Delayed Presentation of Meconium Ileus in an Infant With Cystic Fibrosis.

Pediatrics. 2020 Sep 25;:

Authors: Lahiri T, Sullivan JS, Sartorelli KH, Murphy JJ

Abstract
Although infants with meconium ileus usually present with apparent symptoms shortly after birth, the diagnosis of meconium ileus and cystic fibrosis (CF) may be delayed, awaiting newborn screening (NBS) results. We present the case of an 11-day-old term girl with delayed passage of meconium at 48 hours who had 2 subsequent small meconium stools over the following week. There was a normal feeding history and no signs of abdominal distension or distress. She then presented with an acute abdomen, decompensated shock, bowel perforation, and peritonitis, requiring multiple intestinal surgeries. Her NBS for CF was positive, and CF was ultimately confirmed with mutation analysis. Her course was complicated by prolonged parenteral feedings and mechanical ventilation via tracheostomy. The infant was managed with soy oil, medium chain triglycerides, olive oil, fish oil lipids and experienced only transaminitis without cholestasis and no chronic liver sequelae, with subsequent normalization of her transaminases without treatment. Because her only symptom was decreased stool output and NBS results were unavailable, the CF diagnosis was delayed until she presented in extremis. Delayed meconium passage and decreased stool output during the first week of life should lead to suspicion and additional evaluation for CF while awaiting NBS results. Careful monitoring is indicated to prevent serious, life-threatening complications. The use of soy oil, medium chain triglycerides, olive oil, fish oil lipids for infants requiring prolonged parenteral nutrition may also be considered proactively to prevent cholestasis, particularly for high risk groups.

PMID: 32978295 [PubMed - as supplied by publisher]

Evidence of early increased sialylation of airway mucins and defective mucociliary clearance in CFTR-deficient piglets.

J Cyst Fibros. 2020 Sep 23;:

Authors: Caballero I, Ringot-Destrez B, Si-Tahar M, Barbry P, Guillon A, Lantier I, Berri M, Chevaleyre C, Fleurot I, Barc C, Ramphal R, Pons N, Paquet A, Lebrigand K, Baron C, Bähr A, Klymiuk N, Léonard R, Robbe-Masselot C

Abstract
BACKGROUND: Bacterial colonization in cystic fibrosis (CF) lungs has been directly associated to the loss of CFTR function, and/or secondarily linked to repetitive cycles of chronic inflammation/infection. We hypothesized that altered molecular properties of mucins could contribute to this process.
METHODS: Newborn CFTR+/+ and CFTR-/- were sacrificed before and 6 h after inoculation with luminescent Pseudomonas aeruginosa into the tracheal carina. Tracheal mucosa and the bronchoalveolar lavage (BAL) fluid were collected to determine the level of mucin O-glycosylation, bacteria binding to mucins and the airways transcriptome. Disturbances in mucociliary transport were determined by ex-vivo imaging of luminescent Pseudomonas aeruginosa.
RESULTS: We provide evidence of an increased sialylation of CF airway mucins and impaired mucociliary transport that occur before the onset of inflammation. Hypersialylation of mucins was reproduced on tracheal explants from non CF animals treated with GlyH101, an inhibitor of CFTR channel activity, indicating a causal relationship between the absence of CFTR expression and the sialylation of mucins. This increased sialylation was correlated to an increased adherence of P. aeruginosa to mucins. In vivo infection of newborn CF piglets by live luminescent P. aeruginosa demonstrated an impairment of mucociliary transport of this bacterium, with no evidence of pre-existing inflammation.
CONCLUSIONS: Our results document for the first time in a well-defined CF animal model modifications that affect the O-glycan chains of mucins. These alterations precede infection and inflammation of airway tissues, and provide a favorable context for microbial development in CF lung that hallmarks this disease.

PMID: 32978064 [PubMed - as supplied by publisher]

Phytomedicines (medicines derived from plants) for sickle cell disease.

