride secretion is decreased by Resveratrol in ileal porcine tissue.

BMC Res Notes. 2018 Oct 11;11(1):719

Authors: Hoppe S, Breves G, Klinger S

Abstract
OBJECTIVE: Chloride (Cl-) secretion is crucial for intestinal fluid secretion. Therefore, effects of the polyphenol Resveratrol (RSV) on Cl- secretion have been investigated. In a previous study, we observed effects of RSV on forskolin-induced Cl- secretion in the porcine jejunum but not the ileum although RSV itself induced a transepithelial ion current that may represent Cl- secretion in the ileum. The aim of this study was to gain further insights regarding the effects of RSV on characteristics of Cl- secretion in the porcine ileum using the Ussing chamber technique (recording of short circuit currents (Isc) as a measure for epithelial net ion transfer).
RESULTS: RSV increased the Isc in the porcine ileum but not in the porcine jejunum as is already known. This increase was absent in a Cl--free buffer system, indicating that RSV indeed induces Cl- secretion. However, the carbachol-induced Isc was significantly inhibited by RSV indicating an inhibition of Ca2+-induced Cl- secretion. The cellular basis for these contradictory, segment specific results of RSV on Cl- secretion has to be subjected to further studies. The results also underline, that is difficult to generalize effects of RSV between different intestinal locations, organs, cell culture models or species.

PMID: 30309374 [PubMed - indexed for MEDLINE]

Highly mucus permeating and zeta potential changing self-emulsifying drug delivery systems: A potent gene delivery model for causal treatment of cystic fibrosis.

Int J Pharm. 2018 Dec 27;:

Authors: Griesser J, Hetényi G, Federer C, Steinbring C, Ellemunter H, Niedermayr K, Bernkop-Schnürch A

Abstract
AIM: It was the aim of the study to develop self-emulsifying drug delivery systems (SEDDS) with the ability to change their zeta potential towards higher values at the adsorption membrane and in this way facilitate the release of the DNA-cetrimonium complex and enhance transfection.
METHODS: Plasmid DNA was complexed via hydrophobic ion pairing utilizing various surfactants and the complex was incorporated into SEDDS achieving a payload of 1% (m/v). Log PSEDDS/water of the complex was determined. SEDDS were characterized regarding droplet size, zeta potential, stability and toxicity. Alkaline phosphatase presented in the sputum of cystic fibrosis patients was quantified using 4-nitrophenyl phosphate disodium salt and 5-bromo-4-chloro-1H-indol-3-yl phosphate dipotassium salt as substrates. SEDDS containing 0.4% (m/v) 1,2-dipalmitoyl-sn-glycero-3-phosphate monosodium salt were characterized regarding their zeta potential changing properties utilizing isolated alkaline phosphatase and cystic fibrosis sputum. The mucus permeating properties of SEDDS were evaluated via Transwell method using cystic fibrosis sputum. Finally, the transfection efficiency of incorporated plasmid DNA was investigated.
RESULTS: Cetrimonium bromide showed the highest precipitation efficiency of 99.5±2.72% for the complexation of pDNA. SEDDS containing propylene glycol, Capmul PG-8, Captex 300, Captex 355, Captex 8000, Cremophor EL, Cremophor RH-40 and Brij O10 showed stable emulsions with a droplet size between 20 and 100nm and zeta potential <-3mV over 4 hours. SEDDS demonstrated highly protective effect against enzymatic degradation and moderate cell viability on freshly obtained pulmonary tissue. The pDNA-cetrimonium complex incorporated into SEDDS revealed a log PSEDDS/water of about 2. A concentration of 0.879±0.103U/g alkaline phosphatase was found in the sputum of cystic fibrosis patients. SEDDS containing 1,2-dipalmitoyl-sn-glycero-3-phosphate monosodium salt showed a high potential of changing the zeta potential by applying isolated alkaline phosphatase as well as cystic fibrosis sputum along with high mucus permeating properties. Formulation C demonstrated the highest transfection efficiency with a 7.2-fold increased fluorescence intensity compared to naked pDNA.
CONCLUSION: The novel developed zeta potential changing SEDDS are opening versatile opportunities for the treatment of cystic fibrosis caused by gene mutation.

PMID: 30594687 [PubMed - as supplied by publisher]

Cost-effectiveness of the withdrawl of treatment with inhaled colistin in patients with adult bronchiectasis not due to cystic fibrosis colonized by Pseudomonas aeruginosa.

