Periodontal Status and Subgingival Biofilms in Cystic Fibrosis Adults.

Pol J Microbiol. 2019 Sep;68(3):377-382

Authors: Pawlaczyk-Kamieńska T, Śniatała R, Batura-Gabryel H, Borysewicz-Lewicka M, Cofta S

Abstract
The aim of this study was to assess the periodontal status of cystic fibrosis (CF) adult patients and to evaluate whether there is a correlation between the bacterial population of the subgingival biofilm and the health status of the periodontal tissues in this group of adults. The study involved 22 cystic fibrosis adult patients. The periodontal condition was assessed using Plaque Index (PLI), Gingival Index (GI), and Probing Pocket Depth (PPD). The gingival sulcus samples were analyzed by the Real-Time PCR assay (RT-PCR). Majority of patients showed moderate or severe bacterial dental plaque accumulation, but none of them had clinical symptoms of periodontal diseases. RT-PCR showed the presence of periopathogens in 50% of patients. Red complex microorganisms were detected in 9.09%, orange complex in 27.27%, and green complex in 31.82% of the samples analyzed. In cystic fibrosis patients colonized by periopathogens, the periodontal markers were significantly higher in comparison to not colonized by periopathogens patients. Despite the widespread presence of bacterial dental deposits in the cystic fibrosis adult patients examined, none of them has clinical symptoms of periodontal disease; however, the presence of periodontal pathogens in subgingival biofilm may represent a possible risk factor of this disease in the future. An unsatisfactory level of oral hygiene in any patient with cystic fibrosis indicates a need to focus on standards of dental care for such patients.
The aim of this study was to assess the periodontal status of cystic fibrosis (CF) adult patients and to evaluate whether there is a correlation between the bacterial population of the subgingival biofilm and the health status of the periodontal tissues in this group of adults. The study involved 22 cystic fibrosis adult patients. The periodontal condition was assessed using Plaque Index (PLI), Gingival Index (GI), and Probing Pocket Depth (PPD). The gingival sulcus samples were analyzed by the Real-Time PCR assay (RT-PCR). Majority of patients showed moderate or severe bacterial dental plaque accumulation, but none of them had clinical symptoms of periodontal diseases. RT-PCR showed the presence of periopathogens in 50% of patients. Red complex microorganisms were detected in 9.09%, orange complex in 27.27%, and green complex in 31.82% of the samples analyzed. In cystic fibrosis patients colonized by periopathogens, the periodontal markers were significantly higher in comparison to not colonized by periopathogens patients. Despite the widespread presence of bacterial dental deposits in the cystic fibrosis adult patients examined, none of them has clinical symptoms of periodontal disease; however, the presence of periodontal pathogens in subgingival biofilm may represent a possible risk factor of this disease in the future. An unsatisfactory level of oral hygiene in any patient with cystic fibrosis indicates a need to focus on standards of dental care for such patients.

PMID: 31880883 [PubMed - in process]

Effects of Long-Term Exercise on Liver Cyst in Polycystic Liver Disease Model Rats.

Med Sci Sports Exerc. 2019 Dec 26;:

Authors: Sato Y, Qiu J, Miura T, Kohzuki M, Ito O

Abstract
BACKGROUND: Polycystic liver disease (PLD) is a hereditary liver disease with progressive enlargement of fluid-filled liver cysts, which causes abdominal discomfort and worsens quality of life. Long-term exercise has beneficial effects in various organs, but the effects of long-term exercise on PLD are unclear. Therefore, the aim of this study was to investigate whether long-term exercise inhibits liver cyst formation and fibrosis.
METHODS: Polycystic kidney (PCK) rats, a model of PLD, were randomly divided into a sedentary group and a long-term exercise group, which underwent treadmill running for 12weeks (28 m/min, 60 min/day, 5 days/week). Sprague-Dawley (SD) rats were set as a control group. After 12 weeks, exercise capacity, histology and signaling cascades of PLD were examined.
RESULTS: Compared with control SD rats, PCK rats showed a low exercise capacity before exercise protocol. After 12 weeks, the exercise improved the exercise capacity and ameliorated liver cyst formation and fibrosis. The exercise also significantly decreased the number of Ki-67 positive cells, the expression of cystic fibrosis transmembrane conductance regulator, aquaporin 1, transforming growth factor -β and type 1 collagen and the phosphorylation of extracellular signal-regulated kinase, mammalian target of rapamycin and S6, and increased the phosphorylation of AMP-activated protein kinase in the liver of PCK rats.
CONCLUSIONS: The present results indicated that long-term exercise with a moderate intensity ameliorates liver cyst formation and fibrosis with the inhibition of signaling cascades responsible for cellular proliferation and fibrosis in PCK rats.

