Notice NOT-HL-18-606 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-AI-18-005 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity announcement (FOA) is to solicit applications for the Sexually Transmitted Infections Cooperative Research Centers (STI CRC) program. This STI CRC program will facilitate multidisciplinary, synergistic collaborations to support the development of vaccines to control and prevent sexually transmitted infections (STIs) caused by the following pathogens, which have limited candidates in the product development pipeline: Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum. In addition, the FOA will support the development of prophylactic vaccines for herpes simplex virus (HSV).

Prediction of platinum-based chemotherapy efficacy in lung cancer based on LC-MS metabolomics approach.

J Pharm Biomed Anal. 2018 Feb 23;154:95-101

Authors: Peng F, Liu Y, He C, Kong Y, Ouyang Q, Xie X, Liu T, Liu Z, Peng J

Abstract
Lung cancer is the common cause of cancer-related death worldwide. Platinum-based chemotherapy is the cornerstone of treatment for lung cancer. Platinum sensitivity is a major possibility for effective cancer treatment. In this study, several potential biomarkers were identified for evaluating and predicting the response to platinum-based chemotherapy. LC-MS-based metabolomics was performed on plasma samples from 43 lung cancer patients with different chemotherapy efficacy. By combing multivariate statistical analysis, pathway analysis with correlation analysis, 8 potential biomarkers were significantly associated with platinum chemotherapy response. Moreover, a prediction model with these biomarkers involved in citric acid cycle, glutamate metabolism and amino acid metabolism, showed 100% sensitivity and 100% specificity for predicting chemotherapy response in a validation set. Interestingly, 2-hydroxyglutaric acid (2-HG) as an oncometabolite accumulated in lung cancer was remarkably elevated in the partial response (PR) patients. Collectively, our findings implicated that metabolomics can serve as a potential tool to select lung cancer patients that are more likely to benefit from the platinum-based treatment.

PMID: 29544107 [PubMed - as supplied by publisher]

Rationale, design and preliminary results of the Quebec Warfarin Cohort Study.

Clin Cardiol. 2018 Mar 15;:

Authors: Perreault S, Shahabi P, Côté R, Dumas S, Rouleau-Mailloux É, Feroz Zada Y, Provost S, Mongrain I, Dorais M, Huynh T, Kouz S, Diaz A, Blostein M, de Denus S, Turgeon J, Ginsberg J, Lelorier J, Lalonde L, Busque L, Kassis J, Talajic M, Tardif JC, Dubé MP

Abstract
BACKGROUND: Over- and under-coagulation with warfarin is associated with hemorrhagic and thromboembolic events, respectively. Genetic and clinical factors affect warfarin response, and the causes of this variability remain unclear. We present descriptive statistics and test for predictors of poor anticoagulation control.
METHODS: The Quebec Warfarin Cohort (QWC) comprises 1,059 new warfarin users, with prospective follow up using telephone questionnaires every 3 months for one year, and using healthcare administrative databases (RAMQ and Med-Echo) for 5-year prior to cohort entry and up to 10-years following active patient participation. Genetic material was collected and genotyping of CYP2C9 and VKORC1 genes was conducted. Measured outcomes included the percentage of time patients spent within, anticoagulation control, warfarin dose, bleeding, and thromboembolic events. We report the baseline characteristics and outcomes after 1-year of follow-up. Poor anticoagulation control was defined as TTR <60% in 3- to 12-month interval.
RESULTS: Participants had a mean age of 71 years and 62% were men. The most common indication for warfarin was atrial fibrillation. Mean time in the therapeutic range (TTR) was 56% (±25) in the 3-month following warfarin initiation, and 70% (±21) in the 3- to 12-month interval. During follow up, the rate of stroke or systemic embolism was 1.8 events per 100 person-years and 3.3 events per 100 person-years for major bleeding events. Independent predictors of poor anticoagulation control were chronic kidney disease, heart failure, dyslipidemia, and age.
CONCLUSIONS: The QWC represents a good research opportunity to investigate clinical and genetic factors in a warfarin anticoagulated population.

