Dry powder aerosol containing muco-inert particles for excipient enhanced growth pulmonary drug delivery.

Nanomedicine. 2020 Jul 02;:102262

Authors: Chai G, Hassan A, Meng T, Lou L, Ma J, Simmers R, Zhou L, Rubin BK, Zhou QT, Longest PW, Hindle M, Xu Q

Abstract
Tenacious sputum poses a critical diffusion barrier for aerosol antibiotics used to treat cystic fibrosis (CF) lung infection. We conducted a proof-of-concept study using dense poly(ethylene glycol) coated polystyrene nanoparticles (PS-PEG NPs) as model muco-inert particles (MIP) formulated as a powder using an excipient enhanced growth (EEG) strategy, aiming to minimize extrathoracic airway loss, maximize deposition in the airway and further overcome the sputum barrier in the CF lungs. The EEG aerosol formulation containing PS-PEG MIP was prepared by spray drying and produced discrete spherical particles with geometric diameter of approximately 2μm; and>80% of the powder dose was delivered from a new small-animal dry powder inhaler (DPI). The MIP released from the EEG aerosol had human airway mucus and CF sputum diffusion properties comparable to the suspension formulation. These properties make this formulation a promising pulmonary drug delivery system for CF lung infections.

PMID: 32623017 [PubMed - as supplied by publisher]

BAL inflammatory markers can predict pulmonary exacerbations in children with cystic fibrosis.

Chest. 2020 Jul 02;:

Authors: Ishak A, Stick SM, Turkovic L, Ranganathan SC, King L, Harrison J, Sly PD, Caudri D, Schultz A, AREST CF

Abstract
BACKGROUND: Pulmonary exacerbations in cystic fibrosis are characterized by airway inflammation and may cause irreversible lung damage. Early identification of such exacerbations may facilitate early initiation of treatment, thereby potentially reducing long-term morbidity.
RESEARCH QUESTION: Is it possible to predict pulmonary exacerbations in children with cystic fibrosis using inflammatory markers obtained from bronchoalveolar lavage (BAL) fluid?
STUDY DESIGN: and Methods: A longitudinal analysis of children aged 0-7 years included in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) study between 2005 and 2015. The association between inflammatory markers from annual BAL fluid and time to pulmonary exacerbation requiring hospital admission in the six-month period post-BAL was analysed using Kaplan-Meier curves and Weibull regression, adjusting for annually repeated measurements. Admissions for Pseudomonas eradication were excluded in the main analysis, due to the standard policy in participating centres to treat Pseudomonas in-hospital.
RESULTS: 976 BAL samples from 308 children were analysed. After exclusion of admissions for Pseudomonas eradication (n=43), there were 145 pulmonary exacerbations recorded within six months of BAL; median time-to-exacerbation was 31 days (interquartile range 9-100). In univariate analyses, high interleukin-8 (hazard ratio (HR) 2.25 for 75th vs. 25th percentile, 95%-CI 1.87-2.72), neutrophil elastase (HR) 3.00, 95%-CI 2.03-4.42), and high neutrophil percentage (HR 1.80 for 75th vs. 25th percentile, 95%-CI 1.56-2.04) were all significantly associated with risk for a pulmonary exacerbation (p<0.001). The inflammatory markers remained significant predictors after adjustment for clinical predictive variables.
INTERPRETATION: Inflammatory markers in BAL fluid are significant predictors of pulmonary exacerbations in young children with cystic fibrosis. The development of non-invasive measures of lung inflammation may facilitate routine surveillance of cystic fibrosis.

PMID: 32622821 [PubMed - as supplied by publisher]

Evaluation of airway and circulating inflammatory biomarkers for cystic fibrosis drug development.

