Vitamin D supplementation in patients with cystic fibrosis: A systematic review and meta-analysis.

J Cyst Fibros. 2020 Dec 18;:

Authors: Juhász MF, Varannai O, Németh D, Szakács Z, Kiss S, Izsák VD, Martonosi ÁR, Hegyi P, Párniczky A

Abstract
Despite routine supplementation, vitamin D insufficiency is often seen in cystic fibrosis (CF) patients on account of pancreatic insufficiency. Vitamin D is a crucial component of bone health and affects nearly all cells of the immune system. However, clinical benefits or harms associated with supplementation are poorly documented. In this systematic review, we included randomized controlled trials (RCTs) that compared vitamin D supplementation with placebo (i.e. 'non-increased dose') in CF patients. Analysing the 8 included RCTs, the intervention group had significantly higher serum 25-hydroxyvitamin D (se25OHD) levels, but there were no significant differences found in the quantitative synthesis of clinical outcomes, including bone disease-, respiratory status- and immunological status-related outcomes. Based on our current results, while a higher vitamin D dose elevates se25OHD, it does not seem to influence clinical outcomes. Future RCTs should include outcomes of past studies and apply longer follow-up periods to document long-term patient-important outcomes.

PMID: 33349585 [PubMed - as supplied by publisher]

CFTR-function and ventilation inhomogeneity in individuals with cystic fibrosis.

J Cyst Fibros. 2020 Dec 18;:

Authors: Bernasconi N, Kieninger E, Shaw M, Kurz J, Moeller A, Ratjen F, Rochat I, Stanojevic S, Singer F

Abstract
BACKGROUND: Increased (abnormal) ventilation inhomogeneity in individuals with mild Cystic Fibrosis (CF) lung disease may become a treatable trait for small-molecule therapeutics improving Cystic Fibrosis Transmembrane Regulator (CFTR) function. The relationship between CFTR function and ventilation inhomogeneity is unknown. We aimed to identify and quantify increased ventilation inhomogeneity in relation to CFTR function.
METHODS: This was an international, multi-center, cross-sectional study. We collated data from individuals aged 3-25 years with minimal (CFTR-MF) or residual (CFTR-RF) function of a variety of CFTR genotypes and FEV1 ≥ 70% predicted. We measured lung function using nitrogen multiple-breath washout and spirometry. We compared lung clearance index (LCI) and FEV1 between individuals with CFTR-MF vs CFTR-RF using a mixed effects multi-variable linear regression model to account for study differences and a logistic model based on propensity-score matching to adjust for possible confounding.
RESULTS: We included 141 with CFTR-MF and 35 with CFTR-RF. LCI (> 1.96 z-score) was elevated in 71.6% individuals with CFTR-MF and in 40.0% with CFTR-RF. FEV1 (< -1.96 z-score) was reduced in 11.3% individuals with CFTR-MF and in 5.7% with CFTR-RF. The mean difference (95% CI) of LCI and FEV1 between CFTR-MF and CFTR-RF was 3.71 (1.63 to 5.79) and -0.40 (-0.83 to 0.02) z-score. The LCI differences were similar after adjustment for confounders and in individuals with normal FEV1.
CONCLUSION: Increased ventilation inhomogeneity is associated with less CFTR function. In individuals with mild CF lung disease, LCI can identify and quantify increased ventilation inhomogeneity, a candidate treatable trait.

PMID: 33349584 [PubMed - as supplied by publisher]

The impact of SARS-CoV-2 on the cystic fibrosis foundation therapeutics development network.

J Cyst Fibros. 2020 Dec 15;:

Authors: Pearson K, Mayer-Hamblett N, Goss CH, Retsch-Bogart GZ, VanDalfsen JM, Burks P, Rosenbluth D, Clancy JP, Hoffman A, Nichols DP

Abstract
The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) global pandemic significantly impacted CF clinical research within the Cystic Fibrosis Foundation Therapeutics Development Network (CFF TDN). A Research Electronic Data Capture (REDCap) survey was developed and sent to network sites to monitor and understand the impact on research teams, ongoing and anticipated clinical research, and specific clinical and research procedures. Key findings indicated an early impact on participant enrollment, research team stability, and procedures such as spirometry and sputum induction. These trends steadily improved over the months as research activities began to recover across the TDN. While SARS-CoV-2 created a significant challenge it also highlights new opportunities to expand CF research with greater focus on data collection outside of research centers and increased access for remote participation.

