Biol Chem. 2021 Sep 10. doi: 10.1515/hsz-2021-0243. Online ahead of print.

ABSTRACT

The gold standard for the diagnosis of bacterial infections in clinical samples is based on culture tests that are time-consuming and labor-intense. For these reasons, an extraordinary effort has been made to identify biomarkers as the tools for sensitive, rapid and accurate identification of pathogenic microorganisms. Moreover, biomarkers have been tested to distinguish colonization from infection, monitor disease progression, determine the clinical status of patients or predict clinical outcomes. This mini-review describes Pseudomonas aeruginosa and Staphylococcus aureus biomarkers, which contribute to pathogenesis and have been used in culture-independent bacterial identification directly from patient samples.

PMID:34505460 | DOI:10.1515/hsz-2021-0243

Hum Mol Genet. 2021 Sep 9:ddab260. doi: 10.1093/hmg/ddab260. Online ahead of print.

ABSTRACT

Limb-girdle muscular dystrophy 3 (LGMDR3) is caused by mutations in the SGCA gene coding for α-sarcoglycan (SG). Together with β- γ- and δ-SG, α-SG forms a tetramer embedded in the dystrophin associated protein complex (DAPC) crucial for protecting the sarcolemma from mechanical stresses elicited by muscle contraction. Most LGMDR3 cases are due to missense mutations, which result in non-properly folded, even though potentially functional α-SG. These mutants are prematurely discarded by the cell quality control. Lacking one subunit, the SG-complex is disrupted. The resulting loss of function leads to sarcolemma instability, muscle fiber damage and progressive limb muscle weakness. LGMDR3 is severely disabling and, unfortunately, still incurable. Here we propose the use of small molecules, belonging to the class of cystic fibrosis transmembrane regulator (CFTR) correctors, for recovering mutants of α-SG defective in folding and trafficking. Specifically, CFTR corrector C17 successfully rerouted the SG-complex containing the human R98H-α-SG to the sarcolemma of hind-limb muscles of a novel LGMDR3 murine model. Notably, the muscle force of the treated model animals was fully recovered. To our knowledge, this is the first time that a compound designated for cystic fibrosis (CF) is successfully tested in a muscular dystrophy and may represent a novel paradigm of treatment for LGMDR3 as well as different other indications in which a potentially functional protein is prematurely discarded as folding-defective. Furthermore, the use of small molecules for recovering the endogenous mutated SG has an evident advantage over complex procedures such as gene or cell transfer.

PMID:34505136 | DOI:10.1093/hmg/ddab260

J Cyst Fibros. 2021 Sep 2:S1569-1993(21)01367-9. doi: 10.1016/j.jcf.2021.08.026. Online ahead of print.

NO ABSTRACT

PMID:34503930 | DOI:10.1016/j.jcf.2021.08.026

J Cyst Fibros. 2021 Sep 6:S1569-1993(21)01365-5. doi: 10.1016/j.jcf.2021.08.024. Online ahead of print.

NO ABSTRACT

PMID:34503929 | DOI:10.1016/j.jcf.2021.08.024

Bioorg Med Chem. 2021 Aug 5;46:116349. doi: 10.1016/j.bmc.2021.116349. Online ahead of print.

ABSTRACT

Human epithelial 15-lipoxygenase-2 (h15-LOX-2, ALOX15B) is expressed in many tissues and has been implicated in atherosclerosis, cystic fibrosis and ferroptosis. However, there are few reported potent/selective inhibitors that are active ex vivo. In the current work, we report newly discovered molecules that are more potent and structurally distinct from our previous inhibitors, MLS000545091 and MLS000536924 (Jameson et al, PLoS One, 2014, 9, e104094), in that they contain a central imidazole ring, which is substituted at the 1-position with a phenyl moiety and with a benzylthio moiety at the 2-position. The initial three molecules were mixed-type, non-reductive inhibitors, with IC50 values of 0.34 ± 0.05 μM for MLS000327069, 0.53 ± 0.04 μM for MLS000327186 and 0.87 ± 0.06 μM for MLS000327206 and greater than 50-fold selectivity versus h5-LOX, h12-LOX, h15-LOX-1, COX-1 and COX-2. A small set of focused analogs was synthesized to demonstrate the validity of the hits. In addition, a binding model was developed for the three imidazole inhibitors based on computational docking and a co-structure of h15-LOX-2 with MLS000536924. Hydrogen/deuterium exchange (HDX) results indicate a similar binding mode between MLS000536924 and MLS000327069, however, the latter restricts protein motion of helix-α2 more, consistent with its greater potency. Given these results, we designed, docked, and synthesized novel inhibitors of the imidazole scaffold and confirmed our binding mode hypothesis. Importantly, four of the five inhibitors mentioned above are active in an h15-LOX-2/HEK293 cell assay and thus they could be important tool compounds in gaining a better understanding of h15-LOX-2's role in human biology. As such, a suite of similar pharmacophores that target h15-LOX-2 both in vitro and ex vivo are presented in the hope of developing them as therapeutic agents.

