Why Airway Gland Secretions Are Abnormally Sticky in Cystic Fibrosis, and Why Not Much Can Be Done About It.

Dev Cell. 2020 Aug 24;54(4):427-428

Authors: Widdicombe JH

Abstract
In this issue of Developmental Cell, Xie et al. show that in cystic fibrosis, airway gland mucus gels form under conditions of high acidity and protein concentration. This causes them to be unusually stiff. This abnormal rheology cannot be corrected by changing pH or calcium levels in the bathing medium.

PMID: 32841592 [PubMed - as supplied by publisher]

Physical exercise as a tool to minimize the consequences of the Covid-19 quarantine: an overview for cystic fibrosis.

Pediatr Pulmonol. 2020 Aug 25;:

Authors: Fernandez-Del-Valle M, Donadio MVF, Pérez-Ruiz M

Abstract
Coronavirus (SARS-CoV-2) outbreak leading to the coronavirus disease (Covid-19) has become a global pandemic. Patients with Cystic Fibrosis (CF) are considered of major risk, as respiratory tract infections are more severe than in the general population, with a higher risk of complications and a negative impact on lung function. The performance of physical exercise is considered as key for its well-known general benefits and also as a complementary method to help airway clearance. Therefore, physical exercise is also considered as key in the therapeutic strategy during the quarantine period. However, the impossibility to perform exercise with appropriate prescription and monitoring is of considerable worry to health care professionals. Thus, alternative strategies, such as online measures to monitor this therapy and, consequently, to achieve a safe and effective dose is highly needed. Exercise regimens should include strength and endurance, as well as balance and flexibility exercises. Patients are highly encouraged to participate in exercise programs to maintain fitness and exercise should be continued during the quarantine period. This commentary provides a summary of the main effects and benefits of physical exercise, as well as the main recommendations for its adequate execution, including exercise modality, frequency, intensity and volume. This article is protected by copyright. All rights reserved.

PMID: 32841519 [PubMed - as supplied by publisher]

The psychosocial burden of inflammatory bowel disease in adolescents and young adults.

Intern Med J. 2020 Aug 25;:

Authors: Halloran J, McDermott B, Ewais T, Begun J, Karatela S, D'Emden H, Corias C, Denny S

Abstract
BACKGROUND AND AIM: This study examined the psychosocial burden of inflammatory bowel disease (IBD) in young people aged 15-25 years attending a tertiary specialist health centre for adolescents and young adults in Brisbane.
METHODS: Young people with IBD provided demographic information and psychosocial data via a cross-sectional self-report survey. Psychosocial data included the Kessler Psychological Distress Scale (K-10), Perceived Stress Scale (PSS-10), Brief Illness Perception Questionnaire (Brief IPQ), World Health Organisation Wellbeing Index (WHO-5), Pediatric Quality of Life Inventory (PedsQL), Short Quality of Life Questionnaire for IBD (SIBDQ), Multidimensional Scale of Perceived Social Support (MSPSS), Connor Davidson Resilience Scale 2 (CD-RISC2), and the Multidimensional Health Locus of Control Scale (MHLC).
RESULTS: Surveys were collected from 51 young people with IBD and compared with surveys from 210 young people with juvenile rheumatic disease (n=31), phenylketonuria (n=21), cystic fibrosis (n=33), renal transplants (n=14), and craniomaxillofacial conditions (n=111). On the psychosocial domains, 41% of young people with IBD had poor wellbeing and 37% were at risk of depression. When assessed against the comparison group, young people with IBD reported higher depressive symptoms (p=0.04), worse illness perceptions (p<0.01), and lower internal locus of control (p<0.01).
CONCLUSION: Early recognition and treatment of depression and other psychosocial comorbidities within integrated pathways of care is crucial in adolescents and young adults with IBD and likely to improve the course of IBD and their overall health and wellbeing. Interventions aimed at enhancing self-efficacy and increasing public awareness are also likely to be helpful. This article is protected by copyright. All rights reserved.

PMID: 32840949 [PubMed - as supplied by publisher]

How good is end of life care for patients dying with cystic fibrosis?