J Cyst Fibros. 2020 Jul 01;:

Authors: Jain R, Baines A, Khan U, Wagner BD, Sagel SD

Abstract
INTRODUCTION: Biomarkers of inflammation in blood and sputum can play a critical role in anti-inflammatory drug development in cystic fibrosis (CF). The objectives of this analysis were to examine relationships between airway and systemic measurements of inflammation, associations between inflammatory biomarkers and FEV1, differences in airway and systemic inflammation by baseline covariates, reproducibility of serum biomarkers, and to assess the effects of freezing and delayed processing on sputum analyte measurements.
METHODS: We analyzed baseline and serial concentrations of inflammatory markers in blood and induced sputum collected from individuals with CF ages 10 years and older who participated in a multicenter clinical trial.
RESULTS: Among circulating biomarkers, serum high sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA) correlated most strongly with each other (rs = 0.85). Comparing sputum-based inflammation measurements, sputum neutrophil elastase and myeloperoxidase (MPO) were the most highly correlated (rs = 0.88). Markers most strongly correlated with ppFEV1 were serum hsCRP (rs = -0.55), SAA (rs =-0.58), and sputum neutrophil elastase (rs = -0.53). Within-subject standard deviation was consistently lower than between-subject standard deviation for all serum biomarkers. Serum calprotectin and MPO had the highest ratio of between-to-within subject variability. Freezing and delayed sputum processing were not associated with significant differences in measurements of sputum neutrophil elastase, IL-1β, or MPO.
CONCLUSIONS: Among the biomarkers analyzed, serum hsCRP and sputum neutrophil elastase are promising candidates to include in CF anti-inflammatory clinical trials to avoid redundancy, minimize variation, and serve as correlates of lung disease severity and change.

PMID: 32622665 [PubMed - as supplied by publisher]

Ubiquitination of Disease-Causing CFTR Variants in a Microsome-Based Assay.

Anal Biochem. 2020 Jul 01;:113829

Authors: Estabrooks SK, Brodsky JL

Abstract
Soluble secreted proteins and membrane proteins are subjected to protein quality control pathways during their synthesis in the endoplasmic reticulum (ER) and delivery to other destinations. Foremost among these quality control pathways is the selection of misfolded proteins for ER-associated degradation (ERAD). A growing number of diseases, including Cystic Fibrosis, are linked to the ERAD pathway. In most cases, a membrane protein known as the Cystic Fibrosis Transmembrane Conductance Regulator, or CFTR, is prematurely degraded by ERAD. Cell-based assays and in vitro studies have elucidated factors required for the recognition and degradation of CFTR, yet mechanistic details on how these factors target specific disease-causing variants is limited. Given the possibility that variants might exhibit unique susceptibilities to ubiquitin modification, which is required for proteasome-mediated degradation, we devised an assay that recapitulates this event. Here, we demonstrate that ER-enriched membranes from transfected human cells support CFTR ubiquitination when combined with radiolabeled ubiquitin and isolated enzymes in the ubiquitination cascade. We also show that select disease-causing variants are ubiquitinated more extensively than wild-type channels and to varying degrees. Our system provides a platform to examine how other purified factors impact CFTR ubiquitination and the ubiquitination of additional disease-associated membrane proteins.

PMID: 32621804 [PubMed - as supplied by publisher]

[Cystic fibrosis and computed tomography of the lungs].

Radiologe. 2020 Jul 03;:

Authors: Bischoff A, Weinheimer O, Eichinger M, Stahl M, Sommerburg O, Kauczor HU, Mall MA, Wielpütz MO

Abstract
With its high detail of morphological changes in lung parenchyma and airways as well as the possibilities for three-dimensional reconstruction, computed tomography (CT) represents a solid tool for the diagnosis and follow-up in patients suffering from cystic fibrosis (CF). Guidelines for standardized CT image acquisition in CF patients are still missing. In the mostly younger CF patients, an important issue is the well-considered use of radiation in CT imaging. The use of intravenous contrast agent is mainly restricted to acute emergency diagnostics. Typical morphological findings in CF lung disease are bronchiectasis, mucus plugging, or signs of decreased ventilation (air trapping) which can be detected with CT even in early stages. Various scoring systems that have become established over time are used to grade disease severity and for structured follow-up, e.g., in clinical research studies. With the technical development of CT, a number of postprocessing software tools were developed to help clinical reporting and overcome interreader differences for a standardized quantification. As an imaging modality free of ionizing radiation, magnetic resonance imaging (MRI) is becoming increasingly important in the diagnosis and follow-up of CF patients and is already frequently a substitute for CT for long-term follow-up at numerous specialized centers.

