Funding Opportunity PA-18-824 from the NIH Guide for Grants and Contracts. The National Institute on Aging (NIA) invites applications for new exploratory research projects (R21) involving secondary analyses of data and/or stored biospecimens from the CALERIE (Comprehensive Assessment of Long- term Effects of Reducing Intake of Energy) trial. Noteworthy features of the CALERIE trial are the substantial size of the trial, the comprehensive physiologic, psychologic, quality of life, and cognitive assessments conducted, as well as the extensive collection of biological samples which include serum, plasma, urine, and biopsies from skeletal muscle (vastus lateralis) and adipose tissue (subcutaneous abdominal).

Funding Opportunity PA-18-823 from the NIH Guide for Grants and Contracts. The National Institute on Aging (NIA) invites applications for research projects (R01) involving secondary analyses of data and/or stored biospecimens from the CALERIE (Comprehensive Assessment of Long- term Effects of Reducing Intake of Energy) trial. The goal of this funding opportunity announcement (FOA) is to encourage analyses that will lead to a more detailed understanding of the effects of caloric restriction (CR) on risk factors for chronic diseases, as well as, the cellular/molecular mechanisms mediating the effects of sustained CR in humans.

Funding Opportunity RFA-HD-19-014 from the NIH Guide for Grants and Contracts. The goal of this funding opportunity announcement (FOA) is to advance the field of population dynamics research by increasing research impact, innovation, and productivity; developing junior scientists; and maximizing the efficiency of research support.

Notice NOT-EB-18-016 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-189 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-188 from the NIH Guide for Grants and Contracts

Notice NOT-CA-18-076 from the NIH Guide for Grants and Contracts

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Related Articles

Changing Trends in Computational Drug Repositioning.

Pharmaceuticals (Basel). 2018 Jun 05;11(2):

Authors: Yella JK, Yaddanapudi S, Wang Y, Jegga AG

Abstract
Efforts to maximize the indications potential and revenue from drugs that are already marketed are largely motivated by what Sir James Black, a Nobel Prize-winning pharmacologist advocated-"The most fruitful basis for the discovery of a new drug is to start with an old drug". However, rational design of drug mixtures poses formidable challenges because of the lack of or limited information about in vivo cell regulation, mechanisms of genetic pathway activation, and in vivo pathway interactions. Hence, most of the successfully repositioned drugs are the result of "serendipity", discovered during late phase clinical studies of unexpected but beneficial findings. The connections between drug candidates and their potential adverse drug reactions or new applications are often difficult to foresee because the underlying mechanism associating them is largely unknown, complex, or dispersed and buried in silos of information. Discovery of such multi-domain pharmacomodules-pharmacologically relevant sub-networks of biomolecules and/or pathways-from collection of databases by independent/simultaneous mining of multiple datasets is an active area of research. Here, while presenting some of the promising bioinformatics approaches and pipelines, we summarize and discuss the current and evolving landscape of computational drug repositioning.

PMID: 29874824 [PubMed]

Related Articles

Association Between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients.

Front Pharmacol. 2018;9:542

Authors: Tavares LC, Marcatto LR, Soares RAG, Krieger JE, Pereira AC, Santos PCJL

Abstract
The ideal dose of the oral anticoagulant warfarin varies widely among patients, mainly due to genetic factors. Genetic variations that impact warfarin pharmacokinetics and the vitamin K cycle are plausible candidates for being associated with warfarin dose requirements. Therefore, the aim of this study was to assess whether polymorphisms in the ABCB1 and CYP4F2 genes were associated with stable warfarin dose requirements in Brazilian patients. This retrospective study included samples from 309 individuals. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A were performed by polymerase chain reaction followed by melting curve analysis (HRM-PCR) and TaqMan® genotyping assay, respectively. Stable doses were adjusted in a linear multiple regression model for age, gender, body mass index, self-reported race, use of amiodarone, CYP2C9 (*2 and *3), VKORC1 c.1639G>A, and ABCB1 c.3435C>T or CYP4F2 c.1297G>A. By performing a univariate analysis of variance, we found that the warfarin patients who carry ABCB1 c.3435T variant alleles (CT and TT genotypes) need fewer warfarin stable doses in comparison with the individuals that are CC wild-type: 2.5 (p = 0.003) and 4.3 (p < 0.001) mg/week less, respectively, for the overall group of patients on stable anticoagulation therapeutics (n = 309); and 5.5 (p = 0.006) and 10.2 (p < 0.001) mg/week less, respectively, for the self-declared non-white stable subgroup (n = 76). No statistically significant differences in dose requirements were observed according to CYP4F2 genotypes. In conclusion, our results suggest ABCB1 c.3435C>T variant may influence warfarin dose requirements in Brazilian patients, when associated with other genotypic, demographic and clinical factors.