PMID: 33349583 [PubMed - as supplied by publisher]

A Transparent Approach to Calculate Detection Rate and Residual Risk for Carrier Screening.

J Mol Diagn. 2021 Jan;23(1):91-102

Authors: Leung ML, McAdoo S, Watson D, Stumm K, Harr M, Wang X, Chung CH, Mafra F, Nesbitt AI, Hakonarson H, Santani A

Abstract
Carrier screening involves detection of carrier status for genes associated with recessive conditions. A negative carrier screening test result bears a nonzero residual risk (RR) for the individual to have an affected child. The RR depends on the prevalence of specific conditions and the detection rate (DR) of the test itself. Herein, we provide a detailed approach for calculating DR and RR. DR was calculated on the basis of the sum of disease allele frequencies (DAFs) of pathogenic variants found in published literature. As a proof of concept, DAF data for cystic fibrosis were compared with society guidelines. The DAF data calculated by this method were consistent with the published cystic fibrosis guideline. In addition, we compared DAF for four genes (ABCC8, ASPA, GAA, and MMUT) across three laboratories, and outlined the likely reasons for discrepancies between these laboratories. The utility of carrier screening is to support couples with information while making reproductive choices. Accurate development of DR and RR is therefore critical. The method described herein provides an unbiased and transparent process to collect, calculate, and report these data.

PMID: 33349347 [PubMed - in process]

Increased Fecal Calprotectin Is Associated with Worse Gastrointestinal Symptoms and Quality of Life Scores in Children with Cystic Fibrosis.

J Clin Med. 2020 Dec 17;9(12):

Authors: Beaufils F, Mas E, Mittaine M, Addra M, Fayon M, Delhaes L, Clouzeau H, Galode F, Lamireau T, Bui S, Enaud R

Abstract
In cystic fibrosis (CF), cystic fibrosis transmembrane regulator (CFTR) dysfunction leads to digestive disorders that promote intestinal inflammation and dysbiosis enhancing gastrointestinal symptoms. In pancreatic insufficiency CF patients, both intestinal inflammation and dysbiosis, are associated with an increase in the fecal calprotectin (FC) level. However, associations between the FC level, gastrointestinal symptoms, and quality of life (QoL) remain poorly studied. We aimed to assess such associations in pancreatic insufficiency CF children. The FC level was measured in pancreatic insufficiency CF children's stool samples. Children and their parents completed two questionnaires: The Gastrointestinal Symptoms Scales 3.0-PedsQLTM and the Quality of Life Pediatric Inventory 4.0-PedsQLTM. Lower scores indicated worse symptomatology or QoL. Thirty-seven CF children were included. A FC level above 250 µg/g was associated with worse gastrointestinal symptoms and QoL scores. The FC level was inversely correlated with several gastrointestinal scores assessed by children (i.e., Total, "Heart Burn Reflux", "Nausea and Vomiting", and "Gas and Bloating"). Several QoL scores were correlated with gastrointestinal scores. The FC level was weakly associated with clinical parameters. Some gastrointestinal and QoL scores were related to disease severity associated parameters. In CF, the FC level, biomarker previously related to intestinal inflammation and dysbiosis, was associated with worse digestive symptoms and QoL scores.

PMID: 33348735 [PubMed]

Graphene-Doped Tin Oxide Nanofibers and Nanoribbons as Gas Sensors to Detect Biomarkers of Different Diseases through the Breath.

Sensors (Basel). 2020 Dec 17;20(24):

Authors: Sánchez-Vicente C, Santos JP, Lozano J, Sayago I, Sanjurjo JL, Azabal A, Ruiz-Valdepeñas S

Abstract
This work presents the development of tin oxide nanofibers (NFs) and nanoribbons (NRs) sensors with graphene as a dopant for the detection of volatile organic compounds (VOCs) corresponding to different chronic diseases (asthma, chronic obstructive pulmonary disease, cystic fibrosis or diabetes). This research aims to determine the ability of these sensors to differentiate between gas samples corresponding to healthy people and patients with a disease. The nanostructures were grown by electrospinning and deposited on silicon substrates with micro-heaters integrated. The morphology of NFs and NRs was characterized by Scanning Electron Microscopy (SEM). A gas line was assembled and programmed to measure a wide range of gases (ethanol, acetone, NO and CO) at different concentrations simulating human breath conditions. Measurements were made in the presence and absence of humidity to evaluate its effect. The sensors were able to differentiate between the concentrations corresponding to a healthy person and a patient with one of the selected diseases. These were sensitive to biomarkers such as acetone and ethanol at low operating temperatures (with responses above 35%). Furthermore, CO and NO response was at high temperatures (above 5%). The sensors had a rapid response, with times of 50 s and recovery periods of about 10 min.

