Challenging scenarios in nontuberculous mycobacterial infection in cystic fibrosis.

Pediatr Pulmonol. 2019 Dec 10;:

Authors: Martiniano SL, Esther CR, Haworth CS, Kasperbauer SH, Zemanick ET, Caverly LJ

Abstract
This review summarizes the discussion of a session held during the 2018 North American Cystic Fibrosis (CF) Conference titled "Challenging Cases in Nontuberculous Mycobacterial (NTM) Management." In this session, a multidisciplinary panel of NTM experts discussed clinical challenges related to the management of NTM infection in people with CF in which decision-making falls outside of the Cystic Fibrosis Foundation/European Cystic Fibrosis Society NTM guidelines. Topics discussed included managing newly acquired NTM infection, selecting and monitoring treatment regimens, determining treatment endpoints, and caring for patients after NTM treatment.

PMID: 31821718 [PubMed - as supplied by publisher]

Pred-MutHTP: Prediction of disease-causing and neutral mutations in human transmembrane proteins.

Hum Mutat. 2019 Dec 10;:

Authors: Kulandaisamy A, Zaucha J, Sakthivel R, Frishman D, Michael Gromiha M

Abstract
Membrane proteins are unique in that segments thereof concurrently reside in vastly different physicochemical environments: the extracellular space, the lipid bilayer, and the cytoplasm. Accordingly, the effects of missense variants disrupting their sequence depend greatly on the characteristics of the environment of the protein segment affected as well as the function it performs. Because membrane proteins have many crucial roles (transport, signal transduction, cell adhesion, etc.), compromising their functionality often leads to diseases including cancers, diabetes mellitus or cystic fibrosis. Here, we report a suite of sequence-based computational methods "Pred-MutHTP" for discriminating between disease-causing and neutral alterations in their sequence. With a data set of 11,846 disease-causing and 9,533 neutral mutations, we obtained an accuracy of 74% and 78% with 10-fold group-wise cross-validation and test set, respectively. The features used in the models include evolutionary information, physiochemical properties, neighboring residue information, and specialized membrane protein attributes incorporating the number of transmembrane segments, substitution matrices specific to membrane proteins as well as residue distributions occurring in specific topological regions. Across 11 disease classes, the method achieved accuracies in the range of 75-85%. The model designed specifically for the transmembrane segments achieved an accuracy of 85% on the test set with a sensitivity and specificity of 86% and 83%, respectively. This renders our method the current state-of-the-art with regard to predicting the effects of variants in the transmembrane protein segments. Pred-MutHTP allows predicting the effect of any variant occurring in a membrane protein-available at https://www.iitm.ac.in/bioinfo/PredMutHTP/.

PMID: 31821684 [PubMed - as supplied by publisher]

The association between variants in the CFTR gene and nonobstructive male infertility: A meta-analysis.

Andrologia. 2019 Dec 10;:e13475

Authors: Yang L, Ren Z, Yang B, Zhou J, Peng Z, Fang K, Wang L, Liu S, Lu D, Dong Q

Abstract
The association of genetic variants and congenital bilateral absence of the vas deferens (CBAVD) has been well acknowledged. By contrast, the link between nonobstructive azoospermia (NOA) or oligospermia and alterations in the cystic fibrosis transmembrane conductive regulator (CFTR) remains inconclusive. To clarify the problem, a meta-analysis was performed out after systematically searching Pubmed, Web of Science, Embase and the Chinese national knowledge infrastructure (CNKI) database. As we know, the ∆F508 and IVS8-5T gene mutations are the most studied genetic variants in CFTR gene. We reviewed the data from male patients who underwent the aforementioned genetic test. Our study revealed that the IVS8-5T mutation may be positively associated with the risk of nonobstructive male infertility (odds ratio (OR) 1.69; 95% CI: 1.12-2.55). This association strengthened when concerning NOA (OR: 2.62; 95% CI: 1.49-4.61). However, the ∆F508 mutation seemed to be a smaller contributing factor to this risk (OR: 1.63; 95% CI: 0.86-3.08). Our study aims to clarify the association between the ∆F508 and IVS8-5T gene mutations and nonobstructive male infertility. Therefore, screening for the IVS8-5T mutation in the CFTR gene may be recommended for men with NOA or severe oligozoospermia seeking assisted reproductive technology (ART).