BMJ Support Palliat Care. 2020 Aug 24;:

Authors: Miller M, Lee R, Yates S, Billett HC, Bourke S, Flight WG, Quibell R

Abstract
BACKGROUND: Cystic Fibrosis (CF) is a life-limiting illness. Audit of the care of patients dying of CF has not been published to date.
METHODS: Newcastle and Oxford teams adapted the National Audit of Care at the End of Life and agreed additional questions that were particularly pertinent for patients dying as a consequence of their CF. Data were extracted and analysed for 15 patients.
RESULTS: On recognition that the patient was dying, the CF teams were less good at reviewing the need for physiological observations (50% vs national 70%) but better at reviewing the need for capillary blood glucose monitoring, oxygen support and intravenous antibiotics compared with the national average for all patients.On recognition that the patient was dying, the CF teams were better at assessing pain (87% vs national 80%) and breathlessness (93% vs national 73%), but less good at assessing nausea and vomiting (47% vs national 74%).There was documented evidence that 100% of families and 64% of patients were aware that the patient was at risk of dying.
CONCLUSION: Comparing care of this sample of patients dying with CF against the national data is a useful first step in understanding that many aspects of care are of high quality. This audit identifies the need to offer earlier conversations to patients as their voices may be missing from the conversation. Undertaking a national audit would provide a more reliable and a fuller picture.

PMID: 32839209 [PubMed - as supplied by publisher]

Dornase alfa and rate of lung function decline in European patients with cystic fibrosis: A retrospective registry cohort study.

J Cyst Fibros. 2020 Aug 21;:

Authors: McKone EF, Jackson AD, Fletcher G, Kirwan L

PMID: 32839093 [PubMed - as supplied by publisher]

Naturally Derived Membrane Lipids Impact Nanoparticle-Based Messenger RNA Delivery.

Cell Mol Bioeng. 2020 May 26;:1-12

Authors: Kim J, Jozic A, Sahay G

Abstract
Introduction: Lipid based nanoparticles (LNPs) are clinically successful vectors for hepatic delivery of nucleic acids. These systems are being developed for non-hepatic delivery of mRNA for the treatment of diseases like cystic fibrosis or retinal degeneration as well as infectious diseases. Localized delivery to the lungs requires aerosolization. We hypothesized that structural lipids within LNPs would provide features of integrity which can be tuned for attributes required for efficient hepatic and non-hepatic gene delivery. Herein, we explored whether naturally occurring lipids that originate from the cell membrane of plants and microorganisms enhance mRNA-based gene transfection in vitro and in vivo and whether they assist in maintaining mRNA activity after nebulization.
Methods: We substituted DSPC, a structural lipid used in a conventional LNP formulation, to a series of naturally occurring membrane lipids. We measured the effect of these membrane lipids on size, encapsulation efficiency and their impact on transfection efficiency. We further characterized LNPs after nebulization and measured whether they retained their transfection efficiency.
Results: One plant-derived structural lipid, DGTS, led to a significant improvement in liver transfection of mRNA. DGTS LNPs had similar transfection ability when administered in the nasal cavity to conventional LNPs. In contrast, we found that DGTS LNPs had reduced transfection efficiency in cells pre-and post-nebulization while maintaining size and encapsulation similar to DSPC LNPs.
Conclusions: We found that structural lipids provide differential mRNA-based activities in vitro and in vivo which also depend on the mode of administration. Understanding influence of structural lipids on nanoparticle morphology and structure can lead to engineering potent materials for mRNA-based gene therapy applications.

PMID: 32837581 [PubMed - as supplied by publisher]

Cortisol regulates insulin-like growth-factor binding protein (igfbp) gene expression in Atlantic salmon parr.

Mol Cell Endocrinol. 2020 Aug 21;:110989

Authors: Breves JP, Springer-Miller RH, Chenoweth DA, Paskavitz AL, Chang AYH, Regish AM, Einarsdottir IE, Björnsson BT, McCormick SD

