Factors influencing clinical trial participation for adult and pediatric patients with cystic fibrosis.

J Cyst Fibros. 2020 Sep 05;:

Authors: Lee M, Hu XY, Desai S, Kwong E, Fu J, Flores E, Lazosky L, Wilcox PG, Mcllwaine M, Chilvers M, Yang C, Rayment JH, Quon BS

Abstract
There remains a limited understanding of the factors influencing clinical trial participation for individuals with Cystic Fibrosis (CF). A comprehensive survey was developed to examine the interests, preferences, and barriers/facilitators to research and clinical trial participation for CF patients. A consecutive sample of 198 CF adults attending the St. Paul's Hospital CF Clinic and parents of children with CF attending the BC Children's Hospital CF Clinic from Vancouver, Canada were surveyed. Parents of pediatric patients were less comfortable with blood collection, required more safety data prior to participating, and were more concerned about potential side effects. Very few respondents (<10%) appeared able/willing to fulfill the typical requirements to participate in a phase 1 clinical trial. Overall, there were more similarities than differences between the responses of adult and parents of pediatric CF patients. The patient-centered information can be used to inform the design of future clinical trials to enhance feasibility.

PMID: 32900673 [PubMed - as supplied by publisher]

Characterization of the Burkholderia cenocepacia J2315 Surface-Exposed Immunoproteome.

Vaccines (Basel). 2020 Sep 06;8(3):

Authors: Sousa SA, Seixas AMM, Mandal M, Rodríguez-Ortega MJ, Leitão JH

Abstract
Infections by the Burkholderia cepacia complex (Bcc) remain seriously life threatening to cystic fibrosis (CF) patients, and no effective eradication is available. A vaccine to protect patients against Bcc infections is a highly attractive therapeutic option, but none is available. A strategy combining the bioinformatics identification of putative surface-exposed proteins with an experimental approach encompassing the "shaving" of surface-exposed proteins with trypsin followed by peptide identification by liquid chromatography and mass spectrometry is here reported. The methodology allowed the bioinformatics identification of 263 potentially surface-exposed proteins, 16 of them also experimentally identified by the "shaving" approach. Of the proteins identified, 143 have a high probability of containing B-cell epitopes that are surface-exposed. The immunogenicity of three of these proteins was demonstrated using serum samples from Bcc-infected CF patients and Western blotting, validating the usefulness of this methodology in identifying potentially immunogenic surface-exposed proteins that might be used for the development of Bcc-protective vaccines.

PMID: 32899969 [PubMed]

Novel ANO1 Inhibitor from Mallotus apelta Extract Exerts Anticancer Activity through Downregulation of ANO1.

Int J Mol Sci. 2020 Sep 04;21(18):

Authors: Seo Y, Anh NH, Heo Y, Park SH, Kiem PV, Lee Y, Yen DTH, Jo S, Jeon D, Tai BH, Nam NH, Minh CV, Kim SH, Nhiem NX, Namkung W

Abstract
Anoctamin1 (ANO1), a calcium-activated chloride channel, is frequently overexpressed in several cancers, including human prostate cancer and oral squamous cell carcinomas. ANO1 plays a critical role in tumor growth and maintenance of these cancers. In this study, we have isolated two new compounds (1 and 2) and four known compounds (3-6) from Mallotus apelta. These compounds were evaluated for their inhibitory effects on ANO1 channel activity and their cytotoxic effects on PC-3 prostate cancer cells. Interestingly, compounds 1 and 2 significantly reduced both ANO1 channel activity and cell viability. Electrophysiological study revealed that compound 2 (Ani-D2) is a potent and selective ANO1 inhibitor, with an IC50 value of 2.64 μM. Ani-D2 had minimal effect on cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel activity and intracellular calcium signaling. Notably, Ani-D2 significantly reduced ANO1 protein expression levels and cell viability in an ANO1-dependent manner in PC-3 and oral squamous cell carcinoma CAL-27 cells. In addition, Ani-D2 strongly reduced cell migration and induced activation of caspase-3 and cleavage of PARP in PC-3 and CAL-27 cells. This study revealed that a novel ANO1 inhibitor, Ani-D2, has therapeutic potential for the treatment of several cancers that overexpress ANO1, such as prostate cancer and oral squamous cell carcinoma.