PMID: 31880641 [PubMed - as supplied by publisher]

The diagnosis of hypersensitivity to antibiotics is rarely confirmed by allergy work-up in cystic fibrosis patients.

Pediatr Allergy Immunol. 2019 Dec 27;:

Authors: Braun C, Reix P, Durieu I, Nove-Josserand R, Durupt S, Ohlmann C, Mainguy C, Nicolas JF, Nosbaum A, Jubin V

Abstract
BACKGROUND: Cystic fibrosis (CF) patients receive many antibiotic treatments for recurrent respiratory infections and frequently report antibiotic hypersensitivity reactions (HSRs).
METHODS: In this retrospective study, medical records of CF patients were reviewed to clarify the clinical features, the culprit antibiotics and the prevalence of antibiotic HSRs in the CF population.
RESULTS: From 601 CF patients, 95 suspected antibiotic HSRs occurred in 60 patients (prevalence of 10.0%). β-lactams were the most common inducers but cotrimoxazole was also frequently involved. 76 of 95 suspected HSRs were assessed by allergy work-up including skin tests (43/76 reactions) and/or drug reintroduction as a full course of the culprit antibiotic (73/76 reactions). From the 43 suspected HSRs that were skin tested, only 3 had positive skin tests and were not subjected to drug readministration. All the other 73 suspected HSRs received a full course of the culprit antibiotic: HSR symptoms recurred in 10/73 cases and therefore were considered as confirmed antibiotic HSRs; for the remaining 63 suspected HSRs that did not relapse after drug readministration, the diagnosis of antibiotic HSRs was excluded. In summary, 13/76 suspected HSRs were confirmed as antibiotic HSRs.
CONCLUSION: The prevalence of suspected and confirmed antibiotic HSRs in CF patients appears similar to that reported in the general population. Of note, most of the antibiotic Suspected HSRs are not confirmed after allergology work-up. A complete allergy work-up appears therefore crucial to make a correct diagnosis and to avoid unnecessary contra-indication of major antibiotics.

PMID: 31880334 [PubMed - as supplied by publisher]

The genetics and genomics of cystic fibrosis.

J Cyst Fibros. 2019 Dec 23;:

Authors: Sharma N, Cutting GR

Abstract
Genetics is the branch of biology concerned with study of individual genes and how they work whereas genomics is involved with the analysis of all genes and their interactions. Both of these approaches have been applied extensively to CF. Identification of the CFTR gene initiated the dissection of CF genetics at the molecular level. Subsequently, thousands of variants were found in the gene and the functional consequences of a subset have been studied in detail. The completion of the human genome ushered in a new phase of study where the role of genes beyond CFTR could be evaluated for their contribution to the severity of CF. This will be a brief overview of the contribution of these complementary methods to our understanding of CF pathogenesis.

PMID: 31879237 [PubMed - as supplied by publisher]

Burkholderia cepacia complex: 11 years of surveillance in patients with Cystic Fibrosis in Posadas, Argentina.

Rev Argent Microbiol. 2019 Dec 23;:

Authors: Martina PF, Martinez M, Rivas S, Leguizamón L, Von Specht M, Ferreras J

Abstract
Cystic fibrosis patients with Burkholderia cepacia complex pulmonary infections have high morbidity and mortality. Worldwide, this disease is undergoing substantial epidemiological changes. Advances in the diagnosis and treatment have conditioned an increase in child survival as well as in the proportion of affected adults. In order to know our reality, we refer to an epidemiological study in 64 CF patients during 11 years of surveillance, focusing on infections caused by Burkholderia species. Conventional and automated phenotypic tests, restriction fragment length polymorphism-recA, recA gene sequencing, and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry were applied. Bacterial isolates were also tested for antimicrobial susceptibility patterns. The prevalence of Burkholderia cepacia complex was 9.4%. Based on recA gene sequencing, the most common species identified were Burkholderia cenocepacia (67.3%) and Burkholderia vietnamiensis (20.3%). Ceftazidime and meropenem were the most active, inhibiting 53% and 46% of isolates, respectively. This report represents the first systematic study of Burkholderia infections in our CF population since beginning of monitoring and treatment and highlights the importance of continued longitudinal studies.

PMID: 31879049 [PubMed - as supplied by publisher]

Effects of aerobic interval training on glucose tolerance in children and adolescents with cystic fibrosis: a randomized trial protocol.