Cochrane Database Syst Rev. 2020 Sep 25;9:CD004448

Authors: Oniyangi O, Cohall DH

Abstract
BACKGROUND: Sickle cell disease, a common recessively inherited haemoglobin disorder, affects people from sub-Saharan Africa, the Middle East, Mediterranean basin, Indian subcontinent, Caribbean and South America. It is associated with complications and a reduced life expectancy. Phytomedicines (medicine derived from plants in their original state) encompass many of the plant remedies from traditional healers which the populations most affected would encounter. Laboratory research and limited clinical trials have suggested positive effects of phytomedicines both in vivo and in vitro. However, there has been little systematic appraisal of their benefits. This is an updated version of a previously published Cochrane Review.
OBJECTIVES: To assess the benefits and risks of phytomedicines in people with sickle cell disease of all types, of any age, in any setting.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, the International Standard Randomised Controlled Trial Number Register (ISRCTN), the Allied and Complimentary Medicine Database (AMED), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Dates of most recent searches: Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Trials Register: 17 March 2020; ISRCTN: 19 April 2020; AMED: 18 May 2020; ClinicalTrials.gov: 24 April 2020; and the WHO ICTRP: 27 July 2017.
SELECTION CRITERIA: Randomised or quasi-randomised trials with participants of all ages with sickle cell disease, in all settings, comparing the administration of phytomedicines, by any mode to placebo or conventional treatment, including blood transfusion and hydroxyurea.
DATA COLLECTION AND ANALYSIS: Both authors independently assessed trial quality and extracted data.
MAIN RESULTS: Three trials (212 participants) of three phytomedicines: Niprisan® (also known as Nicosan®), Ciklavit® and a powdered extract of Pfaffia paniculata were included. The Phase IIB (pivotal) trial suggests that Niprisan® may be effective in reducing episodes of severe painful sickle cell disease crisis over a six-month period (low-quality evidence). It did not appear to affect the risk of severe complications or the level of anaemia (low-quality evidence). The single trial of Cajanus cajan (Ciklavit®) reported a possible benefit to individuals with painful crises, and a possible adverse effect (non-significant) on the level of anaemia (low-quality evidence). We are uncertain of the effect of Pfaffia paniculata on the laboratory parameters and symptoms of SCD (very low-quality of evidence). No adverse effects were reported with Niprisan® and Pfaffia paniculata (low- to very low-quality evidence).
AUTHORS' CONCLUSIONS: While Niprisan® appeared to be safe and effective in reducing severe painful crises over a six-month follow-up period, further trials are required to assess its role in managing people with SCD and the results of its multicentre trials are awaited. Currently, no conclusions can be made regarding the efficacy of Ciklavit® and the powdered root extract of Pfaffia paniculata in managing SCD. Based on the published results for Niprisan® and in view of the limitations in data collection and analysis of the three trials, phytomedicines may have a potential beneficial effect in reducing painful crises in SCD. This needs to be further validated in future trials. More trials with improved study design and data collection are required on the safety and efficacy of phytomedicines used in managing SCD.

PMID: 32977351 [PubMed - as supplied by publisher]

[Management of Primary Ciliary Dyskinesia].

Pneumologie. 2020 Sep 25;:

Authors: Raidt J, Brillault J, Brinkmann F, Jung A, Koerner-Rettberg C, Koitschev A, Linz-Keul H, Nüßlein T, Ringshausen FC, Röhmel J, Rosewich M, Werner C, Omran H

Abstract
Primary Ciliary Dyskinesia (PCD, MIM 242650) is a rare, hereditary multiorgan disease characterized by malfunction of motile cilia. Hallmark symptom is a chronic airway infection due to mucostasis leading to irreversible lung damage that may progress to respiratory failure. There is no cure for this genetic disease and evidence-based treatment is limited. Until recently, there were no randomized controlled trials performed in PCD, but this year, data of the first placebo-controlled trial on pharmacotherapy in PCD were published. This cornerstone in the management of PCD was decisive for reviewing currently used treatment strategies. This article is a consensus of patient representatives and clinicians, which are highly experienced in care of PCD-patients and provides an overview of the management of PCD. Treatments are mainly based on expert opinions, personal experiences, or are deduced from other lung diseases, notably cystic fibrosis (CF), COPD or bronchiectasis. Most strategies focus on routine airway clearance and treatment of recurrent respiratory tract infections. Non-respiratory symptoms are treated organ specific. To generate further evidence-based knowledge, other projects are under way, e. g. the International PCD-Registry. Participating in patient registries facilitates access to clinical and research studies and strengthens networks between centers. In addition, knowledge of genotype-specific course of the disease will offer the opportunity to further improve and individualize patient care.