PMID: 32899792 [PubMed - in process]

Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems.

Int J Mol Sci. 2020 Sep 03;21(17):

Authors: Pibiri I, Melfi R, Tutone M, Di Leonardo A, Pace A, Lentini L

Abstract
Cystic fibrosis (CF) patients develop a severe form of the disease when the cystic fibrosis transmembrane conductance regulator (CFTR) gene is affected by nonsense mutations. Nonsense mutations are responsible for the presence of a premature termination codon (PTC) in the mRNA, creating a lack of functional protein. In this context, translational readthrough-inducing drugs (TRIDs) represent a promising approach to correct the basic defect caused by PTCs. By using computational optimization and biological screening, we identified three new small molecules showing high readthrough activity. The activity of these compounds has been verified by evaluating CFTR expression and functionality after treatment with the selected molecules in cells expressing nonsense-CFTR-mRNA. Additionally, the channel functionality was measured by the halide sensitive yellow fluorescent protein (YFP) quenching assay. All three of the new TRIDs displayed high readthrough activity and low toxicity and can be considered for further evaluation as a therapeutic approach toward the second major cause of CF.

PMID: 32899265 [PubMed - in process]

TRPV4 and purinergic receptor signalling pathways are separately linked in airway epithelia to CFTR and TMEM16A chloride channels.

J Physiol. 2019 12;597(24):5859-5878

Authors: Genovese M, Borrelli A, Venturini A, Guidone D, Caci E, Viscido G, Gambardella G, di Bernardo D, Scudieri P, Galietta LJV

Abstract
KEY POINTS: Eact is a putative pharmacological activator of TMEM16A. Eact is strongly effective in recombinant Fischer rat thyroid (FRT) cells but not in airway epithelial cells with endogenous TMEM16A expression. Transcriptomic analysis, gene silencing and functional studies in FRT cells reveal that Eact is actually an activator of the Ca2+ -permeable TRPV4 channel. In airway epithelial cells TRPV4 and TMEM16A are expressed in separate cell types. Intracellular Ca2+ elevation by TRPV4 stimulation leads to CFTR channel activation.
ABSTRACT: TMEM16A is a Ca2+ -activated Cl- channel expressed in airway epithelial cells, particularly under conditions of mucus hypersecretion. To investigate the role of TMEM16A, we used Eact, a putative TMEM16A pharmacological activator. However, in contrast to purinergic stimulation, we found little effect of Eact on bronchial epithelial cells under conditions of high TMEM16A expression. We hypothesized that Eact is an indirect activator of TMEM16A. By a combination of approaches, including short-circuit current recordings, bulk and single cell RNA sequencing, intracellular Ca2+ imaging and RNA interference, we found that Eact is actually an activator of the Ca2+ -permeable TRPV4 channel and that the modest effect of this compound in bronchial epithelial cells is due to a separate expression of TMEM16A and TRPV4 in different cell types. Importantly, we found that TRPV4 stimulation induced activation of the CFTR Cl- channel. Our study reveals the existence of separate Ca2+ signalling pathways linked to different Cl- secretory processes.

PMID: 31622498 [PubMed - indexed for MEDLINE]

Current development of CFTR potentiators in the last decade.

Eur J Med Chem. 2020 Jul 15;204:112631

Authors: Spanò V, Venturini A, Genovese M, Barreca M, Raimondi MV, Montalbano A, Galietta LJV, Barraja P

Abstract
Cystic fibrosis (CF) is a genetic disorder produced by the loss of function of CFTR, a main chloride channel involved in transepithelial salt and water transport. CFTR function can be rescued by small molecules called "potentiators" which increase gating activity of CFTR on epithelial surfaces. High throughput screening (HTS) assays allowed the identification of new chemical entities endowed with potentiator properties, further improved through medicinal chemistry optimization. In this review, the most relevant classes of CFTR potentiators developed in the last decade were explored, focusing on structure-activity relationships (SAR) of the different chemical entities, as a useful tool for the improvement of their pharmacological activity.

PMID: 32898816 [PubMed - as supplied by publisher]

Evolutionary genomics of niche-specific adaptation to the cystic fibrosis lung in Pseudomonas aeruginosa.