Abstract
The growth hormone (Gh)/insulin-like growth-factor (Igf)/Igf binding protein (Igfbp) system regulates growth and osmoregulation in salmonid fishes, but how this system interacts with other endocrine systems is largely unknown. Given the well-documented consequences of mounting a glucocorticoid stress response on growth, we hypothesized that cortisol inhibits anabolic processes by modulating the expression of hepatic igfbp mRNAs. Atlantic salmon (Salmo salar) parr were implanted intraperitoneally with cortisol implants (0, 10, and 40 μg g-1 body weight) and sampled after 3 or 14 days. Cortisol elicited a dose-dependent reduction in specific growth rate (SGR) after 14 days. While plasma Gh and Igf1 levels were unchanged, hepatic igf1 mRNA was diminished and hepatic igfbp1b1 and -1b2 were stimulated by the high cortisol dose. Plasma Igf1 was positively correlated with SGR at 14 days. Hepatic gh receptor (ghr), igfbp1a, -2a, -2b1, and -2b2 levels were not impacted by cortisol. Muscle igf2, but not igf1 or ghr, levels were stimulated at 3 days by the high cortisol dose. As both cortisol and the Gh/Igf axis promote seawater (SW) tolerance, and particular igfbps respond to SW exposure, we also assessed whether cortisol coordinates the expression of branchial igfbps and genes associated with ion transport. Cortisol stimulated branchial igfbp5b2 levels in parallel with Na+/K+-ATPase (NKA) activity and nka-α1b, Na+/K+/2Cl--cotransporter 1 (nkcc1), and cystic fibrosis transmembrane regulator 1 (cftr1) mRNA levels. The collective results indicate that cortisol modulates the growth of juvenile salmon via the regulation of hepatic igfbp1s whereas no clear links between cortisol and branchial igfbps previously shown to be salinity-responsive could be established.

PMID: 32835784 [PubMed - as supplied by publisher]

Rescue of respiratory failure in pulmonary alveolar proteinosis due to pathogenic MARS1 variants.

Pediatr Pulmonol. 2020 Aug 24;:

Authors: Lenz D, Stahl M, Seidl E, Schöndorf D, Brennenstuhl H, Gesenhues F, Heinzmann T, Longerich T, Mendes MI, Prokisch H, Salomons GS, Schön C, Smith DEC, Sommerburg O, Wagner M, Westhoff JH, Reiter K, Staufner C, Griese M

Abstract
BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a heterogeneous condition with more than 100 different underlying disorders that need to be differentiated to target therapeutic options, which are generally limited.
METHODS: The clinical course of two brothers with pathogenic variants in the methionyl-tRNA synthetase (MARS)1 gene was compared to previously published patients, functional studies in patient-derived fibroblasts were performed, and therapeutic options evaluated.
RESULTS: The younger brother was diagnosed with PAP at the age of one year. Exome sequencing revealed the homozygous MARS1 variant p.(Arg598Cys), leading to interstitial lung and liver disease (ILLD). At two years of age, following surgery hypoglycemia was detected, the pulmonary condition deteriorated, and the patient developed multiorgan failure. Six therapeutic whole lung lavages (WLL) were necessary to improve respiratory insufficiency. Methionine supplementation was started and a high protein diet ensured, leading to complete respiratory recovery. The older brother, homozygous for the same MARS1 variant, had a long-known distinct eating preference of methionine-rich food and showed a less severe clinical phenotype. Decreased aminoacylation activity confirmed the pathogenicity of p.(Arg598Cys) in vitro. In agreement with our review of currently published ILLD patients, the presence of hepatopathy, developmental delay, muscular hypotonia, and anemia support the multisystemic character of the disease.
CONCLUSIONS: Catabolic events can provoke severe deterioration of the pulmonary situation in ILLD with a need for repetitive WLL. Although the precise role of oral methionine supplementation and high protein intake are unknown, we observed an apparent treatment benefit, which needs to be evaluated systematically in controlled trials. This article is protected by copyright. All rights reserved.

PMID: 32833345 [PubMed - as supplied by publisher]

Physical activity in children and adolescents with cystic fibrosis: a systematic review and meta-analysis.

Pediatr Pulmonol. 2020 Aug 24;:

Authors: Puppo H, Torres-Castro R, Vasconcello-Castillo L, Acosta-Dighero R, Sepúlveda-Cáceres N, Quiroga-Marabolí P, Romero JE, Vilaró J