PMID: 32621155 [PubMed - as supplied by publisher]

A Case of Persistent Muscle Cramps in an American Football Player With Cystic Fibrosis.

Cureus. 2020 Jun 14;12(6):e8621

Authors: Wise P, Lafferty L, Phillips SF

Abstract
Exercised-associated muscle cramp (EAMC) is a common occurrence in sports medicine. We highlight a 17-year-old male high-school football player with a history of cystic fibrosis and hyponatremic seizure, who presented for recurrent EAMC. After establishing an appropriate electrolyte replacement and hydration plan, he was able to complete his season with minimal symptoms. This case highlights the importance of hydration and nutrition planning when managing athletes with cystic fibrosis.

PMID: 32617241 [PubMed]

COVID-19 network: the response of an Italian reference Institute to research challenges about a new pandemia.

Clin Microbiol Infect. 2020 Jun 30;:

Authors: Bandera A, Aliberti S, Gualtierotti R, Baldini M, Blasi F, Cesari M, Costantino G, Fracanzani AL, Gori A, Montano N, Monzani V, Nobili A, Peyvandi F, Pesenti A, Prati D, Valenti L, Fusetti G, Scudeller L, Bosari S, COVID19 Network, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Scientific Direction, Department of Transfusion Medicine and Biobank, Infectious Diseases Unit, Internal Medicine, Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Internal Medicine, Immunology and Allergology, Respiratory Unit and Cystic Fibrosis Adult Center, Cardiology Unit, Emergency Medicine, Acute Internal Medicine, Internal Medicine, Internal Medicine and Metabolic Diseases, Geriatric Unit, Istituto di Ricerche Farmacologiche Mario Negri IRCCS

PMID: 32619733 [PubMed - as supplied by publisher]

Editorial for "Echo Time-Dependence of Observed Lung T1 in Patients With Cystic Fibrosis and Correlation With Clinical Metrics".

J Magn Reson Imaging. 2020 Jul 03;:e27277

Authors: Beckmann N

PMID: 32619307 [PubMed - as supplied by publisher]

Multidrug-resistant bacteria in lung transplantation.

Curr Opin Organ Transplant. 2020 Jun 30;:

Authors: Dominguez F, Blodget E

Abstract
PURPOSE OF REVIEW: The review of infections in lung transplantation is beyond the scope of this article as it is a comprehensive topic, however we aim to focus on infections with multidrug-resistant (MDR) microorganisms in this patient population.
RECENT FINDINGS: New emerging clinical studies have provided data regarding outcomes in lung transplant recipients with MDR bacterial infections.
SUMMARY: Isolation of MDR bacteria from lung donors preoperatively has not been associated with worse outcomes in recipients. Patients with cystic fibrosis colonized with MDR bacteria do not have increased 1 year mortality rates compared to those without MDR bacteria.

PMID: 32618718 [PubMed - as supplied by publisher]

Hemoglobin A1c and fructosamine correlate in a patient with sickle cell disease and diabetes on chronic transfusion therapy.

