J Cyst Fibros. 2021 Feb 19:S1569-1993(21)00039-4. doi: 10.1016/j.jcf.2021.02.004. Online ahead of print.

ABSTRACT

BACKGROUND: The lung clearance index (LCI) is increasingly used as an outcome in clinical trials of patients with mild cystic fibrosis (CF) lung disease. Yet, understanding the impact of standard CF respiratory therapy on LCI is needed. We assessed to what degree withdrawal of nebulised dornase alfa affected LCI in school-age children with CF not receiving CFTR modulators or hydrator therapy.

METHODS: A single-centre, randomised, controlled, parallel group study to determine effects of one month's withdrawal of nebulised dornase alfa (intervention) in 5-18 years old children with CF. Remaining chronic maintenance therapy stayed unchanged. Outcome measures were assessed at two visits one month apart. Primary outcome was absolute change in LCI. Secondary outcomes were FEV1, FEF25-75 and CF Questionnaire-revised (CFQ-R) respiratory symptom score. Possible harmful effects were assessed by comparing the occurrence of pulmonary exacerbations between groups.

RESULTS: Twenty-eight children (median age 10.4 [interquartile range: 7.6; 13.5] years) with CF received standard care (n = 14) or intervention (n = 14). Compared with the control group, LCI increased (worsened) 1.74 (95% confidence interval: 0.62; 2.86) during withdrawal of dornase alfa, while FEV1 (-6.8% predicted) and FEF25-75 (-13.1% predicted) decreased significantly. Change in CFQ-R respiratory symptom score and the occurrence of pulmonary exacerbations did not differ significantly between groups.

CONCLUSIONS: One month's withdrawal of dornase alfa caused increasing ventilation inhomogeneity and deteriorating FEV1 and FEF25-75 in school-age children with mild CF. Hence, adherence to dornase alfa optimally needs to be addressed when using LCI and spirometric parameters as endpoints, even in short-term clinical trials.

PMID:33619014 | DOI:10.1016/j.jcf.2021.02.004

J Cyst Fibros. 2021 Feb 19:S1569-1993(21)00038-2. doi: 10.1016/j.jcf.2021.02.003. Online ahead of print.

ABSTRACT

Highly effective CFTR modulator drug therapy is increasingly available to those with cystic fibrosis. Multiple observational research studies are now being conducted to better understand the impacts of this important therapeutic milestone on long-term outcomes, patient care needs, and future research priorities. PROMISE is a large, multi-disciplinary academic study focused on the broad impacts of starting elexacaftor/tezacaftor/ivacaftor in the US population age 6 years and older. The many areas of investigation and rationale for each are discussed by organ systems, along with recognition of remaining important questions that will not be addressed by this study alone. Knowledge gained through this and multiple complementary studies around the world will help to understand important health outcomes, clinical care priorities, and research needs for a large majority of people treated with these or similarly effective medications targeting the primary cellular impairment in cystic fibrosis.

PMID:33619012 | DOI:10.1016/j.jcf.2021.02.003

Baby bottle and other disinfection devices used during travel to low electrical voltage (110V) regions: a practical experiment with implications for baby, lactating mothers and patient safety.

Travel Med Infect Dis. 2021 Feb 18;:101991

Authors: Stirling J, Moore JE, Bell J, Millar BC

Abstract
BACKGROUND: Baby bottle steam disinfectors are important for the disinfection of devices used with baby nutrition, lactating mothers and respiratory patients (e.g. nebulisers). There have been no reports to date describing the effect of incorrect voltage on thermal performance. It was the aim of this study to evaluate thermal output, at low (110V) voltage compared to 220V. Such data will determine if variation in voltage, results in temperature differences, constituting a microbiological safety risk.
METHODS: Thermal performance was evaluated by positioning calibrated thermocouple probes in multiple locations operating the device at 110V and 220-240V.
RESULTS: Within the upper tray at 220-240V, a maximum temperature (TempMAX) of 100oC was achieved, with the unit remaining at 90oC for 420 secs (A0=3000), whereas at 110V, TempMAX = 71.1oC, remaining at >70oC for 630 secs. Most importantly, when the lower tray of the device was examined at 110V, TempMAX = 48.6oC at one location, remaining >40oC for 1140 secs, whereas at 220-240V, the lowest temperature achieved was 86.1oC, with an A0 equivalence of A0=60.
CONCLUSIONS: This study showed that input voltage of 110V to the baby bottle steam disinfector had an adverse effect on thermal performance, by not achieving intended time/temperature combinations, compared to 220-240V. Parents of babies and infants need to be made aware of the microbiological safety risks of operating such devices outside the manufacturers' specification. For the safety of babies, infants, mothers and patients, users must ensure that such devices are always operated safely within manufacturer's specifications and instructions for use.