PMID: 29542828 [PubMed - as supplied by publisher]

Pharmacogenomics of Hypertension and Preeclampsia: Focus on Gene-Gene Interactions.

Front Pharmacol. 2018;9:168

Authors: Luizon MR, Pereira DA, Sandrim VC

Abstract
Hypertension is a leading cause of cardiovascular mortality, but only about half of patients on antihypertensive therapy achieve blood pressure control. Preeclampsia is defined as pregnancy-induced hypertension and proteinuria, and is associated with increased maternal and perinatal mortality and morbidity. Similarly, a large number of patients with preeclampsia are non-responsive to antihypertensive therapy. Pharmacogenomics may help to guide the personalized treatment for non-responsive hypertensive patients. There is evidence for the association of genetic variants with variable response to the most commonly used antihypertensive drugs. However, further replication is needed to confirm these associations in different populations. The failure to replicate findings from single-locus association studies has prompted the search for novel statistical methods for data analysis, which are required to detect the complex effects from multiple genes to drug response phenotypes. Notably, gene-gene interaction analyses have been applied to pharmacogenetic studies, including antihypertensive drug response. In this perspective article, we present advances of considering the interactions among genetic polymorphisms of different candidate genes within pathways relevant to antihypertensive drug response, and we highlight recent findings related to gene-gene interactions on pharmacogenetics of hypertension and preeclampsia. Finally, we discuss the future directions that are needed to unravel additional genes and variants involved in the responsiveness to antihypertensive drugs.

PMID: 29541029 [PubMed]

The management of epilepsy in children and adults.

Med J Aust. 2018 Mar 19;208(5):226-233

Authors: Perucca P, Scheffer IE, Kiley M

Abstract
The International League Against Epilepsy has recently published a new classification of epileptic seizures and epilepsies to reflect the major scientific advances in our understanding of the epilepsies since the last formal classification 28 years ago. The classification emphasises the importance of aetiology, which allows the optimisation of management. Antiepileptic drugs (AEDs) are the main approach to epilepsy treatment and achieve seizure freedom in about two-thirds of patients. More than 15 second generation AEDs have been introduced since the 1990s, expanding opportunities to tailor treatment for each patient. However, they have not substantially altered the overall seizure-free outcomes. Epilepsy surgery is the most effective treatment for drug-resistant focal epilepsy and should be considered as soon as appropriate trials of two AEDs have failed. The success of epilepsy surgery is influenced by different factors, including epilepsy syndrome, presence and type of epileptogenic lesion, and duration of post-operative follow-up. For patients who are not eligible for epilepsy surgery or for whom surgery has failed, trials of alternative AEDs or other non-pharmacological therapies, such as the ketogenic diet and neurostimulation, may improve seizure control. Ongoing research into novel antiepileptic agents, improved techniques to optimise epilepsy surgery, and other non-pharmacological therapies fuel hope to reduce the proportion of individuals with uncontrolled seizures. With the plethora of gene discoveries in the epilepsies, "precision therapies" specifically targeting the molecular underpinnings are beginning to emerge and hold great promise for future therapeutic approaches.

PMID: 29540143 [PubMed - in process]

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/03/16

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Management of Anaplastic Thyroid Carcinoma: the Fruits from the ATC Research Consortium of Japan.

