Acta Chim Slov. 2020 Jun;67(2):666-673.

ABSTRACT

There are over 70.000 patients with cystic fibrosis (CF) in the world and numerous sequence variations in the CFTR gene have been reported but the clinical significance of all of them is still not known. There are currently 195 patients with the c.3140-26A>G (legacy name 3272-26A>G) variant in the CFTR gene listed in the European Cystic Fibrosis Society Patient Registry (ECFSPR) and only 4 are homozygous. We present longitudinal clinical data of one of these patients who is managed in our CF Center at the University Children's Hospital in Ljubljana and compare it with the patient data from the ECFSPR and the CFTR2 database in which additional 3 homozygous patients are described. Moreover, the effect of the detected variant in the described patient was evaluated on the RNA level in nasal epithelial cells. The variant was shown to result in aberrant splicing introducing a frameshift and a premature termination codon while normal transcript was not detected. Alternative spliced mutant transcripts in other tissues or the presence of spliceosome-mediated RNA trans-splicing could explain the mild clinical presentation of patients with this variant in homozygous state.

PMID:33855558

Endocrinol Diabetes Metab. 2020 Nov 30;4(2):e00208. doi: 10.1002/edm2.208. eCollection 2021 Apr.

ABSTRACT

BACKGROUND: Hyperglycaemia may contribute to failure to recover from pulmonary exacerbations in cystic fibrosis (CF). We aimed to evaluate the prevalence and mechanism of hyperglycaemia during and post-exacerbations.

METHODS: Nine paediatric CF patients, not on insulin, hospitalized for intravenous antibiotics, underwent an oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) upon admission (visit 1) and an OGTT 2 weeks (visit 2) and 6 weeks to 12 months later when at stable baseline (visit 3). Insulin and glucose levels were measured before, 30, 60 and 120 min after glucose ingestion during OGTT. Hyperglycaemia on OGTT was defined according to the American Diabetes Association criteria as abnormal OGTT or consistent with diabetes. Hyperglycaemia on CGM was defined as CGM time above 140 mg/dL > 4.5%.

RESULTS: At visit 1, 8/9 patients had hyperglycaemia on both CGM and OGTT (2 diabetes and 6 abnormal OGTT). At visit 2, 5/8 had hyperglycaemia (all abnormal OGTT). At visit 3, (median (IQR) time since visit 1, 4.9 (3.8-6.3) months), 5/7 had hyperglycaemia (2 diabetes and 3 abnormal OGTT). At visits 1, 2 and 3, respectively, mean (SD) 2-hour OGTT glucose was 175.8 (42.3), 146.3 (31.9) and 176.9 (51.7) mg/dL. CGM time above 140 mg/dL at visit 1 was 25.3% (16.9). Insulin AUC decreased from visit 2 (median (IQR) 5449 (3321-8123) mcIU-min/mL) to visit 3 (3234 (2913-3680) mcIU-min/mL).

CONCLUSION: Hyperglycaemia is prevalent during paediatric CF exacerbations; it appears to improve with exacerbation treatment but to worsen later in association with decreased insulin secretion.

PMID:33855211 | PMC:PMC8029509 | DOI:10.1002/edm2.208

Oman Med J. 2021 Mar 31;36(2):e243. doi: 10.5001/omj.2021.28. eCollection 2021 Mar.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that affects multisystems in the body, particularly the lungs and digestive system. We report a case of an Omani newborn who presented with meconium ileus and high suspicion of CF. Thus, full CFTR gene sequencing was performed, which revealed a homozygous unreported C.4242+1G>C novel gene mutation. Both parents were found to be heterozygous for this mutation. This case sheds light on the importance of the extensive genetic testing of typical CF cases in the absence of family history or during neonatal presentations, especially when the sweat test cannot be performed and the diagnosis can be challenging.

PMID:33854794 | PMC:PMC8019455 | DOI:10.5001/omj.2021.28

BMC Pulm Med. 2021 Apr 14;21(1):121. doi: 10.1186/s12890-021-01471-0.

ABSTRACT

BACKGROUND: People with cystic fibrosis (pwCF) derive several physiological and psychological benefits from regular physical activity (PA), but the practice is lower than recommended. Knowledge about the facilitators of and barriers to PA at the individual level is important to act positively on PA behaviors. This study validated the Cystic Fibrosis Decisional Balance for Physical Activity scale (CF-DB-PA) for adults with CF.