PMID: 33610764 [PubMed - as supplied by publisher]

Prostaglandin E2 stimulates anion and fluid secretion triggered by lipopolysaccharide in rat vaginal epithelium.

Mol Cell Endocrinol. 2021 Feb 18;:111219

Authors: Zhang YL, Liu W, Xu JB, Sun Q, Qiu ZE, Chen L, Huang J, Zhu YX, Zhou WL

Abstract
Prostaglandin E2 (PGE2) is a principal lipid mediator mediating various biological processes including immune responses and fluid secretion. As the first line of host defense against infection, vaginal epithelium plays orchestrated roles in vaginal innate immunity. However, the effect of PGE2 triggered by pro-inflammatory stimuli on vaginal epithelium remains elusive. This study aims to investigate the regulatory role of PGE2 on vaginal epithelium after lipopolysaccharide (LPS) stimulation. RT-PCR and western blot analysis revealed that E-prostanoid (EP) receptors EP2 and EP4 were expressed in rat vagina. Basolateral application of PGE2 induced anion secretion mediated by cystic fibrosis transmembrane conductance regulator (CFTR) via EP-adenylate cyclase-cAMP signaling pathway in rat vaginal epithelial cells. The in vivo study showed that PGE2 promoted fluid secretion in rat vagina. Moreover, LPS stimulation facilitated cyclooxygenase-dependent PGE2 synthesis and vaginal fluid secretion in vivo. Conclusively, LPS stimulation triggered epithelium-derived PGE2 production in vaginal epithelium, leading to CFTR-mediated anion secretion and luminal flushing. This study might provide valuable insight into the physiological role of PGE2 during vaginal bacterial infection.

PMID: 33610642 [PubMed - as supplied by publisher]

Beyond phenotype: The genomic heterogeneity of co-infecting Mycobacterium abscessus smooth and rough colony variants in cystic fibrosis patients.

J Cyst Fibros. 2021 Feb 17;:

Authors: Gutiérrez AV, Baron SA, Sardi FS, Saad J, Coltey B, Reynaud-Gaubert M, Drancourt M

Abstract
Two unrelated cystic fibrosis patients were co-infected with Mycobacterium abscessus smooth and rough phenotypes. Smooth M. abscessus is proposed as the infecting form, and the subsequent loss of glycopeptidolipids in the host leads to a rough phenotype. Whole-genome sequencing (WGS) diagnosed two different M. abscessus strains in patient N°1 but only one strain in patient N°2. In patient N°1, rough isolate had novel mutations potentially involved in smooth-to-rough morphology changes. In patient N°2, four genes were present in only the smooth isolate. In addition, we obtained different susceptibility profiles in the four clinical isolates. We revealed a new paradigm describing a cystic fibrosis patient infected with two different clones, including a rough isolate, and identifying a rough M. abscessus clone that did not lose glycopeptidolipids. We propose WGS for the identification of heterogenic isolates and genetic determinants of antimicrobial resistance, which we believe will positively influence treatment prognosis.

PMID: 33610476 [PubMed - as supplied by publisher]

Neutrophil extracellular traps, disease severity, and antibiotic response in bronchiectasis: an international, observational, multicohort study.

Lancet Respir Med. 2021 Feb 16;:

Authors: Keir HR, Shoemark A, Dicker AJ, Perea L, Pollock J, Giam YH, Suarez-Cuartin G, Crichton ML, Lonergan M, Oriano M, Cant E, Einarsson GG, Furrie E, Elborn JS, Fong CJ, Finch S, Rogers GB, Blasi F, Sibila O, Aliberti S, Simpson JL, Huang JTJ, Chalmers JD

