Preclinical Studies of a Rare CF-Causing Mutation in the Second Nucleotide Binding Domain (c.3700A>G) Show Robust Functional Rescue in Primary Nasal Cultures by Novel CFTR Modulators.

J Pers Med. 2020 Nov 05;10(4):

Authors: Laselva O, McCormack J, Bartlett C, Ip W, Gunawardena TNA, Ouyang H, Eckford PDW, Gonska T, Moraes TJ, Bear CE

Abstract
The combination therapies ORKAMBITM and TRIKAFTATM are approved for people who have the F508del mutation on at least one allele. In this study we examine the effects of potentiator and corrector combinations on the rare mutation c.3700A>G. This mutation produces a cryptic splice site that deletes six amino acids in NBD2 (I1234-R1239del). Like F508del it causes protein misprocessing and reduced chloride channel function. We show that a novel cystic fibrosis transmembrane conductance regulator CFTR modulator triple combination (AC1, corrector, AC2-2, co-potentiator and AP2, potentiator), rescued I1234-R1239del-CFTR activity to WT-CFTR level in HEK293 cells. Moreover, we show that although the response to ORKAMBI was modest in nasal epithelial cells from two individuals homozygous for I1234-R1239del-CFTR, a substantial functional rescue was achieved with the novel triple combination. Interestingly, while both the novel CFTR triple combination and TRIKAFTATM treatment showed functional rescue in gene-edited I1234-R1239del-CFTR-expressing HBE cells and in nasal cells from two CF patients heterozygous for I1234-R1239del/W1282X, nasal cells homozygous for I1234-R1239del-CFTR showed no significant response to the TRIKAFTATM combination. These data suggest a potential benefit of CFTR modulators on the functional rescue of I1234-R1239del -CFTR, which arises from the rare CF-causing mutation c.3700A>G, and highlight that patient tissues are crucial to our full understanding of functional rescue in rare CFTR mutations.

PMID: 33167369 [PubMed]

Mining Public Mass Spectrometry Data to Characterize the Diversity and Ubiquity of P. aeruginosa Specialized Metabolites.

Metabolites. 2020 Nov 05;10(11):

Authors: Lybbert AC, Williams JL, Raghuvanshi R, Jones AD, Quinn RA

Abstract
Pseudomonas aeruginosa is a ubiquitous environmental bacterium that causes chronic infections of burn wounds and in the lungs of cystic fibrosis (CF) patients. Vital to its infection is a myriad of specialized metabolites that serve a variety of biological roles including quorum sensing, metal chelation and inhibition of other competing bacteria. This study employed newly available algorithms for searching individual tandem mass (MS/MS) spectra against the publicly available Global Natural Product Social Molecular Networking (GNPS) database to identify the chemical diversity of these compounds and their presence in environmental, laboratory and clinical samples. For initial characterization, the metabolomes of eight clinical isolates of P. aeruginosa were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and uploaded to GNPS for spectral searching. Quinolones, rhamnolipids, phenazines and siderophores were identified and characterized; including the discovery of modified forms of the iron chelator pyochelin. Quinolones were highly diverse with the three base forms Pseudomonas quinolone signal 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), 4-heptyl-4(1H)-quinolone (HHQ) and 2-heptyl-4-quinolone-N-oxide (HQNO) having extensive variation in the length of their acyl chain from as small as 3 carbons to as large as 17. Rhamnolipids were limited to either one or two sugars with a limited set of fatty acyl chains, but the base lipid form without the rhamnose was also detected. These specialized metabolites were identified from diverse sources including ant-fungal mutualist dens, soil, plants, human teeth, feces, various lung mucus samples and cultured laboratory isolates. Their prevalence in fecal samples was particularly notable as P. aeruginosa is not known as a common colonizer of the human gut. The chemical diversity of the compounds identified, particularly the quinolones, demonstrates a broad spectrum of chemical properties within these the metabolite groups with likely significant impacts on their biological functions. Mining public data with GNPS enables a new approach to characterize the chemical diversity of biological organisms, which includes enabling the discovery of new chemistry from pathogenic bacteria.

PMID: 33167332 [PubMed]

Cell Membrane Transporters Facilitate the Accumulation of Hepatocellular Flucloxacillin Protein Adducts: Implication in Flucloxacillin-Induced Liver Injury.