Abstract
BACKGROUND: Exercise and physical activity (PA) are essential components of the care of cystic fibrosis (CF) patients. Lower PA levels have been associated with worse pulmonary function, aerobic fitness, glycemic control, and bone mineral density. Most people with CF do not engage in the recommended amounts of PA.
OBJECTIVE: To determine the level of PA in children and adolescents with CF.
METHODS: A systematic review with meta-analysis was conducted without language restrictions in five databases. Were included studies that analyzed PA measured by objective and subjective instruments in children and adolescents with CF. Two independent reviewers analyzed the studies, extracted the data, and assessed the quality of evidence. The risk of bias of the included studies was assessed with the National Heart, Lung, and Blood Institute's risk-of-bias tool.
RESULTS: Of the 1,535 reports returned by the initial search, 20 articles reporting on 785 patients were included in the data synthesis. The forest plot showed that the CF group had a similar moderate-to-vigorous PA (MVPA) (mean difference -7.79, 95%CI -15.65 to 0.08 min/day; p = 0.05) and sedentary time (mean difference -50.81, 95%CI -109.96 to 8.35 min/day; p = 0.09) to the control group.
CONCLUSION: Children and adolescents with CF have a similar MVPA and sedentary time compared to controls. There are many options, subjective and objective, for assessing PA in this population. Optimal tool selection should guarantee more valid results. This article is protected by copyright. All rights reserved.

PMID: 32833341 [PubMed - as supplied by publisher]

Cystic Fibrosis Year in Review 2019: Section 1 CFTR Modulators.

Pediatr Pulmonol. 2020 Aug 24;:

Authors: Savant AP, McColley SA

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

PMID: 32833326 [PubMed - as supplied by publisher]

Viral vector manufacturing: quality attributes of rAAV used in clinical development.

J Biomol Tech. 2020 Aug;31(Suppl):S43

Authors: Alcudia J, Wright JF

Abstract
Recombinant Adeno-Associated Virus (rAAV) are widely used for human gene therapy, now the basis for two licensed products (for RPE65-/-, and SMA) and numerous other investigational treatments for a range of diseases including hemophilia, cystic fibrosis, muscular dystrophy & many neurological disorders. Process development is complex, time consuming & expensive, with scale-up being a major technology challenge for commercialization. While progress has been made to implement clinical vector production (upstream) and purification (downstream) processes at large scale, required for high dose indications, many challenges remain in vector design, manufacturing methodology & product characterization. Ongoing innovation is required to understand the critical quality attributes of AAV vectors for human use, & to establish suitable and standardized analytical systems to monitor and control clinical manufacturing processes & characterize the purified vector products. 'Research-grade' vectors are not subject to the same control criteria; however, similar approaches are utilized on a routine basis in cores and research labs to manufacture viral vectors for discovery, investigational product development & IND-supporting studies. In that regard, academic centers should promote and implement good practices and make transferable protocols to accelerate gene therapy drug development. At the GVVC a high-throughput platform has been optimized to produce custom rAAVs with a rapid turnaround and rigorous analytical methods for quality control. These include qualified qPCR titer methodology, purity using a range of tests & functional activity (infectivity) verificdation of the recombinant virus. Furthermore, this core facility borrows from GXP practice for carefully segregated workflow to prevent product cross-contamination in a high throughput environment. the GVVC facility has manufactured over 5000 custom AAV vector batches for Stanford researchers & neuroscientists world-wide.

PMID: 32831797 [PubMed - as supplied by publisher]

Retropharyngeal abscess in a post-lung transplant cystic fibrosis patient with prior cervical fusion: a case study.

BMC Pulm Med. 2020 Aug 24;20(1):224

Authors: Ladores S, Bray LA, Brown J, Corcoran J, Jordan J, Buczek E

Abstract
BACKGROUND: Cystic fibrosis (CF) is a chronic, genetic, incurable disease that affects primarily the respiratory and gastrointestinal systems. End-stage lung disease is the leading cause of death in people with CF, and lung transplant is required to preserve life. Anti-rejection medications are necessary post-transplant; however, these medications lower immune response and increase susceptibility to bacterial infections. Complications from infections post lung-transplant account for approximately 30% of CF-related deaths. Retropharyngeal abscess (RPA) is a rare deep neck infection that occurs most commonly in children. This is the case of a 45-year-old Caucasian male with CF who developed a retropharyngeal abscess post wisdom teeth extraction that seeded into hardware from a previous cervical disc fusion.
CASE PRESENTATION: The patient presented to the emergency department with severe neck and shoulder pain, limited range of motion in his arm and neck, and dysphonia. He reported feeling pain for 10 days and suspected the pain was caused by a weightlifting injury. The patient reported low-grade fever 5 days prior, which responded to acetaminophen. He was afebrile upon admission and in no respiratory distress. Diagnostic labs revealed WBC 22,000/uL and CRP 211 mg/L. The CT scan showed a large abscess in the retropharyngeal space between C2-C7. The immediate concern was airway obstruction and need for possible intubation or tracheostomy. The patient was transferred to ENT service with neurosurgery and transplant consults. The RPA was drained and lavaged. The cervical hardware was discovered to be infected and was removed. The source of the RPA infection was determined to be from the patient's wisdom teeth extraction 6 months prior to RPA. The patient received 8 weeks of intravenous ceftriaxone for Streptococcus pneumoniae bacteremia and underwent revision of his cervical fusion 3 months after hardware removal.
CONCLUSIONS: Clinicians should consider prophylactic antimicrobial therapy for immunocompromised patients when they are at increased risk for transient bacteremia such as following invasive procedures (e.g., tooth extraction). Prophylactic antimicrobial therapy could prevent potentially life-threatening infections such as RPA in immunocompromised patients.