PMID: 31820482 [PubMed - as supplied by publisher]

Gut Microbiota in Children With Cystic Fibrosis: A Taxonomic and Functional Dysbiosis.

Sci Rep. 2019 Dec 09;9(1):18593

Authors: Coffey MJ, Nielsen S, Wemheuer B, Kaakoush NO, Garg M, Needham B, Pickford R, Jaffe A, Thomas T, Ooi CY

Abstract
Intestinal dysbiosis has been observed in children with cystic fibrosis (CF), yet the functional consequences are poorly understood. We investigated the functional capacity of intestinal microbiota and inflammation in children with CF. Stool samples were collected from 27 children with CF and 27 age and gender matched healthy controls (HC) (aged 0.8-18 years). Microbial communities were investigated by iTag sequencing of 16S rRNA genes and functional profiles predicted using Tax4Fun. Inflammation was measured by faecal calprotectin and M2-pyruvate kinase. Paediatric CF gastrointestinal microbiota demonstrated lower richness and diversity compared to HC. CF samples exhibited a marked taxonomic and inferred functional dysbiosis when compared to HC. In children with CF, we predicted an enrichment of genes involved in short-chain fatty acid (SCFA), antioxidant and nutrient metabolism (relevant for growth and nutrition) in CF. The notion of pro-inflammatory GI microbiota in children with CF is supported by positive correlations between intestinal inflammatory markers and both genera and functional pathways. We also observed an association between intestinal genera and both growth z-scores and FEV1%. These taxonomic and functional changes provide insights into gastrointestinal disease in children with CF and future gastrointestinal therapeutics for CF should explore the aforementioned pathways and microbial changes.

PMID: 31819107 [PubMed - in process]

Dietary intake in cystic fibrosis and its role in glucose metabolism.

Clin Nutr. 2019 Nov 19;:

Authors: Armaghanian N, Atkinson F, Taylor N, Kench A, Brand-Miller J, Markovic T, Steinbeck K

Abstract
BACKGROUND: Dietary intervention in cystic fibrosis (CF) has historically focused on high-energy diets to address malnutrition, with little attention on diet quality. With increased survival, CF complications such as impaired glucose tolerance (IGT) and cystic fibrosis related diabetes (CFRD) have increased in prevalence. In the absence of consensus on the management of IGT, the role of dietary intake, specifically carbohydrate quality, requires consideration.
AIMS: The aims of this study were to: 1) determine nutritional quality of dietary intake at an adult CF clinic and compare this to the Australian Dietary Guidelines 2) explore relationships between dietary intake, including glycaemic index (GI) and glycaemic load (GL), and glucose response variables using continuous glucose monitoring (CGM).
METHODS: Adults attending a Sydney hospital were recruited to undergo CGM for five-seven days and record dietary intake using a food record over the CGM period. The relationship between variables of dietary intake, including GI and GL and variables of glycaemic response, including mean amplitude of glycaemic excursions (MAGE), percentage of time in hyperglycaemic and euglycaemic range, were determined.
RESULTS: Eighteen participants completed the study with 87 full days of dietary and CGM data. Dietary intake was higher than recommendations in the Australian Dietary Guidelines in relation to grains and protein foods and only slightly higher in saturated fat. Bivariate correlations showed dietary GI was significantly positively associated with percentage of time in hyperglycaemic range. Dietary GL was significantly associated with SD, MAGE and percentage of time in euglycaemic range on CGM. Results remained significant when controlled for energy intake in partial correlation analyses.
CONCLUSIONS: This study suggests GI and GL may be important dietary factors influencing glucose metabolism in CF. Further studies exploring low GI or GL diets as a dietary intervention in CF are the next step.

PMID: 31818530 [PubMed - as supplied by publisher]

Association of bone mineral density with lung function in a Chinese general population: the Xinxiang rural cohort study.