PMID: 32977348 [PubMed - as supplied by publisher]

Evaluation of the GenoType NTM-DR assay performance for the identification and molecular detection of antibiotic resistance in Mycobacterium abscessus complex.

PLoS One. 2020;15(9):e0239146

Authors: Bouzinbi N, Marcy O, Bertolotti T, Chiron R, Bemer P, Pestel-Caron M, Peuchant O, Guet-Revillet H, Fangous MS, Héry-Arnaud G, Ouedraogo AS, Bañuls AL, Godreuil S

Abstract
The first objective of this study was to determine the GenoType NTM-DR assay performance for subspecies identification in Mycobacterium abscessus complex isolates. The second objective was to evaluate the GenoType NTM-DR assay ability to detect clarithromycin and amikacin resistance in M. abscessus complex isolates compared with drug susceptibility testing (DST) and PCR sequencing of the erm(41), rrl and rrs genes. The concordance between the GenoType NTM-DR and MLST results concerning subspecies identification was 100%. The wild type and mutated alleles of the rrl and rrs genes were detected by the GenoType NTM-DR assay and PCR sequencing with 100% (115/115) agreement. Similarly, 100% concordance between GenoType NTM-DR and DST was observed for clarithromycin and amikacin testing. Sensitivity for the detection of clarithromycin and amikacin resistance was 100%. The GenoType NTM-DR assay provides a robust and complementary tool to the gold standard methods (MLST and broth microdilution) for subspecies identification and drug resistance detection.

PMID: 32976521 [PubMed - as supplied by publisher]

Tracking the genome of four Pseudomonas aeruginosa isolates that have a defective Las quorum-sensing system, but are still virulent.

Access Microbiol. 2020;2(7):acmi000132

Authors: Martínez-Carranza E, García-Reyes S, González-Valdez A, Soberón-Chávez G

Abstract
In this work we analysed the whole genome extended multilocus sequence typing (wgMLST) of four Pseudomonas aeruginosa strains that are characterized by being virulent despite having a defective Las quorum-sensing (QS) system, and compare them with the wgMLST of the PAO1 and PA14 type strains. This comparison was done to determine whether there was a genomic characteristic that was common to the strains with an atypical QS response. The analysed strains include two environmental isolates (ID 4365 isolated from the Indian Ocean, and M66 isolated from the Churince water system in Cuatro Ciénegas Coahuila, México), one veterinary isolate (strain 148 isolated from the stomach of a dolphin) and a clinical strain (INP43 that is a cystic fibrosis pediatric isolate). We determine that the six analysed strains have a core genome of 4689 loci that was used to construct a wgMLST-phylogeny tree. Using the cano-wgMLST_BacCompare software we found that there was no common genomic characteristic to the strains with an atypical QS-response and we identify ten loci that are highly discriminatory of the six strains' phylogeny so that their MLST can reconstruct the wgMLST-phylogeny tree of these strains. We discuss here the nature of these ten highly discriminatory genes in the context of P. aeruginosa virulence and evolution.

PMID: 32974595 [PubMed]

Fostering Innovation in the Treatment of Chronic Polymicrobial Cystic Fibrosis-Associated Infections Exploring Aspartic Acid and Succinic Acid as Ciprofloxacin Adjuvants.