Mol Biol Evol. 2020 Sep 08;:

Authors: Dettman JR, Kassen R

Abstract
The comparative genomics of the transition of the opportunistic pathogen Pseudomonas aeruginosa from a free-living environmental strain to one that causes chronic infection in the airways of cystic fibrosis (CF) patients remain poorly studied. Chronic infections are thought to originate from colonization by a single strain sampled from a diverse, globally distributed population, followed by adaptive evolution to the novel, stressful conditions of the CF lung. However, we do not know whether certain clades are more likely to form chronic infections than others and we lack a comprehensive view of the suite of genes under positive selection in the CF lung. We analyzed whole genome sequence data from 1000 P. aeruginosa strains with diverse ecological provenances including the CF lung. CF isolates were distributed across the phylogeny, indicating little genetic predisposition for any one clade to cause chronic infection. Isolates from the CF niche experienced stronger positive selection on core genes than those derived from environmental or acute infection sources, consistent with recent adaptation to the lung environment. Genes with the greatest differential positive selection in the CF niche include those involved in core cellular processes like metabolism, energy production, and stress response as well as those linked to patho-adaptive processes like antibiotic resistance, cell wall and membrane modification, quorum sensing, biofilms, mucoidy, motility, and iron homeostasis. Many genes under CF-specific differential positive selection had regulatory functions, consistent with the idea that regulatory mutations play an important role in rapid adaptation to novel environments.

PMID: 32898270 [PubMed - as supplied by publisher]

Patients with Cystic Fibrosis and Advanced Lung Disease Benefit from Lumacaftor/Ivacaftor Treatment.

Pediatr Pulmonol. 2020 Sep 08;:

Authors: Ejiofor LCK, Mathiesen IHM, Jensen-Fangel S, Olesen HV, Skov M, Philipsen LKD, Pedersen CL, Pressler T

Abstract
BACKGROUND: Several studies have assessed safety and efficacy outcomes for Lumacaftor/Ivacaftor therapy. We report on Lumacaftor/Ivacaftor's impact on lung function, physical performance, and Health-Related Quality of Life (HRQOL) in a subpopulation of Danish people with Cystic Fibrosis (PWCF) with advanced pulmonary disease who would not fulfill inclusion criteria for these studies.
METHODS: This follow-up study examined Lumacaftor/Ivacaftor's effect in a highly selected CF population. Inclusion criteria included low percent predicted Forced Expiratory Volume in one second (ppFEV1 ), fast deteriorating ppFEV1 , low Body Mass Index (BMI), and difficult-to-treat infections. Primary endpoints included change in ppFEV1 slope, Cardiopulmonary Exercise Testing (CPET), and all domains of the Cystic Fibrosis Questionnaire-Revised (CFQ-R). Secondary outcomes included change in ppFEV1 , BMI z-score (zBMI), and sweat chloride concentration.
RESULTS: A total of 21 patients homozygous for the F508del mutation and a median ppFEV1 of 38.7 were included. We found significant improvements in ppFEV1 (+4.2 p<0.01, +5.8 p<0.01, +4.8 p<0.01 and +3.8 p=0.03 ppFEV1 after three, six, nine and 12 months of treatment compared to baseline), ppFEV1 slope (+6.84 ppFEV1 /year between the year before and the year after treatment initiation; p=0.02), and saturation at CPET initiation (+1.4%, p<0.02) and termination (+2.6%, p<0.01) after six months of treatment. Finally, HRQOL improved significantly in all CFQ-R domains except Emotion and Treat.
CONCLUSIONS: Our findings suggest that Lumacaftor/Ivacaftor reduces lung function decline, improves lung function, physical performance, and HRQOL to a greater extent in PWCF with severe lung disease than previously recognized. This article is protected by copyright. All rights reserved.

PMID: 32897653 [PubMed - as supplied by publisher]

Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis.

N Engl J Med. 2020 Sep 07;:

Authors: Chalmers JD, Haworth CS, Metersky ML, Loebinger MR, Blasi F, Sibila O, O'Donnell AE, Sullivan EJ, Mange KC, Fernandez C, Zou J, Daley CL, WILLOW Investigators

Abstract
BACKGROUND: Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases.
METHODS: In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed.
RESULTS: Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo.
CONCLUSIONS: In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes. (Funded by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917.).