Pediatr Blood Cancer. 2020 Jul 03;:e28499

Authors: McLean A, Wright F, deJong N, Skinner S, Loughlin CE, Levenson A, Carden MA

Abstract
In patients with sickle cell disease (SCD) and diabetes mellitus (DM), hemoglobin A1c (HbA1c ) is unreliable and the American Diabetes Association recommends monitoring long-term glycemia by measuring serum glucose, but use of serum fructosamine (SF), a measurement independent of red cell lifespan, has been reported. SF as a screen for DM in SCD, however, is not standardized and its relationship to serum glucose has not been validated. Further, screening for DM was not adequately addressed in the 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines for SCD management. Blood transfusions, an important treatment for some patients with SCD, can also impact HbA1c . We present a case of a patient with SCD and cystic fibrosis-related diabetes on monthly chronic transfusions therapy (CTT) who had well-correlated "steady state" HbA1c and SF levels over time, suggesting for the first time these markers may actually be useful when following long-term glycemic control in patients with SCD on CTT programs.

PMID: 32618413 [PubMed - as supplied by publisher]

Hematopoietic stem cell transplantation for people with sickle cell disease.

Cochrane Database Syst Rev. 2020 Jul 03;7:CD007001

Authors: Oringanje C, Nemecek E, Oniyangi O

Abstract
BACKGROUND: Sickle cell disease is a genetic disorder involving a defect in the red blood cells due to its sickled hemoglobin. The main therapeutic interventions include preventive and supportive measures. Hematopoietic stem cell transplantations are carried out with the aim of replacing the defective cells and their progenitors (hematopoietic (i.e. blood forming) stem cells) in order to correct the disorder. This is an update of a previously published review.
OBJECTIVES: To determine whether stem cell transplantation can improve survival and prevent symptoms and complications associated with sickle cell disease. To examine the risks of stem cell transplantation against the potential long-term gain for people with sickle cell disease.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Group's Haemoglobinopathies Trials Register complied from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library) and quarterly searches of MEDLINE. We also searched trial registries for ongoing trials up to April 2020. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 09 December 2019.
SELECTION CRITERIA: Randomized controlled and quasi-randomized trials that compared any method of stem cell transplantation with either each other or with any of the preventive or supportive interventions (e.g. periodic blood transfusion, use of hydroxyurea, antibiotics, pain relievers, supplemental oxygen) in people with sickle cell disease irrespective of the type of sickle cell disease, gender and setting.
DATA COLLECTION AND ANALYSIS: No trials were eligible for inclusion in the review.
MAIN RESULTS: We identified 12 potentially-eligible trials by the searches; we excluded 11 of these and the remaining trial is an ongoing trial that may be eligible for inclusion in a future version of the review.
AUTHORS' CONCLUSIONS: Reports on the use of hematopoietic stem cell transplantation improving survival and preventing symptoms and complications associated with sickle cell disease are currently limited to observational and other less robust studies. We did not find any eligible randomized controlled trials assessing the benefit or risk of hematopoietic stem cell transplantations. However, there is an ongoing quasi-randomized trial comparing hematopoietic stem cell transplantation with standard care, Thus, this systematic review identifies the need for a multicentre randomized controlled trial assessing the benefits and possible risks of hematopoietic stem cell transplantations comparing sickle status and severity of disease in people with sickle cell disease.

PMID: 32617981 [PubMed - in process]

Altered iron metabolism in cystic fibrosis macrophages: the impact of CFTR modulators and implications for Pseudomonas aeruginosa survival.

Sci Rep. 2020 Jul 02;10(1):10935

Authors: Hazlett HF, Hampton TH, Aridgides DS, Armstrong DA, Dessaint JA, Mellinger DL, Nymon AB, Ashare A

Abstract
Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in chronic bacterial lung infections and tissue damage. CF macrophages exhibit reduced bacterial killing and increased inflammatory signaling. Iron is elevated in the CF lung and is a critical nutrient for bacteria, including the common CF pathogen Pseudomonas aeruginosa (Pa). While macrophages are a key regulatory component of extracellular iron, iron metabolism has yet to be characterized in human CF macrophages. Secreted and total protein levels were analyzed in non-CF and F508del/F508del CF monocyte derived macrophages (MDMs) with and without clinically approved CFTR modulators ivacaftor/lumacaftor. CF macrophage transferrin receptor 1 (TfR1) was reduced with ivacaftor/lumacaftor treatment. When activated with LPS, CF macrophage expressed reduced ferroportin (Fpn). After the addition of exogenous iron, total iron was elevated in conditioned media from CF MDMs and reduced in conditioned media from ivacaftor/lumacaftor treated CF MDMs. Pa biofilm formation and viability were elevated in conditioned media from CF MDMs and biofilm formation was reduced in the presence of conditioned media from ivacaftor/lumacaftor treated CF MDMs. Defects in iron metabolism observed in this study may inform host-pathogen interactions between CF macrophages and Pa.