METHODS: French adults with CF were recruited in several specialist centres in France. The CF-DB-PA scale was validated following a quantitative study protocol comprising four stages: (1) tests of the clarity and relevance of a preliminary 44-item version and reduction analysis, (2) confirmatory factor analysis and tests of dimensionality through equation modelling analysis, (3) tests of reliability with Cronbach alphas for the internal consistency and a test-retest with a 2-to-3 week interval for temporal stability, and 4) tests of construct validity with Spearman correlations to measure the associations between each subscale and the theoretically related constructs (i.e., quality of life, PA and exercise tolerance).

RESULTS: A total of 201 French adults with CF participated in the validation study. The CF-DB-PA comprises 23 items divided into two factors: facilitators of and barriers to PA. Each factor is divided into three subscales: physical, psychological and environmental. The factors (facilitators and barriers) can be used independently or combined as a whole. A general score of decisional balance for PA can also be calculated. The bi-factor model presented satisfactory adjustment indexes: χ2 (194) = 362.33; p < .001; TLI = .87; CFI = .90; RMSEA = .067. The scale showed satisfactory internal consistency (Cronbach's α = .77). The test-retest reliability was not significant for either subscale, indicating stability over time. The facilitators subscale correlated significantly with the self-reported score of PA (r = .33, p < .01) and quality of life (r = .24, p < .05). The barriers subscale correlated significantly with the self-reported scores of PA (r = - .42, p > .01), quality of life (r = - .44, p < .01), exercise tolerance (r = - .34, p < .01) and spirometry tests (r = - .30, p < .05).

CONCLUSIONS: The CF-DB-PA is a reliable and valid questionnaire assessing the decisional balance for PA, the facilitators of and the barriers to PA for adults with CF in French-speaking samples.

PMID:33853554 | DOI:10.1186/s12890-021-01471-0

BMC Pediatr. 2021 Apr 14;21(1):174. doi: 10.1186/s12887-021-02636-w.

ABSTRACT

BACKGROUND: Childhood hypoglycemia in combination with hepatomegaly is suspicious for inborn errors of metabolism. Cystic fibrosis typically presents with failure to thrive, pulmonary and gastrointestinal symptoms. Hepatic involvement and hypoglycemia can occur in a significant number of patients, although hepatomegaly is uncommon.

CASE PRESENTATION: A 28 months old boy was presented with recurrent upper airways infections, progressive lethargy and weight loss. Clinically hepatomegaly was the main presenting feature and hypoglycemia (minimum 1.4 mmol/l) was noted as were elevated transaminases. The patient did not produce enough sweat to analyze it. Infectious causes for hepatitis were excluded and a broad metabolic work-up initiated. A therapy with starch was initiated to control hypoglycemia. In further course loose stools were reported and pancreatic elastase was found to be reduced. A further sweat test yielded pathological chloride concentration and genetic testing confirmed the diagnosis of cystic fibrosis.

CONCLUSIONS: Cystic fibrosis is a systemic disease and less common presentations need to be considered. Even in the age of CF-newborn screening in many countries CF needs to be ruled out in typical and atypical clinical presentations and diagnostics need to be repeated if inconclusive.

PMID:33853553 | DOI:10.1186/s12887-021-02636-w

Pediatr Pulmonol. 2021 Apr 14. doi: 10.1002/ppul.25399. Online ahead of print.

ABSTRACT

These "rules" are suggestions for clinicians who order chest computed tomography (CTs). The first three address CT scanning technique and the ordering details that we find cause the most confusion. The next three are on patient preparation, and specifically the use of sedation and anesthesia. Radiation risk is next, and we end with three, more philosophical, rules on how we can best work together as clinicians and imagers. This is not a complete or systematic review. You won't find detailed references (or any references for that matter), descriptions of the latest techniques, or lists of sample protocols. We hope that the reader will consult his or her imaging colleagues when more specific guidance is needed. The goal of this article is to provide simple answers to frequently asked questions and to address some of the concerns that arise when deciding how to perform a chest CT scan in a child. These are the opinions of the authors, two pediatric radiologists with special interest in chest imaging and 50 years combined experience in working with clinical colleagues to provide the best imaging care for their patients. We hope that sharing these thoughts will help to decrease confusion and increase understanding to the benefit of the children we serve.