PMID: 32897034 [PubMed - as supplied by publisher]

Genistein-Calcitriol Mitigates Hyperosmotic Stress-Induced TonEBP, CFTR Dysfunction, VDR Degradation and Inflammation in Dry Eye Disease.

Clin Transl Sci. 2020 Aug 16;:

Authors: Panigrahi T, D'Souza S, Shetty R, Padmanabhan Nair A, Ghosh A, Jacob Remington Nelson E, Ghosh A, Sethu S

Abstract
Dry eye disease (DED) signs and symptoms are causally associated with increased ocular surface (OS) inflammation. Modulation of key regulators of aberrant OS inflammation is of interest for clinical management. We investigated the status and the potential to harness key endogenous protective factors, such as cystic fibrosis transmembrane conductance regulator (CFTR) and vitamin D receptor (VDR) in hyperosmotic stress-associated inflammation in patients with DED and in vitro. Conjunctival impression cytology samples from control subjects (n = 11) and patients with DED (n = 15) were used to determine the status of hyperosmotic stress (TonEBP/NFAT5), inflammation (IL-6, IL-8, IL-17A/F, TNFα, MMP9, and MCP1), VDR, and intracellular chloride ion (GLRX5) by quantitative polymerase chain reaction and/or immunofluorescence. Human corneal epithelial cells (HCECs) were used to study the effect of CFTR activator (genistein) and vitamin D (calcitriol) in hyperosmotic stress (HOs)-induced response in vitro. Western blotting was used to determine the expression of these proteins, along with p-p38. Significantly, higher expression of inflammatory factors, TonEBP, GLRX5, and reduced VDR were observed in patients with DED and in HOs-induced HCECs in vitro. Expression of TonEBP positively correlated with expression of inflammatory genes in DED. Increased TonEBP and GLRX5 provides confirmation of osmotic stress and chloride ion imbalance in OS epithelium in DED. These along with reduced VDR suggests dysregulated OS homeostasis in DED. Combination of genistein and calcitriol reduced HOs-induced TonEBP, inflammatory gene expression, and p-p38, and abated VDR degradation in HCECs. Henceforth, this combination should be further explored for its relevance in the management of DED.

PMID: 32896986 [PubMed - as supplied by publisher]

Molar mass effect in food and health.

Food Hydrocoll. 2020 Sep 03;:106110

Authors: Nishinari K, Fang Y

Abstract
It is demanded to supply foods with good quality for all the humans. With the advent of aging society, palatable and healthy foods are required to improve the quality of life and reduce the burden of finance for medical expenditure. Food hydrocolloids can contribute to this demand by versatile functions such as thickening, gelling, stabilising, and emulsifying, controlling texture and flavour release in food processing. Molar mass effects on viscosity and diffusion in liquid foods, and on mechanical and other physical properties of solid and semi-solid foods and films are overviewed. In these functions, the molar mass is one of the key factors, and therefore, the effects of molar mass on various health problems related to noncommunicable diseases or symptoms such as cancer, hyperlipidemia, hyperglycemia, constipation, high blood pressure, knee pain, osteoporosis, cystic fibrosis and dysphagia are described. Understanding these problems only from the viewpoint of molar mass is limited since other structural characteristics, conformation, branching, blockiness in copolymers such as pectin and alginate, degree of substitution as well as the position of the substituents are sometimes the determining factor rather than the molar mass. Nevertheless, comparison of different behaviours and functions in different polymers from the viewpoint of molar mass is expected to be useful to find a common characteristics, which may be helpful to understand the mechanism in other problems.

PMID: 32895590 [PubMed - as supplied by publisher]

Rheumatoid arthritis in a patient with cystic fibrosis: challenging treatment options.

BMJ Case Rep. 2020 Sep 06;13(9):

Authors: Delaney-Nelson KL, Henry SM, Siva C

Abstract
A 26-year-old Caucasian male patient with a history of cystic fibrosis presented with a 6-month history of diffuse joint pain and swelling. He was found to have active synovitis in bilateral wrists and proximal interphalangeal joints of the hands on physical examination. He was diagnosed with seropositive rheumatoid arthritis since he had positive anti-cyclic citrullinated peptide antibodies and erosions on hand and foot X-rays. The patient has responded well to abatacept which may have less infection risk compared with other biological therapies.