PMID: 32616918 [PubMed - in process]

Quantification of muco-obstructive lung disease variability in mice via laboratory X-ray velocimetry.

Sci Rep. 2020 Jul 02;10(1):10859

Authors: Werdiger F, Donnelley M, Dubsky S, Murrie RP, Carnibella RP, Samarage CR, How YY, Zosky GR, Fouras A, Parsons DW, Morgan KS

Abstract
To effectively diagnose, monitor and treat respiratory disease clinicians should be able to accurately assess the spatial distribution of airflow across the fine structure of lung. This capability would enable any decline or improvement in health to be located and measured, allowing improved treatment options to be designed. Current lung function assessment methods have many limitations, including the inability to accurately localise the origin of global changes within the lung. However, X-ray velocimetry (XV) has recently been demonstrated to be a sophisticated and non-invasive lung function measurement tool that is able to display the full dynamics of airflow throughout the lung over the natural breathing cycle. In this study we present two developments in XV analysis. Firstly, we show the ability of laboratory-based XV to detect the patchy nature of cystic fibrosis (CF)-like disease in β-ENaC mice. Secondly, we present a technique for numerical quantification of CF-like disease in mice that can delineate between two major modes of disease symptoms. We propose this analytical model as a simple, easy-to-interpret approach, and one capable of being readily applied to large quantities of data generated in XV imaging. Together these advances show the power of XV for assessing local airflow changes. We propose that XV should be considered as a novel lung function measurement tool for lung therapeutics development in small animal models, for CF and for other muco-obstructive diseases.

PMID: 32616726 [PubMed - in process]

Inhaled antibiotics therapy for stable non-cystic fibrosis bronchiectasis: a meta-analysis.

Ther Adv Respir Dis. 2020 Jan-Dec;14:1753466620936866

Authors: Xu MJ, Dai B

Abstract
BACKGROUND: The optimum antibiotic therapy for non-cystic fibrosis bronchiectasis (NCFB) has yet to be determined. A meta-analysis was conducted to evaluate the efficacy and safety of inhaled antibiotics in adults with stable NCFB.
METHODS: PubMed, EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials were searched through November 2019.
RESULTS: A total of 16 randomized controlled trials (RCTs), recruiting 2748 NCFB patients, were finally included. Inhaled antibiotics treatment significantly reduced the sputum bacterial load [standard mean difference (SMD) = -0.74, 95% CI: -1.16-0.32, p < 0.001, I2 = 68.1%], prolonged median time [hazard risk (HR) = 0.73, 95% confidence interval (CI): 0.57-0.93, p < 0.001, I2 = 53.6%] and reduced frequency [incidence rate ratio (IRR) = 0.74, 95% CI 0.63-0.87, p < 0.001, I2 = 20.5%] of exacerbations, with good tolerance. However, it failed to improve Pseudomonas aeruginosa eradication, [forced expiratory volume in 1 s (FEV1)] % predicted, quality of life questionnaire (QoL-B) and St. George's respiratory questionnaire (SGRQ) scores, and may induce higher risk of P. aeruginosa resistance. Subgroup analysis showed Ciprofloxacin was more effective than other antibiotics in reducing bacterial load (SMD = -1.35, 95% CI: -1.85-0.85, I2 = 63.4%, p = 0.042).
CONCLUSION: Inhaled antibiotics therapy holds great promise for stable NCFB as it is effective in reducing sputum bacterial load and the risk of acute attack, delaying disease progression, and is well tolerated. Although this study brings some constructive ideas in the field of clinical medication, further clinical trials should be carried out, particularly in solving drug-resistance and improving health-related quality of life (HRQoL), which we believe will finally provide benefits for patients suffering from bronchiectasis. The reviews of this paper are available via the supplemental material section.

