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High prevalence of malaria in a non-endemic setting: comparison of diagnostic tools and patient outcome during a four-year survey (2013-2017).

Wed, 02/07/2018 - 12:32

High prevalence of malaria in a non-endemic setting: comparison of diagnostic tools and patient outcome during a four-year survey (2013-2017).

Malar J. 2018 Feb 05;17(1):63

Authors: Calderaro A, Piccolo G, Montecchini S, Buttrini M, Rossi S, Dell'Anna ML, De Remigis V, Arcangeletti MC, Chezzi C, De Conto F

Abstract
BACKGROUND: Malaria is no longer endemic in Italy since 1970 when the World Health Organization declared Italy malaria-free, but it is now the most commonly imported disease. The aim of the study was to analyse the trend of imported malaria cases in Parma, Italy, during January 2013-June 2017, reporting also the treatment and the outcome of cases, exploring the comparison of the three diagnostic tests used for malaria diagnosis: microscopy, immunochromatographic assay (ICT) (BinaxNOW®) and Real-time PCR assays detecting Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale curtisi, Plasmodium ovale wallikeri, and Plasmodium knowlesi.
RESULTS: Of the 288 patients with suspected malaria, 87 were positive by microscopy: 73 P. falciparum, 2 P. vivax, 8 P. ovale, 1 P. vivax/P. ovale, 1 P. malariae and 2 Plasmodium sp. All samples were positive by ICT except 6. Plasmodial DNA was revealed in the 87 cases and in 2 additional cases showing P. falciparum-specific bands by ICT, as follows: 75 P. falciparum, 2 P. vivax, 6 P. ovale curtisi, 3 P. ovale wallikeri, 1 P. malariae, and 2 mixed infections. 72 patients were foreigners and 17 Italians travelling for tourism or business. The majority of these patients presented with fever at blood collection and did not have chemoprophylaxis. No fatal cases were observed and the drug mostly used was quinine observing a negative blood smear or a parasitaemia < 0.001% after 48-72 h' therapy.
CONCLUSIONS: The study shows an update and a thorough analysis of imported malaria cases in the area of Parma during 4.5 years from the point of view of the total case management, clinical and diagnostic. The prevalence of malaria in such area in the considered period was especially due to immigrants mostly from Africa. Molecular methods were more sensitive and specific than microscopy and ICT, both detecting additional cases of P. falciparum malaria missed by microscopy and correctly identifying the Plasmodium species of medical interest. The data reported in this study may stimulate the clinicians in non-endemic areas to suspect malaria also in cases, where the most typical symptoms are absent, and the parasitologists to confirm the results of microscopy, remaining the reference method, with molecular methods to avoid misdiagnosis.

PMID: 29402283 [PubMed - in process]

DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood.

Tue, 02/06/2018 - 14:34
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DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood.

Sci Adv. 2018 Jan;4(1):eaao4364

Authors: Tobi EW, Slieker RC, Luijk R, Dekkers KF, Stein AD, Xu KM, Biobank-based Integrative Omics Studies Consortium, Slagboom PE, van Zwet EW, Lumey LH, Heijmans BT

Abstract
Although it is assumed that epigenetic mechanisms, such as changes in DNA methylation (DNAm), underlie the relationship between adverse intrauterine conditions and adult metabolic health, evidence from human studies remains scarce. Therefore, we evaluated whether DNAm in whole blood mediated the association between prenatal famine exposure and metabolic health in 422 individuals exposed to famine in utero and 463 (sibling) controls. We implemented a two-step analysis, namely, a genome-wide exploration across 342,596 cytosine-phosphate-guanine dinucleotides (CpGs) for potential mediators of the association between prenatal famine exposure and adult body mass index (BMI), serum triglycerides (TG), or glucose concentrations, which was followed by formal mediation analysis. DNAm mediated the association of prenatal famine exposure with adult BMI and TG but not with glucose. DNAm at PIM3 (cg09349128), a gene involved in energy metabolism, mediated 13.4% [95% confidence interval (CI), 5 to 28%] of the association between famine exposure and BMI. DNAm at six CpGs, including TXNIP (cg19693031), influencing β cell function, and ABCG1 (cg07397296), affecting lipid metabolism, together mediated 80% (95% CI, 38.5 to 100%) of the association between famine exposure and TG. Analyses restricted to those exposed to famine during early gestation identified additional CpGs mediating the relationship with TG near PFKFB3 (glycolysis) and METTL8 (adipogenesis). DNAm at the CpGs involved was associated with gene expression in an external data set and correlated with DNAm levels in fat depots in additional postmortem data. Our data are consistent with the hypothesis that epigenetic mechanisms mediate the influence of transient adverse environmental factors in early life on long-term metabolic health. The specific mechanism awaits elucidation.