PMID:34500187 | DOI:10.1016/j.bmc.2021.116349

Pediatr Pulmonol. 2021 Sep 9. doi: 10.1002/ppul.25659. Online ahead of print.

NO ABSTRACT

PMID:34499822 | DOI:10.1002/ppul.25659

Vestn Otorinolaringol. 2021;86(4):73-78. doi: 10.17116/otorino20218604173.

ABSTRACT

Cystic fibrosis is genetic multisystem disorder with a predominant lesion of the respiratory tract. The duration and quality of life of these patients depends on the state of respiratory function. Progressive lung dysfunction is still the leading cause of mortality patients with cystic fibrosis. End-stage lung diseases in patients with cystic fibrosis, lung transplantation is a viable method of treatment. It has the ability to prolong life of these patients. Survival in cystic fibrosis has steadily increased medical treatment and post-transplant. Chronic rhinosinusitis (with nasal polys and without) impacts almost all cystic fibrosis patients, leading to significant reductions in quality of life. Chronic rhinosinusitis with nasal polyps is prevalent in the cystic fibrosis patients, and it is often a recalcitrant infection with multidrug resistant organisms. Medical therapies such as nasal irrigations, nasal steroids, and antibiotics are critical for managing symptoms, but functional endoscopic sinus surgery is necessary for refractory cases. The unified airway hypothesis suggests that sanitation bacterial infection in the upper airway can also decrease bacterial burden in the lungs. The article presents a clinical case of successful endoscopic sinus surgery in a 15-year-old patient with chronic rhinosinusitis with nasal polyps and cystic fibrosis after lung transplantation. The intervention was performed under General anesthesia and controlled hypotension. Bilateral antrostomy, ethmoidectomy and Draf IIb frontal sinusotomy were performed by endoscopic endonasal approach. There were no intra - and post-operative rhinosurgical or lung complications. The follow-up period was 18 months. At present, there is no relapse of chronic polypous rhinosinusitis, and there are no indications for revision intervention.

PMID:34499452 | DOI:10.17116/otorino20218604173

Vestn Otorinolaringol. 2021;86(4):59-66. doi: 10.17116/otorino20218604159.

ABSTRACT

Cystic fibrosis (cystic fibrosis) is an important medical and social problem. The main clinical manifestations that determine the prognosis and outcome of this disease are changes in the respiratory and digestive systems. In recent years, there has been an understanding of the importance of assessing pathological changes in the nasal cavity and paranasal sinuses in patients with cystic fibrosis.

RESEARCH OBJECTIVES: Assess the efficacy of topical antibacterial therapy in adult cystic fibrosis patients after surgery on nasal cavity structures and paranasal sinuses.

MATERIAL AND METHODS: In the clinic for ear, nose and throat diseases at Sechenov University, 46 adult patients with cystic fibrosis and chronic rhinosinusitis were observed; all patients underwent extended endoscopic polysinusotomy. According to clinical studies, Isofra nasal spray is highly effective and safe in the treatment of patients with infectious diseases of the nasal cavity, nasopharynx and paranasal sinuses.

FINDINGS: The use of Isofra nasal spray (the active ingredient is framycetin sulfate) in our clinic in patients with cystic fibrosis against the background of basic therapy (inhalation with bronchodilators and mucolytics, intranasal topical steroids), had a positive effect on the microbial landscape in the nasal cavity in patients with cystic fibrosis in the postoperative period and allowed to reduce the need for the appointment of systemic antibacterial drugs.

PMID:34499450 | DOI:10.17116/otorino20218604159

Pediatr Pulmonol. 2021 Sep 9. doi: 10.1002/ppul.25667. Online ahead of print.

ABSTRACT

BACKGROUND: Exercise testing is important in people with cystic fibrosis (pwCF). The aim was to develop an incremental maximal step test to assess exercise capacity across the range of pwCF, without floor or ceiling effects, within restrictions of space, and infection prevention.

METHODS: The step test was developed in adults with stable CF. Subjects assisted in selecting: step height, start rate, increments, stage and test duration parameters. Equipment to externally pace and time the test and measure exercise parameters were selected. Reasons for stopping, criteria for achieving a maximal test, and key outcome measures were determined. Documentation to record and standardize the test and instructions to set up the metronome and timer App were developed. Infection control practices were considered.