Abstract
BACKGROUND: Bronchiectasis is predominantly a neutrophilic inflammatory disease. There are no established therapies that directly target neutrophilic inflammation because little is understood of the underlying mechanisms leading to severe disease. Neutrophil extracellular trap (NET) formation is a method of host defence that has been implicated in multiple inflammatory diseases. We aimed to investigate the role of NETs in disease severity and treatment response in bronchiectasis.
METHODS: In this observational study, we did a series of UK and international studies to investigate the role of NETs in disease severity and treatment response in bronchiectasis. First, we used liquid chromatography-tandem mass spectrometry to identify proteomic biomarkers associated with disease severity, defined using the bronchiectasis severity index, in patients with bronchiectasis (n=40) in Dundee, UK. Second, we validated these biomarkers in two cohorts of patients with bronchiectasis, the first comprising 175 patients from the TAYBRIDGE study in the UK and the second comprising 275 patients from the BRIDGE cohort study from centres in Italy, Spain, and UK, using an immunoassay to measure NETs. Third, we investigated whether pathogenic bacteria had a role in NET concentrations in patients with severe bronchiectasis. In a separate study, we enrolled patients with acute exacerbations of bronchiectasis (n=20) in Dundee, treated with intravenous antibiotics for 14 days and proteomics were used to identify proteins associated with treatment response. Findings from this cohort were validated in an independent cohort of patients who were admitted to the same hospital (n=20). Fourth, to assess the potential use of macrolides to reduce NETs in patients with bronchiectasis, we examined two studies of long-term macrolide treatment, one in patients with bronchiectasis (n=52 from the UK) in which patients were given 250 mg of azithromycin three times a week for a year, and a post-hoc analysis of the Australian AMAZES trial in patients with asthma (n=47) who were given 500 mg of azithromycin 3 times per week for a year.
FINDINGS: Sputum proteomics identified that NET-associated proteins were the most abundant and were the proteins most strongly associated with disease severity. This finding was validated in two observational cohorts, in which sputum NETs were associated with bronchiectasis severity index, quality of life, future risk of hospital admission, and mortality. In a subgroup of 20 patients with acute exacerbations, clinical response to intravenous antibiotic treatment was associated with successfully reducing NETs in sputum. Patients with Pseudomonas aeruginosa infection had a lessened proteomic and clinical response to intravenous antibiotic treatment compared with those without Pseudomonas infections, but responded to macrolide therapy. Treatment with low dose azithromycin was associated with a significant reduction in NETs in sputum over 12 months in both bronchiectasis and asthma.
INTERPRETATION: We identified NETs as a key marker of disease severity and treatment response in bronchiectasis. These data support the concept of targeting neutrophilic inflammation with existing and novel therapies.
FUNDING: Scottish Government, British Lung Foundation, and European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC).

PMID: 33609487 [PubMed - as supplied by publisher]

The Upd3 cytokine couples inflammation to maturation defects in Drosophila.

Curr Biol. 2021 Feb 12;:

Authors: Romão D, Muzzopappa M, Barrio L, Milán M

Abstract
Developmental transitions, such as puberty or metamorphosis, are tightly controlled by steroid hormones and can be delayed by the appearance of growth abnormalities, developmental tumors, or inflammatory disorders such as inflammatory bowel disease or cystic fibrosis.1-4 Here, we used a highly inflammatory epithelial model of malignant transformation in Drosophila5,6 to unravel the role of Upd3-a cytokine with homology to interleukin-6-and the JAK/STAT signaling pathway in coupling inflammation to a delay in metamorphosis. We present evidence that Upd3 produced by malignant and nearby cell populations signals to the prothoracic gland-an endocrine tissue primarily dedicated to the production of the steroid hormone ecdysone-to activate JAK/STAT and bantam microRNA (miRNA) and to delay metamorphosis. Upd cytokines produced by the tumor site contribute to increasing the systemic levels of Upd3 by amplifying its expression levels in a cell-autonomous manner and by inducing Upd3 expression in neighboring tissues in a non-autonomous manner, culminating in a major systemic response to prevent larvae from initiating pupa transition. Our results identify a new regulatory network impacting on ecdysone biosynthesis and provide new insights into the potential role of inflammatory cytokines and the JAK/STAT signaling pathway in coupling inflammation to delays in puberty.

PMID: 33609452 [PubMed - as supplied by publisher]

Immune transcriptomes of highly exposed SARS-CoV-2 asymptomatic seropositive versus seronegative individuals from the Ischgl community.