J Nippon Med Sch. 2018;85(1):18-27

Authors: Sugitani I, Onoda N, Ito KI, Suzuki S

Abstract
Anaplastic thyroid carcinoma (ATC) accounts for only 1 to 2% of all thyroid carcinomas, but it is one of the most lethal neoplasms in humans. To obtain further insights into this "orphan disease," we have established the ATC Research Consortium of Japan (ATCCJ) in 2009. It represents a multicenter registry for ATC that have been treated in Japan. To date, 67 institutions have taken part in the collaborative research system and over 1,200 cases have been accumulated in its database. Using this big data, several retrospective studies were carried out to evaluate 1) prognostic factors to determine initial treatment policy, 2) significance of extended radical surgery for Stage IVB cases, 3) characteristics of ATC incidentally found on pathological examination and 4) pathological features of ATC with long-term survival. Moreover, the ATCCJ has conducted an investigator-initiated, nationwide, prospective clinical trial since 2012; namely, the feasibility, safety and efficacy study of weekly paclitaxel administration for patients with ATC (UMIN: 000008574). Revised Japanese guidelines for treatment of thyroid tumors are going to adopt the recommendations from the results of this research. Since 2016, the ATCCJ has started the phase II study assessing the efficacy and safety of lenvatinib, a newly developed tyrosine kinase inhibitor for ATC (UMIN: 000020773). Our nationwide clinical trial network will strengthen the activity to recruit orphan disease patients and may discover new strategies to conquer this dismal malignancy in the near future.

PMID: 29540641 [PubMed - in process]

Dopaminergic and Opioid Pathways Associated with Impulse Control Disorders in Parkinson's Disease.

Front Neurol. 2018;9:109

Authors: Erga AH, Dalen I, Ushakova A, Chung J, Tzoulis C, Tysnes OB, Alves G, Pedersen KF, Maple-Grødem J

Abstract
Introduction: Impulse control disorders (ICDs) are frequent non-motor symptoms in Parkinson's disease (PD), with potential negative effects on the quality of life and social functioning. ICDs are closely associated with dopaminergic therapy, and genetic polymorphisms in several neurotransmitter pathways may increase the risk of addictive behaviors in PD. However, clinical differentiation between patients at risk and patients without risk of ICDs is still troublesome. The aim of this study was to investigate if genetic polymorphisms across several neurotransmitter pathways were associated with ICD status in patients with PD.
Methods: Whole-exome sequencing data were available for 119 eligible PD patients from the Norwegian ParkWest study. All participants underwent comprehensive neurological, neuropsychiatric, and neuropsychological assessments. ICDs were assessed using the self-report short form version of the Questionnaire for Impulsive-Compulsive Disorders in PD. Single-nucleotide polymorphisms (SNPs) from 17 genes were subjected to regression with elastic net penalization to identify candidate variants associated with ICDs. The area under the curve of receiver-operating characteristic curves was used to evaluate the level of ICD prediction.
Results: Among the 119 patients with PD included in the analysis, 29% met the criteria for ICD and 63% were using dopamine agonists (DAs). Eleven SNPs were associated with ICDs, and the four SNPs with the most robust performance significantly increased ICD predictability (AUC = 0.81, 95% CI 0.73-0.90) compared to clinical data alone (DA use and age; AUC = 0.65, 95% CI 0.59-0.78). The strongest predictive factors were rs5326 in DRD1, which was associated with increased odds of ICDs, and rs702764 in OPRK1, which was associated with decreased odds of ICDs.
Conclusion: Using an advanced statistical approach, we identified SNPs in nine genes, including a novel polymorphism in DRD1, with potential application for the identification of PD patients at risk for ICDs.

PMID: 29541058 [PubMed]

Detection of mutations in MYOC, OPTN, NTF4, WDR36 and CYP1B1 in Chinese juvenile onset open-angle glaucoma using exome sequencing.