BMC Pulm Med. 2019 Dec 09;19(1):239

Authors: Zeng X, Liu D, Zhao X, Chao L, Li Y, Li H, Li W, Gui L, Wu W

Abstract
BACKGROUND: Bone mineral density (BMD) has been positively associated with lung function in patients diagnosed with respiratory diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. However, the relationship between BMD and lung function is inconsistent in the general population.
METHODS: To investigate the association between BMD and lung function in a Chinese general population, a total of 1024 adults aged 40-70 years old from Qiliying (an industrial polluted exposure area) and Langgongmiao (the reference area with non-industrial pollution) were recruited and underwent BMD and spirometry tests.
RESULTS: Both BMD and lung function levels were lower in the exposed area compared to the reference area. In addition, BMD and lung function levels were also lower in females compared to males. Both Spearman and partial correlation analyses showed that BMD was positively correlated with FVC and FEV1. After adjusting linear regression analyses for potential confounding factors, every 0.1 g/cm2 drop in BMD was associated with 53.0 mL decrease in FVC and 33.5 mL decrease in FEV1.
CONCLUSIONS: A reduction of BMD is associated with lower lung function in a general population from China.

PMID: 31818275 [PubMed - in process]

Health-Related Quality of Life and Home Enteral Nutrition in Children with Neurological Impairment: Report from a Multicenter Survey.

Nutrients. 2019 Dec 05;11(12):

Authors: Dipasquale V, Ventimiglia M, Gramaglia SMC, Parma B, Funari C, Selicorni A, Armano C, Salvatore S, Romano C

Abstract
We aimed to measure the health-related quality of life (HRQoL) of children with neurological impairment (NI) on home enteral nutrition (HEN). An original survey among the caregivers of NI children on HEN for ≥ 12 months followed in three Italian centers (Messina, Como and Varese) was carried out between January 2013 and September 2018. The questionnaire was made up of 12 issues focused on the frequency with which certain situations associated with HEN are perceived, and grouped into physical and psychological/social dimensions. The results were analyzed statistically according to the age of the children, underlying disease, and the HEN programs' duration. In total, 80 caregivers were approached, and 75 surveys were completed (an overall response rate of 93.7%). Nearly all the caregivers reported a satisfying HRQoL, ranging from acceptable (n = 6, 8%), to good (n = 22, 29.3%), to excellent (n = 47, 62.7%). A significant correlation was found between HRQoL and underlying NI-associated disease (p = 0.001). Our data showed that HEN positively affects the QoL of NI children and their caregivers. This should encourage healthcare providers to consider this nutritional intervention early in the approach to this group of patients, in order to prevent or reduce QoL impairment.

PMID: 31817352 [PubMed - in process]

Dynamic predictive probabilities to monitor rapid cystic fibrosis disease progression.

Stat Med. 2019 Dec 09;:

Authors: Szczesniak RD, Su W, Brokamp C, Keogh RH, Pestian JP, Seid M, Diggle PJ, Clancy JP

Abstract
Cystic fibrosis (CF) is a progressive, genetic disease characterized by frequent, prolonged drops in lung function. Accurately predicting rapid underlying lung-function decline is essential for clinical decision support and timely intervention. Determining whether an individual is experiencing a period of rapid decline is complicated due to its heterogeneous timing and extent, and error component of the measured lung function. We construct individualized predictive probabilities for "nowcasting" rapid decline. We assume each patient's true longitudinal lung function, S(t), follows a nonlinear, nonstationary stochastic process, and accommodate between-patient heterogeneity through random effects. Corresponding lung-function decline at time t is defined as the rate of change, S'(t). We predict S'(t) conditional on observed covariate and measurement history by modeling a measured lung function as a noisy version of S(t). The method is applied to data on 30 879 US CF Registry patients. Results are contrasted with a currently employed decision rule using single-center data on 212 individuals. Rapid decline is identified earlier using predictive probabilities than the center's currently employed decision rule (mean difference: 0.65 years; 95% confidence interval (CI): 0.41, 0.89). We constructed a bootstrapping algorithm to obtain CIs for predictive probabilities. We illustrate real-time implementation with R Shiny. Predictive accuracy is investigated using empirical simulations, which suggest this approach more accurately detects peak decline, compared with a uniform threshold of rapid decline. Median area under the ROC curve estimates (Q1-Q3) were 0.817 (0.814-0.822) and 0.745 (0.741-0.747), respectively, implying reasonable accuracy for both. This article demonstrates how individualized rate of change estimates can be coupled with probabilistic predictive inference and implementation for a useful medical-monitoring approach.