Chem Res Toxicol. 2020 Nov 10;:

Authors: Waddington JC, Ali SE, Penman SL, Whitaker P, Hamlett J, Chadwick A, Naisbitt DJ, Park BK, Meng X

Abstract
Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver reactions. Although expression of HLA-B*57:01 increases susceptibility, little is known about the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the presentation of flucloxacillin-modified peptides by the risk allele. In this study, the binding of flucloxacillin to proteins of liver-like cells was characterized. Flucloxacillin was shown to bind to proteins localized in bile canaliculi regions, coinciding with the site of clinical disease. The localization of flucloxacillin was mediated primarily by the membrane transporter multidrug resistance-associated protein 2. Modification of multiple proteins by flucloxacillin in bile canaliculi regions may provide a potential local source of neo-antigens for HLA presentation in the liver.

PMID: 33169987 [PubMed - as supplied by publisher]

Longitudinal changes in exercise capacity among adult cystic fibrosis patients.

Adv Respir Med. 2020;88(5):420-423

Authors: Boutou AK, Manika K, Hajimitrova M, Pitsiou G, Giannakopoulou P, Sourla E, Kioumis I

Abstract
INTRODUCTION: Longitudinal data regarding changes in exercise capacity among adult cystic fibrosis (CF) patients are currently scarce. The aim of this brief report was to assess changes in exercise capacity among adult CF patients with stable and mild-to-moderate disease eight years after their initial evaluation.
MATERIAL AND METHODS: Maximum cardiopulmonary exercise testing (CPET) was utilized. Other assessments included Doppler echocardiography, the 6-minute walking test, spirometry, and lung volume evaluation.
RESULTS: Eleven (6 male, 5 female) patients completed both evaluations (initial and after eight years). During follow-up, indices of ventilatory impairment (such as ventilatory reserve; p=0.019, and ventilatory equivalent for carbon dioxide; p = 0.047) deterio-rated significantly following a decline in respiratory function measurements. Peak oxygen uptake (VO2), both as an absolute (26.6 ± 8.46 vs 23.89 ± 6.16 mL/kg/min; p = 0.098) and as a % of predicted value (71.21 ± 16.54 vs 70.60 ± 15.45; p = 0.872), did not deteriorate. This is also true for oxygen pulse (p = 0.743), left heart ejection fraction (p = 0.574), and pulmonary artery systolic pressure (p = 0.441). However, the anaerobic threshold, both as an absolute (p = 0.009) and as a % of predicted value (p = 0.047), was significantly lower during follow-up.
CONCLUSION: In adult CF patients with stable, mild-to-moderate disease, a peak VO2 may be preserved for several years. However, even in these patients, deconditioning is present.

PMID: 33169814 [PubMed - in process]

Targeted deubiquitination rescues distinct trafficking-deficient ion channelopathies.

Nat Methods. 2020 Nov 09;:

Authors: Kanner SA, Shuja Z, Choudhury P, Jain A, Colecraft HM

Abstract
Impaired protein stability or trafficking underlies diverse ion channelopathies and represents an unexploited unifying principle for developing common treatments for otherwise dissimilar diseases. Ubiquitination limits ion channel surface density, but targeting this pathway for the purposes of basic study or therapy is challenging because of its prevalent role in proteostasis. We developed engineered deubiquitinases (enDUBs) that enable selective ubiquitin chain removal from target proteins to rescue the functional expression of disparate mutant ion channels that underlie long QT syndrome (LQT) and cystic fibrosis (CF). In an LQT type 1 (LQT1) cardiomyocyte model, enDUB treatment restored delayed rectifier potassium currents and normalized action potential duration. CF-targeted enDUBs synergistically rescued common (ΔF508) and pharmacotherapy-resistant (N1303K) CF mutations when combined with the US Food and Drug Administation (FDA)-approved drugs Orkambi (lumacaftor/ivacaftor) and Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor). Altogether, targeted deubiquitination via enDUBs provides a powerful protein stabilization method that not only corrects diverse diseases caused by impaired ion channel trafficking, but also introduces a new tool for deconstructing the ubiquitin code in situ.

PMID: 33169015 [PubMed - as supplied by publisher]

SHORT-TERM EFFECTS OF APPROPRIATE EMPIRICAL ANTIMICROBIAL TREATMENT WITH CEFTOLOZANE/TAZOBACTAM IN A SWINE MODEL OF NOSOCOMIAL PNEUMONIA.