PMID: 33348560 [PubMed - in process]

The Multifaceted Roles of MicroRNAs in Cystic Fibrosis.

Diagnostics (Basel). 2020 Dec 17;10(12):

Authors: De Palma FDE, Raia V, Kroemer G, Maiuri MC

Abstract
Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

PMID: 33348555 [PubMed]

Preface.

Arch Pediatr. 2020 Feb;27 Suppl 1:eS2-eS3

Authors: Girodon E, Fajac I

PMID: 32172932 [PubMed - indexed for MEDLINE]

Variant classifications, databases and genotype-phenotype correlations.

Arch Pediatr. 2020 Feb;27 Suppl 1:eS13-eS18

Authors: Raynal C, Corvol H

Abstract
Because CFTR gene studies now represent one of the most frequent genetic analyses routinely performed worldwide, the number of rare CFTR variants identified in various clinical situations, regularly increases. To provide appropriate diagnosis and prognosis to CF patients as well as appropriate genetic counseling to families, the clinical impact and the phenotypic spectrum of variants identified by diagnostic techniques need to be characterized. Three complementary locus specific databases, called CFTR1, CFTR2 and CFTR-France were developed to address these issues. Besides, the growing knowledge of the CF pathophysiology and the technical evolution in molecular biology allowed to identify candidate modifier genes, regulatory loci, epigenetic profiles and trans-regulators that could help to refine genotype-phenotype correlations at the individual level. These different factors may contribute to the large phenotypic variability between patients with CF, even when they carry identical CFTR variants, regarding lung function, meconium ileus susceptibility or the risk for developing CFTR-related diabetes and liver disease. Finally, the availability of new therapies that target the CFTR protein for numbers of CF patients led to the identification of 'good' and 'poor' responders, thus raising questions of pharmacogenetics factors that may influence treatment efficiency as a novel feature of the complexity of CF patients' management. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

PMID: 32172930 [PubMed - indexed for MEDLINE]

Editorial.

Arch Pediatr. 2020 Feb;27 Suppl 1:eS1

Authors: Durieu I

PMID: 32172929 [PubMed - indexed for MEDLINE]

Expert panel consensus recommendations for diagnosis and treatment of secondary osteoporosis in children.

Pediatr Rheumatol Online J. 2020 Feb 24;18(1):20

Authors: Galindo-Zavala R, Bou-Torrent R, Magallares-López B, Mir-Perelló C, Palmou-Fontana N, Sevilla-Pérez B, Medrano-San Ildefonso M, González-Fernández MI, Román-Pascual A, Alcañiz-Rodríguez P, Nieto-Gonzalez JC, López-Corbeto M, Graña-Gil J

Abstract
BACKGROUND: Osteoporosis incidence in children is increasing due to the increased survival rate of patients suffering from chronic diseases and the increased use of drugs that can damage bones. Recent changes made to the definition of childhood osteoporosis, along with the lack of guidelines or national consensuses regarding its diagnosis and treatment, have resulted in a wide variability in the approaches used to treat this disease. For these reasons, the Osteogenesis Imperfecta and Childhood Osteoporosis Working Group of the Spanish Society of Pediatric Rheumatology has sounded the need for developing guidelines to standardize clinical practice with regard to this pathology.
METHODS: An expert panel comprised of 6 pediatricians and 5 rheumatologists carried out a qualitative literature review and provided recommendations based on evidence, when that was available, or on their own experience. The level of evidence was determined for each section using the Oxford Centre for Evidence-based Medicine (CEBM) system. A Delphi survey was conducted for those recommendations with an evidence level of IV or V. This survey was sent to all members of the SERPE. All recommendations that had a level of agreement higher or equal to 70% were included.
RESULTS: Fifty-one recommendations, categorized into eight sections, were obtained. Twenty-four of them presented an evidence level 4 or 5, and therefore a Delphi survey was conducted. This was submitted electronically and received a response rate of 40%. All recommendations submitted to the Delphi round obtained a level of agreement of 70% or higher and were therefore accepted.
CONCLUSION: In summary, we present herein guidelines for the prevention, diagnosis and treatment of secondary childhood osteoporosis based on the available evidence and expert clinical experience. We believe it can serve as a useful tool that will contribute to the standardization of clinical practice for this pathology. Prophylactic measures, early diagnosis and a proper therapeutic approach are essential to improving bone health, not only in children and adolescents, but also in the adults they will become in the future.