Sci Rep. 2021 Feb 19;11(1):4243

Authors: Lee HK, Knabl L, Pipperger L, Volland A, Furth PA, Kang K, Smith HE, Knabl L, Bellmann R, Bernhard C, Kaiser N, Gänzer H, Ströhle M, Walser A, von Laer D, Hennighausen L

Abstract
SARS-CoV-2 infection ranges from asymptomatic to severe with lingering symptomatology in some. This prompted investigation of whether or not asymptomatic disease results in measurable immune activation post-infection. Immune activation following asymptomatic SARS-CoV-2 infection was characterized through a comparative investigation of the immune cell transcriptomes from 43 asymptomatic seropositive and 52 highly exposed seronegative individuals from the same community 4-6 weeks following a superspreading event. Few of the 95 individuals had underlying health issues. One seropositive individual reported Cystic Fibrosis and one individual reported Incontinentia pigmenti. No evidence of immune activation was found in asymptomatic seropositive individuals with the exception of the Cystic Fibrosis patient. There were no statistically significant differences in immune transcriptomes between asymptomatic seropositive and highly exposed seronegative individuals. Four positive controls, mildly symptomatic seropositive individuals whose blood was examined 3 weeks following infection, showed immune activation. Negative controls were four seronegative individuals from neighboring communities without COVID-19. All individuals remained in their usual state of health through a five-month follow-up after sample collection. In summary, whole blood transcriptomes identified individual immune profiles within a community population and showed that asymptomatic infection within a super-spreading event was not associated with enduring immunological activation.

PMID: 33608566 [PubMed - as supplied by publisher]

Hospice care access inequalities: a systematic review and narrative synthesis.

BMJ Support Palliat Care. 2021 Feb 19;:

Authors: Tobin J, Rogers A, Winterburn I, Tullie S, Kalyanasundaram A, Kuhn I, Barclay S

Abstract
BACKGROUND: Inequalities in access to hospice care is a source of considerable concern; white, middle-class, middle-aged patients with cancer have traditionally been over-represented in hospice populations.
OBJECTIVE: To identify from the literature the demographic characteristics of those who access hospice care more often, focusing on: diagnosis, age, gender, marital status, ethnicity, geography and socioeconomic status.
DESIGN: Systematic literature review and narrative synthesis.
METHOD: Searches of Medline, PsycINFO, CINAHL, Web of Science, Assia and Embase databases from January 1987 to end September 2019 were conducted. Inclusion criteria were peer-reviewed studies of adult patients in the UK, Australia, New Zealand and Canada, receiving inpatient, day, outpatient and community hospice care. Of the 45 937 titles retrieved, 130 met the inclusion criteria. Narrative synthesis of extracted data was conducted.
RESULTS: An extensive literature search demonstrates persistent inequalities in hospice care provision: patients without cancer, the oldest old, ethnic minorities and those living in rural or deprived areas are under-represented in hospice populations. The effect of gender and marital status is inconsistent. There is a limited literature concerning hospice service access for the LGBTQ+ community, homeless people and those living with HIV/AIDS, diabetes and cystic fibrosis.
CONCLUSION: Barriers of prognostic uncertainty, institutional cultures, particular needs of certain groups and lack of public awareness of hospice services remain substantial challenges to the hospice movement in ensuring equitable access for all.

PMID: 33608254 [PubMed - as supplied by publisher]

Generation of two induced pluripotent stem cell lines (RCMGi004-A and -B) from human skin fibroblasts of a cystic fibrosis patient with compound heterozygous F508del/W1282X mutations in CFTR gene.

Stem Cell Res. 2021 Feb 10;52:102232

Authors: Kondrateva E, Demchenko A, Slesarenko Y, Pozhitnova V, Yasinovsky M, Amelina E, Tabakov V, Voronina E, Lavrov A, Smirnikhina S

Abstract
Skin fibroblasts obtained from a 28-year-old man with clinically manifested and genetically proven (F508del/W1282X) cystic fibrosis were successfully transformed into induced pluripotent stem cells (iPSCs) by using non-viral, non-integrating, self-replicating RNA reprogramming vectorthat contains five reprogramming factors: OCT4, KLF4, SOX2, GLIS1, and c-MYC as well as a puromycin-resistance gene. Two iPSC lines showed a normal karyotype, expressed pluripotency markers and exhibited the potential to differentiate into three germ layers in spontaneous differentiation assay. These iPSC lines may be subsequently used for development of a personalized etiotropic treatment,disease modelling, cell differentiation and organoid formation, pharmacological investigations and drug screening.