Sci Rep. 2018 Mar 14;8(1):4498

Authors: Huang C, Xie L, Wu Z, Cao Y, Zheng Y, Pang CP, Zhang M

Abstract
Juvenile onset open-angle glaucoma (JOAG) affects patients before 40 years of age, causing high intraocular pressure and severe optic nerve damage. To expand the mutation spectrum of the causative genes in JOAG, with a view to identify novel disease-causing mutations, we investigated MYOC, OPTN, NTF4, WDR36 and CYP1B1 in a cohort of 67 unrelated Chinese JOAG patients. Whole exome sequencing was used to identify possible pathogenic mutations, which were further excluded in normal controls. After sequencing and the use of a database pipeline, as well as predictive assessment filtering, we identified a total of six mutations in three genes, MYOC, OPTN and CYP1B1. Among them, 2 heterozygous mutations in MYOC (c. 1109C > T, p. (P370L); c. 1150G > C, p. (D384H)), 2 heterozygous mutations in OPTN (c. 985A > G, p.(R329G); c. 1481T > G, p. (L494W)) and 2 homozygous mutations in CYP1B1 (c. 1412T > G, p.(I471S); c. 1169G > A, p.(R390H)) were identified as potentially causative mutations. No mutation was detected in NTF4 or WDR36. Our results enrich the mutation spectra and frequencies of MYOC, OPTN and CYP1B1 in JOAG among the Chinese population. Further studies are needed to address the pathogenicity of each of the mutations detected in this study.

PMID: 29540704 [PubMed - in process]

Related Articles

Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases.

J Neuromuscul Dis. 2016 05 27;3(2):209-225

Authors: Punetha J, Kesari A, Uapinyoying P, Giri M, Clarke NF, Waddell LB, North KN, Ghaoui R, O'Grady GL, Oates EC, Sandaradura SA, Bönnemann CG, Donkervoort S, Plotz PH, Smith EC, Tesi-Rocha C, Bertorini TE, Tarnopolsky MA, Reitter B, Hausmanowa-Petrusewicz I, Hoffman EP

Abstract
BACKGROUND: Molecular diagnostics in the genetic myopathies often requires testing of the largest and most complex transcript units in the human genome (DMD, TTN, NEB). Iteratively targeting single genes for sequencing has traditionally entailed high costs and long turnaround times. Exome sequencing has begun to supplant single targeted genes, but there are concerns regarding coverage and needed depth of the very large and complex genes that frequently cause myopathies.
OBJECTIVE: To evaluate efficiency of next-generation sequencing technologies to provide molecular diagnostics for patients with previously undiagnosed myopathies.
METHODS: We tested a targeted re-sequencing approach, using a 45 gene emulsion PCR myopathy panel, with subsequent sequencing on the Illumina platform in 94 undiagnosed patients. We compared the targeted re-sequencing approach to exome sequencing for 10 of these patients studied.
RESULTS: We detected likely pathogenic mutations in 33 out of 94 patients with a molecular diagnostic rate of approximately 35%. The remaining patients showed variants of unknown significance (35/94 patients) or no mutations detected in the 45 genes tested (26/94 patients). Mutation detection rates for targeted re-sequencing vs. whole exome were similar in both methods; however exome sequencing showed better distribution of reads and fewer exon dropouts.
CONCLUSIONS: Given that costs of highly parallel re-sequencing and whole exome sequencing are similar, and that exome sequencing now takes considerably less laboratory processing time than targeted re-sequencing, we recommend exome sequencing as the standard approach for molecular diagnostics of myopathies.

PMID: 27854218 [PubMed - indexed for MEDLINE]

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/03/16

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Investigating Evolutionarily Conserved Molecular Mechanisms Controlling Gene Expression in the Notochord.

Adv Exp Med Biol. 2018;1029:81-99

Authors: Maguire JE, Pandey A, Wu Y, Di Gregorio A

Abstract
Ascidian embryos have been employed as model systems for studies of developmental biology for well over a century, owing to their desirable blend of experimental advantages, which include their rapid development, traceable cell lineage, and evolutionarily conserved morphogenetic movements. Two decades ago, the development of a streamlined electroporation method drastically reduced the time and cost of transgenic experiments, and, along with the elucidation of the complete genomic sequences of several ascidian species, propelled these simple chordates to the forefront of the model organisms available for studies of regulation of gene expression. Numerous ascidian sequences with tissue-specific enhancer activity were isolated and rapidly characterized through systematic in vivo experiments that would require several weeks in most other model systems. These cis-regulatory sequences include a large collection of notochord enhancers, which have been used to visualize notochord development in vivo, to generate mutant phenotypes, and to knock down genes of interest. Moreover, their detailed characterization has allowed the reconstruction of different branches of the notochord gene regulatory network. This chapter describes how the use of transgenic techniques has rendered the ascidian Ciona a competitive model organism for studies of notochord development, evolution, and gene regulation.