Trials. 2019 Dec 26;20(1):768

Authors: Monteiro KS, Azevedo MP, Jales LM, da Silva FEP, Arrais RF, de Mendonça KMPP

Abstract
BACKGROUND: Individuals with cystic fibrosis (CF) may develop CF-related diabetes (CFDR). This comorbidity is related to a poorer quality of life, microvascular complications, a decline in lung function, and an increase in exacerbations, as well as delayed growth and puberty. Evidence exists that physical exercise contributes to glycemic control in individuals with non-CF-related diabetes. This exercise is usually continuous with moderate intensity and long duration, which can cause muscle dyspnea and fatigue in CF individuals. Aerobic interval training (AIT) emerges as a safe and effective alternative for treating these individuals. The objective of this study is to evaluate the effects of AIT on glucose tolerance in children and adolescents with CF.
METHODS: This study will be a two-arm, prospectively registered, randomized controlled trial with blind assessors and twenty 6- to 18-year-old individuals with cystic fibrosis (CF) from two different Brazilian states. People with CF will be randomly allocated to either the experimental or control group using block randomization, stratified by puberty stage,. Participants from both groups will receive an educational intervention and will be asked to continue their usual daily treatment for the full duration of the study. Those in the experimental group will perform AIT on a cycle ergometer at home three times a week, for 8 consecutive weeks. The sample characterization will include an assessment of puberty stage, socioeconomic status, dyspnea, and anthropometry. The primary outcome will be the change in glucose tolerance, while the secondary outcomes will include lung function, exercise tolerance, respiratory muscle strength, quality of life, and CF exacerbations. All outcomes will be assessed at baseline, week 9, and week 17.
DISCUSSION: This is the first study to evaluate the effects of AIT on glucose tolerance in children and adolescents with CF. This study will serve as a basis for guiding clinical practice and decision-making in treating glucose intolerance and CF-related diabetes (CFRD) in children and adolescents with CF.
TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System: NCT03653949. Registered on August 31, 2018.

PMID: 31878961 [PubMed - in process]

Autophagy, an important therapeutic target for pulmonary fibrosis diseases.

Clin Chim Acta. 2019 Dec 23;:

Authors: Zhao H, Wang Y, Qiu T, Liu W, Yao P

Abstract
As an evolutionarily conserved intracellular degradation pathway, autophagy is essential to cellular homeostasis. Several studies have demonstrated that autophagy showed an important effect on some pulmonary fibrosis diseases, including idiopathic pulmonary fibrosis (IPF), cystic fibrosis lung disease, silicosis and smoking-induced pulmonary fibrosis. For example, autophagy mitigates the pathological progression of IPF by regulating the apoptosis of fibroblasts and the senescence of alveolar epithelial cells. In addition, autophagy ameliorates cystic fibrosis lung disease via rescuing transmembrane conductance regulators (CFTRs) to the plasma membrane. Furthermore, autophagy alleviates the silica-induced pulmonary fibrosis by decreasing apoptosis of alveolar epithelial cells in silicosis. However, excessive macrophage autophagy aggravates the pathogenesis of silicosis fibrosis by promoting the proliferation and migration of lung fibroblasts in silicosis. Autophagy is also involved in smoking-induced pulmonary fibrosis, coal workers' pneumoconiosis, ionizing radiation-mediated pulmonary fibrosis and heavy metal nanoparticle-mediated pulmonary fibrosis. In this review, the role and signalling mechanisms of autophagy in the progression of pulmonary fibrosis diseases have been systematically analysed. It has provided a new insight into the therapeutic potential associated with autophagy in pulmonary fibrosis diseases. In conclusion, the targeting of autophagy might prove to be a prospective avenue for the therapeutic intervention of pulmonary fibrosis diseases.

PMID: 31877297 [PubMed - as supplied by publisher]

Duration of antibiotic therapy in non-cystic fibrosis bronchiectasis.

Curr Pulmonol Rep. 2019 Dec;8(4):160-165

Authors: Somayaji R, Goss CH

Abstract
Purpose of review: a)We conducted a review of the current evidence relating to antibiotic duration in the short and long-term management of non-cystic fibrosis bronchiectasis.
Recent findings: b)In non-cystic fibrosis pulmonary exacerbations, evidence is primarily based on expert consensus and recent guidelines recommend antibiotic durations of approximately 14 days. Chronic antibiotics (oral or inhaled) are recommended in patients with frequent exacerbations or with chronic Pseudomonas aeruginosa airways infection. Macrolides are the best studied therapies for long-term use with evidence for effect limited to a 12 month duration. Encouragingly, there are increased efforts to develop registries and conduct larger population level studies to improve patient care.
Summary: c)There is a paucity of evidence for optimal antibiotic strategies in exacerbations and chronic maintenance in persons with non-cystic fibrosis bronchiectasis. Rationally designed studies which utilize a registry and population-based approach will be critical to build evidence-based strategies to optimize management of non-cystic fibrosis bronchiectasis.