Front Cell Infect Microbiol. 2020;10:441

Authors: Silva E, Monteiro R, Grainha T, Alves D, Pereira MO, Sousa AM

Abstract
Cystic fibrosis (CF) disease provokes the accumulation of thick and viscous sputum in the lungs, favoring the development of chronic and polymicrobial infections. Pseudomonas aeruginosa is the main bacterium responsible for these chronic infections, and much of the difficulty involved in eradicating it is due to biofilm formation. However, this could be mitigated using adjuvant compounds that help or potentiate the antibiotic action. Therefore, the main goal of this study was to search for substances that function as adjuvants and also as biofilm-controlling compounds, preventing or dismantling P. aeruginosa biofilms formed in an in vitro CF airway environment. Dual combinations of compounds with subinhibitory (1 and 2 mg/L) and inhibitory concentrations (4 mg/L) of ciprofloxacin were tested to inhibit the bacterial growth and biofilm formation (prophylactic approach) and to eradicate 24-h-old P. aeruginosa populations, including planktonic cells and biofilms (treatment approach). Our results revealed that aspartic acid (Asp) and succinic acid (Suc) restored ciprofloxacin action against P. aeruginosa. Suc combined with 2 mg/L of ciprofloxacin (Suc-Cip) was able to eradicate bacteria, and Asp combined with 4 mg/L of ciprofloxacin (Asp-Cip) seemed to eradicate the whole 24-h-old populations, including planktonic cells and biofilms. Based on biomass depletion data, we noted that Asp induced cell death and Suc seemed somehow to block or reduce the expression of ciprofloxacin resistance. As far as we know, this kind of action had not been reported up till now. The presence of Staphylococcus aureus and Burkholderia cenocepacia did not affect the efficacy of the Asp-Cip and Suc-Cip therapies against P. aeruginosa and, also important, P. aeruginosa depletion from polymicrobial communities did not create a window of opportunity for these species to thrive. Rather the contrary, Asp and Suc also improved ciprofloxacin action against B. cenocepacia. Further studies on the cytotoxicity using lung epithelial cells indicated toxicity of Suc-Cip caused by the Suc. In conclusion, we provided evidences that Asp and Suc could be potential ciprofloxacin adjuvants to eradicate P. aeruginosa living within polymicrobial communities. Asp-Cip and Suc-Cip could be promising therapeutic options to cope with CF treatment failures.

PMID: 32974221 [PubMed - in process]

Consequences of CRISPR-Cas9-Mediated CFTR Knockout in Human Macrophages.

Front Immunol. 2020;11:1871

Authors: Zhang S, Shrestha CL, Wisniewski BL, Pham H, Hou X, Li W, Dong Y, Kopp BT

Abstract
Macrophage dysfunction is fundamentally related to altered immunity in cystic fibrosis (CF). How genetic deficits in the cystic fibrosis transmembrane conductance regulator (CFTR) lead to these defects remains unknown. Rapid advances in genomic editing such as the clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9) system provide new tools for scientific study. We aimed to create a stable CFTR knockout (KO) in human macrophages in order to study how CFTR regulates macrophage function. Peripheral blood monocytes were isolated from non-CF healthy volunteers and differentiated into monocyte-derived macrophages (MDMs). MDMs were transfected with a CRISPR Cas9 CFTR KO plasmid. CFTR KO efficiency was verified and macrophage halide efflux, phagocytosis, oxidative burst, apoptosis, and cytokine functional assays were performed. CFTR KO in human MDMs was efficient and stable after puromycin selection. CFTR KO was confirmed by CFTR mRNA and protein expression. CFTR function was abolished in CFTR KO MDMs. CFTR KO recapitulated known defects in human CF MDM (CFTR class I/II variants) dysfunction including (1) increased apoptosis, (2) decreased phagocytosis, (3) reduced oxidative burst, and (4) increased bacterial load. Activation of the oxidative burst via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase assembly was diminished in CFTR KO MDMs (decreased phosphorylated p47phox). Cytokine production was unchanged or decreased in response to infection in CFTR KO MDMs. In conclusion, we developed a primary human macrophage CFTR KO system. CFTR KO mimics most pathology observed in macrophages obtained from persons with CF, which suggests that many aspects of CF macrophage dysfunction are CFTR-dependent and not just reflective of the CF inflammatory milieu.

PMID: 32973772 [PubMed - in process]

Rheological analysis of sputum from patients with chronic bronchial diseases.

Sci Rep. 2020 Sep 24;10(1):15685

Authors: Patarin J, Ghiringhelli É, Darsy G, Obamba M, Bochu P, Camara B, Quétant S, Cracowski JL, Cracowski C, Robert de Saint Vincent M

Abstract
Bronchial diseases are characterised by the weak efficiency of mucus transport through the lower airways, leading in some cases to the muco-obstruction of bronchi. It has been hypothesised that this loss of clearance results from alterations in the mucus rheology, which are reflected in sputum samples collected from patients, making sputum rheology a possible biophysical marker of these diseases and their evolution. However, previous rheological studies have focused on quasi-static viscoelastic (linear storage and loss moduli) properties only, which are not representative of the mucus mobilisation within the respiratory tract. In this paper, we extend this approach further, by analysing both quasi-static and some dynamic (flow point) properties, to assess their usability and relative performance in characterising several chronic bronchial diseases (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) and distinguishing them from healthy subjects. We demonstrate that pathologies influence substantially the linear and flow properties. Linear moduli are weakly condition-specific and even though the corresponding ranges overlap, distinct levels can be identified. This directly relates to the specific mucus structure in each case. In contrast, the flow point is found to strongly increase in muco-obstructive diseases, which may reflect the complete failure of mucociliary clearance causing episodic obstructions. These results suggest that the analysis of quasi-static and dynamic regimes in sputum rheology is in fact useful as these regimes provide complementary markers of chronic bronchial diseases.