PMID: 32615859 [PubMed - in process]

Negotiations between the NHS and Vertex on access to lumacaftor and ivacaftor become protracted.

Lancet Respir Med. 2019 09;7(9):739-740

Authors: Burki TK

PMID: 31353281 [PubMed - indexed for MEDLINE]

Preoperative blood transfusions for sickle cell disease.

Cochrane Database Syst Rev. 2020 Jul 02;7:CD003149

Authors: Estcourt LJ, Kimber C, Trivella M, Doree C, Hopewell S

Abstract
BACKGROUND: Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Surgical interventions are more common in people with SCD, and occur at much younger ages than in the general population. Blood transfusions are frequently used prior to surgery and several regimens are used but there is no consensus over the best method or the necessity of transfusion in specific surgical cases. This is an update of a Cochrane Review.
OBJECTIVES: To determine whether there is evidence that preoperative blood transfusion in people with SCD undergoing elective or emergency surgery reduces mortality and perioperative or sickle cell-related serious adverse events. To compare the effectiveness of different transfusion regimens (aggressive or conservative) if preoperative transfusions are indicated in people with SCD.
SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 28 January 2020 We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 19 September 2019.
SELECTION CRITERIA: All randomised controlled trials and quasi-randomised controlled trials comparing preoperative blood transfusion regimens to different regimens or no transfusion in people with SCD undergoing elective or emergency surgery. There was no restriction by outcomes examined, language or publication status.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and the risk of bias and extracted data.
MAIN RESULTS: Three trials with 990 participants were eligible for inclusion in the review. There were no ongoing trials identified. These trials were conducted between 1988 and 2011. The majority of people included had haemoglobin (Hb) SS SCD. The majority of surgical procedures were considered low or intermediate risk for developing sickle cell-related complications. Aggressive versus simple red blood cell transfusions One trial (551 participants) compared an aggressive transfusion regimen (decreasing sickle haemoglobin to less than 30%) to a simple transfusion regimen (increasing haemoglobin to 100 g/L). This trial re-randomised participants and therefore quantitative analysis was only possible on two subsets of data: participants undergoing cholecystectomy (230 participants); and participants undergoing tonsillectomy or adenoidectomy surgeries (107 participants). Data were not combined as we do not know if any participant received both surgeries. Overall, the quality of the evidence was very low across different outcomes according to GRADE methodology. This was due to the trial being at high risk of bias primarily due to lack of blinding, indirectness and the outcome estimates being imprecise. Cholecystectomy subgroup results are reported in the abstract. Results for both subgroups were similar. There was no difference in all-cause mortality between people receiving aggressive transfusions and those receiving conservative transfusions. No deaths occurred in either subgroup. There were no differences between the aggressive transfusion group and conservative transfusion group in the number of people developing: • an acute chest syndrome, risk ratio (RR) 0.84 (95% confidence interval (CI) 0.38 to 1.84) (one trial, 230 participants, very low-quality evidence); • vaso-occlusive crisis, risk ratio 0.30 (95% CI 0.09 to 1.04) (one trial, 230 participants, very low quality evidence); • serious infection, risk ratio 1.75 (95% CI 0.59 to 5.18) (one trial, 230 participants, very low-quality evidence); • any perioperative complications, RR 0.75 (95% CI 0.36 to 1.55) (one trial, 230 participants, very low-quality evidence); • a transfusion-related complication, RR 1.85 (95% CI 0.89 to 3.88) (one trial, 230 participants, very low-quality evidence). Preoperative transfusion versus no preoperative transfusion Two trials (434 participants) compared a preoperative transfusion plus standard care to a group receiving standard care. Overall, the quality of the evidence was low to very low across different outcomes according to GRADE methodology. This was due to the trials being at high risk of bias due to lack of blinding, and outcome estimates being imprecise. One trial was stopped early because more people in the no transfusion arm developed an acute chest syndrome. There was no difference in all-cause mortality between people receiving preoperative transfusions and those receiving no preoperative transfusions (two trials, 434 participants, no deaths occurred). There was significant heterogeneity between the two trials in the number of people developing an acute chest syndrome, a meta-analysis was therefore not performed. One trial showed a reduced number of people developing acute chest syndrome between people receiving preoperative transfusions and those receiving no preoperative transfusions, risk ratio 0.11 (95% confidence interval 0.01 to 0.80) (65 participants), whereas the other trial did not, RR 4.81 (95% CI 0.23 to 99.61) (369 participants). There were no differences between the preoperative transfusion groups and the groups without preoperative transfusion in the number of people developing: • a vaso-occlusive crisis, Peto odds ratio (OR) 1.91 (95% confidence interval 0.61 to 6.04) (two trials, 434 participants, very low-quality evidence). • a serious infection, Peto OR 1.29 (95% CI 0.29 to 5.71) (two trials, 434 participants, very low-quality evidence); • any perioperative complications, RR 0.24 (95% CI 0.03 to 2.05) (one trial, 65 participants, low-quality evidence). There was an increase in the number of people developing circulatory overload in those receiving preoperative transfusions compared to those not receiving preoperative transfusions in one of the two trials, and no events were seen in the other trial (no meta-analysis performed).
AUTHORS' CONCLUSIONS: There is insufficient evidence from randomised trials to determine whether conservative preoperative blood transfusion is as effective as aggressive preoperative blood transfusion in preventing sickle-related or surgery-related complications in people with HbSS disease. There is very low quality evidence that preoperative blood transfusion may prevent development of acute chest syndrome. Due to lack of evidence this review cannot comment on management for people with HbSC or HbSβ+ disease or for those with high baseline haemoglobin concentrations.