PMID: 31816119 [PubMed - as supplied by publisher]

Update on long-term outcomes for chronic rhinosinusitis in cystic fibrosis.

Curr Opin Otolaryngol Head Neck Surg. 2019 Dec 06;:

Authors: Chang MT, Patel ZM

Abstract
PURPOSE OF REVIEW: This article reviews the existing body of literature regarding long-term outcomes of various treatments for chronic rhinosinusitis (CRS) in the cystic fibrosis population.
RECENT FINDINGS: The management of CRS in cystic fibrosis involves a multitude of medical and surgical therapies. Despite their high usage amongst clinicians, corticosteroids and antibiotics currently have little outcome data supporting their use. There is emerging evidence demonstrating beneficial outcomes for DNAse mucolytics and molecular modulators of cystic fibrosis transmembrane conductor regulator (CFTR). Endoscopic sinus surgery (ESS) improves sinonasal outcomes in cystic fibrosis CRS; however, the benefit on pulmonary outcomes remains unclear.
SUMMARY: Successful management of CRS in cystic fibrosis requires multimodal and multidisciplinary care. The long-term outcome data is variable for different treatment modalities. There is recent evidence supporting the role of DNAse mucolytics, CFTR-targeting therapies, and ESS in management of cystic fibrosis CRS.

PMID: 31815863 [PubMed - as supplied by publisher]

Somatic growth in cystic fibrosis.

Curr Opin Endocrinol Diabetes Obes. 2019 Dec 04;:

Authors: Lavi E, Gileles-Hillel A, Zangen D

Abstract
PURPOSE OF REVIEW: Cystic fibrosis (CF) is commonly associated with compromised growth especially in severe cases when the pulmonary function (PFT) deteriorates. As growth optimization is an important aspect of CF management, this review will summarize the current knowledge on the prevalence of growth failure in CF patients, and focus on the mechanisms leading to poor growth, on the association of poor linear growth with reduced PFT and on recombinant human growth hormone (rhGH) therapy in CF patients.
RECENT FINDINGS: Despite the improvement in CF care in the last 2 decades, compromised linear growth is still quite prevalent. The pathophysiology of growth failure in CF is multifactorial. Malnutrition due to decreased energy intake increased energy expenditure and malabsorption of ingested nutrients secondary to pancreatic insufficiency, all probably play a major role in growth restriction. In addition, chronic inflammation characteristic of CF may contribute to growth failure via alteration in the GH-insulin-like growth factor 1 signaling and other changes in the growth plate. rhGH and new CFTR modulators may improve some growth parameters.
SUMMARY: Beyond optimizing nutrition and malabsorption, and controlling chronic inflammation, children with CF may benefit from the anabolic effects of rhGH therapy to improve their anthropometric parameters. Whether this translates into better PFT and improved long-term outcomes is yet to be determined.

PMID: 31815786 [PubMed - as supplied by publisher]

Strong toll-like receptor responses in cystic fibrosis patients are associated with higher lung function.

J Cyst Fibros. 2019 Dec 05;:

Authors: Kosamo S, Hisert KB, Dmyterko V, Nguyen C, Black RA, Holden TD, Radella F, Cotten PA, Goss CH, Aitken ML, Wurfel MM

Abstract
BACKGROUND: Cystic fibrosis (CF) airways disease varies widely among patients with identical cystic fibrosis transmembrane conductance regulator (CFTR) genotypes. Robust airway inflammation is thought to be deleterious in CF; inter-individual variation in Toll-like receptor (TLR)-mediated innate immune inflammatory responses (TMIIR) might account for a portion of the phenotypic variation. We tested if TMIIR in people with CF are different than those of healthy controls, and whether higher TMIIR in people with CF are associated with reduced lung function.
METHODS: We cultured whole blood from clinically stable subjects with CF (n = 76) and healthy controls (n = 45) with TLR agonists, and measured cytokine production and expression of TLR-associated genes. We tested for differences in TLR-stimulated cytokine levels between subjects with CF and healthy subjects, and for associations between cytokine and gene expression levels with baseline lung function (forced expiratory volume in one second percent predicted (FEV1%)) and decline in FEV1% over time.
RESULTS: TMIIR in blood from subjects with CF were lower than in healthy controls. Expression of TLR regulators SARM1, TOLLIP, and AKT1 were downregulated in CF. In subjects with CF we found that lower TLR4-agonist-induced IL-8 was associated with lower FEV1% at enrollment (p<0.001) and with greater five year FEV1% decline (p<0.001).
CONCLUSIONS: TMIIR were lower in people with CF relative to healthy controls; however, unexpectedly, greater whole blood TMIIR were positively associated with lung function in people with CF. These findings suggest a complex interaction between inflammation and disease in people with CF.