RESULTS: Eight subjects were recruited to develop the Alfred Step Test Exercise Protocol (A-STEP) on a 20 cm portable step. The A-STEP package included a pre-test information sheet, clinical assessment and instructions, recording worksheet, and the metronome/timer instructions. The test started at 18 steps/minute. Each level increased by two steps/minute to a maximum of 48 steps (Level 16). Results were presented as mean (SD) [range] for: age 30.63 (5.89) [21-39]years; FEV1 58.13 (18.33) [32-89]%; levels: 10.31 (3.29) [6-15.5]. The A-STEP required space of 2m2 and complied with current infection control guidelines.

CONCLUSIONS: The A-STEP is a new incremental maximal step test to assess exercise capacity in pwCF, without floor or ceiling effects. It addresses the issues of space restrictions and the need for strict infection prevention in the clinical setting. This article is protected by copyright. All rights reserved.

PMID:34499432 | DOI:10.1002/ppul.25667

Pediatr Pulmonol. 2021 Sep 9. doi: 10.1002/ppul.25666. Online ahead of print.

ABSTRACT

BACKGROUND: Zinc deficiency is associated with poor growth in children without cystic fibrosis (CF), but its impact on growth in children with CF is unknown.

OBJECTIVE: To determine the prevalence of low serum Zn (sZn) and its relationship with growth in the first three years of life in children with CF.

METHODS: We utilized data from infants with CF who were enrolled in a longitudinal study of nutrition and lung health and had sZn measured as part of clinical care. Cross-sectional correlations between sZn levels and growth z-scores were assessed by Pearson's correlation coefficient. To identify factors associated with sZn status and its association to longitudinal growth patterns, multiple regression analysis with repeated measures were performed using generalized estimating equations.

RESULTS: A total of 106 sZn measurements from 53 infants were identified. Seventeen infants (32%) had intermittent Zn insufficiency, defined as at least one sZn <70 mcg/dL in their first 3 years of life. There were no significant cross-sectional associations between sZn and growth z-scores. However, analysis of longitudinal growth patterns revealed that weight- and length-for-age z-scores in children with intermittent Zn insufficiency were lower during early infancy and their weight-for-length z-scores at age 3 years were also lower compared to those who were always Zn sufficient.

CONCLUSION: Low sZn occurs in one-third of children with CF in the first 3 years of life. Cross-sectional and longitudinal analyses revealed discrepant associations between sZn and growth. Therefore, prospective studies are needed to understand the role of Zn in growth in CF. This article is protected by copyright. All rights reserved.

PMID:34499426 | DOI:10.1002/ppul.25666

Microbiol Resour Announc. 2021 Sep 9;10(36):e0057221. doi: 10.1128/MRA.00572-21. Epub 2021 Sep 9.

ABSTRACT

Here, we report the genome sequence of PA291, a nonmucoid, multidrug-resistant strain of Pseudomonas aeruginosa isolated from cystic fibrosis sputum. Short reads were de novo assembled into 190 contigs and scaffold assembled to a length of 6.26 Mbp. PhiSpy predicts that PA291 is free of prophages.

PMID:34498926 | DOI:10.1128/MRA.00572-21

BMJ Case Rep. 2021 Sep 8;14(9):e246507. doi: 10.1136/bcr-2021-246507.

NO ABSTRACT

PMID:34497060 | DOI:10.1136/bcr-2021-246507

J Cyst Fibros. 2021 Sep 5:S1569-1993(21)01355-2. doi: 10.1016/j.jcf.2021.08.014. Online ahead of print.

ABSTRACT

BACKGROUND: In late 2012, ivacaftor became available in the UK for people with cystic fibrosis (CF) aged 6 years and over with a G551D mutation. Long-term changes in treatment patterns have not previously been reported. We investigated long-term treatment patterns in people with CF with a G551D mutation who took ivacaftor and compared these with non-ivacaftor-treated cohorts using the UK Cystic Fibrosis Registry.

METHODS: Using 2007-2018 data we compared treatment patterns between four cohorts: 1: ivacaftor-treated; 2: ivacaftor era (2013-2018), ineligible genotype (no G551D mutation); 3: pre-ivacaftor era (2007-2012), eligible genotype (G551D mutation); 4: pre-ivacaftor era, ineligible genotype. Treatments included: inhaled antibiotics, dornase alfa, hypertonic saline, chronic oral antibiotics and supplementary feeding.