PMID: 29542082 [PubMed - in process]

Macrolide antibiotics for bronchiectasis.

Cochrane Database Syst Rev. 2018 Mar 15;3:CD012406

Authors: Kelly C, Chalmers JD, Crossingham I, Relph N, Felix LM, Evans DJ, Milan SJ, Spencer S

Abstract
BACKGROUND: Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation and distortion of the smaller airways. Bacterial colonisation of the damaged airways leads to chronic cough and sputum production, often with breathlessness and further structural damage to the airways. Long-term macrolide antibiotic therapy may suppress bacterial infection and reduce inflammation, leading to fewer exacerbations, fewer symptoms, improved lung function, and improved quality of life. Further evidence is required on the efficacy of macrolides in terms of specific bacterial eradication and the extent of antibiotic resistance.
OBJECTIVES: To determine the impact of macrolide antibiotics in the treatment of adults and children with bronchiectasis.
SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted all searches on 18 January 2018.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) of at least four weeks' duration that compared macrolide antibiotics with placebo or no intervention for the long-term management of stable bronchiectasis in adults or children with a diagnosis of bronchiectasis by bronchography, plain film chest radiograph, or high-resolution computed tomography. We excluded studies in which participants had received continuous or high-dose antibiotics immediately before enrolment or before a diagnosis of cystic fibrosis, sarcoidosis, or allergic bronchopulmonary aspergillosis. Our primary outcomes were exacerbation, hospitalisation, and serious adverse events.
DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of 103 records. We independently screened the full text of 40 study reports and included 15 trials from 30 reports. Two review authors independently extracted outcome data and assessed risk of bias for each study. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures as expected by Cochrane.
MAIN RESULTS: We included 14 parallel-group RCTs and one cross-over RCT with interventions lasting from 8 weeks to 24 months. Of 11 adult studies with 690 participants, six used azithromycin, four roxithromycin, and one erythromycin. Four studies with 190 children used either azithromycin, clarithromycin, erythromycin, or roxithromycin.We included nine adult studies in our comparison between macrolides and placebo and two in our comparison with no intervention. We included one study with children in our comparison between macrolides and placebo and one in our comparison with no intervention.In adults, macrolides reduced exacerbation frequency to a greater extent than placebo (OR 0.34, 95% confidence interval (CI) 0.22 to 0.54; 341 participants; three studies; I2 = 65%; moderate-quality evidence). This translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 8). Data show no differences in exacerbation frequency between use of macrolides (OR 0.31, 95% CI 0.08 to 1.15; 43 participants; one study; moderate-quality evidence) and no intervention. Macrolides were also associated with a significantly better quality of life compared with placebo (MD -8.90, 95% CI -13.13 to -4.67; 68 participants; one study; moderate-quality evidence). We found no evidence of a reduction in hospitalisations (OR 0.56, 95% CI 0.19 to 1.62; 151 participants; two studies; I2 = 0%; low-quality evidence), in the number of participants with serious adverse events, including pneumonia, respiratory and non-respiratory infections, haemoptysis, and gastroenteritis (OR 0.49, 95% CI 0.20 to 1.23; 326 participants; three studies; I2 = 0%; low-quality evidence), or in the number experiencing adverse events (OR 0.83, 95% CI 0.51 to 1.35; 435 participants; five studies; I2 = 28%) in adults with macrolides compared with placebo.In children, there were no differences in exacerbation frequency (OR 0.40, 95% CI 0.11 to 1.41; 89 children; one study; low-quality evidence); hospitalisations (OR 0.28, 95% CI 0.07 to 1.11; 89 children; one study; low-quality evidence), serious adverse events, defined within the study as exacerbations of bronchiectasis or investigations related to bronchiectasis (OR 0.43, 95% CI 0.17 to 1.05; 89 children; one study; low-quality evidence), or adverse events (OR 0.78, 95% CI 0.33 to 1.83; 89 children; one study), in those receiving macrolides compared to placebo. The same study reported an increase in macrolide-resistant bacteria (OR 7.13, 95% CI 2.13 to 23.79; 89 children; one study), an increase in resistance to Streptococcus pneumoniae (OR 13.20, 95% CI 1.61 to 108.19; 89 children; one study), and an increase in resistance to Staphylococcus aureus (OR 4.16, 95% CI 1.06 to 16.32; 89 children; one study) with macrolides compared with placebo. Quality of life was not reported in the studies with children.
AUTHORS' CONCLUSIONS: Long-term macrolide therapy may reduce the frequency of exacerbations and improve quality of life, although supporting evidence is derived mainly from studies of azithromycin, rather than other macrolides, and predominantly among adults rather than children. However, macrolides should be used with caution, as limited data indicate an associated increase in microbial resistance. Macrolides are associated with increased risk of cardiovascular death and other serious adverse events in other populations, and available data cannot exclude a similar risk among patients with bronchiectasis.