PMID: 31813753 [PubMed - as supplied by publisher]

Respiratory physical therapy techniques recommended for patients with cystic fibrosis treated in specialized centers.

Braz J Phys Ther. 2019 Nov 29;:

Authors: Donadio MVF, Campos NE, Vendrusculo FM, Stofella AM, Almeida ACDS, Ziegler B, Schivinski CIS, Santuzzi CH, Sarges EDSNF, Gonçalves FM, Ribeiro MÂGO, Santana NN, de Paiva SB, de Godoy VCWP, Aquino EDS

Abstract
BACKGROUND: Respiratory therapy is a part of the treatment of patients with cystic fibrosis (CF). However, there is no information about the main factors influencing the recommendation of the use of different techniques or devices by physical therapists from different specialized centers.
OBJECTIVE: To determine the respiratory therapy techniques recommended for the treatment of patients with CF seen in specialized treatment centers in Brazil.
METHODS: This is a descriptive study including a sample of Brazilian CF specialized treatment centers. Data on demographics, spirometric variables, and recommended respiratory therapy treatment techniques were collected.
RESULTS: Twelve specialized treatment centers with a total of 974 patients were included (13.5±11.3 years old and FEV1 (%) 75.7±27.9). The most recommended techniques were huffing (61.1 % of patients), high frequency oral oscillation (HFOO) (52.0 %), and positive expiratory pressure (PEP) (45.3 %). Most often, recommendation was to perform treatment once (54.8 % of patients) or twice (34 %) a day. There was great variability in the recommendation among the different states. When data were separated by age, there was a predominance of performing conventional and manual techniques in infants and preschool children. There were no significant variations according to pulmonary function. Based on the literature, techniques based on volume, huffing, and PEP were most prevalently performed in international centers.
CONCLUSION: The most recommended treatment techniques for patients with CF in Brazil are huffing, HFOO, and PEP, followed by volume-based techniques. There were geographical variations in the preferred treatment techniques, as well as based on patient age, but not based on the level of pulmonary function.

PMID: 31810864 [PubMed - as supplied by publisher]

Evaluating Long-Term Benefits of Chronic Azithromycin: Furthering Our Quest for Precision Medicine.

Am J Respir Crit Care Med. 2019 Dec 06;:

Authors: Saiman L, Schechter MS

PMID: 31810394 [PubMed - as supplied by publisher]

Determining the pathogenicity of CFTR missense variants: Multiple comparisons of in silico predictors and variant annotation databases.

Genet Mol Biol. 2019 Jul-Sep;42(3):560-570

Authors: Michels M, Matte U, Fraga LR, Mancuso ACB, Ligabue-Braun R, Berneira EFR, Siebert M, Sanseverino MTV

Abstract
Pathogenic variants in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) are responsible for cystic fibrosis (CF), the commonest monogenic autosomal recessive disease, and CFTR-related disorders in infants and youth. Diagnosis of such diseases relies on clinical, functional, and molecular studies. To date, over 2,000 variants have been described on CFTR (~40% missense). Since few of them have confirmed pathogenicity, in silico analysis could help molecular diagnosis and genetic counseling. Here, the pathogenicity of 779 CFTR missense variants was predicted by consensus predictor PredictSNP and compared to annotations on CFTR2 and ClinVar. Sensitivity and specificity analysis was divided into modeling and validation phases using just variants annotated on CFTR2 and/or ClinVar that were not in the validation datasets of the analyzed predictors. After validation phase, MAPP and PhDSNP achieved maximum specificity but low sensitivity. Otherwise, SNAP had maximum sensitivity but null specificity. PredictSNP, PolyPhen-1, PolyPhen-2, SIFT, nsSNPAnalyzer had either low sensitivity or specificity, or both. Results showed that most predictors were not reliable when analyzing CFTR missense variants, ratifying the importance of clinical information when asserting the pathogenicity of CFTR missense variants. Our results should contribute to clarify decision making when classifying the pathogenicity of CFTR missense variants.