PMID:33852774 | DOI:10.1002/ppul.25399

JMIR Hum Factors. 2021 Apr 14;8(2):e21270. doi: 10.2196/21270.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a life-limiting genetic disease that causes chronic lung infections. We developed an internet-based decision aid (DA) to help patients with CF make better informed decisions regarding treatments and advance care planning. We built the DA around two major treatment decisions: whether to have a lung transplant and whether to agree to invasive mechanical ventilation (intubation).

OBJECTIVE: This study aims to conduct usability testing of the InformedChoices CF DA among key stakeholder groups.

METHODS: We performed a patient needs assessment using think-aloud usability testing with patients with CF, their surrogates, and CF clinicians. Think-aloud participants provided feedback while navigating the DA, and after viewing, they answered surveys. Transcripts from the think-aloud sessions and survey results were categorized into common, generalizable themes and optimizations for improving content, comprehension, and navigation. We assessed the ease of use of the DA (System Usability Scale) and also assessed the participants' perceptions regarding the overall tone, with an emphasis on emotional reactions to the DA content, level of detail, and usefulness of the information for making decisions about either intubation or lung transplantation, including how well they understood the information and were able to apply it to their own decision-making process. We also assessed the DA's ease of navigation, esthetics, and whether participants were able to complete a series of usability tasks (eg, locating specific information in the DA or using the interactive survival estimates calculator) to ensure that the website was easy to navigate during the clinic-based advance care planning discussions.

RESULTS: A total of 12 participants from 3 sites were enrolled from March 9 to August 30, 2018, for the usability testing: 5 CF clinicians (mean age 48.2, SD 12.0 years), 5 adults with CF, and 2 family and surrogate caregivers of people with CF (mean age of CF adults and family and surrogate caregivers 38.8, SD 10.8 years). Among the 12 participants, the average System Usability Scale score for the DA was 88.33 (excellent). Think-aloud analysis identified 3 themes: functionality, visibility and navigation, and content and usefulness. Areas for improvement included reducing repetition, enhancing comprehension, and changing the flow. Several changes to improve the content and usefulness of the DA were recommended, including adding information about alternatives to childbearing, such as adoption and surrogacy. On the basis of survey responses, we found that the navigation of the site was easy for clinicians, patients, and surrogates who participated in usability testing.

CONCLUSIONS: Usability testing revealed areas of potential improvement. Testing also yielded positive feedback, suggesting the DA's future success. Integrating changes before implementation should improve the DA's comprehension, navigation, and usefulness and lead to greater adoption.

PMID:33851921 | DOI:10.2196/21270

Transl Androl Urol. 2021 Mar;10(3):1467-1478. doi: 10.21037/tau-19-681.

ABSTRACT

Obstructive azoospermia (OA) is a rare cause of male infertility, with Congenital Bilateral Absence of The Vas Deferens (CBAVD) being a major cause. A wealth of literature has established an irrefutable link between CFTR mutations and CBAVD, with CBAVD affecting almost all men with cystic fibrosis (CF) disease and a significant portion of men that are CFTR mutation carriers. In the past two decades, assisted reproductive technologies have made the prospect of fathering children a viable possibility in this subset of men, using a combination of sperm extraction techniques and intracystoplasmic sperm injection (ICSI). In order to assess techniques for sperm retrieval, as well as reproductive outcomes, a systemic search of the MEDLINE database was conducted for all articles pertaining to management options for CBAVD, and also all reports describing outcomes of these procedures in the CBAVD population. Both epididymal and testicular sperm extraction (TESE) are viable options for men with CBAVD, and though rigorous data are lacking, live birth rates range from 8% to 50% in most small retrospective series and subset analyses. In addition, there does not appear to be significant differences in the rate of live birth or complications and miscarriages between the various techniques, though further investigation into other factors that limit reproductive potential of men with CFTR mutations and CBAVD is warranted.

PMID:33850781 | PMC:PMC8039579 | DOI:10.21037/tau-19-681

Transl Androl Urol. 2021 Mar;10(3):1391-1400. doi: 10.21037/tau.2020.04.05.