PMID: 29399631 [PubMed - in process]

Neighbourhood walkability and incidence of hypertension: Findings from the study of 429,334 UK Biobank participants.

Tue, 02/06/2018 - 14:34
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Neighbourhood walkability and incidence of hypertension: Findings from the study of 429,334 UK Biobank participants.

Int J Hyg Environ Health. 2018 Feb 02;:

Authors: Sarkar C, Webster C, Gallacher J

Abstract
BACKGROUND: With an estimated one billion hypertension cases worldwide, the role of the built environment in its prevention and control is still uncertain. The present study aims to examine the associations between neighbourhood walkability and hypertension in a large and diverse population-based cohort.
MATERIALS AND METHODS: We examined the association between neighbourhood walkability and blood pressure outcomes for N = 429,334 participants drawn from the UK Biobank and aged 38-73 years. Neighbourhood walkability was objectively modelled from detailed building footprint-level data within multi-scale functional neighbourhoods (1.0-, 1.5- and 2.0-kilometer street catchments of geocoded dwelling). A series of linear and modified Poisson regression models were employed to examine the association between walkability and outcomes of diastolic blood pressure (DBP in mmHg), systolic blood pressure (SBP in mmHg) and prevalent hypertension adjusting for socio-demographic, lifestyle and related physical environmental covariates. We also examined the relationship between walkability and change in blood pressure for a sub-sample of participants with follow-up data and tested for interaction effects of age, sex, employment status, neighbourhood SES, residential density and green exposure.
RESULTS: Neighbourhood walkability within one-kilometer street catchment was beneficially associated with all the three blood pressure outcomes, independent of all other factors. Each interquartile increment in walkability was associated with the lower blood pressure outcomes of DBP (β = -0.358, 95% CI: -0.42, -0.29 mmHg), SBP (β = -0.833, 95% CI: -0.95, -0.72 mmHg) as well as reduced hypertension risk (RR = 0.970, 95% CI: 0.96, 0.98). The results remained consistent across spatial and temporal scales and were sensitive to sub-groups, with pronounced protective effects among female participants, those aged between 50 and 60 years, in employment, residing in deprived, high density and greener areas.
CONCLUSION: This large population-based cohort found evidence of protective association between neighbourhood walkability and blood pressure outcomes. Given the enduring public health impact of community design on individual behaviour and lifestyle, of particular interest, are the targetted upstream-level interventions in city design aimed at optimizing walkability. Further long term studies are required to assess its sustained effects upon hypertension prevention and control.

PMID: 29398408 [PubMed - as supplied by publisher]

A Genome-Wide Association Study Finds Genetic Associations with Broadly-Defined Headache in UK Biobank (N=223,773).

Tue, 02/06/2018 - 14:34
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A Genome-Wide Association Study Finds Genetic Associations with Broadly-Defined Headache in UK Biobank (N=223,773).

EBioMedicine. 2018 Jan 31;:

Authors: Meng W, Adams MJ, Hebert HL, Deary IJ, McIntosh AM, Smith BH

Abstract
BACKGROUND: Headache is the most common neurological symptom and a leading cause of years lived with disability. We sought to identify the genetic variants associated with a broadly-defined headache phenotype in 223,773 subjects from the UK Biobank cohort.
METHODS: We defined headache based on a specific question answered by the UK Biobank participants. We performed a genome-wide association study of headache as a single entity, using 74,461 cases and 149,312 controls.
RESULTS: We identified 3343 SNPs which reached the genome-wide significance level of P<5×10-8. The SNPs were located in 28 loci, with the top SNP of rs11172113 in the LRP1 gene having a P value of 4.92×10-47. Of the 28 loci, 14 have previously been associated with migraine. Among 14 new loci, rs77804065 with a P value of 5.87×10-15 in the LINC02210-CRHR1 gene was the top SNP. Significant relationships between multiple brain tissues and genetic associations were identified through tissue expression analysis. We also identified significant positive genetic correlations between headache and many psychological traits.
CONCLUSIONS: Our results suggest that brain function is closely related to broadly-defined headache. In addition, we found that many psychological traits have genetic correlations with headache.

PMID: 29397368 [PubMed - as supplied by publisher]

Freeze-dried spermatozoa: An alternative biobanking option for endangered species.

Tue, 02/06/2018 - 14:34
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Freeze-dried spermatozoa: An alternative biobanking option for endangered species.

