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[Requirements for a cross-location biobank IT infrastructure : Survey of stakeholder input on the establishment of a biobank network of the German Biobank Alliance (GBA)].

Wed, 04/25/2018 - 22:04
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[Requirements for a cross-location biobank IT infrastructure : Survey of stakeholder input on the establishment of a biobank network of the German Biobank Alliance (GBA)].

Pathologe. 2018 Apr 24;:

Authors: Schüttler C, Buschhüter N, Döllinger C, Ebert L, Hummel M, Linde J, Prokosch HU, Proynova R, Lablans M

Abstract
BACKGROUND: The large number of biobanks within Germany results in a high degree of heterogeneity with regard to the IT components used at the respective locations. Within the German Biobank Alliance (GBA), 13 biobanks implement harmonized processes for the provision of biomaterial and accompanying data.
OBJECTIVES: The networking of the individual biobanks and the associated harmonisation of the IT infrastructure should facilitate access to biomaterial and related clinical data.
METHODS: For this purpose, the relevant target groups were first identified in order to determine their requirements for IT solutions to be developed in a workshop.
RESULTS: Of the seven identified interest groups, three were initially invited to a first round of discussions. The stakeholder input expressed resulted in a catalogue of requirements with regard to IT support for (i) a sample and data request, (ii) the handling of patient consent and inclusion, and (iii) the subsequent evaluation of the sample and data request.
CONCLUSIONS: The next step is to design the IT solutions as prototypes based on these requirements. In parallel, further user groups are being surveyed in order to be able to further concretise the specifications for development.

PMID: 29691676 [PubMed - as supplied by publisher]

Biological Insights Into Muscular Strength: Genetic Findings in the UK Biobank.

Wed, 04/25/2018 - 22:04
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Biological Insights Into Muscular Strength: Genetic Findings in the UK Biobank.

Sci Rep. 2018 Apr 24;8(1):6451

Authors: Tikkanen E, Gustafsson S, Amar D, Shcherbina A, Waggott D, Ashley EA, Ingelsson E

Abstract
We performed a large genome-wide association study to discover genetic variation associated with muscular strength, and to evaluate shared genetic aetiology with and causal effects of muscular strength on several health indicators. In our discovery analysis of 223,315 individuals, we identified 101 loci associated with grip strength (P <5 × 10-8). Of these, 64 were associated (P < 0.01 and consistent direction) also in the replication dataset (N = 111,610). eQTL analyses highlighted several genes known to play a role in neuro-developmental disorders or brain function, and the results from meta-analysis showed a significant enrichment of gene expression of brain-related transcripts. Further, we observed inverse genetic correlations of grip strength with cardiometabolic traits, and positive correlation with parents' age of death and education. We also showed that grip strength had shared biological pathways with indicators of frailty, including cognitive performance scores. By use of Mendelian randomization, we provide evidence that higher grip strength is protective of both coronary heart disease (OR = 0.69, 95% CI 0.60-0.79, P < 0.0001) and atrial fibrillation (OR = 0.75, 95% CI 0.62-0.90, P = 0.003). In conclusion, our results show shared genetic aetiology between grip strength, and cardiometabolic and cognitive health; and suggest that maintaining muscular strength could prevent future cardiovascular events.

PMID: 29691431 [PubMed - in process]

Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

Wed, 04/25/2018 - 22:04
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Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

Nat Commun. 2018 Apr 24;9(1):1613

Authors: Emdin CA, Khera AV, Chaffin M, Klarin D, Natarajan P, Aragam K, Haas M, Bick A, Zekavat SM, Nomura A, Ardissino D, Wilson JG, Schunkert H, McPherson R, Watkins H, Elosua R, Bown MJ, Samani NJ, Baber U, Erdmann J, Gupta N, Danesh J, Chasman D, Ridker P, Denny J, Bastarache L, Lichtman JH, D'Onofrio G, Mattera J, Spertus JA, Sheu WH, Taylor KD, Psaty BM, Rich SS, Post W, Rotter JI, Chen YI, Krumholz H, Saleheen D, Gabriel S, Kathiresan S

Abstract
Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

PMID: 29691411 [PubMed - in process]

Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study.