PMID: 33607467 [PubMed - as supplied by publisher]

Failed eradication therapy of new onset Pseudomonas aeruginosa infections in cystic fibrosis children is associated with bacterial resistance to neutrophil functions.

J Infect Dis. 2021 Feb 19;:

Authors: Kwong K, Benedetti A, Yau Y, Waters V, Nguyen D

Abstract
BACKGROUND: Antibiotics, such as inhaled tobramycin are used to eradicate new onset Pseudomonas aeruginosa (PA) infections in cystic fibrosis (CF) patients but frequently fail due to reasons poorly understood. We hypothesized that PA isolates' resistance to neutrophil antibacterial functions was associated with failed eradication in patients harboring those strains.
METHODS: We analyzed all PA isolates from a cohort of 39 CF children with new onset PA infections undergoing tobramycin eradication therapy, where N=30 patients had eradicated and N=9 patients had persistent infection. We characterized several bacterial phenotypes and measured the isolates' susceptibility to neutrophil antibacterial functions using in vitro assays of phagocytosis and intracellular bacterial killing.
RESULTS: PA isolates from persistent infections were more resistant to neutrophil functions, with lower phagocytosis and intracellular bacterial killing compared to those from eradicated infections. In multivariable analyses, in vitro neutrophil responses were positively associated with twitching motility, and negatively with mucoidy. In vitro neutrophil phagocytosis was a predictor of persistent infection following tobramycin even after adjustment for clinical risk factors.
CONCLUSIONS: PA isolates from new onset CF infection show strain-specific susceptibility to neutrophil antibacterial functions, and infection with PA isolates resistant to neutrophil phagocytosis is an independent risk factor for failed tobramycin eradication.

PMID: 33606875 [PubMed - as supplied by publisher]

Lung Transplantation for Cystic Fibrosis in Turkey: First Report.

Exp Clin Transplant. 2021 Feb 17;:

Authors: Vayvada M, Halis AN, Saribas E, Uygun Kizmaz Y, Çardak ME, Erkilic A, Tasci E

Abstract
OBJECTIVES: Lung transplant is the most important treatment approach that improves the life expectancy and quality of life for patients with cystic fibrosis with end-stage lung disease. In this study, we retros-pectively analyzed patients with cystic fibrosis who were referred to our lung transplant program in Turkey.
MATERIALS AND METHODS: We evaluated 14 patients with cystic fibrosis who were referred to our lung transplant clinic between December 2016 and December 2019. The characteristics of the patients at the time of referral to our lung transplant clinic, survival, and lung transplant results were recorded.
RESULTS: Four patients died on the wait list, 3 patients were not eligible for lung transplant, and lung transplant was performed in 7 patients. The mean age of all patients was 22.8 years (range, 11-41 years), and the mean age for patients who underwent lung transplant was 27.5 years (range, 21-41 years). The mean time of suitable donor offer or survival life was 140 days in the patients who were referred for lung transplant. The 1-year mortality rate was 28.6% (2 of 7 patients) after lung transplant. One patient died of chronic lung allograft dysfunction at the 25th month after lung transplant. Four patients were alive without any problems.
CONCLUSIONS: Lung transplant is the final treatment method for patients with cystic fibrosis with terminal period lung disease. To provide the best benefit, patients should be evaluated for transplant early. Cystic fibrosis care clinics and lung transplant clinics should work in coordination in order to increase the number of lung transplants and improve outcomes.

PMID: 33605204 [PubMed - as supplied by publisher]

Diaphragmatic thickness and excursion by lung ultrasound in pediatric chronic pulmonary diseases.

J Ultrasound. 2021 Feb 18;:

Authors: Ishak SR, Sakr HM

Abstract
PURPOSE: Many patients with chronic pulmonary diseases, such as interstitial lung disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis, suffer from dyspnea and exercise intolerance. Reduced lung compliance is the main cause of the patients' dyspnea, but weak respiratory muscles could be an additional factor. The diaphragm is considered the major respiratory muscle. Our study aimed to detect diaphragmatic thickness and excursion by ultrasound in pediatric patients with chronic pulmonary diseases to assess respiratory muscle weakness in these patients.
METHODS: A case-control study was conducted on 130 patients with pediatric chronic pulmonary diseases (childhood interstitial lung diseases, cystic fibrosis, and non-cystic fibrosis bronchiectasis) and 100 control subjects. Ultrasound was used to detect diaphragmatic excursion and thickness, which were correlated with the severity of the disease, both clinically and functionally.
RESULTS: The right and left diaphragmatic excursions were significantly lower in the patients (19.469 ± 9.984 and 18.5 ± 10.131, respectively) than in the control subjects (29.6 ± 14.131 and 25.6 ± 12.827, respectively) (p values of 0.002 and 0.019). In contrast, the difference in the right and left diaphragmatic thicknesses between the patients and the controls was statistically insignificant (p values of 0.884 and 0.344). The left diaphragmatic excursion was positively correlated with the patients' age and weight, while both the right and the left diaphragmatic excursion significantly correlated with the patients' height, FEV1/FVC ratio, and heart rate.
CONCLUSION: The diaphragmatic excursion is lower in children and adolescents with chronic pulmonary diseases than in healthy control subjects. The diaphragmatic excursion is positively correlated with patients' age, weight, height, FEV1/FVC ratio, and heart rate.

PMID: 33604840 [PubMed - as supplied by publisher]

Virtual Screening Approach to Identifying a Novel and Tractable Series of Pseudomonas aeruginosa Elastase Inhibitors.

ACS Med Chem Lett. 2021 Feb 11;12(2):217-227

Authors: Leiris S, Davies DT, Sprynski N, Castandet J, Beyria L, Bodnarchuk MS, Sutton JM, Mullins TMG, Jones MW, Forrest AK, Pallin TD, Karunakar P, Martha SK, Parusharamulu B, Ramula R, Kotha V, Pottabathini N, Pothukanuri S, Lemonnier M, Everett M

Abstract
Novel therapies are required to treat chronic bacterial infections in cystic fibrosis (CF) sufferers. The most common pathogen responsible for these infections is Pseudomonas aeruginosa, which persists within the lungs of CF sufferers despite intensive antibiotic treatment. P. aeruginosa elastase (also known as LasB or pseudolysin) is a key virulence determinant that contributes to the pathogenesis and persistence of P. aeruginosa infections in CF patients. The crucial role of LasB in pseudomonal virulence makes it a good target for the development of an adjuvant drug for CF treatment. Herein we discuss the discovery of a new series of LasB inhibitors by virtual screening and computer assisted drug design (CADD) and their optimization leading to compounds 29 and 39 (K i = 0.16 μM and 0.12 μM, respectively).

PMID: 33603968 [PubMed]

Antibiotic use evaluation in hospitalized pediatric patients with respiratory tract infections: A retrospective chart review study.

Curr Drug Saf. 2021 Feb 17;:

Authors: Mahboobipour AA, Baniasadi S, Shahrebabaki ES, Nejad ST, Hassanzad M

Abstract
INTRODUCTION: Respiratory tract infections (RTIs) are a common cause of antibiotic usage in hospitalized pediatric patients. Inappropriate use of antibiotics may lead to the emergence of multidrug-resistant microorganisms and increased treatment costs.
OBJECTIVE: This study was designed to assess antibiotic usage in hospitalized pediatric patients with RTIs.
METHODS: Medical charts of the patients admitted to the pediatric ward (PW) and pediatric intensive care unit (PICU) of a tertiary respiratory center were reviewed. Patients' demographic and clinical data including gender, age, weight, history of allergy, length of hospital stay, clinical diagnosis, prescribed antibiotics (indication, dose, and frequency of administration) were collected. The appropriateness of antibiotic usage was evaluated in each patient according to international guidelines.
RESULTS: Two hundred seventy-nine hospitalized patients were included in the study. The most common reason for hospitalization was pneumonia (38%), followed by cystic fibrosis (20.1%) and bronchitis (5%). The most commonly used antimicrobial agents were ceftriaxone, azithromycin, and clindamycin which guideline adherence for their usage was 85.3%, 23.3%, and 47%; respectively. Inappropriate dose selection was the main reason for non-adherence to the guidelines. The adherence rate to RTIs' guidelines (considering all parameters for each patient) was 27.6%. Multivariate logistic regression analysis demonstrated CF and prescription of azithromycin are predictors of guideline non-adherence.
CONCLUSION: We found relatively low adherence to international guidelines in our center that could be related to restricted definitions of optimal antibiotic therapy. Despite most patients received logical antimicrobial therapy, actions should be taken into account to reach optimal antibiotic usage.