PMID: 32973305 [PubMed - in process]

Innovation in Aerosol Drug Delivery During Adult Mechanical Ventilation.

Respir Care. 2020 Oct;65(10):1624-1625

Authors: Berlinski A

PMID: 32973105 [PubMed - in process]

Positive orientation and posttraumatic growth in mothers of children with cystic fibrosis - mediating role of coping strategies.

J Pediatr Nurs. 2020 Sep 21;:

Authors: Byra S, Zubrzycka R, Wójtowicz P

Abstract
PURPOSE: Analyzing the relationship between positive orientation and post-traumatic growth (PTG) in mothers of children with cystic fibrosis including the mediating role of coping strategies.
DESIGN AND METHODS: This is a cross-sectional study using questionnaires. The sample was 144 mothers of children with cystic fibrosis (average age 37.25 years, SD = 6.50) recruited in the CF Foundation MATIO in Poland. The main measures included the Post-traumatic Growth Inventory (PTGI), The Positivity Scale, and the Coping Orientations to Problems Experienced (COPE). Mediation was tested with Preacher and Hayes' model 4, including coping strategies as a mediator on the relationship between positive orientation and PTG.
RESULTS: Most examined mothers (105-72.91%) revealed high or average levels of posttraumatic growth. Positive orientation was positively (but weakly) correlated with PTGI total and all its dimensions. Additionally, coping strategies, especially focus on problem and seeking emotional support, were mediators between positive orientation and all dimensions of PTG. Full mediation was observed for PTG dimension: changes in relations to others.
CONCLUSION: Positive orientation and coping strategies are important for explaining post-traumatic growth in mothers of children with cystic fibrosis.
PRACTICE IMPLICATIONS: Therapeutic interventions and support programs for mothers of children with cystic fibrosis may increase mothers' awareness of experiencing PTG. Learning effective and flexible stress coping strategies can foster positive changes.

PMID: 32972807 [PubMed - as supplied by publisher]

ELX-02: an investigational read-through agent for the treatment of nonsense mutation related genetic disease.

Expert Opin Investig Drugs. 2020 Sep 24;:

Authors: Kerem E

Abstract
INTRODUCTION: ELX-02, an investigational compound that is structurally an aminoglycoside analogue, induces read-through of nonsense mutations through interaction with the ribosome, through which full-length functional proteins can be produced. It is being developed as a therapy for genetic diseases caused by nonsense mutations such as cystic fibrosis (CF) and nephropathic cystinosis. In Phase 1 clinical trials, 105 volunteers were exposed to ELX-02. To date, ELX-02 is well tolerated and there has been no reported treatment-related serious adverse events or deaths. Areas Covered: The development of this molecule, from its pharmacology to the ongoing Phase 2 clinical trials is discussed. Expert Opinion: Globally, nonsense mutations account for ~11% of all described gene lesions causing inherited monogenetic diseases. In CF and nephropathic cystinosis, they comprise from 10-12% of the disease-causative alleles. ELX-02 is in development as a therapeutic for patients with these alleles as in vitro and in vivo data demonstrated dose-dependent read-through of nonsense mutations to produce full-length, functional proteins. Since read-through efficiency varies between alleles, and mRNA context, careful consideration of target patient populations is required. The results to date support the on-going Phase 2 clinical evaluations of ELX-02 as a read-through agent.

PMID: 32972261 [PubMed - as supplied by publisher]

The first cases of genetically confirmed congenital diarrhea with chloride loss in Slovakia.