PMID: 32831089 [PubMed - as supplied by publisher]

First lung transplantation in a HIV patient in Brazil.

Braz J Infect Dis. 2020 May - Jun;24(3):268-269

Authors: Pola-Dos-Reis F, Camargo LFA, Afonso-Junior JE, Samano MN, Pego-Fernandes PM

PMID: 32553467 [PubMed - indexed for MEDLINE]

What metabolic, osmotic and molecular stress responses tell us about extreme ambient heatwave impacts in fish at low salinities: The case of European seabass, Dicentrarchus labrax.

Sci Total Environ. 2020 Aug 09;749:141458

Authors: Islam MJ, Slater MJ, Kunzmann A

Abstract
Unprecedented shifts in temperature and precipitation patterns in recent decades place multiple abiotic stressors on the fish. In teleosts, metabolic, osmoregulatory, and molecular potential as tolerance responses to extreme ambient heatwave events at different salinities are poorly understood. The study was performed to evaluate the physio-biochemical stress responses and acclimation potential of European seabass, Dicentrarchus labrax maintained at four different salinities followed by an extreme ambient heatwave exposure. Fish were kept at 32, 12, 6, and 2 psu for 35 days followed by a simulated extreme ambient heatwave (33 °C) exposure for 10 days. Fish growth performances, physio-biochemical and molecular responses were recorded. Fish acclimated at 32 and 2 psu exhibited significantly (p < 0.05) decreased growth performance. Serum [Na+] and [Cl-] ions were significantly lowered (p < 0.05) in 32 psu fish on day 10 of heatwave exposure. While serum glucose, triglycerides, and protein tended to decrease during the extreme ambient heatwave exposure, lactate content increased significantly (p < 0.05) in 32 psu fish on day 10. In 32 and 2 psu fish, serum metabolic enzymes, and cortisol levels increased significantly (p < 0.05) during the extreme heatwave exposure. On days 5 and 10, HSP70 mRNA was significantly (p < 0.05) upregulated in kidneys and gills of 32 and 2 psu fish, while Igf1 showed downregulation. In gills of 2 psu fish, ATPase Na+/K+-α1 and NKCC1 expression decreased significantly (p < 0.05) in 2 psu, in contrast, significant upregulation was observed at 32 psu fish during extreme ambient heatwave exposure. On days 5 and 10, cystic fibrosis transmembrane conductance (CFTR) upregulation was significantly lower (p < 0.05) in 32 and 2 psu fish. Results suggest that European seabass held at 12 and 6 psu water fare better physiological fitness during the tested extreme ambient heatwave event (33 °C), providing possible insights into options for future aquaculture management in a warming environment.

PMID: 32829272 [PubMed - as supplied by publisher]

Autophagy markers as mediators of lung injury-implication for therapeutic intervention.

Life Sci. 2020 Aug 20;:118308

Authors: Vishnupriya S, Dharshini LCP, Sakthivel KM, Rasmi RR

Abstract
Lung injury is characterized by inflammatory processes demonstrated as loss of function of the pulmonary capillary endothelial and alveolar epithelial cells. Autophagy is an intracellular digestion system that work as an inducible adaptive response to lung injury which is a resultant of exposure to various stress agents like hypoxia, ischemia-reperfusion and xenobiotics which may be manifested as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), chronic lung injury (CLI), bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), asthma, ventilator-induced lung injury (VILI), ventilator-associated lung injury (VALI), pulmonary fibrosis (PF), cystic fibrosis (CF) and radiation-induced lung injury (RILI). Numerous regulators like LC3B-II, Beclin 1, p62, HIF1/BNIP3 and mTOR play pivotal role in autophagy induction during lung injury possibly for progression/inhibition of the disease state. The present review focuses on the critical autophagic mediators and their potential cross talk with the lung injury pathophysiology thereby bringing to limelight the possible therapeutic interventions.