PMID: 31808782 [PubMed]

Lung T-Cell Profile Alterations are Associated with Bronchiolitis Obliterans Syndrome in Cystic Fibrosis Lung Transplant Recipients.

Lung. 2019 Dec 05;:

Authors: Hayes D, Harhay MO, Nicol KK, Liyanage NPM, Keller BC, Robinson RT

Abstract
The contribution of T-cells after lung transplant (LTx) remains controversial with no current consensus of their role concerning chronic lung allograft dysfunction. Using flow cytometry to assess T-cell subsets of bronchoalveolar lavage fluid (BALF) in 16 cystic fibrosis (CF) LTx recipients, we identified a decline in CD4+ T-cell frequency and an increase in CD8+ T-cell frequency in patients who developed severe bronchiolitis obliterans syndrome (BOS) (N = 10) when comparing baseline (6 months post-LTx) and follow-up (most recent bronchoscopy-clinical or surveillance per protocol). Comparing BOS to No BOS cohorts, significant differences were found in CD4+ T-cell frequency [17.4 (12.5, 28.2) vs 46.6 (44.4, 48.4), p = 0.003] and CD8+ T-cell frequency [65.6 (62.8, 75.3) vs 39.2 (32.2, 43.3), p = 0.014], respectively. The mean difference of the CD4:CD8 ratio was 0.87 units lower (95% CI - 1.44 to - 0.30, p = 0.006) than patients without BOS, while the median difference of the CD4:CD8 ratio was 0.92 units lower (95% CI - 1.83 to - 0.009, p = 0.048). Therefore, our results suggest that T-cell profiles measured through flow cytometry of BALF in the CF LTx population are associated with the development of severe BOS. Further work is needed in larger patient populations to validate our findings and to determine if this is useful for recipients who underwent LTx for other indications.

PMID: 31807920 [PubMed - as supplied by publisher]

Patients with Idiopathic Pulmonary Nontuberculous Mycobacterial Disease Have Normal Th1/Th2 Cytokine Responses but Diminished Th17 Cytokine and Enhanced Granulocyte-Macrophage Colony-Stimulating Factor Production.

Open Forum Infect Dis. 2019 Dec;6(12):ofz484

Authors: Wu UI, Olivier KN, Kuhns DB, Fink DL, Sampaio EP, Zelazny AM, Shallom SJ, Marciano BE, Lionakis MS, Holland SM

Abstract
Objective: Although disseminated nontuberculous mycobacterial infection is attributed to defects in the interleukin (IL)-12/interferon-γ circuit, the immunophenotype of idiopathic pulmonary nontuberculous mycobacterial (PNTM) disease is not well defined.
Method: We phenotyped Th1, Th2, Th17, and Treg cytokines and colony-stimulating factor production from patients with idiopathic PNTM disease. Data were compared with healthy donors, cystic fibrosis (CF), and primary ciliary dyskinesia (PCD) patients with PNTM disease. Both supernatant cytokine production and intracellular cytokines expressed by various leukocyte subpopulations following mitogen and antigen stimulation were assayed by electrochemiluminescence-based multiplex immunoassay and flow cytometry, respectively.
Results: Regardless of antigen or mitogen stimulation, neither intracellular nor extracellular Th1, Th2, and Treg cytokine levels differed between patients and controls. Th17 cells and IL-17A levels were lower in idiopathic PNTM patients, whereas monocyte granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in response to NTM stimulation was higher compared with healthy donors. Besides, distinct cytokine responses following stimulation by Mycobacterium abscessus and Mycobacterium avium were observed consistently within each group.
Conclusions: The IL-12/IFN-γ circuit appeared intact in patients with idiopathic PNTM disease. However, idiopathic PNTM patients had reduced Th17 response and higher mycobacteria-induced monocyte GM-CSF expression.