Antimicrob Agents Chemother. 2020 Nov 09;:

Authors: Motos A, Li Bassi G, Pagliara F, Fernandez-Barat L, Yang H, Xiol EA, Senussi T, Idone FA, Travierso C, Chiurazzi C, Amaro R, Yang M, Bobi J, Rigol M, Nicolau DP, Frigola G, Cabrera R, Ramirez J, Pelosi P, Blasi F, Antonelli M, Artigas A, Vila J, Kollef M, Torres A

Abstract
The rising frequency of MDR/XDR pathogens is making more frequent the inappropriate empirical antimicrobial therapy (IEAT) in nosocomial pneumonia, which is associated with increased mortality. We aim to determine the short-term benefits of appropriate empirical antimicrobial treatment (AEAT) with C/T compared with IEAT with piperacillin/tazobactam(TZP) in MDR Pseudomonas aeruginosa (PA) pneumonia. Twenty-one pigs with pneumonia caused by XDR PA strain (susceptible to C/T but resistant to TZP) were ventilated up to 72h. Twenty-four hours after bacterial challenge, animals were randomized to receive 2-day treatment with either intravenous saline (untreated) or 50-25 mg/kg of C/T (AEAT) or 200-25 mg/kg of TZP (IEAT), every 8h. The primary outcome was the PA burden in lung tissue and the histopathology injury. PA burden in tracheal secretions and bronchoalveolar lavage (BAL) fluid, the development of antibiotic resistance and inflammatory markers were secondary outcomes. Overall PA lung burden was 5.30[4.00-6.30], 4.04[3.64-4.51], and 4.04[3.05-4.88] log10CFU/g in the untreated, AEAT and IEAT groups, respectively(p=0.299), without histopathological differences (p=0.556). In contrast, in tracheal secretions (p<0.001) and BAL fluid(p=0.002), bactericidal efficacy was higher in AEAT group. Increased minimum inhibitory concentration to TZP was found in 3 animals, while resistance to C/T did not develop. IL-1β was significantly downregulated by AEAT, in comparison to other groups(p=0.031). In a mechanically ventilated swine model of XDR P. aeruginosa pneumonia, appropriate initial treatment with C/T decreased respiratory secretions' bacterial burden, prevented development of resistance, achieved pharmacodynamic target and may reduce systemic inflammation. Yet, after only 2 days of treatment, P. aeruginosa tissue concentrations were moderately affected.

PMID: 33168605 [PubMed - as supplied by publisher]

The virtual CF clinic: Implications for sputum microbiology.

J Cyst Fibros. 2020 Nov 06;:

Authors: Moore JE, Millar BC, McCaughan J, O'Neill D, Bell J, Crossan A, Rendall JC

Abstract
The COVID19 pandemic has shifted the paradigm of how outpatient clinics are delivered within CF care, resulting in a significant reduction of patient visits to CF centres. One consequence of this has been a reduction in the number of sputa/cough swabs that patients submit for routine analysis. This report examines why it is important to maintain optimal sputum microbiology and explores (i). the microbiological efficiency of postal submission of sputum specimens from the community and (ii) the regulatory conditions that must be met through postal submission of respiratory specimens. Virtual clinics have now been established within CF care and it is incumbent on each speciality within the CF MDT to explore ways to nurture and support their individual contribution to the success of the virtual clinic. Within microbiology, adopting innovative approaches to sputum collection in the community and transportation via postal services will allow for continued microbiological vigilance thereby supporting patient safety.

PMID: 33168478 [PubMed - as supplied by publisher]

Successful biodegradable stent insertion in an infant with severe bronchomalacia and cystic fibrosis.

J Cyst Fibros. 2020 Nov 06;:

Authors: Harris CA, Brodlie M, O'Brien C, Thomas MF

Abstract
We report the first case of biodegradable airway stent insertion for a patient with bronchomalacia and cystic fibrosis (CF). This female infant with antenatally diagnosed cystic fibrosis developed respiratory distress by three weeks of age. On lower airway examination she was found to have severe left main stem bronchomalacia causing left upper lobe hyperinflation and subsequent right upper lobe collapse. By eight weeks of age she developed life-threatening respiratory failure requiring high pressure invasive ventilation. A biodegradable bronchial stent was inserted to the left main bronchus at thirteen weeks of age with successful extubation from invasive respiratory support four days later. A second biodegradable stent was inserted nine weeks later, due to persistent bronchomalacia following stent degradation and redevelopment of oxygen requirement. She was discharged home off all respiratory support eight weeks later and has remained well, requiring no further surgical intervention for bronchomalacia to date, now age three years.