PMID: 32093703 [PubMed - indexed for MEDLINE]

Arterial abnormalities identified in kidneys transplanted into children during the COVID-19 pandemic.

Am J Transplant. 2020 Dec 21;:

Authors: Berteloot L, Berthaud R, Temmam S, Lozach C, Zanelli E, Blanc T, Heloury Y, Capito C, Chardot C, Sarnacki S, Garcelon N, Lacaille F, Charbit M, Pastural M, Rabant M, Boddaert N, Leruez-Ville M, Eloit M, Sermet-Gaudelus I, Dehoux L, Boyer O

Abstract
Graft artery stenosis can have a significant short- and long-term negative impact on renal graft function. From the beginning of the COVID-19 pandemic, we noticed an unusual number of graft arterial anomalies following kidney transplant (KTx) in children. Nine children received a KTx at our center between February and July 2020, eight boys and one girl, of median age 10 years. Seven presented Doppler features suggesting arterial stenosis, with an unusual extensive pattern. For comparison, over the previous five-year period, persistent spectral Doppler arterial anomalies (focal anastomotic stenoses) following KTx were seen in 5% of children at our center. We retrospectively evidenced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in 5/7 children with arterial stenosis. The remaining two patients had received a graft from a deceased adolescent donor with a positive serology at D0. These data led us to suspect immune post-viral graft vasculitis, triggered by SARS-CoV-2. Because the diagnosis of COVID-19 is challenging in children, we recommend pre-transplant monitoring of graft recipients and their parents by monthly RT-PCR and serology. We suggest balancing the risk of post-viral graft vasculitis against the risk of prolonged dialysis when considering transplantation in a child during the pandemic.

PMID: 33346946 [PubMed - as supplied by publisher]

A Population Pharmacokinetic Modeling Approach to Determine the Efficacy of Intravenous Amikacin in Children with Cystic Fibrosis.

Ther Drug Monit. 2020 Dec 17;Publish Ahead of Print:

Authors: Woillard JB, Bouchet S, Fayon M, Marquet P, Monchaud C, Bui S

Abstract
BACKGROUND: In children with cystic fibrosis (CF), the currently recommended amikacin dose ranges between 30-35 mg/kg/day; however, data supporting this dosing efficacy is lacking. Herein, the objectives were to develop a non-parametric pharmacokinetic population model (POPPK) for amikacin in children with CF and investigate the efficacy and toxicity at different dose rates for distinct minimum inhibitory concentration (MIC) clinical breakpoints using Monte Carlo simulations.
METHODS: Data from 94 children with CF (613 serum concentrations) from the Bordeaux University Hospital's CF-centre (CRCM) were analyzed. After determination of POPPK parameters and associated influent covariates in Pmetrics, 1000 Monte Carlo simulations were performed for 7 different dose rates between 30 and 60 mg/kg/day, to predict the probability of obtaining peak serum amikacin ≥10 × MIC and trough level ≤ 2.5 mg/L, for MIC values between 1 and 16 mg/L.
RESULTS: The median[min-max] age and weight were 10[0.3-17] years and 29[6-71] kg, respectively, with only 2 children under 1 year of age. Body weight and creatinine clearance significantly impacted the amikacin volume of distribution and clearance. The mean relative bias/root mean squared error (RMSE) between observed and individual predicted concentrations was -0.68%/8.1%. Monte Carlo simulations showed that for sensitive bacteria with MICs≤4, 30 mg/kg/day was most appropriate for a 100% success rate; for bacteria with MICs≥8 [e.g. Pseudomonas aeruginosa (MICamikacin=8)], a dose of at least 40 mg/kg/day allowed a high success probability (90%), with a trough level below 2.5 mg/L.
CONCLUSIONS: For intermediate pathogens, a dose of at least 40 mg/kg/day can improve efficacy, with an acceptable calculated residual trough level in cases of normal or hyperfiltration. As amikacin undergoes renal clearance, which is immature until one year of age, dosing recommendations for this age group may be markedly high, warranting cautious interpretation.