RESULTS: Up to 2012 the percentages of people taking each treatment were similar between the two cohorts defined by genotype and tended to increase by year with a similar slope. Once ivacaftor was introduced, the use of other treatments tended to decrease or remain stable by year for the ivacaftor-treated cohort, whereas it remained stable or increased in the non-ivacaftor-treated cohort. This led to differences in treatment use between the two cohorts in the ivacaftor-era, which became more marked over time.

CONCLUSIONS: We have shown a clear divergence in treatment patterns since the introduction of ivacaftor in a number of key treatments widely used in CF. Further research is needed to investigate whether the differences in treatment patterns are associated with changes in health outcomes.

PMID:34497037 | DOI:10.1016/j.jcf.2021.08.014

Clin Pharmacol Ther. 2021 Sep 8. doi: 10.1002/cpt.2414. Online ahead of print.

ABSTRACT

In vitro cell-based data can be used to support the extension of pharmaceutical approval to patient subsets with unique genetic variants. A set of conditions should be satisfied to support the extension of approval. The disease mechanism should be well-described, and the impact of variants on protein function should be reasonably understood. The incidence data should show that clinical trials for the variants in question are not practical. The overall safety and efficacy of the drug should be clear in adequate and well-controlled clinical trials. The clinical trial should include patients found to be responders and non-responders so that both positive and negative predictive power of the in vitro assay may be measured. The mechanism of action of the drug should be clearly defined and should be consistent with the disease mechanism. The assay system should be qualified including the following points: 1) each variant construct should be confirmed by bidirectional sequencing; 2) the in vitro assay should directly measure the variant protein function in comparison to the reference protein; 3) the assay should be formally validated to the extent possible, clearly demonstrating precision, reproducibility, and sensitivity used to support the efficacy claim; and 4) the primary data should be available for inspection and analytical validation. The overall goal is a robust and validated cell-based system that can be shown to predict the outcome of targeted therapy.

PMID:34496049 | DOI:10.1002/cpt.2414

Rev Paul Pediatr. 2021 Sep 1;40:e2020295. doi: 10.1590/1984-0462/2022/40/2020295. eCollection 2021.

ABSTRACT

OBJECTIVE: To assess the association of sleep disorders with the findings of heart rate variability (HRV) in children and adolescents with cystic fibrosis (CF).

METHODS: Cross-sectional study including children and adolescents aged six to 18 years with a clinical diagnosis of CF. Sociodemographic and clinical data were collected. Sleep disorders were evaluated using baseline nocturnal polysomnography. The autonomic nervous system (ANS) was evaluated through resting HRV.

RESULTS: A total of 30 individuals (11.2 years) with a mean forced expiratory volume in the first second (FEV1) of 62.7% were included. The respiratory disturbance index presented a median of 2.6 and obstructive sleep apnea syndrome (OSAS) was identified in 30%. In the HRV analysis, a mean standard deviation of all inter-beat (RR) intervals (SDNN) of 60.8±45.9ms was found. There was a significant correlation between the HRV low-frequency/high-frequency (LF/HF) global modulation index and the minimum SpO2 during sleep in patients with FEV1<60% (r=0.71; p=0.02). The prevalence of sleep disorders and HRV abnormalities was higher in individuals with lesser pulmonary function (FEV1<60%).

CONCLUSIONS: The results indicate a weak correlation of sleep disorders (minimum SpO2) with HRV parameters (LH/HF) in children and adolescents with CF. When pulmonary function was reduced, a stronger correlation was found, highlighting the influence of disease severity. A high prevalence of ANS disorders, nocturnal hypoxemia, and presence of OSAS was also found.

PMID:34495277 | DOI:10.1590/1984-0462/2022/40/2020295

Rev Paul Pediatr. 2021 Sep 1;40:e2020169. doi: 10.1590/1984-0462/2022/40/2020169. eCollection 2021.

ABSTRACT

OBJECTIVE: Dornase alfa (rhDNase) reduces the viscosity of purulent sputum in the lungs. The use in patients with cystic fibrosis (CF) is proven. However, the evidence of its applicability to other conditions is limited. This study aims to present the authors' experience with the use of rhDNase in non-CF patients admitted to the Pediatric Intensive Care Unit (PICU). At the study center, rhDNase was used during flexible bronchoscopies in 24 cases, of which 20 (83%) had atelectasis and seven (29%) were admitted to PICU. Four patients (57%) were on invasive mechanical ventilation (MV).