Vnitr Lek. 2020;66(3):186-189

Authors: Podracká U, Chocholová M

Abstract
Chloride ions are involved in regulating cell volume, secreting body fluids and maintaining acid-base balance. Hypo/hyperchloraemia in neonates and infants is an emergent situation requiring careful differential diagnosis to detect a cause of the condition. The rare causes of severe hypochloremia include congenital chloridorhea (CLD), characterized by profound bulky diarrhea, high chloride concentration in stool, and severe metabolic alkalosis. CLD is a rare autosomal recessive disease caused by the mutation of the SLC26A3 gene located on chromosome 7q31, which encodes the transmembrane protein in intestinal cells. Genetic defect causes a disorder of intestinal chloride absorption and bicarbonate secretion. Profound diarrhea induces significant losses of water and electrolytes, leading to volume depletion, hyperreninemia, hyperaldosteronism, renal loss of potassium and occasionally to the development of chronic nephropathy. The authors present rare cases of two brothers with genetically confirmed CLD. Both children were born with lower birth weight and shortly after birth required administration to ICU because of notable distended abdomen and diarrhea with severe dehydration and electrolyte imbalance. Significant hypochloraemia (76 mmol/l or 78 mmol/l) and extreme metabolic alkalosis (pH 7.63; HCO3 46 mmol/l and pH 7.73; HCO3 40 mmol/l resp.) were dominant laboratory features. Renal chloride losses and cystic fibrosis were excluded; the chloride concentration test in stool was not available. After intravenous suplementation of electrolytes, the biochemical abnormalities were partially normalized and watery stools persist. In further development, the frequent episodes of dehydratation reguiring the parenteral treatment were present. Renal functions are at age 6 or 2 years resp. normal, but USG signs of nephrocalcinosis in the older boy have been observed. By molecular genetic testing the same genotype in both siblings was identified the previously not described variant c.629_63Ildel (p.Ile210del) and the pathogenic variant in the heterozygous state of the SLC26A3 gene. In persistent watery diarrhea, hypochloraemia, hypokalaemia and metabolic alkalosis, a congenital chloridorhea should be consider. The diagnosis is based on a typical clinical picture of watery diarrhea from neonatal age, evidence of a high chloride concentration in stool > 90 mmol/l and molecular-genetic examination. CLD patients require regular nephrologic monitoring for the risk of chronic nephropathy or functional tubular damage.

PMID: 32972167 [PubMed - in process]

A Data-Driven Approach to Carrier Screening for Common Recessive Diseases.

J Pers Med. 2020 Sep 22;10(3):

Authors: Kiseleva AV, Klimushina MV, Sotnikova EA, Divashuk MG, Ershova AI, Skirko OP, Kurilova OV, Zharikova AA, Khlebus EY, Efimova IA, Pokrovskaya MS, Slominsky PA, Shalnova SA, Meshkov AN, Drapkina OM

Abstract
Genetic screening is an advanced tool for reducing recessive disease burden. Nowadays, it is still unclear as to the number of genes or their variants that are necessary for effective screening. This paper describes the development of a carrier screening custom panel for cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss consisting of 116 variants in the CFTR, PAH, SERPINA1, and GJB2 genes. The approach is based on the cheapest and fastest method, on using a small number of genes, and on the estimation of the effectiveness of carriers' detection. The custom panel was tested on a population-based cohort that included 1244 participants. Genotypes were determined by the TaqMan OpenArray Genotyping platform on the QuantStudio 12K Flex Real-Time PCR System. The frequency of heterozygotes in the Russian population was 16.87% or 1:6 (CI95%: 14.76-19.00% by Clopper-Pearson exact method): in CFTR-2.81% (1:36), PAH-2.33% (1:43), SERPINA1-4.90% (1:20), and GJB2-6.83% (1:15). The data on allele frequencies were obtained for the first time on a Russian population. The panel allows us to identify the vast majority of carriers of recessive diseases in the population. It is an effective approach to carrier screening for common recessive diseases.

PMID: 32971794 [PubMed]

Mucosal humoral immunity in cystic fibrosis - a tangled web of failed proteostasis, infection and adaptive immunity.

EBioMedicine. 2020 Sep 21;60:103035

Authors: Moss RB

PMID: 32971469 [PubMed - as supplied by publisher]

Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays.