PMID: 32895251 [PubMed - in process]

Bacteremia caused by Herbaspirillum huttiense in a newborn.

Enferm Infecc Microbiol Clin. 2019 Aug - Sep;37(7):491

Authors: Liras Hernández MG, Girón de Velasco Sada P, Falces Romero I, Romero Gómez MP

PMID: 30770150 [PubMed - indexed for MEDLINE]

A tale of two pancreases: exocrine pathology and endocrine dysfunction.

Diabetologia. 2020 Oct;63(10):2030-2039

Authors: Rickels MR, Norris AW, Hull RL

Abstract
The islets of Langerhans are well embedded within the exocrine pancreas (the latter comprised of ducts and acini), but the nature of interactions between these pancreatic compartments and their role in determining normal islet function and survival are poorly understood. However, these interactions appear to be critical, as when pancreatic exocrine disease occurs, islet function and insulin secretion frequently decline to the point that diabetes ensues, termed pancreatogenic diabetes. The most common forms of pancreatogenic diabetes involve sustained exocrine disease leading to ductal obstruction, acinar inflammation, and fibro-fatty replacement of the exocrine pancreas that predates the development of dysfunction of the endocrine pancreas, as seen in chronic pancreatitis-associated diabetes and cystic fibrosis-related diabetes and, more rarely, MODY type 8. Intriguingly, a form of tumour-induced diabetes has been described that is associated with pancreatic ductal adenocarcinoma. Here, we review the similarities and differences among these forms of pancreatogenic diabetes, with the goal of highlighting the importance of exocrine/ductal homeostasis for the maintenance of pancreatic islet function and survival and to highlight the need for a better understanding of the mechanisms underlying these diverse conditions. Graphical abstract.

PMID: 32894313 [PubMed - as supplied by publisher]

Converting SMILES to Stacking Interaction Energies.

J Chem Inf Model. 2019 08 26;59(8):3413-3421

Authors: Bootsma AN, Wheeler SE

Abstract
Predicting the strength of stacking interactions involving heterocycles is vital for several fields, including structure-based drug design. While quantum chemical computations can provide accurate stacking interaction energies, these come at a steep computational cost. To address this challenge, we recently developed quantitative predictive models of stacking interactions between druglike heterocycles and the aromatic amino acids Phe, Tyr, and Trp (DOI: 10.1021/jacs.9b00936 ). These models depend on heterocycle descriptors derived from electrostatic potentials (ESPs) computed using density functional theory and provide accurate stacking interactions without the need for expensive computations on stacked dimers. Herein, we show that these ESP-based descriptors can be reliably evaluated directly from the atom connectivity of the heterocycle, providing a means of predicting both the descriptors and the potential for a given heterocycle to engage in stacking interactions without resorting to any quantum chemical computations. This enables the rapid conversion of simple molecular representations (e.g., SMILES) directly into accurate stacking interaction energies using a freely available online tool, thereby providing a way to rank the stacking abilities of large sets of heterocycles.

PMID: 31310532 [PubMed - indexed for MEDLINE]

CFTR mutation compromises spermatogenesis by enhancing miR-15b maturation and suppressing its regulatory target CDC25A†.

Biol Reprod. 2019 07 01;101(1):50-62

Authors: Chen Y, Li X, Liao H, Leung X, He J, Wang X, Li F, Yue H, Xu W

Abstract
MicroRNAs (miRNAs) have recently been shown to be important for spermatogenesis; both DROSHA and Dicer1 KO mice exhibit infertility due to abnormal miRNA expression. However, the roles of individual miRNAs in spermatogenesis remain elusive. Here we demonstrated that miR-15b, a member of the miR-15/16 family, is primarily expressed in testis. A miR-15b transgenic mouse model was constructed to investigate the role of miR-15b in spermatogenesis. Impaired spermatogenesis was observed in miR-15b transgenic mice, suggesting that appropriate expression of miR-15b is vital for spermatogenesis. Furthermore, we demonstrated that overexpression of miR-15b reduced CDC25A gene post-transcriptional activity by targeting the 3'-UTR region of CDC25A, thus regulating spermatogenesis. In vitro results further demonstrated that a mutation in CFTR could affect the interaction between Ago2 with Dicer1 and that Dicer1 activity regulates miR-15b expression. We extended our study to azoospermia patients and found that infertile patients have a significantly higher level of miR-15b in semen and plasma samples. Taken together, we propose that CFTR regulation of miR-15b could be involved in the post-transcriptional regulation of CDC25A in mammalian testis and that miR-15b is important for spermatogenesis.