PMID: 33168477 [PubMed - as supplied by publisher]

Therapeutic potential for coxibs-nitric oxide releasing hybrids in cystic fibrosis.

Eur J Med Chem. 2020 Oct 31;:112983

Authors: Consalvi S, Poce G, Ghelardini C, Di Cesare Mannelli L, Patrignani P, Bruno A, Anzini M, Calderone V, Martelli A, Testai L, Giordani A, Biava M

Abstract
This review discusses the rational for further studies of COX-2 inhibitors-NO releaser hybrids (NO-Coxibs) in the pharmacological treatment of the airway inflammation in Cystic Fibrosis (CF). Our research group developed several classes of NO-Coxibs for the pharmacological treatment of arthritis, and among them several compounds showed an outstanding in vivo efficacy and good pharmacokinetic properties. The good antiinflammatory properties displayed by these compounds during the previous screening could, by itself, suggest appropriate candidates for further testing in CF.

PMID: 33168231 [PubMed - as supplied by publisher]

Nebulizer Breathing Treatments at Home.

Am J Respir Crit Care Med. 2020 08 01;202(3):P7-P8

Authors: Sockrider M

PMID: 32735176 [PubMed - indexed for MEDLINE]

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In vitro activity of ceftolozane-tazobactam and ceftazidime-avibactam against Pseudomonas aeruginosa isolated from patients with cystic fibrosis.

Diagn Microbiol Infect Dis. 2020 Sep 11;99(2):115204

Authors: Nolan PJ, Jain R, Cohen L, Finklea JD, Smith TT

Abstract
Pseudomonas aeruginosa is a commonly isolated pathogen in adults with cystic fibrosis (CF). Antimicrobial resistance is an escalating problem due to chronic colonization and frequent antimicrobial exposure. Ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) exhibit promising activity against antimicrobial resistant organisms, including P. aeruginosa. A retrospective review was conducted comparing the in vitro activities of C/T and CZA against 42 P. aeruginosa isolates from the respiratory tract of 32 adults with CF. The first isolate per patient per year that underwent susceptibility testing for C/T, CZA, and colistin was included. C/T was more susceptible than CZA (60% versus 43%). Thirty-eight (90%) isolates were considered highly drug resistant and demonstrated higher C/T susceptibilities compared to CZA (55% versus 45%). These results suggest using C/T while awaiting susceptibilities when standard antipseudomonal agents cannot be used.

PMID: 33152675 [PubMed - as supplied by publisher]

Lipoxin A4 promotes reduction and antibiotic efficacy against Pseudomonas aeruginosa biofilm.

Prostaglandins Other Lipid Mediat. 2020 Nov 02;:106505

Authors: Thornton JM, Walker JM, Sundarasivarao PYK, Spur BW, Rodriguez A, Yin K

Abstract
Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic bacterium commonly found in wound infections and airways of cystic fibrosis patients. P. aeruginosa readily forms biofilms which can reduce the efficacy of antibiotics used to eradicate the pathogen. We have previously shown that a Specialized Pro-resolving Mediator (SPM), Lipoxin A4 (LxA4) is a quorum sensing inhibitor which can reduce P. aeruginosa virulence. In this study, we examined the direct actions of LxA4 and RvD2 on P. aeruginosa biofilm formation and virulence gene expression. The influence of LxA4 on antibiotic efficacy and the combined effects on biofilm formation were also investigated. LxA4 and RvD2 reduced P. aeruginosa biofilm formation and virulence gene expression. LxA4 increased ciprofloxacin inhibition on biofilm formation but did not affect ciprofloxacin's action on non-adherent bacteria. On the other hand, LxA4 increased bacterial killing action of imipenem but did not affect imipenem's action on biofilm. We also found that LxA4 can increase ciprofloxacin's bacterial killing ability in established biofilm. Together these results suggest that LxA4 has direct effects on P. aeruginosa biofilm formation and can increase antibiotic efficacy directly.

PMID: 33152529 [PubMed - as supplied by publisher]

[Myelinosomes: A new pathway of protein quality control].