Anim Reprod Sci. 2018 Jan 31;:

Authors: Anzalone DA, Palazzese L, Iuso D, Martino G, Loi P

Abstract
In addition to the iconic wild species, such as the pandas and Siberian tigers, an ever-increasing number of domestic species are also threatened with extinction. Biobanking of spermatozoa could preserve genetic heritages of extinct species, and maintain biodiversity of existing species. Because lyophilized spermatozoa retain fertilizing capacity, the aim was to assess whether freeze-dried spermatozoa are an alternative option to save endangered sheep breeds. To achieve this objective, semen was collected from an Italian endangered sheep breed (Pagliarola), and a biobank of cryopreserved and freeze-dried spermatozoa was established, and evaluated using IVF (for frozen spermatozoa) and ICSI procedures (for frozen and freeze-dried spermatozoa). As expected, the fertilizing capacity of cryopreserved Pagliarola's spermatozoa was comparable to commercial semen stocks. To evaluate the activating capability of freeze-dried spermatozoa, 108 MII sheep oocytes were subjected to ICSI, and allocated to two groups: 56 oocytes were activated by incubation with ionomycin (ICSI-FDSa) and 52 were not activated (ICSI-FDSna). Pronuclear formation (2PN) was investigated at 14-16 h after ICSI in fixed presumptive zygotes. Only artificially activated oocytes developed into blastocysts after ICSI. In the present study, freeze-dried ram spermatozoa induced blastocyst development following ICSI at a relatively high proportion, providing evidence that sperm lyophilization is an alternative, low cost storage option for biodiversity preservation of domestic species.

PMID: 29397252 [PubMed - as supplied by publisher]

Medications that relax the lower oesophageal sphincter and risk of oesophageal cancer: An analysis of two independent population-based databases.

Tue, 02/06/2018 - 14:34
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Medications that relax the lower oesophageal sphincter and risk of oesophageal cancer: An analysis of two independent population-based databases.

Int J Cancer. 2018 Feb 03;:

Authors: Spence AD, Busby J, Murchie P, Kunzmann AT, McMenamin ÚC, Coleman HG, Johnston BT, O'Rorke MA, Murray LJ, Iversen L, Lee AJ, Cardwell CR

Abstract
Excessive lower oesophageal sphincter relaxation increases gastro-oesophageal acid reflux, an oesophageal adenocarcinoma risk factor. Medications that relax this sphincter (benzodiazepines, calcium channel blockers, nitrates, β2 agonists and xanthines) could promote cancer. These medications were investigated in two independent datasets. In the Scottish Primary Care Clinical Informatics Unit (PCCIU) database, a nested case-control study of oesophageal cancer was performed using GP prescription records. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for medication use and oesophageal cancer. In UK Biobank, a cohort study was conducted using self-reported medication use. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs for medication use and oesophageal cancer, and by tumour subtype. Overall, 1,979 oesophageal cancer patients were matched to 9,543 controls in PCCIU, and 355 of 475,768 participants developed oesophageal cancer in UK Biobank. None of the medications investigated were significantly associated with oesophageal cancer risk apart from β2 agonists, which were associated with increased oesophageal cancer risk in PCCIU (adjusted OR 1.38, 95% CI 1.12, 1.70) but not in UK Biobank (adjusted HR 1.21, 95% CI 0.70, 2.08). Medications that relax the lower oesophageal sphincter were not associated with oesophageal cancer, apart from β2 agonists. This increased cancer risk in β2 agonist users merits further investigation. This article is protected by copyright. All rights reserved.

PMID: 29396851 [PubMed - as supplied by publisher]

The RD-Connect Registry & Biobank Finder: a tool for sharing aggregated data and metadata among rare disease researchers.

Tue, 02/06/2018 - 14:34
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The RD-Connect Registry & Biobank Finder: a tool for sharing aggregated data and metadata among rare disease researchers.

Eur J Hum Genet. 2018 Feb 02;:

Authors: Gainotti S, Torreri P, Wang CM, Reihs R, Mueller H, Heslop E, Roos M, Badowska DM, de Paulis F, Kodra Y, Carta C, Martìn EL, Miller VR, Filocamo M, Mora M, Thompson M, Rubinstein Y, Posada de la Paz M, Monaco L, Lochmüller H, Taruscio D

Abstract
In rare disease (RD) research, there is a huge need to systematically collect biomaterials, phenotypic, and genomic data in a standardized way and to make them findable, accessible, interoperable and reusable (FAIR). RD-Connect is a 6 years global infrastructure project initiated in November 2012 that links genomic data with patient registries, biobanks, and clinical bioinformatics tools to create a central research resource for RDs. Here, we present RD-Connect Registry & Biobank Finder, a tool that helps RD researchers to find RD biobanks and registries and provide information on the availability and accessibility of content in each database. The finder concentrates information that is currently sparse on different repositories (inventories, websites, scientific journals, technical reports, etc.), including aggregated data and metadata from participating databases. Aggregated data provided by the finder, if appropriately checked, can be used by researchers who are trying to estimate the prevalence of a RD, to organize a clinical trial on a RD, or to estimate the volume of patients seen by different clinical centers. The finder is also a portal to other RD-Connect tools, providing a link to the RD-Connect Sample Catalogue, a large inventory of RD biological samples available in participating biobanks for RD research. There are several kinds of users and potential uses for the RD-Connect Registry & Biobank Finder, including researchers collaborating with academia and the industry, dealing with the questions of basic, translational, and/or clinical research. As of November 2017, the finder is populated with aggregated data for 222 registries and 21 biobanks.