Med Clin (Barc). 2018 Dec 26;:

Authors: Lera Álvarez R, Martínez Moragón E, Morales Suárez Varela M

PMID: 30594304 [PubMed - as supplied by publisher]

A real life evaluation of non invasive ventilation in acute cardiogenic pulmonary edema: a multicenter, perspective, observational study for the ACPE SIMEU study group.

BMC Emerg Med. 2018 Dec 29;18(1):61

Authors: Aliberti S, Rosti VD, Travierso C, Brambilla AM, Piffer F, Petrelli G, Minelli C, Camisa D, Voza A, Guiotto G, Cosentini R, SIMEU ACPE study group

Abstract
BACKGROUND: During the past three decades conflicting evidences have been published on the use of non-invasive ventilation (NIV) in patients with acute cardiogenic pulmonary edema (ACPE). The aim of this study is to describe the management of acute respiratory failure (ARF) due to ACPE in twelve Italian emergency departments (EDs). We evaluated prevalence, characteristics and outcomes of ACPE patients treated with oxygen therapy, continuous positive airway pressure (CPAP) or Bi-level positive airway pressure (BiPAP) on admission to the EDs.
METHODS: In this multicenter, prospective, observational study, consecutive adult patients with ACPE were enrolled in 12 EDs in Italy from May 2009 to December 2013. Three study groups were identified according to the initial respiratory treatment: patients receiving oxygen therapy, those treated with CPAP and those treated with BiPAP. Treatment failure was evaluated as study outcome.
RESULTS: We enrolled 1293 patients with acute cardiogenic pulmonary edema. 273 (21%) began with oxygen, 788 (61%) with CPAP and 232 (18%) with BiPAP. One out of four patient who began with oxygen was subsequently switched to NIV and initial treatment with oxygen therapy had an odds ratio for treatment failure of 3.65 (95% CI: 2.55-5.23, p < 0.001).
CONCLUSIONS: NIV seems to be the first choice for treatment of ARF due to ACPE, showing high clinical effectiveness and representing a rescue option for patients not improving with conventional oxygen therapy.

PMID: 30594135 [PubMed - in process]

Was the Last Ice Age dusty climate instrumental in spreading of the three "Celtic" diseases (hemochromatosis, cystic fibrosis and palmar fibromatosis)?

Med Hypotheses. 2019 Jan;122:134-138

Authors: Kurbel S

Abstract
Cystic fibrosis, hereditary hemochromatosis and palmar fibromatosis are often described as "Celtic", based on their contemporary prevalence. The former two are among genetically defined disorders that seem to provide survival advantages to heterozygote individuals, while severe health problems happen in homozygote mutation carriers. Although palmar fibromatosis has no defined mutations, its prevalence has been linked to the prevalence of Y-Chromosome Haplogroup I that expanded after the Last Ice Age, thus making th distribution of all three "Celtic" diseases dependent on the global climate from 40 to 8 Kya. During the Last Ice Age, the global climate was dry and dark due to dust-laden atmosphere (20-25 times more than today). It has been postulated that skin pigmentation was related to insolation, UV protection and skin synthesis of vitamin D, so when our ancestors moved to Eurasia, individuals with pale skin became advantageous. Deficiency of vitamin D has several health consequences and some of them have been proposed by other authors as important for the spreading of cystic fibrosis mutations: rickets/osteomalacia; susceptibility to diarrheal diseases and tuberculosis and salt induced arterial hypertension. The here proposed link is between vitamin D deficiency and the anaemia of chronic disease that might have facilitated spreading of the hemochromatosis mutation. It seems plausible that the risk of health problems in the offspring of close relatives might have resulted in social taboos of consanguinity in Eurasian protosocieties. Ancient steam bath rituals seem linked to lower incidences of cystic fibrosis in several European populations, thus suggesting health protection in an arid, dusty climate of the last glaciation, that made CFTR mutations in heterozygote carriers less advantageous.

PMID: 30593397 [PubMed - in process]

High-Throughput Sequencing in Respiratory, Critical Care, and Sleep Medicine Research. An Official American Thoracic Society Workshop Report.