PMID: 33346630 [PubMed - as supplied by publisher]

Management of Gastrointestinal and Nutritional Problems in Children with Neurological Impairment: A Survey of Practice.

J Pediatr Gastroenterol Nutr. 2020 Dec 16;Publish Ahead of Print:

Authors: Romano C, Dipasquale V, Van Winckel M, Hulst J, Broekaert I, Bronsky J, Dall'Oglio L, Mis NF, Hojsak I, Orel R, Papadopoulou A, Schaeppi M, Thapar N, Wilschanski M, Sullivan P, Gottrand F

Abstract
OBJECTIVES: The main aim of this study was to determine the impact on clinical practice of the first European Society of Gastroenterology, Hepatology, and Nutrition (ESPGHAN) position paper on the diagnosis and management of nutritional and gastrointestinal problems in children with neurological impairment (NI).
METHODS: In this pilot-study, a web-based questionnaire was distributed between November, 2019 and June, 2020, amongst ESPGHAN members using the ESPGHAN newsletter. Fifteen questions covered the most relevant aspects on nutritional management and gastrointestinal issues of children with NI. A descriptive analysis of responses was performed.
RESULTS: A total of 150 health professionals from 23 countries responded to the survey. A considerable variation in clinical practice concerning many aspects of nutritional and gastrointestinal management of children with NI was observed. The most frequently used method for diagnosing oropharyngeal dysfunction was the direct observation of meals with or without the use of standardised scores (n = 103). Anthropometric measurements were the most commonly used tools for assessing nutritional status (n = 111). The best treatment for gastroesophageal reflux disease (GERD) was considered to be proton pump inhibitor therapy by most (n = 116) participants. Regarding tube feeding, nearly all respondents (n = 114) agreed that gastrostomy is the best enteral access to be used for long-term enteral feeding. Fundoplication was indicated at the time of gastrostomy placement especially in case of uncontrolled GERD.
CONCLUSIONS: More studies are required to address open questions on adequate management of children with NI. Identifying knowledge gaps paves the way for developing updated recommendations and improving patient care.

PMID: 33346573 [PubMed - as supplied by publisher]

The effect of particle size of inhaled tobramycin dry powder on the eradication of Pseudomonas aeruginosa biofilms.

Eur J Pharm Sci. 2020 Dec 17;:105680

Authors: Aljalamdeh R, Price R, Jones MD, Bolhuis A

Abstract
Pseudomonas aeruginosa is the predominant opportunistic bacterium that causes chronic respiratory infections in cystic fibrosis (CF) patients. This bacterium can form biofilms, which are structured communities of cells encased within a self-produced matrix. Such biofilms have a high level of resistance to multiple classes of antibiotics. A widely used treatment of P. aeruginosa lung infections in CF patients is tobramycin dry powder inhalation. The behaviour of particles in the lung has been well studied, and dry powder inhalers are optimised for optimal dispersion of the drug into different zones of the lung. However, one question that has not been addressed is whether the size of an antibiotic particle influences the antibiofilm activity against P. aeruginosa. We investigated this by fractionating tobramycin particles using a Next Generation Impactor (NGI). The fractions obtained were then tested in an in vitro model on P. aeruginosa biofilms. The results indicate that the antibiofilm activity of tobramycin dry powder inhaler can indeed be influenced by the particle size. Against P. aeruginosa biofilms of two clinical isolates, smaller tobramycin particles (aerodynamic diameter <2.82 µm) showed better efficacy by approximately 20% as compared to larger tobramycin particles (aerodynamic diameter <11.7 µm) However, this effect was only observed when biofilms were treated for 3 hours, whereas there was no difference after treatment for 24 hours. This suggests that in our model the rate of dissolution of larger particles limits the effectiveness of tobramycin over a 3-hour time period, which is relevant as this is equivalent to the time in which most tobramycin is cleared from the lung.