PMID: 29396563 [PubMed - as supplied by publisher]

Processing of fallopian tube, ovary, and endometrial surgical pathology specimens: A survey of U.S. laboratory practices.

Tue, 02/06/2018 - 14:34
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Processing of fallopian tube, ovary, and endometrial surgical pathology specimens: A survey of U.S. laboratory practices.

Gynecol Oncol. 2018 Jan 25;:

Authors: Samimi G, Trabert B, Duggan MA, Robinson JL, Coa KI, Waibel E, Garcia E, Minasian LM, Sherman ME

Abstract
OBJECTIVE: Many high-grade serous carcinomas initiate in fallopian tubes as serous tubal intraepithelial carcinoma (STIC), a microscopic lesion identified with specimen processing according to the Sectioning and Extensive Examination of the Fimbria protocol (SEE-Fim). Given that the tubal origin of these cancers was recently recognized, we conducted a survey of pathology practices to assess processing protocols that are applied to gynecologic surgical pathology specimens in clinical contexts in which finding STIC might have different implications.
METHODS: We distributed a survey electronically to the American Society for Clinical Pathology list-serve to determine practice patterns and compared results between practice types by chi-square (χ2) tests for categorical variables. Free text comments were qualitatively reviewed.
RESULTS: Survey responses were received from 159 laboratories (72 academic, 87 non-academic), which reported diverse specimen volumes and percentage of gynecologic samples. Overall, 74.1% of laboratories reported performing SEE-Fim for risk-reducing surgical specimens (82.5% academic versus 65.7% non-academic, p < 0.05). In specimens from surgery for benign indications in which initial microscopic sections showed an unanticipated suspicious finding, 75.9% of laboratories reported using SEE-Fim to process the remainder of the specimen (94.8% academic versus 76.4% non-academic, p < 0.01), and 84.6% submitted the entire fimbriae.
CONCLUSIONS: Changes in the theories of pathogenesis of high-grade serous carcinoma have led to implementation of pathology specimen processing protocols that include detailed analysis of the fallopian tubes. These results have implications for interpreting trends in cancer incidence data and considering the feasibility of developing a bank of gynecologic tissues containing STIC or early cancer precursors.

PMID: 29395311 [PubMed - as supplied by publisher]

Random Survival Forest in practice: a method for modelling complex metabolomics data in time to event analysis.

Tue, 02/06/2018 - 14:34
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Random Survival Forest in practice: a method for modelling complex metabolomics data in time to event analysis.

Int J Epidemiol. 2016 Oct;45(5):1406-1420

Authors: Dietrich S, Floegel A, Troll M, Kühn T, Rathmann W, Peters A, Sookthai D, von Bergen M, Kaaks R, Adamski J, Prehn C, Boeing H, Schulze MB, Illig T, Pischon T, Knüppel S, Wang-Sattler R, Drogan D

Abstract
BACKGROUND: The application of metabolomics in prospective cohort studies is statistically challenging. Given the importance of appropriate statistical methods for selection of disease-associated metabolites in highly correlated complex data, we combined random survival forest (RSF) with an automated backward elimination procedure that addresses such issues.
METHODS: Our RSF approach was illustrated with data from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, with concentrations of 127 serum metabolites as exposure variables and time to development of type 2 diabetes mellitus (T2D) as outcome variable. Out of this data set, Cox regression with a stepwise selection method was recently published. Replication of methodical comparison (RSF and Cox regression) was conducted in two independent cohorts. Finally, the R-code for implementing the metabolite selection procedure into the RSF-syntax is provided.
RESULTS: The application of the RSF approach in EPIC-Potsdam resulted in the identification of 16 incident T2D-associated metabolites which slightly improved prediction of T2D when used in addition to traditional T2D risk factors and also when used together with classical biomarkers. The identified metabolites partly agreed with previous findings using Cox regression, though RSF selected a higher number of highly correlated metabolites.
CONCLUSIONS: The RSF method appeared to be a promising approach for identification of disease-associated variables in complex data with time to event as outcome. The demonstrated RSF approach provides comparable findings as the generally used Cox regression, but also addresses the problem of multicollinearity and is suitable for high-dimensional data.