PMID: 31875166 [PubMed]

Microarray analysis reveals the inhibition of intestinal expression of nutrient transporters in piglets infected with porcine epidemic diarrhea virus.

Sci Rep. 2019 Dec 24;9(1):19798

Authors: Zhang J, Zhao D, Yi D, Wu M, Chen H, Wu T, Zhou J, Li P, Hou Y, Wu G

Abstract
Porcine epidemic diarrhea virus (PEDV) infection can induce intestinal dysfunction, resulting in severe diarrhea and even death, but the mode of action underlying these viral effects remains unclear. This study determined the effects of PEDV infection on intestinal absorption and the expression of genes for nutrient transporters via biochemical tests and microarray analysis. Sixteen 7-day-old healthy piglets fed a milk replacer were randomly allocated to one of two groups. After 5-day adaption, piglets (n = 8/group) were orally administrated with either sterile saline or PEDV (the strain from Yunnan province) at 104.5 TCID50 (50% tissue culture infectious dose) per pig. All pigs were orally infused D-xylose (0.1 g/kg BW) on day 5 post PEDV or saline administration. One hour later, jugular vein blood samples as well as intestinal samples were collected for further analysis. In comparison with the control group, PEDV infection increased diarrhea incidence, blood diamine oxidase activity, and iFABP level, while reducing growth and plasma D-xylose concentration in piglets. Moreover, PEDV infection altered plasma and jejunal amino acid profiles, and decreased the expression of aquaporins and amino acid transporters (L-type amino acid transporter 1, sodium-independent amino acid transporter, B(°,+)-type amino acid transport protein, sodium-dependent neutral amino acid transporter 1, sodium-dependent glutamate/aspartate transporter 3, and peptide transporter (1), lipid transport and metabolism-related genes (lipoprotein lipase, apolipoprotein A1, apolipoprotein A4, apolipoprotein C2, solute carrier family 27 member 2, solute carrier family 27 member 4, fatty acid synthase, and long-chain acyl-CoA synthetase (3), and glucose transport genes (glucose transporter-2 and insulin receptor) in the jejunum. However, PEDV administration increased mRNA levels for phosphoenolpyruvate carboxykinase 1, argininosuccinate synthase 1, sodium/glucose co-transporter-1, and cystic fibrosis transmembrane conductance regulator in the jejunum. Collectively, these comprehensive results indicate that PEDV infection induces intestinal injury and inhibits the expression of genes encoding for nutrient transporters.

PMID: 31875021 [PubMed - in process]

Male Partners of Infertile Couples with Congenital Unilateral Absence of the Vas Deferens are mainly Non-Azoospermic.

Andrology. 2019 Dec 24;:

Authors: Mieusset R, Bieth E, Daudin M, Isus F, Delaunay B, Bujan L, Monteil L, Fauquet I, Huyghe E, Hamdi SM

Abstract
BACKGROUND: Men with congenital unilateral absence of vas deferens (CUAVD) were reported to be mainly azoospermic, with both unilateral renal absence (URA) and mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) but some have neither.
OBJECTIVES: To assess whether in infertile couples the male partners with CUAVD are mainly azoospermic men.
MATERIAL AND METHODS: Retrospective study in a unique university hospital; reproductive, clinical, CFTR analysis and seminal data of male partners of infertile couples (from 1998 to 2018) were analyzed. Diagnosis of CUAVD was based on transrectal ultrasounds (TRUS): complete or partial absence of one vas deferens (VD) with complete contralateral VD confirmed in 63 men. Distribution of sperm count in 3 classes: azoospermia, oligozoospermia or normozoospermia. Ultrasound determination of renal status; seminal biomarkers assays; search for CFTR mutations.
RESULTS: Among the 63 men 39.7% displayed azoospermia, 27% oligozoospermia and 33.3% normozoospermia; 42% of the non azoospermic men (16/38) had previously obtained a natural pregnancy. We found URA in 17/59 patients (29%). Among 50 men with CFTR testing 5 carried an allele associated with Cystic Fibrosis (CF) belonging to the 29 men without renal anomalies, indicating a high allelic frequency (8.6%). The 63 patients displayed high rates of surgical histories for undescended testicles or inguinal hernia, low values of semen volume and of total seminal glycerophosphocholine.
CONCLUSIONS: Our results indicate that men with CUAVD mainly display oligozoospermia or normozoospermia and that they were previously fertile. They clearly confirm, first, that CFTR testing is recommended in CUAVD men and it should be mandatory for those with normal kidneys; and, second, that TRUS is needed for the diagnosis of CUAVD. As CUAVD may be present whatever the sperm count, biological warnings are represented by semen volume and seminal epididymal markers, and clinical warnings by surgical histories of undescended testes or inguinal hernia.