PMID: 32614473 [PubMed - as supplied by publisher]

Echo Time-Dependence of Observed Lung T1 in Patients With Cystic Fibrosis and Correlation With Clinical Metrics.

J Magn Reson Imaging. 2020 Jul 02;:e27271

Authors: Triphan SMF, Stahl M, Jobst BJ, Sommerburg O, Kauczor HU, Schenk JP, Alrajab A, Eichinger M, Mall MA, Wielpütz MO

Abstract
BACKGROUND: Noninvasive monitoring of early abnormalities and therapeutic intervention in cystic fibrosis (CF) lung disease using MRI is important. Lung T1 mapping has shown potential for local functional imaging without contrast material. Recently, it was discovered that observed lung T1 depends on the measurement echo time (TE).
PURPOSE: To examine TE-dependence of observed T1 in patients with CF and its correlation with clinical metrics.
STUDY TYPE: Prospective.
POPULATION: In all, 75 pediatric patients with CF (8.6 ± 6.1 years, range 0.1-23 years), with 32 reexamined after 1 year.
FIELD STRENGTH/SEQUENCE: Patients were examined at 1.5T using an established MRI protocol and a multiecho inversion recovery 2D ultrashort echo time (UTE) sequence for T1 (TE) mapping at five TEs including TE1 = 70 μs.
ASSESSMENT: Morphological and perfusion MRI were assessed by a radiologist (M.W.) with 11 years of experience using an established CF-MRI scoring system. T1 (TE) was quantified automatically. Clinical data including spirometry (FEV1pred%) and lung clearance index (LCI) were collected.
STATISTICAL TESTS: T1 (TE) was correlated with the CF-MRI score, clinical data, and LCI.
RESULTS: T1 (TE) showed a different curvature in CF than in healthy adults: T1 at TE1 was shorter in CF (1157 ms ± 73 ms vs. 1047 ms ± 70 ms, P < 0.001), but longer at TE3 (1214 ms ± 72 ms vs. 1314 ms ± 68 ms, P < 0.001) and later TEs. The correlations of T1 (TE) with patient age (ρTE1-TE5 = -0.55, -0.44, -0.24, -0.30, -0.22), and LCI (ρTE1-TE5 = -0.43, -0.42, -0.33, 0.27, -0.22) were moderate at ultra-short to short TE (P < 0.001) but decreased for longer TE. Moderate but similar correlations at all TE were found with MRI perfusion score (ρTE1-TE5 = -0.43, -0.51, -0.47, -0.46, -0.44) and FEV1pred% (ρTE1-TE5 = +0.44, +0.44, +0.43, +0.40, +0.39) (P < 0.05).
DATA CONCLUSION: TE should be considered when measuring lung T1 , since observed differences between CF and healthy subjects strongly depend on TE. The different variation of correlation coefficients with TE for structural vs. functional metrics implies that TE-dependence holds additional information which may help to discern effects of tissue structural abnormalities and abnormal perfusion.
LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