PMID: 33602106 [PubMed - as supplied by publisher]

Light-regulated allosteric switch enables temporal and subcellular control of enzyme activity.

Elife. 2020 09 23;9:

Authors: Shaaya M, Fauser J, Zhurikhina A, Conage-Pough JE, Huyot V, Brennan M, Flower CT, Matsche J, Khan S, Natarajan V, Rehman J, Kota P, White FM, Tsygankov D, Karginov AV

Abstract
Engineered allosteric regulation of protein activity provides significant advantages for the development of robust and broadly applicable tools. However, the application of allosteric switches in optogenetics has been scarce and suffers from critical limitations. Here, we report an optogenetic approach that utilizes an engineered Light-Regulated (LightR) allosteric switch module to achieve tight spatiotemporal control of enzymatic activity. Using the tyrosine kinase Src as a model, we demonstrate efficient regulation of the kinase and identify temporally distinct signaling responses ranging from seconds to minutes. LightR-Src off-kinetics can be tuned by modulating the LightR photoconversion cycle. A fast cycling variant enables the stimulation of transient pulses and local regulation of activity in a selected region of a cell. The design of the LightR module ensures broad applicability of the tool, as we demonstrate by achieving light-mediated regulation of Abl and bRaf kinases as well as Cre recombinase.

PMID: 32965214 [PubMed - indexed for MEDLINE]

The Gluten Free Diet's Impact on Growth in Children with Celiac Disease in Two Different Countries.

Nutrients. 2020 May 26;12(6):

Authors: Sansotta N, Guandalini S, Romano S, Amirikian K, Cipolli M, Tridello G, Barzaghi S, Jericho H

Abstract
The effects of gluten free diet (GFD) on body mass index (BMI) and growth parameters in pediatric patients with celiac disease (CD) and their dependence on different socio-cultural environments are poorly known. We conducted an international retrospective study on celiac patients diagnosed at the University of Verona, Italy, and at the University of Chicago, Chicago, IL, USA, as underweight. A total of 140 celiac children and 140 controls (mean age 8.4 years) were enrolled in Chicago; 125 celiac children and 125 controls (mean age 7.3 years, NS) in Verona. At time of diagnosis, Italian celiac children had a weight slightly lower (p = 0.060) and a BMI z-score significantly (p < 0.001) lower than their American counterparts. On GFD, Italian celiac children showed an increased prevalence of both underweight (19%) as well as overweight (9%), while American children showed a decrease prevalence of overweight/obese. We concluded that while the GFD had a similar impact on growth of celiac children in both countries, the BMI z-score rose more in American than in Italian celiac children. Additionally, in Italy, there was an alarming increase in the proportion of celiac children becoming underweight. We speculate that lifestyle and cultural differences may explain the observed variations.

PMID: 32466557 [PubMed - indexed for MEDLINE]

Genetic markers for treatment-related pancreatitis in a cohort of Hispanic children with acute lymphoblastic leukemia.

Support Care Cancer. 2021 Feb;29(2):725-731

Authors: Grimes AC, Chen Y, Bansal H, Aguilar C, Perez Prado L, Quezada G, Estrada J, Tomlinson GE

Abstract
PURPOSE: Treatment-related pancreatitis (TRP) is a serious complication occurring in children with acute lymphoblastic leukemia (ALL). Those affected are at high risk for severe organ toxicity and treatment delays that can impact outcomes. TRP is associated with asparaginase, a standard therapeutic agent in childhood ALL. Native American ancestry, older age, high-risk leukemia, and increased use of asparaginase are linked to pancreatitis risk. However, dedicated genetic studies evaluating pancreatitis in childhood ALL include few Hispanics. Thus, the genetic basis for higher risk of pancreatitis among Hispanic children with ALL remains unknown.
METHODS: Cases of children with ALL treated in from 1994 through 2013 were reviewed and identified 14, all Hispanic, who developed pancreatitis related to asparaginase therapy. Forty-six controls consisting of Hispanic children treated on the same regimens without pancreatitis were selected for comparison. Total DNA isolated from whole blood was used for targeted DNA sequencing of 23 selected genes, including genes associated with pancreatitis without ALL and genes involved in asparagine metabolism.
RESULTS: Non-synonymous polymorphisms and frameshift deletions were detected in 15 genes. Most children with TRP had variants in ABAT, ASNS, and CFTR. Notably, children with TRP harbored many more CFTR variants (71.4%) compared with controls (39.1%). Among these, V470M (rs213950) was most frequent (OR 4.27, p = 0.025).
CONCLUSIONS: This is the first study of genetic factors in treatment-related pancreatitis in Hispanic children with ALL. Identifying correlative variants in ethnically vulnerable populations may improve screening to identify which patients with ALL are at greatest risk for pancreatitis.