PMID: 30985893 [PubMed - indexed for MEDLINE]

The impact of segmentation on whole-lung functional MRI quantification: Repeatability and reproducibility from multiple human observers and an artificial neural network.

Magn Reson Med. 2020 Sep 06;:

Authors: Willers C, Bauman G, Andermatt S, Santini F, Sandkühler R, Ramsey KA, Cattin PC, Bieri O, Pusterla O, Latzin P

Abstract
PURPOSE: To investigate the repeatability and reproducibility of lung segmentation and their impact on the quantitative outcomes from functional pulmonary MRI. Additionally, to validate an artificial neural network (ANN) to accelerate whole-lung quantification.
METHOD: Ten healthy children and 25 children with cystic fibrosis underwent matrix pencil decomposition MRI (MP-MRI). Impaired relative fractional ventilation (RFV ) and relative perfusion (RQ ) from MP-MRI were compared using whole-lung segmentation performed by a physician at two time-points (At1 and At2 ), by an MRI technician (B), and by an ANN (C). Repeatability and reproducibility were assess with Dice similarity coefficient (DSC), paired t-test and Intraclass-correlation coefficient (ICC).
RESULTS: The repeatability within an observer (At1 vs At2 ) resulted in a DSC of 0.94 ± 0.01 (mean ± SD) and an unsystematic difference of -0.01% for RFV (P = .92) and +0.1% for RQ (P = .21). The reproducibility between human observers (At1 vs B) resulted in a DSC of 0.88 ± 0.02, and a systematic absolute difference of -0.81% (P < .001) for RFV and -0.38% (P = .037) for RQ . The reproducibility between human and the ANN (At1 vs C) resulted in a DSC of 0.89 ± 0.03 and a systematic absolute difference of -0.36% for RFV (P = .017) and -0.35% for RQ (P = .002). The ICC was >0.98 for all variables and comparisons.
CONCLUSIONS: Despite high overall agreement, there were systematic differences in lung segmentation between observers. This needs to be considered for longitudinal studies and could be overcome by using an ANN, which performs as good as human observers and fully automatizes MP-MRI post-processing.

PMID: 32892445 [PubMed - as supplied by publisher]

Vitamin E supplementation in people with cystic fibrosis.