PMID: 32613717 [PubMed - as supplied by publisher]

Nasal IgE in subjects with allergic and non-allergic rhinitis.

World Allergy Organ J. 2020 Jun;13(6):100129

Authors: Eckrich J, Hinkel J, Fischl A, Herrmann E, Holtappels G, Bachert C, Zielen S

Abstract
Purpose: The prevalence of "ocal allergic rhinitis" within individuals suffering from perennial rhinitis remains uncertain, and patients usually are diagnosed with non-allergic rhinitis. The aim of this study was to evaluate the prevalence of a potential "local allergic rhinitis" in subjects suffering from non-allergic rhinitis in a non-selected group of young students.
Methods: 131 students (age 25.0 ± 5.1 years) with a possible allergic rhinitis and 25 non-allergic controls without rhinitis symptoms (age 22.0 ± 2.0 years) were recruited by public postings. 97 of 131 students with rhinitis were tested positive (≥3 mm) to prick testing with 17 frequent allergens at visit 1. Twenty-four 24 subjects with a house dust mite allergy, 21 subjects with a non-allergic rhinitis, and 18 non-allergic controls were further investigated at visit 2. Blood samples were taken, and nasal secretion was examined. In addition, all groups performed a nasal provocation test with house dust mite (HDM).
Results: In serum and nasal secretion, total IgE and house dust mite specific IgE significantly differed between HDM positive subjects and controls. However, no differences between non-allergic subjects and control subjects were quantifiable. Neither a nasal provocation test nor a nasal IgE to HDM allergens showed a measurable positive response in any of the non-allergic rhinitis subjects as well as the healthy controls, whilst being positive in 13 subjects with HDM allergy.
Conclusions: Nasal IgE is present in subjects with HDM allergy, but not in non-allergic rhinitis. In the investigated non-selected population, exclusive local production of IgE is absent. By implication, therefore, our findings challenge the emerging concept of local allergic rhinitis.Study identifier at ClinicalTrials.gov: NCT02810535.

PMID: 32612737 [PubMed]

Cystic fibrosis: NHS England strikes deal to offer triple combination treatment.

BMJ. 2020 Jul 01;370:m2643

Authors: Iacobucci G

PMID: 32611555 [PubMed - in process]

Macrocyclic Transmembrane Anion Transporters via a One-Pot Condensation Reaction.

Org Lett. 2020 Jul 02;22(13):5104-5108

Authors: Saha P, Madhavan N

Abstract
Synthetic chloride transporters are potential therapeutic agents for cystic fibrosis and cancer. Reported herein are macrocyclic transmembrane chloride transporters prepared by a one-pot condensation reaction. The most efficient macrocycle possesses a fine balance of hydrophobicity for membrane permeation and hydrophilicity for ion recognition. The macrocycle transports chloride ions by forming channels in the membrane. Hydrogen bonds and anion-π interactions assist chloride transport.

PMID: 32610925 [PubMed - in process]