PMID: 33346008 [PubMed - as supplied by publisher]

The clinical use of lung MRI in cystic fibrosis: what, now, how?

Chest. 2020 Dec 17;:

Authors: Dournes G, Walkup LL, Benlala I, Willmering MM, Macey J, Bui S, Laurent F, Woods JC

Abstract
To assess airway and lung parenchymal damage non-invasively in cystic fibrosis (CF), chest MRI has been historically out of the scope of routine clinical imaging due to technical difficulties such as the low proton density and respiratory and cardiac motion. However, technological breakthroughs have recently emerged to dramatically improve lung MRI quality (including signal-to-noise ratio, resolution, speed, contrast). At the same time, novel treatments have changed the landscape of CF clinical care. In this contemporary context, there is a recent consensus that lung MRI can be used clinically to assess CF in a radiation-free manner and enable quantification of lung disease severity. MRI can now achieve 3-dimensional, high-resolution morphological imaging, and beyond this morphological information, MRI may offer the ability to differentiate active inflammation versus scarring tissue sensitively. MRI could also characterize various forms of inflammation for early guidance of treatment. Moreover, functional information from MRI can assess regional, small airway disease with sensitivity to detect small changes even in patients with mild CF. Finally, automated quantification methods have emerged to support the conventional visual analyses for more objective and reproducible assessment of the disease severity. This manuscript aims to review the most recent developments of lung MRI, with a focus on practical application and clinical value in CF, and the perspectives on how these modern techniques may converge and impact patient care soon.

PMID: 33345950 [PubMed - as supplied by publisher]

NKCC1: Newly Found as a Human Disease-Causing Ion Transporter.

Function (Oxf). 2021;2(1):zqaa028

Authors: Koumangoye R, Bastarache L, Delpire E

Abstract
Among the electroneutral Na+-dependent chloride transporters, NKCC1 had until now evaded identification as a protein causing human diseases. The closely related SLC12A transporters, NKCC2 and NCC have been identified some 25 years ago as responsible for Bartter and Gitelman syndromes: two renal-dependent salt wasting disorders. Absence of disease was most surprising since the NKCC1 knockout mouse was shown in 1999 to be viable, albeit with a wide range of deleterious phenotypes. Here we summarize the work of the past 5 years that introduced us to clinical cases involving NKCC1. The most striking cases are of 3 children with inherited mutations, who have complete absence of NKCC1 expression. These cases establish that lack of NKCC1 causes deafness; CFTR-like secretory defects with mucus accumulation in lung and intestine; severe xerostomia, hypotonia, dysmorphic facial features, and severe neurodevelopmental disorder. Another intriguing case is of a patient with a dominant deleterious SLC12A2 allele. This de novo mutation introduced a premature stop codon leading to a truncated protein. This mutant transporter seems to exert dominant-negative effect on wild-type transporter only in epithelial cells. The patient who suffers from lung, bladder, intestine, pancreas, and multiple endocrine abnormalities has, however, normal hearing and cognition. Finally, new reports substantiate the haploinsufficiency prediction of the SLC12A2 gene. Cases with single allele mutations in SLC12A2 have been linked to hearing loss and neurodevelopmental disorders.

PMID: 33345190 [PubMed]

Comparison of bronchial and nasal allergen provocation in children and adolescents with bronchial asthma and house dust mite sensitization.

Pediatr Allergy Immunol. 2020 02;31(2):143-149

Authors: Fischl A, Eckrich J, Passlack V, Klenke SK, Hartmann D, Herrmann E, Schulze J, Zielen S