PMID: 31807607 [PubMed]

Microfluidics as tool to prepare size-tunable PLGA nanoparticles with high curcumin encapsulation for efficient mucus penetration.

Beilstein J Nanotechnol. 2019;10:2280-2293

Authors: Lababidi N, Sigal V, Koenneke A, Schwarzkopf K, Manz A, Schneider M

Abstract
Great challenges still remain to develop drug carriers able to penetrate biological barriers (such as the dense mucus in cystic fibrosis) and for the treatment of bacteria residing in biofilms, embedded in mucus. Drug carrier systems such as nanoparticles (NPs) require proper surface chemistry and small size to ensure their permeability through the hydrogel-like systems. We have employed a microfluidic system to fabricate poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with a muco-penetrating stabilizer (Pluronic), with a tunable hydrodynamic diameter ranging from 40 nm to 160 nm. The size dependence was evaluated by varying different parameters during preparation, namely polymer concentration, stabilizer concentration, solvent nature, the width of the focus mixing channel, flow rate ratio and total flow rate. Furthermore, the influence of the length of the focus mixing channel on the size was evaluated in order to better understand the nucleation-growth mechanism. Surprisingly, the channel length was revealed to have no effect on particle size for the chosen settings. In addition, curcumin was loaded (EE% of ≈68%) very efficiently into the nanoparticles. Finally, the permeability of muco-penetrating PLGA NPs through pulmonary human mucus was assessed; small NPs with a diameter of less than 100 nm showed fast permeation, underlining the potential of microfluidics for such pharmaceutical applications.

PMID: 31807413 [PubMed]

Expiratory flow limitation in intensive care: prevalence and risk factors.

Crit Care. 2019 Dec 05;23(1):395

Authors: Volta CA, Dalla Corte F, Ragazzi R, Marangoni E, Fogagnolo A, Scaramuzzo G, Grieco DL, Alvisi V, Rizzuto C, Spadaro S

Abstract
BACKGROUND: Expiratory flow limitation (EFL) is characterised by a markedly reduced expiratory flow insensitive to the expiratory driving pressure. The presence of EFL can influence the respiratory and cardiovascular function and damage the small airways; its occurrence has been demonstrated in different diseases, such as COPD, asthma, obesity, cardiac failure, ARDS, and cystic fibrosis. Our aim was to evaluate the prevalence of EFL in patients requiring mechanical ventilation for acute respiratory failure and to determine the main clinical characteristics, the risk factors and clinical outcome associated with the presence of EFL.
METHODS: Patients admitted to the intensive care unit (ICU) with an expected length of mechanical ventilation of 72 h were enrolled in this prospective, observational study. Patients were evaluated, within 24 h from ICU admission and for at least 72 h, in terms of respiratory mechanics, presence of EFL through the PEEP test, daily fluid balance and followed for outcome measurements.
RESULTS: Among the 121 patients enrolled, 37 (31%) exhibited EFL upon admission. Flow-limited patients had higher BMI, history of pulmonary or heart disease, worse respiratory dyspnoea score, higher intrinsic positive end-expiratory pressure, flow and additional resistance. Over the course of the initial 72 h of mechanical ventilation, additional 21 patients (17%) developed EFL. New onset EFL was associated with a more positive cumulative fluid balance at day 3 (103.3 ml/kg) compared to that of patients without EFL (65.8 ml/kg). Flow-limited patients had longer duration of mechanical ventilation, longer ICU length of stay and higher in-ICU mortality.
CONCLUSIONS: EFL is common among ICU patients and correlates with adverse outcomes. The major determinant for developing EFL in patients during the first 3 days of their ICU stay is a positive fluid balance. Further studies are needed to assess if a restrictive fluid therapy might be associated with a lower incidence of EFL.

PMID: 31806045 [PubMed - in process]

Ultra-small TPGS-PLGA Hybrid Nanoparticles for Site-specific Delivery of Antibiotics into Pseudomonas Aeruginosa Biofilms in Lungs.