Eur J Med Chem. 2020 Sep 12;208:112833

Authors: Parodi A, Righetti G, Pesce E, Salis A, Tasso B, Urbinati C, Tomati V, Damonte G, Rusnati M, Pedemonte N, Cichero E, Millo E

Abstract
Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. It is caused by different mutations in the cystic fibrosis transmembrane regulator protein (CFTR) gene, with F508del being the most common. During the last years, small-molecule therapy chosen to contrast CF relied on compounds that correct CFTR misfolding and ER retention (correctors such as VX-809), or defective channel gating (potentiators such as VX-770). Combination therapy with the two series of drugs has been applied, leading to the approval of several multi-drugs such as Orkambi. Despite this, this treatment proved to be only partially effective making the search for novel modulators an urgent need to contrast CF. Recently, we reported compound 2a as reference compound of a series of aminoarylthiazole-VX-809 hybrid derivatives exhibiting promising F508del-CFTR corrector ability. Herein, we report exploring the docking mode of the prototype VX-809 and of 2a in order to derive useful guidelines for the rational design of novel optimized analogues. To demonstrate experimentally their effective F508del-CFTR-binding and rescuing potential, the most promising derivatives had been synthesized and evaluated in biological assays including YFP functional assay on F508del-CFTR CFBE41o-cells, trans epithelial electrical resistance (TEER) and surface plasmon resonance (SPR). This multidisciplinary strategy led to the discovery of a second series of hybrids including 7j and 7m endowed with higher potency than the prototype.

PMID: 32971410 [PubMed - as supplied by publisher]

Colistin dry powder inhalation with the Twincer™: An effective and more patient friendly alternative to nebulization.

PLoS One. 2020;15(9):e0239658

Authors: Akkerman-Nijland AM, Grasmeijer F, Kerstjens HAM, Frijlink HW, van der Vaart H, Vonk JM, Hagedoorn P, Rottier BL, Koppelman GH, Akkerman OW

Abstract
BACKGROUND: Nebulization of antimicrobial drugs such as tobramycin and colistin is a cornerstone in the treatment of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa. However, nebulization has a high treatment burden. The Twincer™ is a dry powder inhaler specifically developed for the inhalation of antibiotics such as colistin. The aim of this study was to compare patient outcomes and experience with colistin dry powder by the Twincer with nebulization of colistin or tobramycin in adult CF patients in a real-life setting.
METHODS: This was a retrospective study from 01-01-2015 until 01-07-2018. Effectiveness was evaluated by comparing FEV1 decline and exacerbation rate during a mean of 4.1 years of nebulization therapy prior to the initiation of the Twincer against the same values during a mean of 1.7 years of treatment with the Twincer.
RESULTS: Twenty-one patients were evaluated, of whom twelve could be included in the effectiveness analysis, with a total of twenty patient years. Of all patients 71.4% preferred therapy with the Twincer over nebulization. Twincer use resulted in high treatment adherence with an average adherence rate of 92.5%. There was no significant difference in annual decline in FEV1%pred prior to and after start changing from nebulization to the use of the Twincer powder inhaler (median decline -1.56 [-5.57-5.31] and 1.35 [-8.45-6.36]) respectively, p = 0.45 (linear mixed effect model)). No significant difference was found in the number of intravenous or combined total intravenous and oral antibiotic courses during Twincer therapy compared to when using nebulization (1.68 and 2.49 courses during Twincer therapy versus 1.51 and 2.94 courses during nebulization, p = 0.88 and p = 0.63).
CONCLUSION: Colistin dry powder inhalation with the Twincer is a more patient friendly alternative to nebulization, and we did not observe significant differences in the clinical outcome, regarding lung function and exacerbation rates.

PMID: 32970760 [PubMed - as supplied by publisher]

Cystic Fibrosis Year in Review 2019: Section 2 Pulmonary disease and infections.

Pediatr Pulmonol. 2020 Sep 24;:

Authors: Savant AP, McColley SA

Abstract
During the year 2019, research and case reports/series in the field of cystic fibrosis (CF) were in abundance. To adequately address the large body of CF research published during 2019, the CF year in review will be divided into three sections. This report is the second section, focusing specifically on new research related to pulmonary disease and infections. Additional sections will concentrate on CFTR modulators and the multisystem effects of CF. It is an exciting time to be providing care for patients and their families with CF with all the exciting new discoveries that will be shared in these reviews. This article is protected by copyright. All rights reserved.

PMID: 32970381 [PubMed - as supplied by publisher]

Oral antibiotic prescribing patterns for treatment of pulmonary exacerbations in two large pediatric CF centers.