Ann Am Thorac Soc. 2019 Jan;16(1):1-16

Authors: Hersh CP, Adcock IM, Celedón JC, Cho MH, Christiani DC, Himes BE, Kaminski N, Mathias RA, Meyers DA, Quackenbush J, Redline S, Steiling KA, Tabor HK, Tobin MD, Wurfel MM, Yang IV, Koppelman GH

Abstract
High-throughput, "next-generation" sequencing methods are now being broadly applied across all fields of biomedical research, including respiratory disease, critical care, and sleep medicine. Although there are numerous review articles and best practice guidelines related to sequencing methods and data analysis, there are fewer resources summarizing issues related to study design and interpretation, especially as applied to common, complex, nonmalignant diseases. To address these gaps, a single-day workshop was held at the American Thoracic Society meeting in May 2017, led by the American Thoracic Society Section on Genetics and Genomics. The aim of this workshop was to review the design, analysis, interpretation, and functional follow-up of high-throughput sequencing studies in respiratory, critical care, and sleep medicine research. This workshop brought together experts in multiple fields, including genetic epidemiology, biobanking, bioinformatics, and research ethics, along with physician-scientists with expertise in a range of relevant diseases. The workshop focused on application of DNA and RNA sequencing research in common chronic diseases and did not cover sequencing studies in lung cancer, monogenic diseases (e.g., cystic fibrosis), or microbiome sequencing. Participants reviewed and discussed study design, data analysis and presentation, interpretation, functional follow-up, and reporting of results. This report summarizes the main conclusions of the workshop, specifically addressing the application of these methods in respiratory, critical care, and sleep medicine research. This workshop report may serve as a resource for our research community as well as for journal editors and reviewers of sequencing-based manuscript submissions in our research field.

PMID: 30592451 [PubMed - in process]

Retraction: Phenazine Content in the Cystic Fibrosis Respiratory Tract Negatively Correlates with Lung Function and Microbial Complexity.

Am J Respir Cell Mol Biol. 2019 Jan;60(1):134

Authors:

PMID: 30592444 [PubMed - in process]

The Incidence of Cystic Fibrosis in Central Anatolia Region of Turkey in 2015 and 2016

Balkan Med J. 2018 Dec 28;:

Authors: Hangül M, Pekcan S, Köse M, Acıcan D, Şahlar TE, Erdoğan M, Kendirci M, Güney D, Öznavruz H, Demir O, Ercan Ö, Göçlü F

Abstract
Background: Cystic fibrosis is the most prevalent metabolic chronic disease in Caucasian children in the Europe. Cystic fibrosis has seen approximately 1 in 3000 births in northern European countries. Birth prevalence varies worldwide.
Aim: The aim of this study to determine the incidence of cystic fibrosis in Central Anatolia Region of Turkey by using the new born screening program data.
Study Design: Cross-sectional study.
Methods: We used the records of the new born screening program which is implemented by Konya and Kayseri Provincial Health Directorates.
Results: There were total 119006 live births in Konya and Kayseri, between January 2015 and December 2016. New born screening test was applied to all these babies. In this two years period, there were 22 live born babies diagnosed with cystic fibrosis in Konya with an incidence of 2,9 per 10 000 live births and 13 live born babies diagnosed with cystic fibrosis in Kayseri with an incidence of 2,8 per 10 000 live births.
Conclusion: We found the incidence of cystic fibrosis 2.9 per 10 000 live births in Central Anatolia which is similar to Northern European Countries.

PMID: 30592194 [PubMed - as supplied by publisher]

[Therapeutic education, a source of inspiration for students].

Rev Infirm. 2018 Dec;67(246):43-44

Authors: Lescure S, Dumez S, Texier C, Legendre V, Deprez J, Duhaa M, Benazzouz A

Abstract
Therapeutic education contributes to improving the health of patients suffering from chronic diseases, their quality of life and that of their loved ones. It is complementary and inseparable from treatment and care, symptom relief and prevention of complications. Inspired by the modalities of this approach towards children suffering from cystic fibrosis, students from a nursing training institute in Ile-de-France share their work on this theme.

PMID: 30591136 [PubMed - in process]

Managing cystic fibrosis alongside children's schooling: Family, nurse and teacher perspectives.