PMID: 27591264 [PubMed - indexed for MEDLINE]

New Standards and Updated Best Practices Will Give Modern Biobanking a Boost in Professionalism.

Sat, 02/03/2018 - 15:18

New Standards and Updated Best Practices Will Give Modern Biobanking a Boost in Professionalism.

Biopreserv Biobank. 2018 Feb 02;:

Authors: Simeon-Dubach D, Kozlakidis Z

PMID: 29394095 [PubMed - as supplied by publisher]

The College of American Pathologists Biorepository Accreditation Program: Results from the First 5 Years.

Sat, 02/03/2018 - 15:18

The College of American Pathologists Biorepository Accreditation Program: Results from the First 5 Years.

Biopreserv Biobank. 2018 Feb 02;:

Authors: McCall SJ, Branton PA, Blanc VM, Dry SM, Gastier-Foster JM, Harrison JH, Jewell SD, Dash RC, Obeng RC, Rose J, Mateski DL, Liubinskas A, Robb JA, Ramirez NC, Shea K

Abstract
The College of American Pathologists (CAP) developed the Biorepository Accreditation Program (BAP) in 2012. This program integrates best practices from the International Society for Biological and Environmental Biorepositories, the National Cancer Institute, the Organisation for Economic Cooperation and Development, the Center for Medicare and Medicaid Services, and the CAP Laboratory Accreditation Program. The goal of this elective program is to provide requirements for standardization in biorepository processes that will result in high-quality specimens that can be used to support research, drug discovery, and personalized medicine. CAP uses a peer inspection model to ensure the inspectors have proper expertise and to promote educational efforts through information sharing. Lead inspectors are comprised of pathologists, PhDs, and managers of biorepositories and they are often supported by CAP staff inspectors. Accreditation is a 3-year continuous cycle of quality with a peer inspection occurring at the start of year 1 and a self-inspection and CAP desk assessment at the start of year 2 and 3. At this time 53 biorepositories are fully CAP BAP accredited and 13 are in the process of obtaining accreditation. There are currently 273 established standards with requirement lists customized based on the scope of activities performed by a biorepository. A total of 90 inspections were completed between May 2012 and December 2016. Sixty-one were initial inspections and 29 were reinspections. A total of 527 deficiencies were identified in the areas of Equipment/Instrumentation (22%), Information Technology (18%), Specimen Handling and QC (15%), Quality Management (16%), Personnel (11%), Safety (10%), Facilities (6%), and Regulatory (2%). Assessment of common deficiencies identifies areas of focus for continuous improvement and educational opportunities. Overall success of the program is high based on the current enrollment of 66 biorepositories, anecdotal participant feedback and increasing national recognition of the BAP in federal documents.

PMID: 29394087 [PubMed - as supplied by publisher]

Standardization and Innovation in Paving a Path to a Better Future: An Update of Activities in ISO/TC276/WG2 Biobanks and Bioresources.

Sat, 02/03/2018 - 15:18

Standardization and Innovation in Paving a Path to a Better Future: An Update of Activities in ISO/TC276/WG2 Biobanks and Bioresources.

Biopreserv Biobank. 2018 Feb 02;:

Authors: Furuta K, Allocca CM, Schacter B, Bledsoe MJ, Ramirez NC

Abstract
Recent advances in biotechnology are making it possible to advance science and improve healthcare with increasing speed and precision. Biobanking, as a foundation of the biotechnology infrastructure, is critical to the assurance of quality for many of the key components for these advancing technologies in both the human and nonhuman domains. Biobanking must advance to support the increased complexity and required precision needs of biological resources. Standards development can provide an important link for the research and development community by providing tools to ensure quality, fitness-for-purpose, and reproducibility in biobanking. ISBER has been developing the ISBER Best Practices revision. At the same time, ISO/TC276/ WG2 has been developing an International Standard (IS) ISO/DIS 20387 General requirements for biobanking standard. It is important that ISBER and ISO/TC276/WG2 harmonize and/or align their products to enable members of the diverse biobanking community to tailor their own suite of tools to support their specific needs. The availability of both standards and best practices that are complementary will maximize available support for all biobanks. The increased availability of complementary standards, tools, and best practices will facilitate the path to new biotechnology advances and a better future.

PMID: 29394084 [PubMed - as supplied by publisher]

The 2018 Revision of the ISBER Best Practices: Summary of Changes and the Editorial Team's Development Process.

Sat, 02/03/2018 - 15:18

The 2018 Revision of the ISBER Best Practices: Summary of Changes and the Editorial Team's Development Process.