PMID: 29875668 [PubMed]

Related Articles

Staphylococcus aureus in cystic fibrosis: problem bug or an innocent bystander?

Breathe (Sheff). 2018 Jun;14(2):87-90

Authors: Hurley MN

Abstract
Staphylococcus aureus in cystic fibrosis: problem bug or an innocent bystander? The jury requires more evidence http://ow.ly/HQjk30j3nmL.

PMID: 29877519 [PubMed]

Related Articles

The Role of Inflammation in Venous Thromboembolism.

Front Pediatr. 2018;6:142

Authors: Branchford BR, Carpenter SL

Abstract
Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT), and pulmonary embolism (PE), is becoming increasingly recognized as a cause of morbidity and mortality in pediatrics, particularly among hospitalized children. Furthermore, evidence is accumulating that suggests the inflammatory response may be a cause, as well as consequence, of VTE, but current anticoagulation treatment regimens are not designed to inhibit inflammation. In fact, many established clinical VTE risk factors such as surgery, obesity, cystic fibrosis, sepsis, systemic infection, cancer, inflammatory bowel disease, and lupus likely modulate thrombosis through inflammatory mediators. Unlike other traumatic mechanisms of thrombosis involving vascular transection and subsequent exposure of subendothelial collagen and other procoagulant extracellular matrix materials, inflammation of the vessel wall may initiate thrombosis on an intact vein. Activation of endothelial cells, platelets, and leukocytes with subsequent formation of microparticles can trigger the coagulation system through the induction of tissue factor (TF). Identification of biomarkers to evaluate VTE risk could be of great use to the clinician caring for a patient with inflammatory disease to guide decisions regarding the risk:benefit ratio of various types of potential thromboprophylaxis strategies, or suggest a role for anti-inflammatory therapy. Unfortunately, no such validated inflammatory scoring system yet exists, though research in this area is ongoing. Elevation of C-reactive protein, IL-6, IL-8, and TNF-alpha during a response to systemic inflammation have been associated with increased VTE risk. Consequent platelet activation enhances the prothrombotic state, leading to VTE development, particularly in patients with other risk factors, most notably central venous catheters.

PMID: 29876337 [PubMed]

Related Articles

Performance Evaluation of a New Coulometric Endpoint Method in Sweat Testing and Its Comparison With Classic Gibson&Cooke and Chloridometer Methods in Cystic Fibrosis.

Front Pediatr. 2018;6:133

Authors: Gokdemir Y, Vatansever P, Karadag B, Seyrekel T, Baykan O, Bas Ikızoglu N, Ersu R, Karakoc F, Haklar G

Abstract
Background: The objective of the study was to assess the diagnostic efficacy of the coulometric endpoint method and compare it with classic Gibson&Cooke and chloridometer methods. Methods: This study is a prospective clinical study comparing two conventional sweat testing methods with the coulometric endpoint method in previously diagnosed cystic fibrosis (CF) patients and a non-CF control group. All individuals underwent two simultaneous sweat collections. One sample of sweat, collected by the CFΔ collector coil system, was analyzed by two methods: the titrimetric Cl- measurement (Sherwood® Chloridometer 926S, Sherwood Scientific Ltd., Cambridge, UK) and the coulometric endpoint method (CF Δ Collection System®, UTSAT/Turkey); the second sample was collected from the other forearm by the Gibson&Cooke method and the collected sweat was analyzed by manual titration in accordance with the Schales&Schales method. Within-run and between-run imprecisions were evaluated via Cl- concentrations of 40, 70, and 130 mmol/L samples. Results: One hundred and seventy (60 CF and 110 controls) subjects were included in the study. All three sweat test methods discriminated CF subjects from the healthy individuals. The mean difference between the coulometric endpoint and titrimetric Cl- measurement methods was -1.5 mmol/L, (95% confidence limits of agreement, ranging from -8.9 to 15.9 mmol/L); the mean difference between manual titration vs. coulometric endpoint methods was 12.8 mmol/L, (95% confidence limits of agreement ranging from -9.7 to 45.3 mmol/L) and the mean difference between the manual titration and titrimetric Cl- measurement methods was 11.3 mmol/L, (95% confidence limits of agreement ranging from -7.8 to 40.5 mmol/L) based on a Bland-Altman analysis. In the Receiver operating characteristic (ROC) analysis, made on the basis that Cl- concentration values < 40 mmol/L exclude the CF diagnosis, the coulometric endpoint method resulted in 96.7% sensitivity and 100% specificity for a cut-off value of 58.5 mmol/L (AUC: 0.994; 95% CI = 0.986-1.000; p < 0.001). Conclusions: The coulometric endpoint method can be as reliable as quantitative sweat Cl- analysis and may be considered as a definitive diagnostic tool for CF.