J Child Health Care. 2018 Dec 28;:1367493518814930

Authors: Gathercole K

Abstract
The treatment regimen for children with cystic fibrosis (CF) is vast and is usually undertaken in the family home. Managing CF coincides with other important family routines such as children's participation in education. There is a dearth of research that considers family routines that may influence, and be influenced by how CF is managed. To address this gap, this patient-led study examined how families manage CF alongside children's education in England. Semi-structured interviews were conducted with 14 participants comprising 5 children and young people with CF, 4 parents, 2 CF nurse specialists and 3 teachers. The results revealed that CF routines were organized to minimize disruption to education, although families experienced challenges in meeting all daily health and education demands. Families chose between children doing their treatments or participating in school activities when doing both were not feasible. Treatments were sometimes a barrier to education participation and children's learning. Families found treatment routines restrictive upon children's friendships. Education is a priority for families, which affects how they manage CF. CF clinical teams should consider bidirectional influences between important family routines and families' management of CF, when planning appropriate treatment regimens.

PMID: 30590956 [PubMed - as supplied by publisher]

A novel CFTR gene variant - p.Tyr517* associated with cystic fibrosis: a case report.

Fetal Pediatr Pathol. 2018 Dec 27;:1-4

Authors: Chheda P, Dama T, Goradia D, Pande S, Vinarkar S

Abstract
INTRODUCTION: Cystic fibrosis (CF) is a genetic disease usually diagnosed by clinical findings and abnormal sweat chloride testing.
CASE REPORT: We report a case of an 18-month-old Indian female with clinical findings suggestive of CF referred for genetic confirmation. The CFTR gene was sequenced for 23 mutations as per American College of Medical Genetics (ACMG) guidelines for CF and showed presence of a known common heterozygous delF508 (c.1521_1523delCTT, p.Phe508 del) variant. In addition to delF508 variant, exon 10 of CFTR gene also showed a novel variant c.1551C > G, p.Tyr517*, which was classified as "likely pathogenic" based on recent ACMG variant classification guidelines. The presence of compound heterozygous pathogenic variants along with classical clinical findings, confirmed the diagnosis of CF in this patient.
CONCLUSION: The novel pathogenic variants (missense/nonsense/deletion/duplication) in CFTR gene are often identified and are associated with CF, thus highlighting the need of comprehensive complete CFTR gene analysis.

PMID: 30588852 [PubMed - as supplied by publisher]

Comparison of a micro-electro-mechanical system airflow sensor with the pneumotach in the forced oscillation technique.

Med Devices (Auckl). 2018;11:419-426

Authors: Xu XK, Harvey BP, Lutchen KR, Gelbman BD, Monfre SL, Coifman RE, Forbes CE

Abstract
Purpose: This study supports the use of thin-film micro-electro-mechanical system (MEMS) airflow sensors in the forced oscillation technique.
Materials and methods: The study employed static testing using air flow standards and computer-controlled sound attenuations at 8 Hz. Human feasibility studies were conducted with a testing apparatus consisting of a pneumotach and thin-film MEMS air flow sensors in series. Short-time Fourier transform spectra were obtained using SIGVIEW software.
Results: Three tests were performed, and excellent correlations were observed between the probes. The thin-film MEMS probe showed superior sensitivity to higher frequencies up to 200 Hz.
Conclusion: The results suggest that lower-cost thin-film MEMS can be used for forced oscillation technique applications (including home care devices) that will benefit patients suffering from pulmonary diseases such as asthma, COPD, and cystic fibrosis.

PMID: 30588132 [PubMed]

Measuring prevalence and incidence of chronic conditions in claims and electronic health record databases.

Clin Epidemiol. 2019;11:1-15

Authors: Rassen JA, Bartels DB, Schneeweiss S, Patrick AR, Murk W

Abstract
Background: Health care databases are natural sources for estimating prevalence and incidence of chronic conditions, but substantial variation in estimates limits their interpretability and utility. We evaluated the effects of design choices when estimating prevalence and incidence in claims and electronic health record databases.
Methods: Prevalence and incidence for five chronic diseases at increasing levels of expected frequencies, from cystic fibrosis to COPD, were estimated in the Clinical Practice Research Datalink (CPRD) and MarketScan databases from 2011 to 2014. Estimates were compared using different definitions of lookback time and contributed person-time.
Results: Variation in lookback time substantially affected estimates. In 2014, for CPRD, use of an all-time vs a 1-year lookback window resulted in 4.3-8.3 times higher prevalence (depending on disease), reducing incidence by 1.9-3.3 times. All-time lookback resulted in strong temporal trends. COPD prevalence between 2011 and 2014 in MarketScan increased by 25% with an all-time lookback but stayed relatively constant with a 1-year lookback. Varying observability did not substantially affect estimates.
Conclusion: This framework draws attention to the underrecognized potential for widely varying incidence and prevalence estimates, with implications for care planning and drug development. Though prevalence and incidence are seemingly straightforward concepts, careful consideration of methodology is required to obtain meaningful estimates from health care databases.