Wed, 04/25/2018 - 22:04
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Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study.

Nat Commun. 2018 Apr 24;9(1):1612

Authors: DeBoever C, Tanigawa Y, Lindholm ME, McInnes G, Lavertu A, Ingelsson E, Chang C, Ashley EA, Bustamante CD, Daly MJ, Rivas MA

Abstract
Protein-truncating variants can have profound effects on gene function and are critical for clinical genome interpretation and generating therapeutic hypotheses, but their relevance to medical phenotypes has not been systematically assessed. Here, we characterize the effect of 18,228 protein-truncating variants across 135 phenotypes from the UK Biobank and find 27 associations between medical phenotypes and protein-truncating variants in genes outside the major histocompatibility complex. We perform phenome-wide analyses and directly measure the effect in homozygous carriers, commonly referred to as "human knockouts," across medical phenotypes for genes implicated as being protective against disease or associated with at least one phenotype in our study. We find several genes with strong pleiotropic or non-additive effects. Our results illustrate the importance of protein-truncating variants in a variety of diseases.

PMID: 29691392 [PubMed - in process]

Sex differences in macronutrient intake and adherence to dietary recommendations: findings from the UK Biobank.

Wed, 04/25/2018 - 22:04
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Sex differences in macronutrient intake and adherence to dietary recommendations: findings from the UK Biobank.

BMJ Open. 2018 Apr 24;8(4):e020017

Authors: Bennett E, Peters SAE, Woodward M

Abstract
OBJECTIVES: To characterise sex differences in macronutrient intakes and adherence to dietary recommendations in the UK Biobank population.
DESIGN: Cross-sectional population-based study.
SETTING: UK Biobank Resource.
PARTICIPANTS: 210 106 (52.5% women) individuals with data on dietary behaviour.
MAIN OUTCOME MEASURES: Women-to-men mean differences in nutrient intake in grams and as a percentage of energy and women-to-men ORs in non-adherence, adjusting for age, socioeconomic status and ethnicity.
RESULTS: There were sex differences in energy intake and distribution. Men had greater intakes of energy and were less likely to have energy intakes above the estimated average requirement compared with women. Small, but significant, sex differences were found in the intakes of all macronutrients. For all macronutrients, men had greater absolute intakes while women had greater intakes as a percentage of energy. Women were more likely to have intakes that exceeded recommendations for total fat, saturated fat and total sugar. Men were less likely to achieve the minimum recommended intakes for protein, polyunsaturated fat and total carbohydrate. Over 95% of men and women were non-adherent to fibre recommendations. Sex differences in dietary intakes were moderated by age and to some extent by socioeconomic status.
CONCLUSIONS: There are significant sex differences in adherence to dietary recommendations, particularly for sugar. However, given the increased focus on food groups and dietary patterns for nutritional policy, these differences alone may not be sufficient for policy and health promotion. Future studies that are able to explore the sex differences in intakes of different food groups that are risk factors for diet-related diseases are warranted to improve the current understanding of the differential impact of diet on health in women and men.

PMID: 29691247 [PubMed - in process]

Correlating Clinical Risk Factors and Histological Features in Ruptured and Unruptured Human Intracranial Aneurysms: The Swiss AneuX Study.

Wed, 04/25/2018 - 22:04
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Correlating Clinical Risk Factors and Histological Features in Ruptured and Unruptured Human Intracranial Aneurysms: The Swiss AneuX Study.

J Neuropathol Exp Neurol. 2018 Apr 23;:

Authors: Morel S, Diagbouga MR, Dupuy N, Sutter E, Braunersreuther V, Pelli G, Corniola M, Gondar R, Jägersberg M, Isidor N, Schaller K, Bochaton-Piallat ML, Bijlenga P, Kwak BR