PMID: 31872980 [PubMed - as supplied by publisher]

Validation of Automated Perfusion-Weighted Phase-Resolved Functional Lung (PREFUL)-MRI in Patients With Pulmonary Diseases.

J Magn Reson Imaging. 2019 Dec 24;:

Authors: Behrendt L, Voskrebenzev A, Klimeš F, Gutberlet M, Winther HB, Kaireit TF, Alsady TM, Pöhler GH, Derlin T, Wacker F, Vogel-Claussen J

Abstract
BACKGROUND: Perfusion-weighted (Qw) noncontrast-enhanced proton lung MRI is a promising technique for assessment of pulmonary perfusion, but still requires validation.
PURPOSE: To improve perfusion-weighted phase-resolved functional lung (PREFUL)-MRI, to validate PREFUL with perfusion single photon emission computed tomography (SPECT) as a gold standard, and to compare PREFUL with dynamic contrast-enhanced (DCE)-MRI as a reference.
STUDY TYPE: Retrospective.
POPULATION: Twenty patients with chronic obstructive pulmonary disease (COPD), 14 patients with cystic fibrosis (CF), and 21 patients with chronic thromboembolic pulmonary hypertension (CTEPH) were included.
FIELD STRENGTH/SEQUENCE: For PREFUL-MRI, a spoiled gradient echo sequence and for DCE-MRI a 3D time-resolved angiography with stochastic trajectories sequence were used at 1.5T.
ASSESSMENT: PREFUL-MRI coronal slices were acquired in free-breathing. DCE-MRI was performed in breath-hold with injection of 0.03 mmol/kg bodyweight of gadoteric acid at a rate of 4 cc/s. Perfusion SPECT images were obtained for six CTEPH patients. Images were coregistered. An algorithm to define the appropriate PREFUL perfusion phase was developed using perfusion SPECT data. Perfusion defect percentages (QDP) and Qw-values were calculated for all methods. For PREFUL quantitative perfusion values (PREFULQ ) and for DCE pulmonary blood flow (PBF) was calculated.
STATISTICAL TESTS: Obtained parameters were assessed using Pearson correlation and Bland-Altman analysis.
RESULTS: Qw-SPECT correlated with Qw-DCE (r = 0.50, P < 0.01) and Qw-PREFUL (r = 0.47, P < 0.01). Spatial overlap of QDP maps showed an agreement ≥67.7% comparing SPECT and DCE, ≥64.1% for SPECT and PREFUL, and ≥60.2% comparing DCE and PREFUL. Significant correlations of Qw-PREFUL and Qw-DCE were found (COPD: r = 0.79, P < 0.01; CF: r = 0.77, P < 0.01; CTEPH: r = 0.73, P < 0.01). PREFULQ /PBF correlations were similar/lower (CF, CTEPH: P > 0.12; COPD: P < 0.01) compared to Qw-PREFUL/DCE correlations. PREFULQ -values were higher/similar compared to PBF-values (COPD, CF: P < 0.01; CTEPH: P = 0.026).
DATA CONCLUSION: The automated PREFUL algorithm may allow for noncontrast-enhanced pulmonary perfusion assessment in COPD, CF, and CTEPH patients comparable to DCE-MRI.
LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

PMID: 31872556 [PubMed - as supplied by publisher]

Controlled delivery of ciprofloxacin and ivacaftor via sinus stent in a preclinical model of Pseudomonas sinusitis.

Int Forum Allergy Rhinol. 2019 Dec 23;:

Authors: Lim DJ, McCormick J, Skinner D, Zhang S, Elder JB, McLemore JG, Allen M, West JM, Grayson JW, Rowe SM, Woodworth BA, Cho DY