ABSTRACT

Cystic fibrosis (CF) is a rare autosomal-recessive disorder manifested as multisystem organ dysfunction. The cystic fibrosis transmembrane conductance regulator (CFTR) protein functions as an ion transporter on the epithelium of exocrine glands, regulating secretion viscosity. The CFTR gene, encoded on chromosome 7, is required for the production and trafficking of the intact and functional CFTR protein. Literally thousands of human CFTR allelic mutations have been identified, each with varying impact on protein quality and quantity. As a result, individuals harboring CFTR mutations present with a spectrum of symptoms ranging from CF to normal phenotypes. Those with loss of function but without full CF may present with CFTR-related disorders (CFTR-RDs) including male infertility, sinusitis, pancreatitis, atypical asthma and bronchitis. Studies have demonstrated associations between higher rates of CFTR mutations and oligospermia, epididymal obstruction, congenital bilateral absence of the vas deferens (CBAVD), and idiopathic ejaculatory duct obstruction (EDO). Genetic variants are detected in over three-quarters of men with CBAVD, the reproductive abnormality most classically associated with CFTR aberrations. Likewise, nearly all men with clinical CF will have CBAVD. Current guidelines from multiple groups recommend CFTR screening in all men with clinical CF or CBAVD though a consensus on the minimum number of variants for which to test is lacking. CFTR testing is not recommended as routine screening for men with other categories of infertility. While available CFTR panels include 30 to 96 of the most common variants, complete gene sequencing should be considered if there is a high index of suspicion in a high-risk couple (e.g., partner is CFTR mutation carrier). CF treatments to date have largely targeted end-organ complications. Novel CFTR-modulator treatments aim to directly target CFTR protein dysfunction, effectively circumventing downstream complications, and possibly preventing symptoms like vasal atresia at a young age. Future gene therapies may also hold promise in preventing or reversing genetic changes that lead to CF and CFTR-RD.

PMID:33850775 | PMC:PMC8039587 | DOI:10.21037/tau.2020.04.05

Exp Ther Med. 2021 Jun;21(6):585. doi: 10.3892/etm.2021.10017. Epub 2021 Apr 2.

ABSTRACT

In the physiopathology of cystic fibrosis (CF), oxidative stress implications are recognized and widely accepted. The cystic fibrosis transmembrane conductance regulator (CFTR) defects disrupt the intracellular redox balance causing CF pathological hallmarks. Therefore, oxidative stress together with aberrant expression levels of detoxification genes and microRNAs (miRNAs/miRs) may be associated with clinical outcome. Using total RNA extracted from epithelial nasal cells, the present study analyzed the expression levels of oxidative stress genes and one miRNA using quantitative PCR in a representative number of patients with CF compared with in healthy individuals. The present pilot study revealed the existence of an association among CFTR, genes involved in the oxidative stress response and miR-125b. The observed downregulation of CFTR gene expression was accompanied by increased expression levels of Nuclear factor erythroid derived-2 like2 and its targets NAD(P)H:Quinone Oxidoreductase and glutathione S-transferase 1. Moreover, the expression levels of heme oxygenase-1 (HO-1) and miR-125b were positively correlated with a forced expiratory volume in 1 sec (FEV1) >60% in patients with CF with chronic Pseudomonas aeruginosa lung infection (r=0.74; P<0.001 and r=0.57; P<0.001, respectively). The present study revealed the activation of an inducible, but not fully functional, oxidative stress response to protect airway cells against reactive oxygen species-dependent injury in CF disease. Additionally, the correlations of HO-1 and miR-125b expression with an improved FEV1 value suggested that these factors may synergistically protect the airway cells from oxidative stress damage, inflammation and apoptosis. Furthermore, HO-1 and miR-125b may be used as prognostic markers explaining the wide CF phenotypic variability as an additional control level over the CFTR gene mutations.

PMID:33850557 | PMC:PMC8027740 | DOI:10.3892/etm.2021.10017

Respir Res. 2021 Apr 13;22(1):106. doi: 10.1186/s12931-021-01697-w.

ABSTRACT

BACKGROUND: Cystic fibrosis is a debilitating, autosomal recessive disease which results in chronic upper and lower airway infection and inflammation. In this study, four adult patients presenting with cystic fibrosis and chronic rhinosinusitis were recruited. Culture and molecular techniques were employed to evaluate changes in microbial profiles, host gene expression and antimicrobial resistance (AMR) in the upper respiratory tract over time.