Med Sci (Paris). 2020 Nov;36(11):1012-1017

Authors: Marina Y, Ravel C, Anne-Sophie N, Béré E, Bourmeyster N

Abstract
Maintenance of cell proteostasis relies on two degradation pathways: proteasome and autophagy. Here we describe a new proteostasis pathway avoiding degradation of abnormal proteins yet carrying them outside the cell using nanovesicles called myelinosomes. These myelinosomes are produced in pathological or stress situations in relation with genetic or environmental factors. Myelinosome vesicles are nano-sized multi-stacked membrane structures, resembling myelin sheath. It has recently been shown in two models of genetic diseases (Huntington's disease and cystic fibrosis) that myelinosomes are important for eliminating mutant proteins in an unusual secretory process, thus preventing their accumulation and aggregation in cells.

PMID: 33151848 [PubMed - as supplied by publisher]

NT-proBNP Levels and Cardiopulmonary Function in Children with Sickle Cell Disease.

Pediatr Pulmonol. 2020 Nov 05;:

Authors: Feld L, Fiorino EK, Aygun B, Appiah-Kubi A, Mitchell EC, Jackson S, Mehran R, Fishbein J, Santiago MT

Abstract
Patients with Sickle Cell Disease (SCD) are living longer and subsequently more apt to develop cardiopulmonary dysfunction. NT-proBNP levels have been used in adults with SCD to assess for pulmonary hypertension and mortality. While the incidence of PH is low in pediatrics, it is reasonable to presume that NT-proBNP levels can be used to assess risk for the development of cardiopulmonary morbidity. We hypothesized that NT-proBNP levels would be increased in patients with SCD compared to age-adjusted healthy children; additionally, these levels would be associated with labs indicative of hemolysis and would demonstrate evidence of obstructive lung disease and cardiac dysfunction. We retrospectively evaluated patients with SCD, 8-18 years old, at a large, tertiary care children's hospital. NT-proBNP levels were assessed in correlation with hemolytic lab work, spirometry, and echocardiographic data. The age group 8-14 years old, 75% of our cohort's population, had a median NT-proBNP of 70pg/mL, greater than their age-adjusted counterparts (52pg/mL). NT-proBNP levels were associated with an increased degree of hemolysis when compared with hemoglobin (Hb) [r = -0.43, p < 0.0001], reticulocyte count [r = 0.25, p = 0.01] and lactate dehydrogenase (LDH) levels [r = 0.47, p < 0.0001]. An inverse trend was found between NT-proBNP and spirometric data. Lastly, a positive correlation was found between NT-proBNP and diastolic left ventricular size [r = 0.28, p = 0.047]. The correlations found suggest that NT-proBNP may be used prospectively to identify patients with SCD at increased risk for the development of cardiopulmonary dysfunction. This article is protected by copyright. All rights reserved.

PMID: 33151019 [PubMed - as supplied by publisher]

Multi-stimuli controlled release of a transmembrane chloride ion carrier from a sulfonium-linked procarrier.

Org Biomol Chem. 2020 Nov 05;:

Authors: Das S, Biswas O, Akhtar N, Patel A, Manna D

Abstract
In recent times, anion transporters have received substantial consideration due to their ability to disrupt the ionic equilibrium across membrane bilayers. While numerous Cl- ion transporters were developed for channelopathies, unfortunately, poor aqueous solubility precluded their bioapplicability. Herein, we demonstrate the development of a multi-stimuli activatable anion transport approach to induce regulated transport of Cl- ions across membranes under specific conditions. The sulfonium-based procarrier was initially inactive, but the transmembrane transport of Cl- ions was activated in the presence of stimuli such as glutathione (GSH), reactive oxygen species (ROS) and light. The release of the hydrophobic anionophore from the aqueous-soluble procarrier under specific conditions leads to the successful transport of Cl- ions. Under physiological conditions, these anion carriers follow an antiport exchange mechanism to transport Cl- ions across lipid bilayers. Such multi-stimuli activatable procarriers have great potential to combat various types of channelopathies, including cancer, cystic fibrosis, kidney stones, myotonia, and others.

PMID: 33150918 [PubMed - as supplied by publisher]

Cell-based non-invasive prenatal diagnosis in a pregnancy at risk of cystic fibrosis.