Abstract
BACKGROUND: Bronchial allergen provocation (BAP) is an established tool for the diagnosis of allergy in patients with asthma, but its use is limited by the potential risk of severe asthmatic reactions. Nasal provocation testing (NPT) may be an alternative safe method and does not require sophisticated equipment.
OBJECTIVE: The aim of this prospective study was to evaluate the concordance of both methods in patients with asthma and house dust mite (HDM) sensitization.
METHODS: A total of 112 patients with HDM sensitization underwent BAP and had the following parameters analysed: decrease in FEV1, exhaled NO, and total and specific IgE. Within 12 weeks, NPT with HDM was performed in 74 patients with a median age of 9 years (range, 5-16 years). The results were evaluated using the Lebel score which quantifies major symptoms like rhinorrhea, nasal obstruction, sneezes and minor symptoms, such as pruritus, conjunctivitis and pharyngitis.
RESULTS: Fifty-seven of 74 patients had an early asthmatic reaction, of which 41 were identified using the Lebel score. The Lebel score had a sensitivity of 71.9% and a positive predictive value (PPV) of 89.1%. In addition, an eNO ≥ 10 ppb (AUC 0.78), a specific IgE Dermatophagoïdes pteronyssinus ≥ 25.6 kU/L (AUC 0.76) and a specific IgE Dermatophagoïdes farinae ≥ 6.6 kU/L (AUC 0.78) were good predictors of an early asthmatic reaction.
CONCLUSION: A sequential use of NPT prior to BAP is justified to establish the relevance of HDM allergy. In patients with a negative NPT, BAP is still recommended to rule out a HDM-induced asthmatic reaction.

PMID: 31660641 [PubMed - indexed for MEDLINE]

Nanotechnology in pulmonary medicine.

Curr Opin Pharmacol. 2020 Dec 17;56:85-92

Authors: Doroudian M, O' Neill A, Mac Loughlin R, Prina-Mello A, Volkov Y, Donnelly SC

Abstract
Nanotechnology in medicine-nanomedicine-is extensively employed to diagnose, treat, and prevent pulmonary diseases. Over the last few years, this brave new world has made remarkable progress, offering opportunities to address historical clinical challenges in pulmonary diseases including multidrug resistance, adverse side effects of conventional therapeutic agents, novel imaging, and earlier disease detection. Nanomedicine is also being applied to tackle the new emerging infectious diseases, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), influenza A virus subtype H1N1 (A/H1N1), and more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review we provide both a historical overview of the application of nanomedicine to respiratory diseases and more recent cutting-edge approaches such as nanoparticle-mediated combination therapies, novel double-targeted nondrug delivery system for targeting, stimuli-responsive nanoparticles, and theranostic imaging in the diagnosis and treatment of pulmonary diseases.

PMID: 33341460 [PubMed - as supplied by publisher]

Ototoxicity in cystic fibrosis patients receiving intravenous tobramycin for acute pulmonary exacerbation: Ototoxicity following tobramycin treatment.

J Cyst Fibros. 2020 Dec 16;:

Authors: Harruff EE, Kil J, Ortiz MGT, Dorgan D, Jain R, Poth EA, Fifer RC, Kim YJM, Shoup AG, Flume PA

Abstract
Aminoglycosides are commonly used to treat infections in CF patients and are highly ototoxic. The incidence of tobramycin-induced hearing loss, tinnitus, vertigo or dizziness (ototoxicity) varies widely from 0 to 56% secondary to variation in patient enrollment, dosing, audiometry, and ototoxic criteria. The aim of this study is to determine the incidence of ototoxicity after one course of once-daily IV tobramycin in CF patients. Adult CF patients with acute pulmonary exacerbations were enrolled on IV tobramycin (10 mg/kg/d, ≥10 days). Pure-tone audiometry was performed for standard and extended high frequencies in the sensitive range for ototoxicity (SRO). American-Speech-Language-Hearing-Association cochleotoxicity criteria were applied. Distortion product otoacoustic emissions (DPOAE) and the words-in-noise-test (WINT) were assessed. Tinnitus Functional Index (TFI) and Vertigo Symptoms Scale (VSS) were used. Eighteen CF patients, mean age 31.1 (18-59), were enrolled. The incidence of cochleotoxic change from baseline at 2 and 4 weeks post-treatment was 89% and 93%. For DPOAE, a measure of outer hair-cell function, the incidence of ≥5 dB decrease was 82% and 80%. For WINT, a measure of word recognition, the incidence of ≥10% decrease was 17% and 40%. For TFI, the incidence of ≥10pt increase was 12% and 8%, and for VSS, the incidence of ≥6pt increase was 0% and 8%. One course of IV tobramycin was sufficient to cause hearing loss and other ototoxic symptoms four weeks after treatment ended. Audiometric measures were more sensitive to ototoxic change than TFI & VSS. Age and duration of tobramycin treatment were not obvious factors for predicting ototoxicity.

PMID: 33341407 [PubMed - as supplied by publisher]