METHODS: Swab samples from the sinonasal cavity were collected at the time of surgery and at follow-up clinics at regular time intervals for up to 18 months. Nucleic acids were extracted, and DNA amplicon sequencing was applied to describe bacterial and fungal composition. In parallel, RNA was used to evaluate the expression of 17 AMR genes and two inflammatory markers (interleukins 6 and 8) using custom qPCR array cards. Molecular results were compared with routine sinus and sputum culture reports within each patient.

RESULTS: Bacterial amplicon sequencing and swab culture reports from the sinonasal cavity were mostly congruent and relatively stable for each patient across time. The predominant species detected in patients P02 and P04 were Pseudomonas aeruginosa, Staphylococcus aureus in patient P03, and a mixture of Enterobacter and S. aureus in patient P01. Fungal profiles were variable and less subject specific than bacterial communities. Increased expressions of interleukins 6 and 8 were observed in all patients throughout the sampling period compared with other measured genes. The most prevalent AMR gene detected was ampC. However, the prevalence of AMR gene expression was low in all patient samples across varying time-points.

CONCLUSIONS: We observed a surprising degree of stability of sinonasal microbial composition, and inflammatory and AMR gene expression across all patients post sinus surgery.

PMID:33849523 | DOI:10.1186/s12931-021-01697-w

Eur J Pharmacol. 2021 Apr 10:174098. doi: 10.1016/j.ejphar.2021.174098. Online ahead of print.

ABSTRACT

Current cystic fibrosis (CF) treatment strategies are primarily focused on oral/inhaled anti-inflammatories and antibiotics, resulting in a considerable treatment burden for CF patients. Therefore, combination treatments consisting of anti-inflammatories with antibiotics could reduce the CF treatment burden. However, there is an imperative need to understand the potential drug-drug interactions of these combination treatments to determine their efficacy. Thus, this study aimed to determine the interactions of the anti-inflammatory agent Ibuprofen with each of the CF-approved inhaled antibiotics (Tobramycin, Colistin and its prodrug colistimethate sodium/Tadim) and anti-bacterial and anti-inflammatory efficacy. Chemical interactions of the Ibuprofen:antibiotic combinations were elucidated using High-Resolution Mass-Spectrometry (HRMS) and 1H NMR. HRMS showed pairing of Ibuprofen and Tobramycin, further confirmed by 1H NMR whilst no pairing was observed for either Ibuprofen:Colistin or Ibuprofen:Tadim combinations. The anti-bacterial activity of the combinations against Pseudomonas aeruginosa showed that neither paired nor non-paired Ibuprofen:antibiotic therapies altered the anti-bacterial activity. The anti-inflammatory efficacy of the combination therapies was next determined at two different concentrations (Low and High) using in vitro models of NuLi-1 (healthy) and CuFi-1 (CF) cell lines. Differential response in the anti-inflammatory efficacy of Ibuprofen:Tobramycin combination was observed between the two concentrations due to changes in the structural conformation of the paired Ibuprofen:Tobramycin complex at High concentration, confirmed by 1H NMR. In contrast, the non-pairing of the Ibuprofen:Colistin and Ibuprofen:Tadim combinations showed a significant decrease in IL-8 secretion at both the concentrations. Importantly, all antibiotics alone showed anti-inflammatory properties, highlighting the inherent anti-inflammatory properties of these antibiotics.

PMID:33848541 | DOI:10.1016/j.ejphar.2021.174098

Am J Respir Cell Mol Biol. 2021 Apr 13. doi: 10.1165/rcmb.2020-0257OC. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is characterized by chronic airway infection, inflammation, and tissue damage that lead to progressive respiratory failure. NLRP3 and NLRC4 are cytoplasmic pattern recognition receptors that activate the inflammasome, initiating a caspase-1 mediated response. We hypothesized that gain of function inflammasome responses are associated with worse outcomes in children with CF. We genotyped nonsynonymous variants in NLRP3 and the NLRC4 pathway from individuals in the Early Pseudomonas Infection Control (EPIC) Observational Study cohort and tested for association with CF outcomes. We generated knockouts of NLRP3 and NLRC4 in human macrophage-like cells and rescued knockouts with wild-type or variant forms of NLRP3 and NLRC4. We identified a SNP in NLRP3, p.(Q705K), that was associated with a higher rate of Pseudomonas aeruginosa colonization (N=609, p=0.01, HR=2.3, Cox model) and worsened lung function over time as measured by forced expiratory volume in 1 second (FEV1) (N=445, p=0.001, generalized estimating equation). We identified a SNP in NLRC4, p.(A929S), that was associated with a lower rate of P. aeruginosa colonization as part of a composite of rare variants (N=405, p=0.045, HR=0.68, Cox model) and that was individually associated with protection from lung function decline (p<0.001, generalized estimating equation). Rescue of the NLRP3 knockout with the p.(Q705K) variant produced significantly more IL-1β in response to NLRP3 stimulation than rescue with the wild-type (p=0.020, Student's t-test). We identified a subset of children with CF at higher risk of early lung disease progression. Knowledge of these genetic modifiers could guide therapies targeting inflammasome pathways.