PMID: 29876336 [PubMed]

Related Articles

Gender differences in bronchiectasis: a real issue?

Breathe (Sheff). 2018 Jun;14(2):108-121

Authors: Vidaillac C, Yong VFL, Jaggi TK, Soh MM, Chotirmall SH

Abstract
Gender differences in chronic respiratory disease, including cystic fibrosis and non-cystic fibrosis bronchiectasis are clinically apparent and of increasing importance. Differences in disease prevalence, severity and outcome are all described, however, the precise cause of the gender dichotomy and their associated underlying mechanisms have been poorly characterised. A lack of dedicated clinical and epidemiological research focused in this area has led to a paucity of data and therefore a lack of understanding of its key drivers. Diagnosis, disease pathogenesis and treatment response are all complex but important aspects of bronchiectasis with an evident gender bias. Broadening our understanding of the interplay between microbiology, host physiology and the environment in the context of chronic lung diseases, such as bronchiectasis, is critical to unravelling mechanisms driving the observed gender differences. In this review, epidemiological, biological and environmental evidence related to gender in bronchiectasis is summarised. This illustrates gender differences as a "real issue" with the objective of mapping out a future framework upon which a gender-tailored medical approach may be incorporated into the diagnosis, monitoring and treatment of bronchiectasis.
Key points: CF and non-CF bronchiectasis are complex, multifactorial chronic pulmonary diseases with gender-specific differences in their prevalence, clinical presentation and disease severity.Microbiology and host physiology (immune and inflammatory responses) are essential aspects of bronchiectasis that are influenced by gender.Sex steroid hormones vary in type, fluctuating pattern and concentration throughout life and between the genders with a potential central role in bronchiectasis-related gender differences.Gender-focused clinical and/or therapeutic intervention has the potential to narrow the observed gender gap occurring in bronchiectasis-related lung disease.
Educational aims: To summarise the existing knowledge base of gender-related differences in CF and non-CF bronchiectasis.To highlight key areas of importance in the diagnosis, monitoring and treatment of bronchiectasis that is amenable to clinical and/or pharmacological intervention to narrow the existing "gender gap".

PMID: 29875830 [PubMed]

Predicting drug-disease associations and their therapeutic function based on the drug-disease association bipartite network.

Methods. 2018 Jun 04;:

Authors: Zhang W, Yue X, Huang F, Liu R, Chen Y, Ruan C

Abstract
Drug-disease associations provide important information for drug discovery and drug repositioning. Drug-disease associations can induce different effects, and the therapeutic effect attractswidespreadinterest. Therefore, developing drug-disease association prediction methods is an important task, and differentiating therapeutic associations from other associations is also very important. In this paper, we formulate the known drug-disease associations as a bipartite network, and then present a novel representation for drugs and diseases based on the bipartite network and linear neighborhood similarity. Thus, we propose the network topological similarity-based inference method (NTSIM) to predict unobserved drug-disease associations. Further, we extend the work to the association classification, and propose the network topological similarity-based classification method (NTSIM-C) to differentiate therapeutic associations from others. Compared with existing drug-disease association prediction methods, NTSIM can produce superior performances in predicting drug-disease associations, and NTSIM-C can accurately classify drug-disease associations. Further, we analyze the capability of proposed methods by using several case studies. The studies show the usefulness of NTSIM and NTSIM-C in the real applications. In conclusion, NTSIM and NTSIM-C are promising for predicting drug-disease associations and their therapeutic functions.

PMID: 29879508 [PubMed - as supplied by publisher]

Related Articles

Epidemiology of pyoderma gangrenosum: Results from an Italian prospective multicentre study.