ACS Appl Mater Interfaces. 2019 Dec 05;:

Authors: Wan F, Bohr SS, Kłodzińska SN, Jumaa H, Huang Z, Nylander T, Thygesen MB, Sørensen KK, Jensen KJ, Sternberg C, Hatzakis NS, Mørck Nielsen H

Abstract
Inhaled antibiotic treatment of cystic fibrosis (CF)-related bacterial biofilm infections is challenging due to the pathological environment of the lungs. Here, we present an 'environment adaptive' nanoparticle composed of a solid poly lactic-co-glycolic acid (PLGA) core and a mucus-inert, enzymatically cleavable shell of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) for site-specific delivery of antibiotics to bacterial biofilms via aerosol administration. The hybrid nanoparticles with ultra-small size were self-assembled via a nanoprecipitation process by using a facile microfluidic method. The interactions of the nanoparticles with the biological barriers were comprehensively investigated by using cutting-edge techniques (e.g. quartz crystal microbalance with dissipation monitoring, total internal reflection fluorescence microscopy-based particle tracking, in vitro biofilm model cultured in a flow-chamber system, and quantitative imaging analysis). Our results suggest that the mucus-inert, enzymatically cleavable TPGS shell enables the nanoparticles to penetrate through the mucus, accumulate in the deeper layer of the biofilms, and serve as sustained release depot, thereby, improving the killing efficacy of azithromycin (a macrolide antibiotic) against biofilm-forming Pseudomonas aeruginosa. In conclusion, the ultra-small TPGS-PLGA hybrid nanoparticles represent an efficient delivery system to overcome the multiple barriers and release antibiotics with a sustained manner in the vicinity of the biofilm-forming bacteria.

PMID: 31804792 [PubMed - as supplied by publisher]

Treatment for avascular necrosis of bone in people with sickle cell disease.

Cochrane Database Syst Rev. 2019 Dec 05;12:CD004344

Authors: Martí-Carvajal AJ, Solà I, Agreda-Pérez LH

Abstract
BACKGROUND: Avascular necrosis of bone is a frequent and severe complication of sickle cell disease and its treatment is not standardised. This is an update of a previously published Cochrane Review.
OBJECTIVES: To determine the impact of any surgical procedure compared with other surgical interventions or non-surgical procedures, on avascular necrosis of bone in people with sickle cell disease in terms of efficacy and safety.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Additional trials were sought from both ongoing trial registries and the reference lists of papers identified by the search strategy. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 17 September 2019.
SELECTION CRITERIA: Randomized clinical trials comparing specific therapies for avascular necrosis of bone in people with sickle cell disease.
DATA COLLECTION AND ANALYSIS: Each author independently extracted data and assessed trial quality. The quality of the evidence was assessed using GRADE. Given only one trial was identified, meta-analyses were not possible.
MAIN RESULTS: One trial (46 participants) was eligible for inclusion. After randomization eight participants were withdrawn, mainly because they declined to participate in the trial. Data were analysed for 38 participants at the end of the trial. After a mean follow-up of three years, hip core decompression and physical therapy did not show clinical improvement when compared with physical therapy alone using the score from the original trial (an improvement of 18.1 points for those treated with intervention therapy versus an improvement of 15.7 points with control therapy). We are very uncertain whether there is any difference between groups regarding major complications (hip pain, risk ratio 0.95 (95% confidence interval 0.56 to 1.60; vaso-occlusive crises, risk ratio 1.14 (95% confidence interval 0.72 to 1.80; very low quality of evidence); and acute chest syndrome, risk ratio 1.06 (95% confidence interval 0.44 to 2.56; very low quality of evidence)). This trial did not report results on mortality or quality of life.
AUTHORS' CONCLUSIONS: We found no evidence that adding hip core decompression to physical therapy achieves clinical improvement in people with sickle cell disease with avascular necrosis of bone compared to physical therapy alone. However, we highlight that our conclusion is based on one trial with high attrition rates. Further randomized controlled trials are necessary to evaluate the role of hip-core depression for this clinical condition. Endpoints should focus on participants' subjective experience (e.g. quality of life and pain) as well as more objective 'time-to-event' measures (e.g. mortality, survival, hip longevity). The availability of participants to allow adequate trial power will be a key consideration for endpoint choice.

PMID: 31803937 [PubMed - in process]