Biopreserv Biobank. 2018 Feb 02;:

Authors: Campbell LD, Astrin JJ, DeSouza Y, Giri J, Patel AA, Rawley-Payne M, Rush A, Sieffert N

Abstract
An increased need for specimens of reliable and consistent quality for research purposes requires the development of standardized policies and practices for the collection, handling, storage, retrieval, and distribution of specimens and specimen-related data. Providers of specimen resources should strive to incorporate new technologies and state-of-the-science approaches and thus ensure the availability of fit-for-purpose research specimens. Strategies to achieve quality outcomes and performance improvements often include adherence to established standards and implementation of best practices. Although standards represent a rigid set of guidelines that define exactly how a task should be completed, best practices are recommended actions and principles that demonstrate an awareness of standards, solve problems, can be replicated, and work in a given context. Adoption of best practice elements will vary based on the goals and circumstances of a given initiative, and in some instances, may not be possible to implement or may represent an aspirational achievement. In an effort to harmonize the scientific, technical, legal, and ethical issues relevant to repositories of biological and environmental specimens, the International Society for Biological and Environmental Repositories (ISBER) has released the updated ISBER Best Practices: Recommendations for Repositories (ISBER Best Practices). The document provides a comprehensive tool to guide repository professionals in both managerial and technical aspects such as practical details on repository governance, development, and operation; regulatory compliance; and ethical, legal, and social issues relevant to repositories. This summary describes the process for revising the document and summarizes the new topics, updates, and areas of expansion included in the fourth edition of ISBER Best Practices.

PMID: 29393664 [PubMed - as supplied by publisher]

Adipocyte-specific expression of C-type natriuretic peptide suppresses lipid metabolism and adipocyte hypertrophy in adipose tissues in mice fed high-fat diet.

Sat, 02/03/2018 - 15:18

Adipocyte-specific expression of C-type natriuretic peptide suppresses lipid metabolism and adipocyte hypertrophy in adipose tissues in mice fed high-fat diet.

Sci Rep. 2018 Feb 01;8(1):2093

Authors: Bae CR, Hino J, Hosoda H, Son C, Makino H, Tokudome T, Tomita T, Hosoda K, Miyazato M, Kangawa K

Abstract
C-type natriuretic peptide (CNP) is expressed in diverse tissues, including adipose and endothelium, and exerts its effects by binding to and activating its receptor, guanylyl cyclase B. Natriuretic peptides regulate intracellular cGMP and phosphorylated vasodilator-stimulated phosphoprotein (VASP). We recently revealed that overexpression of CNP in endothelial cells protects against high-fat diet (HFD)-induced obesity in mice. Given that endothelial CNP affects adipose tissue during obesity, CNP in adipocytes might directly regulate adipocyte function during obesity. Therefore, to elucidate the effect of CNP in adipocytes, we assessed 3T3-L1 adipocytes and transgenic (Tg) mice that overexpressed CNP specifically in adipocytes (A-CNP). We found that CNP activates the cGMP-VASP pathway in 3T3-L1 adipocytes. Compared with Wt mice, A-CNP Tg mice showed decreases in fat weight and adipocyte hypertrophy and increases in fatty acid β-oxidation, lipolysis-related gene expression, and energy expenditure during HFD-induced obesity. These effects led to decreased levels of the macrophage marker F4/80 in the mesenteric fat pad and reduced inflammation. Furthermore, A-CNP Tg mice showed improved glucose tolerance and insulin sensitivity, which were associated with enhanced insulin-stimulated Akt phosphorylation. Our results suggest that CNP overexpression in adipocytes protects against adipocyte hypertrophy, excess lipid metabolism, inflammation, and decreased insulin sensitivity during HFD-induced obesity.

PMID: 29391544 [PubMed - in process]

Bipolar disorder with binge eating behavior: a genome-wide association study implicates PRR5-ARHGAP8.

Sat, 02/03/2018 - 15:18

Bipolar disorder with binge eating behavior: a genome-wide association study implicates PRR5-ARHGAP8.

Transl Psychiatry. 2018 Feb 02;8(1):40

Authors: McElroy SL, Winham SJ, Cuellar-Barboza AB, Colby CL, Ho AM, Sicotte H, Larrabee BR, Crow S, Frye MA, Biernacka JM