Abstract
BACKGROUND: Pseudomonas aeruginosa is common in chronic rhinosinusitus (CRS) and frequently resistant to antibiotic treatment. We recently described the ciprofloxacin and ivacaftor-releasing biodegradable sinus stent (CISS)-a drug-delivery system that administers ciprofloxacin and the mucociliary activator (ivacaftor) at high local concentrations with prolonged mucosal contact time and sustained delivery. The objective of this study is to evaluate the efficacy of the CISS in a rabbit model of P aeruginosa (PAO1 strain) sinusitis.
METHODS: Ciprofloxacin/ivacaftor (double layer) was coated on biodegradable poly-D/L-lactic acid (PLLA). A total of 10 sinus stents (5 bare PLLA stent controls, 5 CISSs) were placed unilaterally in rabbit maxillary sinuses via dorsal sinusotomy after inducing infection for 1 week with PAO1. Animals were assessed 3 weeks after stent insertion with sinus culture, nasal endoscopy, computed tomography scan, histopathology, and in-vivo sinus potential difference (SPD) assay.
RESULTS: Rabbits treated with CISS had significant reductions in computed tomography (∆ Kerschner scale: control, 0.55 ± 0.92; CISS, -5.92 ± 1.69; p = 0.024) and endoscopy (control, 4.0 ± 0.0; CISS, 1.875 ± 0.74; p = 0.003) scores. A 2-log reduction of PAO1 was observed (control, -2.14 ± 0.77; CISS, 1.84 ± 1.52; p = 0.047). SPD revealed significantly increased Cl- transport in the CISS group compared with the control group (Cl- -free + forskolin ΔPD: control, -4.23 ± 1.04 mV; CISS, -18.36 ± 6.31 mV; p = 0.026). Finally, marked improvements were noted in the histology of the mucosa and submucosa in treated animals.
CONCLUSION: The CISS had robust clinical efficacy in treating P aeruginosa rabbit sinusitis. The innovative design of double-layered drug coating on the surface of the biodegradable stent may provide therapeutic advantages over current treatment strategies for P aeruginosa sinusitis.

PMID: 31872532 [PubMed - as supplied by publisher]

Therapeutic drug monitoring-guided high dose meropenem therapy of a multidrug resistant Acinetobacter baumannii - A case report.

Respir Med Case Rep. 2020;29:100966

Authors: Liebchen U, Paal M, Jung J, Schroeder I, Frey L, Zoller M, Scharf C

Abstract
Background: Infections with multidrug resistant Acinetobacter baumannii in immunocompromised patients are life-threatening. Therapeutic options are rare in this context, but patients are dependent on an effective antibiotic therapy. Thus, new antibiotic strategies are deemed necessary.
Case presentation: This case report recounts the therapeutic drug monitoring-guided meropenem therapy of a 32 years old patient admitted with acute exacerbation of cystic fibrosis. Veno-venous extracorporeal membrane oxygenation was initiated on the first day of admission to the intensive care unit. The patient showed insufficient serum trough levels of meropenem despite the maximum approved dose (2g every 8h) was administered which was due to augmented renal clearance. Through continuous infusion of the same cumulative dose, target levels were reached. On day 17 of admission, the patient underwent successful double-lung-transplant surgery and extracorporeal membrane oxygenation was ended. Unfortunately, the donor's lung was colonized with a multidrug resistant Acinetobacter baumannii that was positive for OXA-23 carbapenemase. Hence a combination therapy of intravenous sulbactam, tigecycline, meropenem and inhalative colistin was established, with a known minimal inhibitory concentration for meropenem of 32 mg/l. Under continuous infusion of 8 g meropenem/day, serum levels exceeded 32 mg/l over 12 days. The patient was transferred from the intensive care unit to a general ward without any signs of infection.
Conclusions: Therapeutic drug monitoring-guided meropenem may be a sound new therapeutic option in eradicating multidrug resistant Acinetobacter and offer a novel therapeutic option in the field of personalized medicine.

PMID: 31871885 [PubMed]

Calcium-activated chloride channel regulator 1 (CLCA1): More than a regulator of chloride transport and mucus production.

World Allergy Organ J. 2019 Nov;12(11):100077

Authors: Liu CL, Shi GP

Abstract
CLCA1 is a member of the CLCA (calcium-activated chloride channel regulator) family and plays an essential role in goblet cell mucus production from the respiratory tract epithelium. CLCA1 also regulates Ca2+-dependent Cl- transport that involves the channel protein transmembrane protein 16A (TMEM16A) and its accessary molecules. CLCA1 modulates epithelial cell chloride current and participates in the pathogenesis of mucus hypersecretory-associated respiratory and gastrointestinal diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonia, colon colitis, cystic fibrosis intestinal mucous disease, ulcerative colitis, and gastrointestinal parasitic infection. Most studies have been focused on the expression regulation of CLCA1 in human specimens. Limited studies used the CLCA1-deficient mice and CLCA1 blocking agents and yielded inconsistent conclusions regarding its role in these diseases. CLCA1 not only regulates mucin expression, but also participates in innate immune responses by binding to yet unidentified molecules on inflammatory cells for cytokine and chemokine production. CLCA1 also targets lymphatic endothelial cells and cancer cells by regulating lymphatic cell proliferation and lymphatic sinus growth in the lymphatic organs and controlling cancer cell differentiation, proliferation, and apoptosis, all which depend on the location of the lymphatic vessels, the type of cancers, the presence of Th2 cytokines, and possibly the availability and type of CLCA1-binding proteins. Here we summarize available studies related to these different activities of CLCA1 to assist our understanding of how this secreted modifier of calcium-activated chloride channels (CaCCs) affects mucus production and innate immunity during the pathogenesis of respiratory, gastrointestinal, and malignant diseases.