Int Wound J. 2018 Jun 06;:

Authors: Monari P, Moro R, Motolese A, Misciali C, Baraldi C, Fanti PA, Caccavale S, Puviani M, Olezzi D, Zampieri P, Trevisan G, Nan K, Fiorentini C, Pellacani G, Gualdi G

Abstract
Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterised by painful, necrotic ulcerations. PG is described as a rare disease: the world-wide incidence is estimated to be around 3 to 10 cases per million population per year. These estimations are based mostly on case reports and retrospective case series; there are no prospective, multicentre studies on the matter. The apparent rarity of PG is in contrast with our clinical perception as dermatologists: in our opinion, PG is not so uncommon. Therefore, we decide to investigate the epidemiology of PG in the Italian population and confirm our clinical suspicions that it is not an orphan disease. We enrolled all patients diagnosed with PG in 8 Italian Dermatological Departments from 1st October 2014 to 1st November 2015, and we recorded their features. Our data, collected from 64 patients, are in accordance with those of the published literature regarding the epidemiology and features of PG. In an Italian population of roughly 8 million inhabitants of 7 provinces, we found an incidence of 5.17 new cases per million population per year. Unlike our predictions before the study, we confirmed the world-wide incidence of PG. To our knowledge, this is the first observational, multicentre study on PG. We hope that it provides a stimulus for further researches on PG and for the creation of an Italian register.

PMID: 29877043 [PubMed - as supplied by publisher]

Related Articles

A cross-sectional quantitative analysis of the natural history of free sialic acid storage disease-an ultra-orphan multisystemic lysosomal storage disorder.

Genet Med. 2018 Jun 06;:

Authors: Zielonka M, Garbade SF, Kölker S, Hoffmann GF, Ries M

Abstract
PURPOSE: Quantitative definition of the natural history of free sialic acid storage disease (SASD, OMIM 604369), an orphan disorder due to the deficiency of the proton-driven carrier SLC17A5.
METHODS: Analysis of published cases with SASD (N = 116) respecting STROBE criteria.
MAIN OUTCOME PARAMETERS: survival and diagnostic delay. Phenotype, phenotype-biomarker associations, and geographical patient distribution were explored.
RESULTS: Median age at disease onset was 0.17 years. Median age at diagnosis was 3 years with a median diagnostic delay of 2.5 years. Median survival was 11 years. The biochemical phenotype clearly predicted the disease course: patients with a urinary free sialic acid excretion below 6.37-fold or an intracellular free sialic acid storage in fibroblasts below 7.37-fold of the mean of normal survived longer than patients with biochemical values above these thresholds. Cluster analysis of disease features suggested a continuous phenotypic spectrum. Patient distribution was panethnic.
CONCLUSION: Combination of neurologic symptoms, visceromegaly, and dysmorphic features and/or nonimmune hydrops fetalis should prompt specific tests for SASD, reducing diagnostic delay. The present quantitative data inform clinical studies and may stimulate and accelerate development of specific therapies. Biomarker-phenotype association is particularly important for both counseling parents and study design.

PMID: 29875421 [PubMed - as supplied by publisher]

Related Articles

Improving risk equalization for individuals with persistently high costs: Experiences from the Netherlands.

Health Policy. 2017 Nov;121(11):1169-1176

Authors: Eijkenaar F, van Vliet RCJA

Abstract
BACKGROUND: Risk-equalization (RE) models in competitive health insurance markets have become increasingly sophisticated. However, these models still have important imperfections. A specific problem in the Netherlands is that insurers are insufficiently compensated for individuals who can persistently be found in the right-end tail of the cost distribution.
OBJECTIVES: The goal of this study is to explore and evaluate options for improving compensation for persistently high-cost individuals in the Dutch basic health insurance.
METHODS: Prescription drugs claims (2012) and administrative data on costs and risk-characteristics (2010-2013) for the entire Dutch population are used to identify high-cost individuals and evaluate improvement options. These options - including new risk-classes and a form of risk-sharing - are evaluated in terms of insurers' incentives for risk-selection and efficiency.
RESULTS: Three significantly undercompensated high-cost groups are identified: users of specific expensive drugs for rare diseases, hemophilia-patients, and individuals whose costs are in the top-0.50% in 3 prior years. The improvement options effectively remove the undercompensations for these groups and lead to a considerable improvement in individual-level model fit. However, the options differ in terms of their (potential) effects on insurers' efficiency incentives.
CONCLUSIONS: Although this study provides useful insights in the possibilities for improving RE-models for persistently high-cost individuals, improving compensation remains challenging and dependent on the ongoing debate regarding coverage and reimbursement of expensive drugs.

PMID: 28942090 [PubMed - indexed for MEDLINE]

Related Articles

Long-term metabolic follow-up and clinical outcome of 35 patients with maple syrup urine disease.