Cochrane Database Syst Rev. 2020 Sep 06;9:CD009422

Authors: Okebukola PO, Kansra S, Barrett J

Abstract
BACKGROUND: People with cystic fibrosis are at an increased risk of fat-soluble vitamin deficiency, including vitamin E. Vitamin E deficiency can cause a host of conditions such as haemolytic anaemia, cerebellar ataxia and cognitive difficulties. Vitamin E supplementation is widely recommended for people with cystic fibrosis and aims to ameliorate this deficiency. This is an updated version of the review.
OBJECTIVES: To determine the effects of any level of vitamin E supplementation on the frequency of vitamin E deficiency disorders in people with cystic fibrosis.
SEARCH METHODS: We searched the Cochrane Group's Cystic Fibrosis Trials Register and also searched international online trial registries for any ongoing clinical trials that were not identified during our register search. Date of last search of the Register: 11 August 2020. Date of last search of international online trial registries: 20 July 2020.
SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials comparing any preparation of vitamin E supplementation to placebo or no supplement, regardless of dosage or duration.
DATA COLLECTION AND ANALYSIS: Two authors extracted outcome data from each study (published information) and assessed the risk of bias of each included study. They assessed the quality of the evidence using GRADE.
MAIN RESULTS: Four studies with a total of 141 participants were included in the review, two of these were in children (aged six months to 14.5 years), and two did not specify participants' age. All studies used different formulations and doses of vitamin E for various durations of treatment (10 days to six months). Two studies compared the supplementation of fat-soluble as well as water-soluble formulations to no supplementation in different arms of the same study. A third study compared a water-soluble formulation to a placebo; and in the fourth study a fat-soluble formulation of vitamin E was assessed against placebo. There was limited detail about randomisation and blinding in the included studies which compromises the quality of the evidence base for the review. The heterogeneous mix of the formulations with differing biovailabilities among these studies also limits the generalisability of the data to the wider cystic fibrosis population. None of the studies in either comparison report the review's primary outcomes of vitamin E total lipid ratio or the incidence of vitamin E-specific deficiency disorders, or the secondary outcomes lung function or quality of life. Water-soluble vitamin E Water-soluble vitamin E may improve serum vitamin E levels compared with control at six months, one study (45 participants), mean difference (MD) 19.74 umol/L (95% confidence interval (CI) 13.48 to 26.00) (low-quality evidence). Similar results were also seen at one month, two studies (32 participants), MD 17.66 umol/L (95% CI 10.59 to 24.74) and at three months, one study (45 participants), MD 11.61 umol/L (95% CI 4.77 to 18.45). Only one study (45 participants) reported weight (secondary outcome of growth and nutritional status) at one and six months, but showed no difference between treatment and control at either time point. Fat-soluble vitamin E Two studies (36 participants) reported higher levels of serum vitamin E at one month with fat-soluble vitamin E compared with control, MD 13.59 umol/L (95% CI 9.52 to 17.66); however, at three months one study (36 participants) showed no difference between treatment and control. No studies in this comparison reported on growth or nutritional status.
AUTHORS' CONCLUSIONS: Vitamin E supplementation may lead to an improvement in vitamin E levels in people with cystic fibrosis, although evidence we assessed was low quality. No data on other outcomes of interest were available to allow conclusions about any other benefits of this therapy. In future, larger studies are needed, especially in people already being treated with enteric-coated pancreatic enzymes and supplemented with vitamin E, to look at more specific outcome measures such as vitamin E status, lung function and nutritional status. Future studies could also look at the optimal dose of vitamin E required to achieve maximal clinical effectiveness.

PMID: 32892350 [PubMed - in process]

Paediatric nasal irrigation: The "fencing" method.

Eur Ann Otorhinolaryngol Head Neck Dis. 2020 Sep 02;:

Authors: de Gabory L, Kérimian M, Sagardoy T, Verdaguer A, Gauchez H

Abstract
Nasal irrigation is a grade A recommendation treatment, which is essential in many pathological conditions. Very heterogeneous practices are observed in paediatrics as a result of poor instruction in this technique. We propose to describe the nasal irrigation technique developed by a team of respiratory physiotherapists in Lille for the management of cystic fibrosis and bronchiolitis. This technique is intended for children over the age of 6 months, as it requires an oral breathing reflex and cough reflex that are not systematically acquired before this age. Nasal irrigation is performed on a 30° upward inclined plane on a calm and cooperative child, away from meals. The child is maintained gently, without pressure, in the fencing position with the head turned away from the practitioner. Using a continuous flow spray, the practitioner grasps the top of the upper nostril and irrigates the nostril for an average of 3 s (6mL per nostril). These steps are then repeated until satisfactory patency is achieved in both nostrils. This technique constitutes a practical tool to help healthcare professionals and parents perform nasal irrigation in young children over the age of 6 months.

PMID: 32891588 [PubMed - as supplied by publisher]

Endoscopic Management of Maxillary Sinus Diseases of Dentoalveolar Origin.

Oral Maxillofac Surg Clin North Am. 2020 Sep 02;:

Authors: McCormick JP, Hicks MD, Grayson JW, Woodworth BA, Cho DY

Abstract
Endoscopic surgery on the maxillary sinus has experienced significant advances in technique and approaches since the maxillary antrostomy was introduced in the 1980s. Disease processes that previously required open surgical approaches to the maxillary sinus can now be treated endoscopically while preserving form and function of the sinus and without injuring the maxillary sinus mucosa or disrupting normal mucociliary clearance. Understanding the techniques described in this article will allow surgeons to appropriately plan treatment strategies for patients with a variety of maxillary sinus diseases from dentoalveolar origin.

PMID: 32891537 [PubMed - as supplied by publisher]