PMID: 31871532 [PubMed]

A Case of Allergic Bronchopulmonary Aspergillosis (ABPA) in a Patient with a History of Cocaine Use and Tuberculosis.

Case Rep Med. 2019;2019:3265635

Authors: Ayoubi N, Jalali S, Kapadia N

Abstract
Aspergillosis refers to a spectrum of disorders that can occur due to colonization with the Aspergillus fungus. Allergic bronchopulmonary aspergillosis (ABPA) is an airway hypersensitivity reaction to the fungus that is almost exclusively seen in patients with cystic fibrosis or asthma. Here, we present a case of ABPA in a patient with a history of chronic cocaine use and tuberculosis and no history of asthma or cystic fibrosis. The patient had presented with progressively worsening dyspnea for three months as well as a 20-pound weight loss. Diagnosis was made with an elevated IgE against Aspergillus and chest CT findings, which included bronchiectasis and tree-in-bud nodular opacities. The patient was treated with IV methylprednisolone followed by a 4-day course of oral prednisone, with significant improvement. It is our hope to make healthcare providers aware of the potential presence of ABPA in chronic cocaine users and patients with tuberculosis, both of which are not traditionally associated with this condition.

PMID: 31871461 [PubMed]

If it's 'only' asthma, why are children still dying?

Arch Dis Child. 2019 Dec 23;:

Authors: Carroll W, Clayton S, Frost S, Gupta A, Holmes S, Nagakumar P, Levy M

PMID: 31871041 [PubMed - as supplied by publisher]

A screen for antibiotic resistance determinants reveals a fitness cost of the flagellum in Pseudomonas aeruginosa.

J Bacteriol. 2019 Dec 23;:

Authors: Rundell EA, Commodore N, Goodman AL, Kazmierczak BI

Abstract
The intrinsic resistance of Pseudomonas aeruginosa to many antibiotics limits treatment options for pseudomonal infections. P. aeruginosa's outer membrane is highly impermeable and decreases antibiotic entry into the cell. We used an unbiased, high-throughput approach to examine mechanisms underlying outer membrane-mediated antibiotic exclusion. Insertion Sequencing (INSeq) identified genes that altered fitness in the presence of linezolid, rifampicin, and vancomycin, antibiotics to which P. aeruginosa is intrinsically resistant. We reasoned that resistance to at least one of these antibiotics would depend on outer membrane barrier function, as previously demonstrated in Escherichia coli and Vibrio cholerae. This approach demonstrated a critical role of the outer membrane barrier in vancomycin fitness, while efflux pumps were primary contributors to fitness in the presence of linezolid and rifampicin. Disruption of flagellar assembly or function was sufficient to confer a fitness advantage to bacteria exposed to vancomycin. These findings clearly show that loss of flagellar function alone can confer a fitness advantage in the presence of an antibiotic.Importance The cell envelope of Gram-negative bacteria renders them intrinsically resistant to many classes of antibiotics. We used Insertion Sequencing to identify genes whose disruption altered the fitness of a highly antibiotic resistant pathogen, Pseudomonas aeruginosa, in the presence of antibiotics usually excluded by the cell envelope. This screen identified gene products involved in outer membrane biogenesis and homeostasis, respiration and efflux as important contributors to fitness. An unanticipated fitness cost of flagellar assembly and function in the presence of the glycopeptide antibiotic vancomycin was further characterized. These findings have clinical relevance for individuals with Cystic Fibrosis who are infected with P. aeruginosa and undergo treatment with vancomycin for a concurrent Staphylococcus aureus infection.

PMID: 31871033 [PubMed - as supplied by publisher]

Utilizing centralized biorepository samples for biomarkers of cystic fibrosis lung disease severity.