PMID: 30588119 [PubMed]

Measuring recovery in health-related quality of life during and after pulmonary exacerbations in patients with cystic fibrosis.

J Cyst Fibros. 2018 Dec 23;:

Authors: Flume PA, Suthoff ED, Kosinski M, Marigowda G, Quittner AL

Abstract
BACKGROUND: We explored the time-dependent impact of pulmonary exacerbations (PEx) on health-related quality of life (HRQoL) using Cystic Fibrosis Questionnaire-Revised (CFQ-R) data from 2 large cystic fibrosis (CF) trials.
METHODS: This exploratory post-hoc analysis evaluated the impact of PEx on CFQ-R domains of functioning in 80 patients with CF (homozygous for F508del-CFTR), aged ≥14 years randomized to placebo in the TRAFFIC and TRANSPORT trials who experienced 1 PEx.
RESULTS: Scores on the CFQ-R were significantly lower within 1 week of PEx start in 8 out of 12 domains (Respiratory Symptoms, Physical Functioning, Emotional Functioning, Health Perceptions, Role Functioning, Social Functioning, Eating, and Vitality). Patients whose PEx was treated with hospitalization or intravenous antibiotics had greater reductions in some domains of HRQoL compared with those treated with oral antibiotics. In the immediate weeks post-PEx, improvement was seen on Emotional Functioning, Respiratory Symptoms, and Health Perceptions, while further decline was seen for Eating, Physical Functioning, Role Functioning, Vitality, and Weight. For some measures (Physical Functioning, Vitality), full recovery to pre-PEx levels took several weeks.
CONCLUSIONS: Pulmonary exacerbations have significant effects on multiple domains of HRQoL, and recovery across multiple domains post-PEx can take several weeks. These findings provide insight into the impact of PEx on patient HRQoL and recovery post-PEx.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT01807923 and NCT01807949.

PMID: 30587335 [PubMed - as supplied by publisher]

Detection of viable but non-culturable Pseudomonas aeruginosa in cystic fibrosis by qPCR: a validation study.

BMC Infect Dis. 2018 Dec 27;18(1):701

Authors: Mangiaterra G, Amiri M, Di Cesare A, Pasquaroli S, Manso E, Cirilli N, Citterio B, Vignaroli C, Biavasco F

Abstract
BACKGROUND: Routine culture-based diagnosis of Pseudomonas aeruginosa lung infection in Cystic Fibrosis (CF) patients can be hampered by the phenotypic variability of the microorganism, including its transition to a Viable But Non-Culturable (VBNC) state. The aim of this study was to validate an ecfX-targeting qPCR protocol developed to detect all viable P. aeruginosa bacteria and to identify VBNC forms in CF sputum samples.
METHODS: The study involved 115 P. aeruginosa strains of different origins and 10 non-P. aeruginosa strains and 88 CF sputum samples, 41 Culture-Positive (CP) and 47 Culture-Negative (CN). Spiking assays were performed using scalar dilutions of a mixture of live and dead P. aeruginosa ATCC 9027 and a pooled P. aeruginosa-free sputum batch. Total DNA from sputum samples was extracted by a commercial kit, whereas a crude extract was obtained from the broth cultures. Extracellular DNA (eDNA) interference was evaluated by comparing the qPCR counts obtained from DNase-treated and untreated aliquots of the same samples. The statistical significance of the results was assessed by the Wilcoxon test and Student's t test.
RESULTS: The newly-developed qPCR protocol identified 96.6% of the P. aeruginosa isolates; no amplification was obtained with strains belonging to different species. Spiking assays supported protocol reliability, since counts always matched the amount of live bacteria, thus excluding the interference of dead cells and eDNA. The protocol sensitivity threshold was 70 cells/ml of the original sample. Moreover, qPCR detected P. aeruginosa in 9/47 CN samples and showed higher bacterial counts compared with the culture method in 10/41 CP samples.
CONCLUSIONS: Our findings demonstrate the reliability of the newly-developed qPCR protocol and further highlight the need for harnessing a non-culture approach to achieve an accurate microbiological diagnosis of P. aeruginosa CF lung infection and a greater understanding of its evolution.

PMID: 30587160 [PubMed - in process]