Abstract
Bipolar disorder (BD) is associated with binge eating behavior (BE), and both conditions are heritable. Previously, using data from the Genetic Association Information Network (GAIN) study of BD, we performed genome-wide association (GWA) analyses of BD with BE comorbidity. Here, utilizing data from the Mayo Clinic BD Biobank (969 BD cases, 777 controls), we performed a GWA analysis of a BD subtype defined by BE, and case-only analysis comparing BD subjects with and without BE. We then performed a meta-analysis of the Mayo and GAIN results. The meta-analysis provided genome-wide significant evidence of association between single nucleotide polymorphisms (SNPs) in PRR5-ARHGAP8 and BE in BD cases (rs726170 OR = 1.91, P = 3.05E-08). In the meta-analysis comparing cases with BD with comorbid BE vs. non-BD controls, a genome-wide significant association was observed at SNP rs111940429 in an intergenic region near PPP1R2P5 (p = 1.21E-08). PRR5-ARHGAP8 is a read-through transcript resulting in a fusion protein of PRR5 and ARHGAP8. PRR5 encodes a subunit of mTORC2, a serine/threonine kinase that participates in food intake regulation, while ARHGAP8 encodes a member of the RhoGAP family of proteins that mediate cross-talk between Rho GTPases and other signaling pathways. Without BE information in controls, it is not possible to determine whether the observed association reflects a risk factor for BE in general, risk for BE in individuals with BD, or risk of a subtype of BD with BE. The effect of PRR5-ARHGAP8 on BE risk thus warrants further investigation.

PMID: 29391396 [PubMed - in process]

Genome-wide analysis of self-reported risk-taking behaviour and cross-disorder genetic correlations in the UK Biobank cohort.

Sat, 02/03/2018 - 15:18

Genome-wide analysis of self-reported risk-taking behaviour and cross-disorder genetic correlations in the UK Biobank cohort.

Transl Psychiatry. 2018 Feb 02;8(1):39

Authors: Strawbridge RJ, Ward J, Cullen B, Tunbridge EM, Hartz S, Bierut L, Horton A, Bailey MES, Graham N, Ferguson A, Lyall DM, Mackay D, Pidgeon LM, Cavanagh J, Pell JP, O'Donovan M, Escott-Price V, Harrison PJ, Smith DJ

Abstract
Risk-taking behaviour is a key component of several psychiatric disorders and could influence lifestyle choices such as smoking, alcohol use, and diet. As a phenotype, risk-taking behaviour therefore fits within a Research Domain Criteria (RDoC) approach, whereby identifying genetic determinants of this trait has the potential to improve our understanding across different psychiatric disorders. Here we report a genome-wide association study in 116,255 UK Biobank participants who responded yes/no to the question "Would you consider yourself a risk taker?" Risk takers (compared with controls) were more likely to be men, smokers, and have a history of psychiatric disorder. Genetic loci associated with risk-taking behaviour were identified on chromosomes 3 (rs13084531) and 6 (rs9379971). The effects of both lead SNPs were comparable between men and women. The chromosome 3 locus highlights CADM2, previously implicated in cognitive and executive functions, but the chromosome 6 locus is challenging to interpret due to the complexity of the HLA region. Risk-taking behaviour shared significant genetic risk with schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, and post-traumatic stress disorder, as well as with smoking and total obesity. Despite being based on only a single question, this study furthers our understanding of the biology of risk-taking behaviour, a trait that has a major impact on a range of common physical and mental health disorders.

PMID: 29391395 [PubMed - in process]

Identification of new biomarkers to promote personalised treatment of patients with inflammatory rheumatic disease: protocol for an open cohort study.

Sat, 02/03/2018 - 15:18

Identification of new biomarkers to promote personalised treatment of patients with inflammatory rheumatic disease: protocol for an open cohort study.

BMJ Open. 2018 Feb 01;8(2):e019325

Authors: Kringelbach TM, Glintborg B, Hogdall EV, Johansen JS, Hetland ML, Biomarker Protocol Study Group

Abstract
INTRODUCTION: The introduction of biological disease-modifying antirheumatic drugs (bDMARDs) has improved the treatment of inflammatory rheumatic diseases dramatically. However, bDMARD treatment failure occurs in 30%-40% of patients due to lack of effect or adverse events, and the tools to predict treatment outcomes in individual patients are currently limited. The objective of the present study is to identify diagnostic, prognostic and predictive biomarkers, which can be used to (1) diagnose inflammatory rheumatic diseases early in the disease course with high sensitivity and specificity, (2) improve prognostication or (3) predict and monitor treatment effectiveness and tolerability for the individual patient.
METHODS AND ANALYSIS: The present study is an observational and translational open cohort study with prospective collection of clinical data and biological materials (primarily blood) in patients with inflammatory rheumatic diseases treated in routine care. Patients contribute with one cross-sectional blood sample and/or are enrolled for longitudinal follow-up on initiation of a new DMARD (blood sampling after 0, 3, 6, 12, 24, 36, 48, 60 months of treatment). Other biological materials will be collected when accessible and relevant. Demographics, disease characteristics, comorbidities and lifestyle factors are registered at inclusion; DMARD treatment and outcomes are collected repeatedly during follow-up. Currently (July 2017), >5000 samples from approximately 3000 patients have been collected. Data will be analysed using appropriate statistical analyses.
ETHICS AND DISSEMINATION: The protocol is approved by the Danish Ethics Committee and the Danish Data Protection Agency. Participants give written and oral informed consent. Biomarkers will be evaluated and published according to the Reporting Recommendations for Tumour Marker (REMARK) prognostic studies, Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and the Standards for Reporting of Diagnostic Accuracy (STARD) guidelines. Results will be published in peer-reviewed scientific journals and presented at international conferences.
TRIAL REGISTRATION NUMBER: NCT03214263.