PMID:33848452 | DOI:10.1165/rcmb.2020-0257OC

Int J Clin Pract. 2021 Apr 13:e14220. doi: 10.1111/ijcp.14220. Online ahead of print.

ABSTRACT

BACKGROUND: During Coronavirus Disease 2019 (COVID-19) outbreak in Lombardia, people were recommended to avoid visiting emergency departments and attending routine clinic visits. In this context it was necessary to understand the psychological reactions of patients with chronic diseases. We evaluated the psychological effects on patients with chronic respiratory conditions and inflammatory bowel disease (IBD) through the analysis of their spontaneous contacts with their referral centers.

METHODS: Cross-sectional study conducted from February 23 to April 27, 2020 in patients, or their parents, who contacted their multidisciplinary teams (MDT). E-mails and phone calls directed to the MDT of the center for cystic fibrosis in Milano and for pediatric IBD in Bergamo, were categorized according to their contents as information on routine disease-management, updates on the patient's health status, COVID-19 news monitoring, empathy towards health professionals, positive feedback and concern of contagion during the emergency.

RESULTS: 1816 contacts were collected during the study period. In Milano, where the majority of patients were affected by CF, 88.7% contacted health professionals by e-mail, with pediatricians receiving the largest volume of emails and phone calls compared to other professionals (P<.001). Compared to Milano, the center for IBD in Bergamo recorded more expression of empathy towards health professionals and thanks for their activity in the COVID-19 emergency (52.4% versus 12.7%, P<.001), as well as positive feedback (64.3% versus 2.7%, P=.003).

CONCLUSION: One of the most important lessons we can learn from COVID-19 is that it is not the trauma itself that can cause psychological consequences but rather the level of balance, or imbalance, between fragility and resources. To feel safe, people need to be able to count on the help of those who represent a bulwark against the threat. This is the role played, even remotely, by health professionals.

PMID:33848388 | DOI:10.1111/ijcp.14220

J Nat Prod. 2021 Apr 13. doi: 10.1021/acs.jnatprod.0c01151. Online ahead of print.

ABSTRACT

The eradication of recurrent Pseudomonas aeruginosa (PA) lung infection in cystic fibrosis (CF) patients may be hampered by the development of persistent bacterial forms, which can tolerate antibiotics through efflux pump overexpression. After demonstrating the efflux pump inhibitory effect of the alkaloid berberine on the PA MexXY-OprM efflux pump, in this study, we tested its ability (80/320 μg/mL) to enhance tobramycin (20xMIC/1000xMIC) activity against PA planktonic/biofilm cultures. Preliminary investigations of the involvement of MexY in PA tolerance to tobramycin treatment, performed on the isogenic pair PA K767 (wild type)/K1525 (ΔmexY) growing in planktonic and biofilm cultures, demonstrated that the ΔmexY mutant K1525 produced a lower (100 and 10 000 times, respectively) amount of tolerant cells than that of the wild type. Next, we grew broth cultures of PAO1, PA14, and 20 PA clinical isolates (of which 13 were from CF patients) in the presence of 20xMIC tobramycin with and without berberine 80 μg/mL. Accordingly, most strains showed a greater (from 10- to 1000-fold) tolerance reduction in the presence of berberine. These findings highlight the involvement of the MexXY-OprM system in the tobramycin tolerance of PA and suggest that berberine may be used in new valuable therapeutic combinations to counteract persister survival.

PMID:33848161 | DOI:10.1021/acs.jnatprod.0c01151

Pediatr Pulmonol. 2021 Apr 13. doi: 10.1002/ppul.25421. Online ahead of print.