Prenat Diagn. 2020 Nov 04;:

Authors: Dahl Jeppesen L, Hatt L, Singh R, Ravn K, Kølvraa M, Schelde P, Uldbjerg N, Vogel I, L Lildballe D

Abstract
OBJECTIVE: We aimed to develop cell-based NIIPT for cystic fibrosis and test a pregnancy at risk of two common pathogenic variants.
METHOD: A pregnant woman carrying monozygotic twins opted for prenatal testing as she and her partner were heterozygote carriers of F508del (c.1521:1523del). The partner was also positive for the CFTR-related variant R117H (c.350G>A). Fetal trophoblasts from maternal blood were enriched and isolated using antibodies and a capillary-based cell-picking instrument. Multiplex PCR-based fragment length analysis was performed on the extracted fetal DNA for STR-genotyping, fetal gender and F508del variant status. The R117H variant status was tested using SNaPshot analysis.
RESULTS: The fetal origin of the isolated cells was varified by detection of two paternally inherited STR alleles and an Y chromosome marker, while no maternal DNA contamination was detected. The direct variant analysis detected F508del heterozygosity and the SNaPshot analysis for R117H detected only the normal allele. Thus, the results showed that the fetuses were healthy carriers of F508del, concordant with the findings of conventional prenatal testing.
CONCLUSION: Cell-based NIPT could accurately state the fetal variant status and distinguish fetal trophoblasts from maternal cells. In the future, cell-based NIPT may provide an accurate less invasive alternative to chorionic villous sampling. This article is protected by copyright. All rights reserved.

PMID: 33150588 [PubMed - as supplied by publisher]

Risk factors for respiratory Aspergillus fumigatus in German Cystic Fibrosis patients and impact on lung function.

Sci Rep. 2020 Nov 04;10(1):18999

Authors: Düesberg U, Wosniok J, Naehrlich L, Eschenhagen P, Schwarz C

Abstract
Airway inflammation and chronic lung infections in cystic fibrosis (CF) patients are mostly caused by bacteria, e.g. Pseudomonas aeruginosa (PA). The role of fungi in the CF lung is still not well elucidated, but evidence for a harmful and complex role is getting stronger. The most common filamentous fungus in CF is Aspergillus fumigatus (AF). Age and continuous antibiotic treatment have been discussed as risk factors for AF colonisation but did not differentiate between transient and persistent AF colonisation. Also, the impact of co-colonisation of PA and AF on lung function is still under investigation. Data from patients with CF registered in the German Cystic Fibrosis Registry database in 2016 and 2017 were retrospectively analysed, involving descriptive and multivariate analysis to assess risk factors for transient or persistent AF colonisation. Age represented an independent risk factor for persistent AF colonisation. Prevalence was low in children less than ten years, highest in the middle age and getting lower in higher age (≥ 50 years). Continuous antibiotic lung treatment was significantly associated with AF prevalence in all age groups. CF patients with chronic PA infection had a lower lung function (FEV1%predicted), which was not influenced by an additional AF colonisation. AF colonisation without chronic PA infection, however, was significantly associated with a lower function, too. Older age up to 49 years and continuous antibiotic use were found to be the main risk factors for AF permanent colonisation. AF might be associated with decrease of lung function if not disguised by chronic PA infection.

PMID: 33149181 [PubMed - in process]

Antibiotic Prophylaxis for Percutaneous Endoscopic Gastrostomy in Children: A Randomised Controlled Trial.

J Pediatr Gastroenterol Nutr. 2020 Nov 03;:

Authors: Alessandri F, Strisciuglio C, Borrazzo C, Cozzi D, Romano C, Betalli P, Villa MP, Parisi P, Ziparo C, Rocco M, Evangelisti M, Pugliese F, Di Nardo G

Abstract
OBJECTIVES: Paediatric studies on the role of antibiotic prophylaxis in the prevention of postoperative infections in children undergoing percutaneous endoscopic gastrostomy (PEG) are lacking. The aim of this study was to assess if a single dose of co-amoxiclav before PEG can decrease the rate of peristomal wound and systemic infection in children.
METHODS: In this prospective, randomised, double blind, multicenter trial, children undergoing PEG were randomized to antibiotic prophylaxis with co-amoxiclav versus placebo and the rate of local and systemic infections were assessed.
RESULTS: Of the 106 patients considered for inclusion, 49 patients were randomized. In the per protocol analysis, the occurrence of wound infection was 5% (1/20) in the antibiotic group and 21% (4/19) in the placebo group [p = 0.13, 16% difference in proportions, OR 0.19, 95% CI 0.02-1.9]. The occurrence of systemic infection was 9% (2/22) in the antibiotic group and 27.2% (6/25) in the placebo group [p = 0.17, 18% difference in proportions, OR 0.32, 95% CI 0.06-1.80%]. Similar results were obtained in intention to treat analysis. Interestingly, the overall infection rate was significantly higher in the placebo group as compared to the antibiotic group (40% vs 13,6%; p = 0.04) and the duration of hospital stay was significantly longer in the placebo group as compared to the antibiotic group (4.4 ± 1.6 vs 3.5 ± 1.05; p = 0.02). The number-needed-to-treat (NTT) to prevent one peristomal infection on average are 6.7 patients.
CONCLUSIONS: A preoperative dose of co-amoxiclav reduces the overall infection rate and the duration of hospital stay. Our data suggest that antibiotic prophylaxis should be recommended in every children undergoing PEG placement.