PMID: 32447501 [PubMed - indexed for MEDLINE]

Inhalable nano into micro dry powders for ivacaftor delivery: The role of mannitol and cysteamine as mucus-active agents.

Int J Pharm. 2020 May 30;582:119304

Authors: Porsio B, Lentini L, Ungaro F, Di Leonardo A, Quaglia F, Giammona G, Cavallaro G

Abstract
In this paper the innovative approach of nano into micro dry powders (NiM) was applied to incorporate into mannitol or mannitol/cysteamine micromatrices ivacaftor-loaded nanoparticles for pulmonary delivery in CF. Nanoparticles composed by a mixture of two polyhydrohydroxyethtylaspartamide copolymers containing loaded with ivacaftor at 15.5% w/w were produced. The nanoparticles were incorporated into microparticles to obtain NiM that were fully characterized in terms of size, morphology, interactions with artificial Cf mucus (CF-AM) as well as for aerodynamic behaviour. Finally the activity of ivacaftor-containing NiM was evaluated by in vitro preliminary experiments. NiM at matrix composed by a mixture of mannitol:cysteamine showed greater ability to reduce CF-AM viscosity whereas that based on just mannitol showed better aerodynamic properties with a FPF of about 25%. All produced NiM showed very good cytocompatibility and the released ivacaftor was able to restore the chroride transport in vitro.

PMID: 32272167 [PubMed - indexed for MEDLINE]

Feasibility study on exhaled-breath analysis by untargeted Selected-Ion Flow-Tube Mass Spectrometry in children with cystic fibrosis, asthma, and healthy controls: Comparison of data pretreatment and classification techniques.

Talanta. 2021 Apr 01;225:122080

Authors: Segers K, Slosse A, Viaene J, Bannier MAGE, Van de Kant KDG, Dompeling E, Van Eeckhaut A, Vercammen J, Vander Heyden Y

Abstract
Selected-Ion Flow-Tube Mass Spectrometry (SIFT-MS) has been applied in a clinical context as diagnostic tool for breath samples using target biomarkers. Exhaled breath sampling is non-invasive and therefore much more patient friendly compared to bronchoscopy, which is the golden standard for evaluating airway inflammation. In the actual pilot study, 55 exhaled breath samples of children with asthma, cystic-fibrosis and healthy individuals were included. Rather than focusing on the analysis of target biomarkers or on the identification of biomarkers, different data analysis strategies, including a variety of pretreatment, classification and discrimination techniques, are evaluated regarding their capacity to distinguish the three classes based on subtle differences in their full scan SIFT-MS spectra. Proper data-analysis strategies are required because these full scan spectra contain much external, i.e. unwanted, variation. Each SIFT-MS analysis generates three spectra resulting from ion-molecule reactions of analyte molecules with H3O+, NO+ and O2+. Models were built with Linear Discriminant Analysis, Quadratic Discriminant Analysis, Soft Independent Modelling by Class Analogy, Partial Least Squares - Discriminant Analysis, K-Nearest Neighbours, and Classification and Regression Trees. Perfect models, concerning overall sensitivity and specificity (100% for both) were found using Direct Orthogonal Signal Correction (DOSC) pretreatment. Given the uncertainty related to the classification models associated with DOSC pretreatments (i.e. good classification found also for random classes), other models are built applying other preprocessing approaches. A Partial Least Squares - Discriminant Analysis model with a combined pre-processing method considering single value imputation results in 100% sensitivity and specificity for calibration, but was less good predictive. Pareto scaling prior to Quadratic Discriminant Analysis resulted in 41/55 correctly classified samples for calibration and 34/55 for cross-validation. In future, the uncertainty with DOSC and the applicability of the promising preprocessing methods and models must be further studied applying a larger representative data set with a more extensive number of samples for each class. Nevertheless, this pilot study showed already some potential for the untargeted SIFT-MS application as a rapid pattern-recognition technique, useful in the diagnosis of clinical breath samples.

PMID: 33592793 [PubMed - in process]