PMID: 29543980 [PubMed - as supplied by publisher]

Nutritional Status the First Two Years of Life in Cystic Fibrosis Diagnosed by Newborn Screening.

J Pediatr Gastroenterol Nutr. 2018 Mar 14;:

Authors: Munck A, Boulkedid R, Weiss L, Foucaud P, Wizla-Derambure N, Reix P, Bremont F, Derelle J, Schroedt J, Alberti C, Gastroenterology and Nutrition Société française de la Mucoviscidose (SFM) Working Group and the ALIMUDE Study Group

Abstract
OBJECTIVE: To evaluate nutritional status and associated factors in a cystic fibrosis (CF) cohort diagnosed by newborn screening and followed up to month 24.
METHODS: A prospective longitudinal multicenter study assessing nutritional status according to pancreatic status, feeding modalities, prescriptions, pulmonary outcome and biological nutritional parameters.
RESULTS: One-hundred-and-five infants were recruited and 99 completed the study. Nutritional care management prevented undernutrition and stunting in those with exocrine pancreatic sufficiency (EPS), but affected (13/87) 15% and (21/86) 24%, respectively, of infants with exocrine pancreatic insufficiency (EPI). The logistic regression model found a positive association between both weight and length z-scores "at risk" at month 24, and initial pulmonary symptoms (OR 0.06, p < 0.01 and OR 0.08, p < 0.01, respectively); these symptoms were less frequent when age at first visit was earlier than 1.2 months (33% versus 67%, p = 0.02); stunting was also associated with high-calorie density intake and Staphylococcus aureus (OR: 0.05, p = 0.01 and OR: 0.17, p < 0.01). Pulmonary outcome did not differ according to pancreatic status; breast feeding for at least 3 months delayed first acquisition of Pseudomonas aeruginosa. Despite sodium and fat-soluble vitamin supplementation, half of both cohorts had low urinary sodium output and half of the EPI cohort had low vitamin D levels.
CONCLUSION: Our data shed light on the fact that stunting was more frequent than undernutrition, while both parameters involved only patients with pancreatic insufficiency. Modalities of feeding were not associated with nutritional status; breast feeding may provide some protection against acquisition of Pseudomonas aeruginosa.

PMID: 29543697 [PubMed - as supplied by publisher]

Ozone disinfection of home nebulizers effectively kills common cystic fibrosis bacterial pathogens.