PMID: 32828942 [PubMed - as supplied by publisher]

SARS-CoV-2 seroprevalence in a Belgian cohort of patients with cystic fibrosis.

J Cyst Fibros. 2020 Aug 11;:

Authors: Berardis S, Verroken A, Vetillart A, Struyf C, Gilbert M, Gruson D, Gohy S

Abstract
BACKGROUND: In Belgium, COVID-19 epidemy began on February 4, 2020 with a peak on April 10, 2020. Patients with cystic fibrosis (CF) followed in the Cliniques universitaires Saint-Luc were rapidly isolated before the government lockdown.
METHODS: After the peak of the epidemy, we measured anti-SARS-CoV-2 IgM and IgG antibodies in 149 patients and collected clinical data.
RESULTS: Only 3 asymptomatic patients presented IgG against the virus. In one patient hospitalized for COVID-19 (positive molecular testing), we did not detect any anti-SARS-CoV-2 antibodies, as in thirty-five other symptomatic patients considered as possible cases.
CONCLUSIONS: Even if respiratory symptoms linked to CF are frequent and compatible with COVID-19, anti-SARS-CoV-2 IgG antibodies were detected only in 3 asymptomatic patients. This reassuring study concerning the risk of COVID-19 in patients with CF illustrates the difficulty to distinguish COVID-19 symptoms from respiratory exacerbations and the need of generalized molecular testing to make a precise diagnosis.

PMID: 32828701 [PubMed - as supplied by publisher]

Under nonlimiting iron conditions pyocyanin is a major antifungal molecule, and differences between prototypic Pseudomonas aeruginosa strains.

Med Mycol. 2020 Aug 22;:

Authors: Sass G, Nazik H, Chatterjee P, Stevens DA

Abstract
Airways of immunocompromised patients, or individuals with cystic fibrosis (CF), are common ground for Pseudomonas aeruginosa and Aspergillus fumigatus infections. Hence, in such a microenvironment both pathogens compete for resources. While under limiting iron conditions the siderophore pyoverdine is the most effective antifungal P. aeruginosa product, we now provide evidence that under nonlimiting iron conditions P. aeruginosa supernatants lack pyoverdine but still possess considerable antifungal activity. Spectrometric analyses of P. aeruginosa supernatants revealed the presence of phenazines, such as pyocyanin, only under nonlimiting iron conditions. Supernatants of quorum sensing mutants of strain PA14, defective in phenazine production, as well as supernatants of the P. aeruginosa strain PAO1, lacked pyocyanin, and were less inhibitory toward A. fumigatus biofilms under nonlimiting iron conditions. When blood as a natural source of iron was present during P. aeruginosa supernatant production, pyoverdine was absent, and phenazines, including pyocyanin, appeared, resulting in an antifungal effect on A. fumigatus biofilms. Pure pyocyanin reduced A. fumigatus biofilm metabolism. In summary, P. aeruginosa has mechanisms to compete with A. fumigatus under limiting and non-limiting iron conditions, and can switch from iron-denial-based to toxin-based antifungal activity. This has implications for the evolution of the microbiome in clinical settings where the two pathogens co-exist. Important differences in the iron response of P. aeruginosa laboratory strains PA14 and PAO1 were also uncovered.
LAY SUMMARY: P. aeruginosa (Pa) and A. fumigatus (Af) form biofilms in lungs of persons with cystic fibrosis and interact via virulence factors. Pa inhibits Af via different factors, depending on the availability of iron from blood. Low iron favors the use of pyoverdine, high iron the use of the toxin pyocyanin.

PMID: 32827431 [PubMed - as supplied by publisher]

Area Under the Curve Achievement of Once Daily Tobramycin in Children with Cystic Fibrosis during Clinical Care.