ABSTRACT

BACKGROUND: Collection of respiratory cultures for airway microbiology surveillance is an essential component of routine clinical care in cystic fibrosis (CF). The COVID-19 global pandemic has necessitated increased use of telehealth, but one limitation of telehealth is the inability to collect respiratory specimens. We initiated a protocol for at-home collection of oropharyngeal (OP) swabs from children with CF.

METHODS: Home respiratory specimen collection was offered during telehealth encounters. Home OP swab kits were sent to participating families via mail with instructions for collection and return. Specimens were returned by overnight shipping or dropped off at a hospital lab for processing and culture. We evaluated demographic data and compared culture results from the home-collected specimen to the most recent specimen collected in clinic. We also tracked the frequency of newly identified Pseudomonas aeruginosa.

RESULTS: Home OP swab kits were sent to families of 33 children with CF (range 1.5-19 yrs). OP swab kits were successfully returned from 19 children (range 1.5-19 yrs). One or more CF pathogens grew from 79% of the specimens. For 4 individuals, the home collected specimen demonstrated new growth of P. aeruginosa.

CONCLUSIONS: Home collection of OP swabs for bacterial culture is feasible in children with CF across a range of ages. Most home-collected specimens demonstrated growth of one or more CF pathogens and results were similar to recent in-clinic specimens, suggesting acceptable sample collection technique. Anti-pseudomonal therapy was initiated for 4 children based on growth of P. aeruginosa from the home respiratory specimen. This article is protected by copyright. All rights reserved.

PMID:33847465 | DOI:10.1002/ppul.25421

Indian J Tuberc. 2021 Apr;68(2):261-265. doi: 10.1016/j.ijtb.2020.09.010. Epub 2020 Sep 16.

ABSTRACT

BACKGROUND: Bronchiectasis severity Index (BSI) score which predicts the severity of the disease along with future exacerbations and mortality rate has been well validated in European patients; however there is paucity of data evaluating its validity in Indian patients. The authors therefore decided to evaluate the utility of BSI to predict exacerbations and mortality rate in patients with post tubercular bronchiectasis presenting to our facility.

METHODS: The study was a retrospective observational study done in patients with bronchiectasis secondary to tuberculosis. These patients were followed up for 4 years. BSI was calculated from different variables and descriptive statistics along with regression analysis were used to evaluate utility of BSI.

RESULTS: A total of 48 patients of post tubercular bronchiectasis were included in the study. Majority of our patients belonged to severe bronchiectasis group seen in 23 patients (48%) while those with mild and moderate bronchiectasis were seen in 13 (27%) and 12 (25%) patients respectively. The exacerbation rate in mild group was comparable to the predicted BSI exacerbation at 1 year while the predicted and observed rates were statistically significant for moderate and severe bronchiectasis group (p value < 0.05). Mortality rates at 1 year were comparable in all the groups of bronchiectasis while it was comparable only in mild and moderate group bronchiectasis at 4 years.

CONCLUSION: Bronchiectasis severity index seems to predict mortality at 1 year in post tuberculosis bronchiectasis. However, it under predicts 1 year and 4 year exacerbation rates. Hence BSI may not be useful as a prognostic tool in Indian patients with bronchiectasis. Larger multi-centred studies may be required to further evaluate the clinical utility of BSI among Indian population.

PMID:33845962 | DOI:10.1016/j.ijtb.2020.09.010

Int J Biochem Cell Biol. 2021 Apr 9:105976. doi: 10.1016/j.biocel.2021.105976. Online ahead of print.

ABSTRACT

The impairment of the CFTR channel activity, a cAMP-activated chloride (Cl-) channel responsible for cystic fibrosis (CF), has been associated with a variety of mitochondrial alterations such as modified gene expression, impairment in oxidative phosphorylation, increased reactive oxygen species (ROS), and a disbalance in calcium homeostasis. The mechanisms by which these processes occur in CF are not fully understood. Previously, we demonstrated a reduced MTND4 expression and a failure in the mitochondrial complex I (mCx-I) activity in CF cells. Here we hypothesized that the activity of CFTR might modulate the mitochondrial fission/fusion balance, explaining the decreased mCx-I. The mitochondrial morphology and the levels of mitochondrial dynamic proteins MFN1 and DRP1 were analysed in IB3-1 CF cells, and S9 (IB3-1 expressing wt-CFTR), and C38 (IB3-1 expressing a truncated functional CFTR) cells. The mitochondrial morphology of IB3-1 cells compared to S9 and C38 cells showed that the impaired CFTR activity induced a fragmented mitochondrial network with increased rounded mitochondria and shorter branches. Similar results were obtained by using the CFTR pharmacological inhibitors CFTR(inh)-172 and GlyH101 on C38 cells. These morphological changes were accompanied by modifications in the levels of the mitochondrial dynamic proteins MFN1, DRP1, and p(616)-DRP1. IB3-1 CF cells treated with Mdivi-1, an inhibitor of the mitochondrial fission, restored the mCx-I activity to values similar to those seen in S9 and C38 cells. These results suggest that the mitochondrial fission/fusion balance is regulated by the CFTR activity and might be a potential target to treat the impaired mCx-I activity in CF.