CASE DESCRIPTION: Two cases of daily rhDNase administration at PICU are presented: patient A was an 8-year-old boy admitted with septic shock and acute respiratory distress syndrome (ARDS). The patient required mechanical ventilation with aggressive settings and experienced several clinical complications. On D50, he started rhDNase treatment with an improvement in FiO2, PaCO2 and PaO2/FiO2 ratio according to radiologic findings. He was extubated on D23 of treatment.Patient B was a 17-month-old girl admitted with a convulsive status epilepticus who experienced respiratory complications (infectious and barotrauma) with ARDS, requiring aggressive ventilation. She initiated rhDNase treatment on D60. During the treatment an improvement in FiO2, PaO2/FiO2 ratio and a tendency of PaCO2 decrease were found. She had radiological improvement. No complications were described.

COMMENTS: RhDNase may be a helpful and safe tool to use in PICU prolonged intubated patients with ventilator-induced lung injury. Further studies are needed to assess and propose valid indications.

PMID:34495270 | DOI:10.1590/1984-0462/2022/40/2020169

Curr Opin Pulm Med. 2021 Sep 7. doi: 10.1097/MCP.0000000000000827. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Cystic fibrosis is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) encoding the CFTR protein, a chloride channel expressed in many epithelial cells. New drugs called CFTR modulators aim at restoring the CFTR protein function and they will benefit most of the patients with cystic fibrosis in the near future. However, more than 10% of CFTR mutations do not produce any CFTR protein for CFTR modulators to act upon, and the purpose of this review is to provide an overview of different approaches pursued to treat patients bearing mutations nonresponsive to CFTR modulators.

RECENT FINDINGS: These different approaches constitute readthrough agents for nonsense mutations, nucleic acid-based therapies, RNA-based or DNA-based, and cell-based therapies. Some approaches using mRNA or cDNA combined with a delivery vehicle are mutation-agnostic therapies. Other approaches, such as the use of tRNA, antisense oligonucleotides, gene editing or cell-based therapies are mutation-specific therapies.

SUMMARY: Most of these approaches are in preclinical development or for some of them, early clinical phases. Many hurdles and challenges will have to be solved before they can be safely translated to patients.

PMID:34494979 | DOI:10.1097/MCP.0000000000000827

Int J Mycobacteriol. 2021 Jul-Sep;10(3):344-345. doi: 10.4103/ijmy.ijmy_113_21.

NO ABSTRACT

PMID:34494580 | DOI:10.4103/ijmy.ijmy_113_21

Expert Opin Drug Saf. 2021 Sep 8. doi: 10.1080/14740338.2021.1978975. Online ahead of print.

ABSTRACT

BACKGROUND: The use of proton pump inhibitors (PPIs) has increased in the last ten years in children. Data regarding their safety profile are limited. The aim of this study was to analyze data from the Italian spontaneous reporting system (SRS) database to evaluate the incidence and characteristics of PPI-related adverse drug reactions (ADRs) in children.

RESEARCH DESIGN AND METHODS: This was an observational, retrospective study analyzing PPI-related ADR reports in children in the Italian SRS database between January 1st, 2001, and December 31st, 2020. ADRs were coded according to the system organ class term level. Factors associated with ADR seriousness were investigated.

RESULTS: Seventy spontaneous reports of ADRs related to PPIs were analyzed. Esomeprazole and lansoprazole caused the highest number of ADRs equally (27% respectively), and the most frequently reported ADRs presented with gastrointestinal (24%) and/or skin manifestations (21.3%). More than a half of PPI prescriptions were off label for pediatric population. Serious ADRs were 19 (27.1%). Serious ADRs were more frequent in reports presenting PPIs combined with other drugs in comparison to reports with PPI single therapies (p=0.03).

CONCLUSIONS: PPI-related ADRs in children are mostly not serious, and combination therapy seems to be associated with ADR seriousness.

PMID:34494498 | DOI:10.1080/14740338.2021.1978975

J Cyst Fibros. 2021 Sep 4:S1569-1993(21)01345-X. doi: 10.1016/j.jcf.2021.08.004. Online ahead of print.

ABSTRACT

Exercise is considered as an important component of the package of care delivered to people with cystic fibrosis (pwCF). However, despite the well-known short-term physiological and psychological benefits, training effects are heterogenous and the transfer of structured exercise programmes to the daily life of pwCF is challenging. Training concepts and strategies developed over the last decades must be adapted to consider the aging population of pwCF with associated comorbidities, and also a new generation of young pwCF that are healthier than ever. In the present review we propose a new framework for optimising the choice among available exercise training procedures and we provide a theoretical and scientifically justified rationale for considering and testing new exercise training modalities. We propose a multidisciplinary approach, considering various physiological, psychological and logistical factors, with the aim to increase effects of exercise training and build positive long-term exercise behaviour.

PMID:34493444 | DOI:10.1016/j.jcf.2021.08.004