PMID: 29391382 [PubMed - in process]

Comparative analysis of micro-RNAs in human papillomavirus-positive versus -negative oropharyngeal cancers.

Sat, 02/03/2018 - 15:18
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Comparative analysis of micro-RNAs in human papillomavirus-positive versus -negative oropharyngeal cancers.

Head Neck. 2016 Nov;38(11):1634-1642

Authors: Mirghani H, Ugolin N, Ory C, Goislard M, Lefèvre M, Baulande S, Hofman P, Guily JL, Chevillard S, Lacave R

Abstract
BACKGROUND: Oncogenic mechanisms of human papillomavirus (HPV)-positive oropharyngeal cancer are still poorly characterized. Analysis of their microRNA expression profile might provide valuable information.
METHODS: The microRNA expression profiles were analyzed by micro-arrays in 26 oropharyngeal cancers. A microRNA signature specific to HPV-status was identified by analyzing a learning/training set consisting of 16 oropharyngeal cancers. The robustness of this signature was further confirmed by blind case-by-case classification of a validation set composed of 10 independent tumors. Putative targeted molecular pathways were proposed using DIANA miRPath online software (http://microrna.gr/mirpath).
RESULTS: We have identified 25 miRNA signatures, which discriminates HPV16-positive oropharyngeal cancer from their HPV-negative counterparts. These 25 microRNAs play a potential role in Wnt and PI3K-pathways, cell-adhesion/cell-polarity, and the cytoskeleton regulation.
CONCLUSION: Our study contributes to a better understanding of pathogenic mechanisms involved in the development of HPV-positive oropharyngeal cancer and in the identification of potential therapeutic molecular targets. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016.

PMID: 27097597 [PubMed - indexed for MEDLINE]

How neuropathology can contribute to the understanding of dementia.

Sat, 02/03/2018 - 15:18
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How neuropathology can contribute to the understanding of dementia.

Neurodegener Dis Manag. 2016 06;6(3):183-6

Authors: Gelpi E

PMID: 27230123 [PubMed - indexed for MEDLINE]

High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB).

Fri, 02/02/2018 - 12:55

High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB).

Haemophilia. 2018 Feb 01;:

Authors: Gebhart J, Hofer S, Panzer S, Quehenberger P, Sunder-Plassmann R, Hoermann G, Eigenbauer E, Haslacher H, Kepa S, Kyrle PA, Eichinger S, Knöbl P, Eischer L, Mannhalter C, Ay C, Pabinger I

Abstract
INTRODUCTION: Data on clinical characteristics and the prevalence of underlying coagulopathies in patients with mild-to-moderate bleeding disorders (MBDs) are scarce.
AIM: We established the Vienna Bleeding Biobank (VIBB) to characterize and thoroughly investigate Austrian patients with MBDs.
RESULTS: Four hundred eighteen patients (female = 345, 82.5%) were included. A platelet function defect (PFD) was diagnosed in 26 (6.2%) and a possible PFD in 30 (7.2%) patients. Eight patients (1.9%) were diagnosed with von Willebrand disease (VWD) (type 1 n = 6; type 2 n = 2), and 29 patients had low VWF (30-50 IU/dL). Deficiencies in factor VIII, IX, XI or XIII were found in 11 (2.6%), 3 (0.7%), 3 (0.7%) and 1 patient(s), 2 patients had dysfibrinogenaemia, and further 2 had possible PFD and FXI deficiency. Probable causal mutations were detected in 8 of 11 patients with FVIII deficiency, 2 of 3 patients with FIX deficiency and 2 of 8 patients with VWD. Three hundred three patients (72.5%) had normal results in the coagulation assays and were categorized as patients with bleeding of unknown cause (BUC). The bleeding score did not differ between patients with and without established diagnosis. A diagnosis of a bleeding disorder was more frequently made in men than in women (49.3% vs 22.9%). Male sex (OR 3.55, 95% CI: 2.02-6.22; P < .001) and blood group 0 (OR 1.86, 95% CI: 1.17-2.94; P = .008) were independently associated with diagnosis of a bleeding disorder.
CONCLUSION: The high rate of patients with BUC despite in-depth haemostatic assessment underlines the incompleteness of available routine laboratory tests. Males with MBDs were more likely to be diagnosed with an established bleeding disorder than females.

PMID: 29388750 [PubMed - as supplied by publisher]