J Cyst Fibros. 2019 Dec 20;:

Authors: Sagel SD, Wagner BD, Ziady A, Kelley T, Clancy JP, Narvaez-Rivas M, Pilewski J, Joseloff E, Sha W, Zelnick L, Setchell KDR, Heltshe SL, Muhlebach MS

Abstract
BACKGROUND: Circulating biomarkers reflective of lung disease activity and severity have the potential to improve patient care and accelerate drug development in CF. The objective of this study was to leverage banked specimens to test the hypothesis that blood-based biomarkers discriminate CF children segregated by lung disease severity.
METHODS: Banked serum samples were selected from children who were categorized into two extremes of phenotype associated with lung function ('mild' or 'severe') based on CF-specific data and were matched on age, gender, CFTR genotype, and P. aeruginosa infection status. Targeted inflammatory proteins, lipids, and discovery metabolite profiles were measured in these serum samples.
RESULTS: The severe cohort, characterized by a lower CF-specific FEV1 percentile, had significantly higher circulating concentrations of high sensitivity C-reactive protein, serum amyloid A, granulocyte colony stimulating factor, and calprotectin compared to the mild cohort. The mild cohort tended to have higher serum linoleic acid concentrations. The metabolite arabitol was lower in the severe cohort while other CF relevant metabolic pathways showed non-significant differences after adjusting for multiple comparisons. A sensitivity analysis to correct for biased estimates that may result from selecting subjects using an extremes of phenotype approach confirmed the protein biomarker findings.
CONCLUSIONS: Circulating inflammatory proteins differ in CF children segregated by lung function. These findings serve to demonstrate the value of maintaining centralized, high quality patient derived samples for future research, with linkage to clinical information to answer testable hypotheses in biomarker development.

PMID: 31870630 [PubMed - as supplied by publisher]

Rapid lung function decline in adults with early-stage cystic fibrosis lung disease.

J Cyst Fibros. 2019 Dec 20;:

Authors: Dasenbrook EC, Fink AK, Schechter MS, Sanders DB, Millar SJ, Pasta DJ, Mayer-Hamblett N

Abstract
RATIONALE: The prevalence of adults living with cystic fibrosis (CF) who have early-stage lung disease is increasing.
OBJECTIVES: Describe the prevalence and evaluate spirometric risk factors associated with the subgroup of patients with early-stage lung disease and FEV1 decline of ≥5% predicted/year.
METHODS: Retrospective cohort study of patients ≥18 years with FEV1% predicted ≥80% included in the US CF Foundation Patient Registry from 2010-2013. Regression models were developed to estimate FEV1 rate of decline. Multivariable logistic analysis was used to assess if spirometric risk factors were associated with FEV1 decline.
MEASUREMENTS AND MAIN RESULTS: 3,029 subjects were in the study cohort. Approximately 15% of the cohort had a substantial decline in lung function ≥5% predicted/year. In multivariable models adjusted for confounders, FEV1/FVC ratio <0.8 (Odds Ratio (OR) 1.63, 95% confidence interval (CI) 1.31 to 2.02) and history of FEV1% predicted variability (OR 2.35,95%CI 1.74 to 3.18) were associated with rapid lung function decline.
CONCLUSIONS: Even among adults with early-stage lung disease, approximately 15% are shown to progress and experience a large decline in lung function. This reinforces the concept that lung function in early-stage CF is not normal or mild. Rather, lung function decline may be delayed, but not avoided, in these individuals. Variability in FEV1% predicted and airway obstruction as measured by FEV1/FVC ratio may identify individuals at increased risk of decline. Adults with early-stage lung disease should be followed in clinic to monitor for onset of decline.

PMID: 31870629 [PubMed - as supplied by publisher]

An exploration into experiences and attitudes regarding risky health behaviours in an adult cystic fibrosis population.

Psychol Health Med. 2019 Dec 23;:1-7

Authors: Keyte R, Egan H, Nash EF, Regan A, Jackson C, Mantzios M

Abstract
Health risk behaviours (HRBs) are prevalent within the cystic fibrosis (CF) population, and there is a lack of research around what influences their engagement. This research explored beliefs associated with HRBs within an adult CF population using qualitative semi-structured interviews. Participants' beliefs towards their CF and its life impact were investigated to explore reasons for engaging in HRB. A desire for normalcy was evident, often accompanied by engagement in everyday HRB as a method of minimising the illness identity. Evidence of a life-orientated illness perspective was also prevalent, with participants engaging in some risky behaviours for fun. Overall, there was a lack of knowledge on the consequences of HRB, with many participants reporting not being informed of these by clinicians. This research highlights a dilemma between clinical recommendations and personal life strategies undertaken by individuals with CF to support their identity.

PMID: 31870175 [PubMed - as supplied by publisher]