Pediatr Pulmonol. 2018 Mar 15;:

Authors: Towle D, Baker V, Schramm C, O'Brien M, Collins MS, Feinn R, Murray TS

Abstract
OBJECTIVE: The Cystic Fibrosis Foundation (CFF) recommends routine nebulizer disinfection for patients but compliance is challenging due to the heavy burden of home care. SoClean® is a user friendly ozone based home disinfection device currently for home respiratory equipment. The objective of this study was to determine whether SoClean® has potential as a disinfection device for families with CF by killing CF associated bacteria without altering nebulizer output.
HYPOTHESIS: Ozone based disinfection effectively kills bacterial pathogens inoculated to home nebulizer equipment without gross changes in nebulizer function.
STUDY DESIGN: Common bacterial pathogens associated with CF were inoculated onto the PariLC® jet nebulizer and bacterial recovery compared with or without varied ozone exposure. In separate experiments, nebulizer output was estimated after repeated ozone exposure by weighing the nebulizer.
RESULTS: Ozone disinfection was time dependent with a 5 min infusion time and 120 min dwell time effectively killing >99.99% bacteria tested including Pseudomonas aeruginosa and Staphylococcus aureus. Over 250 h of repeat ozone exposure did not alter nebulizer output. This suggests SoClean® has potential as a user-friendly disinfection technique for home respiratory equipment.

PMID: 29542874 [PubMed - as supplied by publisher]

Likelihood-based analysis of outcome-dependent sampling designs with longitudinal data.

Stat Med. 2018 Mar 15;:

Authors: Zelnick LR, Schildcrout JS, Heagerty PJ

Abstract
The use of outcome-dependent sampling with longitudinal data analysis has previously been shown to improve efficiency in the estimation of regression parameters. The motivating scenario is when outcome data exist for all cohort members but key exposure variables will be gathered only on a subset. Inference with outcome-dependent sampling designs that also incorporates incomplete information from those individuals who did not have their exposure ascertained has been investigated for univariate but not longitudinal outcomes. Therefore, with a continuous longitudinal outcome, we explore the relative contributions of various sources of information toward the estimation of key regression parameters using a likelihood framework. We evaluate the efficiency gains that alternative estimators might offer over random sampling, and we offer insight into their relative merits in select practical scenarios. Finally, we illustrate the potential impact of design and analysis choices using data from the Cystic Fibrosis Foundation Patient Registry.

PMID: 29542170 [PubMed - as supplied by publisher]

Incidence and risk factors of nephrotoxicity in patients on colistimethate sodium.

Int J Clin Pharm. 2018 Mar 14;:

Authors: Hassan MM, Gaifer Z, Al-Zakwani IS

Abstract
Background Colistin is used to treat gram-negative infections but it's highly associated with nephrotoxicity. Objectives To determine the incidence and risk factors as well as mortality in patients on colistin. Setting Sultan Qaboos University Hospital, Muscat, Oman. Methods This was a retrospective cohort study of patients admitted and who received colistin for ≥ 48 h. The exclusion criteria included inhaled colistin therapy, cystic fibrosis, or pregnancy. The study period was from January 2010 to June 2016. Main outcome measures Nephrotoxicity using the Risk, Injury, Failure, Loss and Endstage kidney disease (RIFLE) criteria. The secondary outcomes were incidence, risk factors and mortality in patients on colistin. Results A total of 123 patients were included. Colistin-associated nephrotoxicity (CAN) occurred in 57 (46%) patients after colistin therapy. As per the RIFLE criteria, 22 (18%) patients were classified as 'at risk', 17 (14%) as 'injury', and 18 (15%) as 'failure'. Multivariate analysis indicated that increasing age (adjusted odds ratio (aOR), 1.03; 95% confidence interval (CI) 1.01-1.06; p = 0.004) and higher APACHE II score (aOR 1.08; 95% CI 1.01-1.16; p = 0.040) were significant predictors for the development of nephrotoxicity. Factors associated with mortality included ICU admission (aOR 23.3; 95% CI 5.04-106; p < 0.001), vasopressin use (aOR 5.54; 95% CI 1.56-19.6; p = 0.008) and higher APACHE II score (aOR 1.15; 95% CI 1.03-1.30; p = 0.027). Conclusions The incidence of CAN was 46%. Increasing age and higher APACHE II score were the risk factors for CAN. Factors associated with mortality at 28 days included ICU admission and higher APACHE II score.