PMID:33845203 | DOI:10.1016/j.biocel.2021.105976

Expert Rev Respir Med. 2021 Apr 12:1-12. doi: 10.1080/17476348.2021.1908131. Online ahead of print.

ABSTRACT

Introduction: In the early stages, lung involvement in cystic fibrosis (CF) can be silent, with disease progression occurring in the absence of clinical symptoms. Irreversible airway damage is present in the early stages of disease; however, reliable biomarkers of early damage due to inflammation and infection that are universally applicable in day-to-day patient management have yet to be identified.Areas covered: At present, the main methods of detecting and monitoring early lung disease in CF are the lung clearance index (LCI), computed tomography (CT), and magnetic resonance imaging (MRI). LCI can be used to detect patients who may require more intense monitoring, identify exacerbations, and monitor responses to new interventions. High-resolution CT detects structural alterations in the lungs of CF patients with the best resolution of current imaging techniques. MRI is a radiation-free imaging alternative that provides both morphological and functional information. The role of MRI for short-term follow-up and pulmonary exacerbations is currently being investigated.Expert opinion: The roles of LCI and MRI are expected to expand considerably over the next few years. Meanwhile, closer collaboration between pulmonology and radiology specialties is an important goal toward improving care and optimizing outcomes in young patients with CF.

PMID:33843417 | DOI:10.1080/17476348.2021.1908131

Hum Reprod. 2021 Apr 11:deab067. doi: 10.1093/humrep/deab067. Online ahead of print.

ABSTRACT

STUDY QUESTION: What are the sperm and egg donor rejection rates after expanded carrier screening (ECS)?

SUMMARY ANSWER: Using an ECS panel looking at 46/47 genes, 17.6% of donors were rejected.

WHAT IS KNOWN ALREADY: The use of ECS is becoming commonplace in assisted reproductive technology, including testing of egg and sperm donors. Most national guidelines recommend rejection of donors if they are carriers of a genetic disease. If the use of ECS increases, there will be a decline in the number of donors available.

STUDY DESIGN, SIZE, DURATION: A review of the current preconception ECS panels available to donors was carried out through an online search. The genetic testing results of donors from Cryos International were analysed to determine how many were rejected on the basis of the ECS.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on gamete donors and their carrier status was provided by Cryos International, who screen donors using their own bespoke ECS panel. The ECS panels identified through the review were compared to the Cryos International panel and data.

MAIN RESULTS AND THE ROLE OF CHANCE: A total of 16 companies and 42 associated ECS panels were reviewed. There were a total of 2673 unique disorders covered by the panels examined, with a mean of 329 disorders screened. None of these disorders were common to all panels. Cryos International screen 46 disorders in males and 47 in females. From 883 candidate donors, 17.6% (155/883) were rejected based on their ECS result. Carriers of alpha-thalassaemia represented the largest proportion of those rejected (19.4%, 30/155), then spinal muscular atrophy (15.5%, 24/155) and cystic fibrosis (14.8%, 23/155).

LIMITATIONS, REASONS FOR CAUTION: Panel information was found on company websites and may not have been accurate.

WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the need for consistent EU regulations and guidelines that allow genetic matching of gamete donors to their recipients, preventing the need to reject donors who are known carriers. A larger ECS panel would be most beneficial; however, this would not be viable without matching of donors and recipients.

STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained. J.C.H. is the founder of Global Women Connected, a platform to discuss women's health issues and the Embryology and PGD Academy, who deliver education in clinical embryology. She has been paid to give a lecture by Cryos in 2019. A-B.S. is an employee of Cryos International.

TRIAL REGISTRATION NUMBER: N/A.

PMID:33842976 | DOI:10.1093/humrep/deab067