PMID: 33148981 [PubMed - as supplied by publisher]

New Insights in Laboratory Testing for COVID-19 Patients: Looking for the Role and Predictive Value of Human epididymis secretory protein 4 (HE4) and the Innate Immunity of the Oral Cavity and Respiratory Tract.

Microorganisms. 2020 Nov 02;8(11):

Authors: Schirinzi A, Cazzolla AP, Lovero R, Lo Muzio L, Testa NF, Ciavarella D, Palmieri G, Pozzessere P, Procacci V, Di Serio F, Santacroce L

Abstract
COVID-19 is a viral pandemic caused by the new coronavirus SARS-CoV-2, an enveloped positive stranded RNA virus. The mechanisms of innate immunity, considered as the first line of antiviral defense, is essential towards viruses. A significant role in host defense of the lung, nasal and oral cavities is played by Human epididymis secretory protein 4 (HE4) HE4 has been demonstrated to be serum inflammatory biomarker and to show a role in natural immunity at the level of oral cavity, nasopharynx and respiratory tract with both antimicrobial/antiviral and anti-inflammatory activity. Several biomarkers like IL-6, presepsin (PSP), procalcitonin (PCT), CRP, D-Dimer have showed a good function as predictor factors for the clinical evolution of COVID-19 patients (mild, severe and critical). The aim of this study was to correlate the blood levels of CRP, IL-6, PSP, PCT, D-Dimer with He4, to identify the predictive values of these biomarkers for the evolution of the disease and to evaluate the possible role of HE4 in the defense mechanisms of innate immunity at the level of oral cavity, nasopharynx and respiratory tract. Of 134 patients admitted at COVID hospital of Policlinico-University of Bari, 86 (58 men age 67.6 ± 12.4 and 28 women age 65.7 ± 15.4) fulfilled the inclusion criteria: in particular, 80 patients (93%) showed prodromal symptoms (smell and/or taste dysfunctions) and other typical clinical manifestations and 19 died (13 men age 73.4 ± 7.7 and 6 women age 74.8 ± 6.7). 48 patients were excluded because 13 finished chemotherapy and 6 radiotherapy recently, 5 presented suspected breast carcinoma, 5 suspected lung carcinoma, 6 suspected ovarian carcinoma or ovary cyst, 1 cystic fibrosis, 3 renal fibrosis and 9 were affected by autoimmune diseases in treatment with monoclonal antibodies. The venous sample was taken for each patient on the admission and during the hospital stay. For each patient, six measurements relating to considered parameters were performed. Significant correlations between He4 and IL-6 levels (r = 0.797), between He4 and PSP (r = 0.621), between He4 and PCT (r = 0.447), between He4 and D-Dimer (r = 0.367), between He4 and RCP (r = 0.327) have been found. ROC curves analysis showed an excellent accuracy for He4 (AUC = 0.92) and IL-6 (AUC = 0.91), a very good accuracy for PSP (AUC = 0.81), a good accuracy for PCT (AUC = 0.701) and D-Dimer (AUC = 0.721) and sufficient accuracy for RCP (AUC = 0.616). These results demonstrated the important correlation between He4, IL6 and PSP, an excellent accuracy of He4 and IL6 and showed a probable role of He4 in the innate immunity in particularly at the level of oral cavity, nasopharynx and respiratory tract. Besides He4 together with IL6 might be involved in the onset of smell and/or taste disorders and it might be used as innovative biomarker to monitor clinical evolution of COVID-19 because He4 could indicate a multi-organ involvement.

PMID: 33147871 [PubMed]