J Inherit Metab Dis. 2017 Nov;40(6):783-792

Authors: Abi-Wardé MT, Roda C, Arnoux JB, Servais A, Habarou F, Brassier A, Pontoizeau C, Barbier V, Bayart M, Leboeuf V, Chadefaux-Vekemans B, Dubois S, Assoun M, Belloche C, Alili JM, Husson MC, Lesage F, Dupic L, Theuil B, Ottolenghi C, de Lonlay P

Abstract
BACKGROUND: Maple syrup urine disease (MSUD) is a rare disease that requires a protein-restricted diet for successful management. Little is known, however, about the psychosocial outcome of MSUD patients. This study investigates the relationship between metabolic and clinical parameters and psychosocial outcomes in a cohort of patients with neonatal-onset MSUD.
METHODS: Data on academic achievement, psychological care, family involvement, and biochemical parameters were collected from the medical records of neonatal MSUD patients treated at Necker Hospital (Paris) between 1964 and 2013.
RESULTS: Thirty-five MSUD patients with a mean age of 16.3 (2.1-49.0) years participated. Metabolic decompensations (plasma leucine >380 μmol/L) were more frequent during the first year of life and after 15 years, mainly due to infection and dietary noncompliance, respectively. Leucine levels increased significantly in adulthood: 61.5% of adults were independent and achieved adequate social and professional integration; 56% needed occasional or sustained psychological or psychiatric care (8/19, with externalizing, mood, emotional, and anxiety disorders being the most common). Patients needing psychiatric care were significantly older [mean and standard deviation (SD) 22.6 (7.7) years] than patients needing only psychological follow-up [mean (SD) 14.3 (8.9) years]. Patients with psychological follow-up experienced the highest lifetime number of decompensations; 45% of families had difficulty coping with the chronic disease. Parental involvement was negatively associated with the number of lifetime decompensations.
CONCLUSION: Adults had increased levels of plasma leucine, consistent with greater chronic toxicity. Psychological care was associated with age and number of decompensations. In addition, parental involvement appeared to be crucial in the management of MSUD patients.

PMID: 28905140 [PubMed - indexed for MEDLINE]

Impact of POR and CYP3A5 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in the Early Post-Operative Period Following Kidney Transplantation.

Ther Drug Monit. 2018 Jun 06;:

Authors: Phupradit A, Vadcharavivad S, Ingsathit A, Kantachuvesiri S, Areepium N, Sra-Ium S, Auamnoy T, Sukasem C, Sumethkul V, Kitiyakara C

Abstract
BACKGROUND: Tacrolimus, a critical dose drug, is widely used in transplantation. Knowing the contribution of genetic factors, which significantly influence tacrolimus variability, is beneficial in the personalization of its starting dose. The significant impact of CYP3A5*3 polymorphisms on tacrolimus exposure has been reported. Conflicting results of the additional influence of POR*28 polymorphisms on tacrolimus pharmacokinetic inter-individual variability have been observed among different populations. The objective of this study was to explore the interaction between POR*28 and CYP3A5*3 polymorphisms and their main effects on tacrolimus trough concentration to dose ratios on day 7 post-kidney-transplantation.
METHODS: Two hundred and sixteen adult kidney transplant recipients participated in this retrospective study. All participants received a twice daily tacrolimus regimen. Blood samples and data were collected on day 7 post-transplantation. A two-way analysis of covariance was performed. Tested covariates were age, hemoglobin, serum albumin, and prednisolone dose.
RESULTS: A 2x2 analysis of covariance (ANCOVA) revealed that, the interaction between CYP3A5 polymorphisms (CYP3A5 expresser and CYP3A5 non-expresser) and POR polymorphisms (POR*28 carrier and POR*28 non-carrier) was not significant (F (1, 209) = 2.473, p = 0.117, ŋp = 0.012). The predicted main effect of CYP3A5 and POR polymorphisms were significant (F (1, 209) = 105.565, p < 0.001, ŋp = 0.336 and F (1, 209) = 4.007, p = 0.047, ŋp = 0.019, respectively). Hemoglobin, age, and steroid dose influenced log C0/dose of tacrolimus (F (1, 209) =20.612, p < 0.001, ŋp = 0.090; F (1, 209) = 14.360, p < 0.001, ŋp = 0.064; and F (1, 209) = 5.512, p = 0.020, ŋp = 0.026, respectively).
CONCLUSIONS: After adjusting for the influences of hemoglobin, age, and prednisolone dose, significant impacts of the CYP3A5 and POR polymorphisms on tacrolimus exposure were found. The effect of POR*28 and CYP3A5*3 polymorphisms during the very early period after kidney transplantation is independent of each other.

PMID: 29878980 [PubMed - as supplied by publisher]