PMID: 29542034 [PubMed - as supplied by publisher]

The Microbial Endocrinology of Pseudomonas aeruginosa: Inflammatory and Immune Perspectives.

Arch Immunol Ther Exp (Warsz). 2018 Mar 14;:

Authors: Yong VFL, Soh MM, Jaggi TK, Mac Aogáin M, Chotirmall SH

Abstract
Pseudomonas aeruginosa is a major pathogen responsible for both acute and chronic infection. Known as a colonising pathogen of the cystic fibrosis (CF) lung, it is implicated in other settings such as bronchiectasis. It has the ability to cause acute disseminated or localised infection particularly in the immunocompromised. Human hormones have been highlighted as potential regulators of bacterial virulence through crosstalk between analogous "quorum sensing" (QS) systems present in the bacteria that respond to mammalian hormones. Pseudomonas aeruginosa is known to utilise interconnected QS systems to coordinate its virulence and evade various aspects of the host immune system activated in response to infection. Several human hormones demonstrate an influence on P. aeruginosa growth and virulence. This inter-kingdom signalling, termed "microbial endocrinology" has important implications for host-microbe interaction during infection and, potentially opens up novel avenues for therapeutic intervention. This phenomenon, supported by the existence of sexual dichotomies in both microbial infection and chronic lung diseases such as CF is potentially explained by sex hormones and their influence on the infective process. This review summarises our current understanding of the microbial endocrinology of P. aeruginosa, including its endogenous QS systems and their intersection with human endocrinology, pathogenesis of infection and the host immune system.

PMID: 29541797 [PubMed - as supplied by publisher]

A c-di-GMP-Modulating Protein Regulates Swimming Motility of Burkholderia cenocepacia in Response to Arginine and Glutamate.

Front Cell Infect Microbiol. 2018;8:56

Authors: Kumar B, Sorensen JL, Cardona ST

Abstract
Burkholderia cenocepacia is an opportunistic bacterium that can thrive in different environments, including the amino acid-rich mucus of the cystic fibrosis (CF) lung. B. cenocepacia responds to the nutritional conditions that mimic the CF sputum by increasing flagellin expression and swimming motility. Individual amino acids also induce swimming but not flagellin expression. Here, we show that modulation of the second messenger cyclic dimeric guanosine monophosphate (c-di-GMP) levels by the PAS-containing c-di-GMP phosphodiesterase, BCAL1069 (CdpA), regulates the swimming motility of B. cenocepacia K56-2 in response to CF sputum nutritional conditions. Heterologous expression of WspR, a diguanylate cyclase, in B. cenocepacia K56-2 caused an increase in c-di-GMP levels and reduced swimming motility but did not affect flagellin expression or flagellar biosynthesis. After insertional mutagenesis of 12 putative genes encoding c-di-GMP metabolizing enzymes, one mutant of the locus BCAL1069 (cdpA), exhibited decreased swimming motility independent of flagellin expression in CF sputum nutritional conditions and an increase in intracellular c-di-GMP levels. The reduced swimming motility phenotype of the BCAL1069 mutant was observed in the presence of arginine and glutamate, but not of histidine, phenylalanine, or proline. The B. cenocepacia CdpA was also found to be involved in regulation of protease activity but not in biofilm formation. Altogether, these results highlight a role of B. cenocepacia BCAL1069 (CdpA) in sensing the nutritional conditions of the CF sputum and eliciting a pathogenic response that includes swimming motility toward amino acids and an increase in protease activity.

PMID: 29541628 [PubMed - in process]