Pediatr Pulmonol. 2020 Sep 24;:

Authors: Hoppe JE, Hinds DM, Colborg A, Wagner BD, Morgan WJ, Rosenfeld M, Zemanick ET, Sanders DB

Abstract
INTRODUCTION: Oral antibiotics are frequently prescribed for outpatient pulmonary exacerbations (PEx) in children with cystic fibrosis (CF). This study aimed to characterize oral antibiotic use for PEx and treatment outcomes at two large U.S. CF centers.
METHODS: Retrospective, descriptive study of oral antibiotic prescribing practices among children with CF ages 6- 17 years over one year. The care setting for antibiotic initiation(clinic or phone encounter) was determined and outcomes were compared.
RESULTS: 763 oral antibiotic courses were prescribed to 312 patients ages 6-17 years (77% of 403 eligible patients) with a median of 2 courses per year (range 1-10). Fifty-eight percent of prescriptions were provided over the phone. Penicillin was the most commonly prescribed antibiotic class (36% of prescriptions) but differences in antibiotic class prescriptions were noted between the two centers. Hospitalizations occurred within 3 months following 19% of oral antibiotic courses. FEV1 recovered to within 90% of prior baseline within 6 months in 87% of encounters; the mean (SD) % recovery was 99.6% (12.1%) of baseline. Outcomes did not differ between phone and clinic prescriptions.
CONCLUSIONS: Phone prescriptions, commonly excluded in studies of PEx, made up more than half of all oral antibiotic courses. Heterogeneity in prescribing patterns was observed between the two centers. Most patients had improvement in FEV1 returning to near their prior baseline, but hospitalizations occurred in one-fifth following oral antibiotic treatment. Efforts to optimize PEx treatment must consider care that occurs over the phone; this is particularly important as the use of telemedicine increases. This article is protected by copyright. All rights reserved.

PMID: 32970375 [PubMed - as supplied by publisher]

Managing Pediatric Foreign Body Ingestions: A 10-Year Experience.

Pediatr Emerg Care. 2020 Sep 21;:

Authors: Dipasquale V, Romano C, Iannelli M, Tortora A, Melita G, Ventimiglia M, Pallio S

Abstract
BACKGROUND: Foreign body (FB) ingestion is a common global issue in pediatrics. Most of the ingested FBs pass through the gastrointestinal tract, but up to 20% of cases require endoscopic removal. In this study, we retrospectively reviewed all pediatric cases of FB ingestion requiring endoscopic removal over a 10-year period in a tertiary hospital to compare the symptoms at presentation and outcomes with those reported in previous studies and to assess the association of the outcomes with patient and FB characteristics.
METHODS: A retrospective chart review of children 16 years or younger who underwent upper endoscopy for FB ingestion from 2008 to 2018 in a tertiary hospital was included. Data on demographics, clinical presentation, characteristics of FBs, endoscopic findings, and outcomes were reviewed. The clinical data were further evaluated to determine the circumstances surrounding FB ingestion, FB management, and patient outcomes. Descriptive analysis of the data was performed using medians, frequencies, and percentage; χ or Fisher exact test was used to assess the dependence between categorical variables.
RESULTS: Eighty-six patients (median age, 5.1 years; 67% males) underwent endoscopy for suspected FB ingestion, with a confirmation rate of 91%. Coins were the most commonly ingested FBs (n = 49, 57%). Most patients were symptomatic (84%); 97% of patients in whom the FB had an esophageal location and all patients in whom the FB was not detected by endoscopy were symptomatic (P = 0.007). The most frequent symptoms were drooling (70%) and unexplained crying (48%). Unexplained crying was more common in younger than in older patients (P < 0.001). The FB was more likely to be located in the esophagus in patients with drooling (P < 0.001) and dysphagia (P < 0.001). The distribution of FB location differed according to the FB type, with coins most frequently located in the esophagus and sharp and other FBs in the stomach (P = 0.023). Only 7 patients (8%) developed mild FB-related mucosal injury. No complications occurred during FB removal. All patients had an uneventful outcome.
CONCLUSIONS: Foreign body ingestion is common among younger children, and the clinical presentation can be variable. The presence or absence of symptoms, as well as the type of symptom, could aid clinicians in implementing diagnosis and proper management approaches in patients who ingest FBs requiring endoscopy.

PMID: 32970025 [PubMed - as supplied by publisher]