Pediatr Pulmonol. 2020 Aug 22;:

Authors: Brockmeyer JM, Wise RT, Burgener EB, Milla C, Frymoyer A

Abstract
BACKGROUND: The area under the concentration-time curve over 24 hours (AUC24 ) is frequently utilized to monitor tobramycin exposure in children with cystic fibrosis (CF). An understanding of exposure target achievement during clinical implementation of an AUC24 based approach in children is limited.
METHODS: A retrospective chart review was performed in children with CF treated with once daily tobramycin and drug concentration monitoring at a pediatric CF center. During clinical care AUC24 was estimated using a traditional log-linear regression approach (LLR). AUC24 was also estimated retrospectively using a pharmacokinetic model-based Bayesian forecasting approach (BF). AUC24 achievement after both approaches were compared.
RESULTS: In 77 treatment courses (mean age 12.7 ± 5.0 years), a target AUC24 100-125 mg*h/L was achieved after starting dose in 21 (27%) and after initial dose adjustment in 35 (45%). In the first 7 days of treatment, 24 (32%) required ≥3 dose adjustments, and the mean number of drug concentrations measured was 7.1 ± 3.2. Examination of a BF approach demonstrated adequate prediction of measured tobramycin concentrations (median bias -2.1% [95% CI -3.1 to -1.4]; median precision 7.6% [95% CI 7.1 to 8.2%]). AUC24 estimates utilizing the BF approach were higher than the LLR approach with a mean difference of 6.4 mg*h/L (95% CI 4.8 to 8.0 mg*h/L).
CONCLUSIONS: Achievement of a narrow AUC24 target is challenging during clinical care, and dose individualization is needed in most children with CF. Implementing a BF approach for estimating AUC24 in children with CF is supported. This article is protected by copyright. All rights reserved.

PMID: 32827334 [PubMed - as supplied by publisher]

Obesity and ethnicity alter gene expression in skin.

Sci Rep. 2020 Aug 21;10(1):14079

Authors: Walker JM, Garcet S, Aleman JO, Mason CE, Danko D, Zuffa S, Swann JR, Krueger J, Breslow JL, Holt PR

Abstract
Obesity is accompanied by dysfunction of many organs, but effects on the skin have received little attention. We studied differences in epithelial thickness by histology and gene expression by Affymetrix gene arrays and PCR in the skin of 10 obese (BMI 35-50) and 10 normal weight (BMI 18.5-26.9) postmenopausal women paired by age and ethnicity. Epidermal thickness did not differ with obesity but the expression of genes encoding proteins associated with skin blood supply and wound healing were altered. In the obese, many gene expression pathways were broadly downregulated and subdermal fat showed pronounced inflammation. There were no changes in skin microbiota or metabolites. African American subjects differed from European Americans with a trend to increased epidermal thickening. In obese African Americans, compared to obese European Americans, we observed altered gene expression that may explain known differences in water content and stress response. African Americans showed markedly lower expression of the gene encoding the cystic fibrosis transmembrane regulator characteristic of the disease cystic fibrosis. The results from this preliminary study may explain the functional changes found in the skin of obese subjects and African Americans.

PMID: 32826922 [PubMed - as supplied by publisher]

Cystic fibrosis in low and middle-income countries (LMIC): A view from four different regions of the world.

Paediatr Respir Rev. 2020 Jul 30;:

Authors: da Silva Filho LVRF, Zampoli M, Cohen-Cymberknoh M, Kabra SK

Abstract
Cystic fibrosis (CF) has been shown to affect people all over the world. While life expectancy for people with CF has increased substantially, CF is still associated with death in infants and young children in many regions, particularly in low and middle-income countries (LMIC). These countries face significant challenges to promote CF diagnosis and improvements to CF care due to financial constraints and a significant burden of other diseases. In this review, we describe the status of CF diagnosis and care in different LMIC settings, from four different parts of the world (Brazil, South Africa, Israel and India). We highlight challenges and opportunities for CF practitioners in LMIC to improve CF care and outcomes. While early CF diagnosis is the key to optimising outcomes, newborn screening may not be feasible for countries with lower CF incidence and higher birth rates, such as India or South Africa. CF therapies and care in LMIC need to be adapted to available resources of these countries. Collaboration initiatives of the global CF community with LMIC may improve CF care in these countries. Most individuals with CF in LMIC are not benefiting from CFTR modulator treatments due to the prohibitive cost of these drugs.

PMID: 32826173 [PubMed - as supplied by publisher]