Abstract
Pathogenesis of intracranial aneurysm is complex and the precise biomechanical processes leading to their rupture are uncertain. The goal of our study was to characterize the aneurysmal wall histologically and to correlate histological characteristics with clinical and radiological factors used to estimate the risk of rupture. A new biobank of aneurysm domes resected at the Geneva University Hospitals (Switzerland) was used. Histological analysis revealed that unruptured aneurysms have a higher smooth muscle cell (SMC) content and a lower macrophage content than ruptured domes. These differences were associated with more collagen in unruptured samples, whereas the elastin content was not affected. Collagen content and type distribution were different between thick and thin walls of unruptured aneurysms. Classification of aneurysm domes based on histological characteristics showed that unruptured samples present organized wall rich in endothelial and SMCs compared with ruptured samples. Finally, aneurysm wall composition was altered in unruptured domes of patients presenting specific clinical factors used to predict rupture such as large dome diameter, dome irregularities, and smoking. Our study shows that the wall of aneurysm suspected to be at risk for rupture undergoes structural alterations relatively well associated with clinical and radiological factors currently used to predict this risk.

PMID: 29688417 [PubMed - as supplied by publisher]

Sex-Related Differences in Patients With Inflammatory Bowel Disease: Results of 2 Prospective Cohort Studies.

Wed, 04/25/2018 - 22:04
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Sex-Related Differences in Patients With Inflammatory Bowel Disease: Results of 2 Prospective Cohort Studies.

Inflamm Bowel Dis. 2018 Apr 21;:

Authors: Severs M, Spekhorst LM, Mangen MJ, Dijkstra G, Löwenberg M, Hoentjen F, van der Meulen-de Jong AE, Pierik M, Ponsioen CY, Bouma G, van der Woude JC, van der Valk ME, Romberg-Camps MJL, Clemens CHM, van de Meeberg P, Mahmmod N, Jansen J, Jharap B, Weersma RK, Oldenburg B, Festen EAM, Fidder HH

Abstract
Background: The understanding of gender differences in inflammatory bowel disease (IBD) patients is an important step towards tailored treatment for the individual patient. The aim of this study was to compare disease phenotype, clinical manifestations, disease activity, and healthcare utilization between men and women with Crohn's disease (CD) and ulcerative colitis (UC).
Methods: Two multicenter observational cohort studies with a prospective design were used to explore the differences between men and women regarding demographic and phenotypic characteristics and healthcare utilization. Detailed data on IBD-phenotype was mainly available from the Dutch IBD Biobank, while the COIN cohort provided healthcare utilization data.
Results: In the Dutch IBD Biobank study, 2118 CD patients and 1269 UC patients were analyzed. Female CD patients were more often current smokers, and male UC patients were more often previous smokers. Early onset CD (<16 years) was more frequently encountered in males than in females (20% versus 12%, P < 0.01). Male CD patients were more often diagnosed with ileal disease (28% versus 20%, P < 0.01) and underwent more often small bowel and ileocecal resection. Extraintestinal manifestations (EIMs) were more often encountered in female IBD patients. In the COIN study, 1139 CD patients and 1213 UC patients were analyzed. Male CD patients used prednisone more often and suffered more often from osteopenia. IBD-specific healthcare costs did not differ between male and female IBD patients.
Conclusions: Sex differences in patients with IBD include age of onset, disease location, and EIM prevalence. No large differences in therapeutic management of IBD were observed between men and women with IBD.

PMID: 29688413 [PubMed - as supplied by publisher]

Causal Impact of Type 2 Diabetes Mellitus on Cerebral Small Vessel Disease: A Mendelian Randomization Analysis.

Wed, 04/25/2018 - 22:04
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Causal Impact of Type 2 Diabetes Mellitus on Cerebral Small Vessel Disease: A Mendelian Randomization Analysis.

Stroke. 2018 Apr 23;:

Authors: Liu J, Rutten-Jacobs L, Liu M, Markus HS, Traylor M

Abstract
BACKGROUND AND PURPOSE: The relationship between type 2 diabetes mellitus (T2D) and cerebral small vessel disease (CSVD) is unclear. We aimed to examine the causal effect of T2D, fasting glucose levels, and higher insulin resistance on CSVD using Mendelian randomization.
METHODS: Five CSVD phenotypes were studied; 2 were clinical outcomes associated with CSVD (lacunar stroke: n=2191/27 297 and intracerebral hemorrhage [ICH]: n=2254/8195 [deep and lobar ICH]), whereas 3 were radiological markers of CSVD (white matter hyperintensities: n=8429; fractional anisotropy [FA]: n=8357; and mean diffusivity: n=8357). We applied 2 complementary analyses to evaluate the association of T2D with CSVD. First, we used summarized data from genome-wide association study to calculate the effects of T2D-related variants on CSVD with inverse-variance weighted and weighted median approaches. Second, we performed a genetic risk score approach to test the effects of T2D-associated variants on white matter hyperintensities, FA, and mean diffusivity using individual-level data in UK Biobank.
RESULTS: T2D was associated with higher risk of lacunar stroke (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.04-1.28; P=0.007) and lower mean FA (OR, 0.78; 95% CI, 0.66-0.92; P=0.004) but not white matter hyperintensities volume (OR, 1.01; 95% CI, 0.97-1.04; P=0.626), higher mean diffusivity (OR, 1.04; 95% CI, 0.89-1.23; P=0.612), ICH (OR, 1.07; 95% CI, 0.95-1.20; P=0.269), lobar ICH (OR, 1.07; 95% CI, 0.89-1.28; P=0.466), or deep ICH (OR, 1.16; 95% CI, 0.99-1.36; P=0.074). Weighted median and penalized median weighted analysis showed similar effect estimates of T2D on lacunar stroke and FA, but with wider CIs, meaning they were not significant. The genetic score on individual-level data was significantly associated with FA (OR, 0.63; 95% CI, 0.45-0.89; P=0.008) after adjusting for potential confounders.
CONCLUSIONS: Our Mendelian randomization study provides evidence to suggest that T2D may be causally associated with CSVD, in particular with lacunar stroke and FA.

PMID: 29686024 [PubMed - as supplied by publisher]

Dendritic cell vaccination for metastatic melanoma: a 14-year monoinstitutional experience.

Wed, 04/25/2018 - 22:04
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Dendritic cell vaccination for metastatic melanoma: a 14-year monoinstitutional experience.

Melanoma Res. 2017 Aug;27(4):351-357

Authors: de Rosa F, Ridolfi L, Fiammenghi L, Petrini M, Granato AM, Ancarani V, Pancisi E, Soldati V, Cassan S, Bulgarelli J, Framarini M, Tauceri F, Migliori G, Brolli C, Gentili G, Petracci E, Nanni O, Riccobon A, Ridolfi R, Guidoboni M

Abstract
Although immunomodulating antibodies are highly effective in metastatic melanoma, their toxicity, related to the activation of T lymphocytes, can be severe. Anticancer vaccines promote a fairly specific response and are very well tolerated, but their effectiveness has yet to be demonstrated. We have been treating patients with advanced melanoma with an autologous dendritic cell vaccine since 2001; to better characterize the safety and efficacy of our product, we designed a retrospective study on all of our patients treated with the vaccine to date. We retrospectively reviewed both case report forms of patients included in clinical trials and medical records of those treated within a compassionate use program. Response was assessed according to the Response Evaluation Criteria In Solid Tumors criteria and toxicity has been graded according to CTCAE 4.0. Although the response rate has been rather low, the median overall survival of 11.4 months and the 1-year survival rate of 46.9% are encouraging, especially considering the fact that data were obtained in a heavily pretreated population and only about one quarter of the patients had received ipilimumab and/or BRAF inhibitors. Multivariate analysis confirmed that the development of an immune response was significantly correlated with a better prognosis (hazard ratio 0.54; P=0.019). The adverse events observed were generally mild and self-limiting. Our analysis confirms the excellent tolerability of our vaccine, making it a potential candidate for combination therapies. As efficacy seems largely restricted to immunoresponsive patients, future strategies should aim to increase the number of these patients.

PMID: 28654547 [PubMed - indexed for MEDLINE]

Grip Strength Is Associated With Cognitive Performance in Schizophrenia and the General Population: A UK Biobank Study of 476559 Participants.

Tue, 04/24/2018 - 15:07
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Grip Strength Is Associated With Cognitive Performance in Schizophrenia and the General Population: A UK Biobank Study of 476559 Participants.

Schizophr Bull. 2018 Apr 19;:

Authors: Firth J, Stubbs B, Vancampfort D, Firth JA, Large M, Rosenbaum S, Hallgren M, Ward PB, Sarris J, Yung AR

Abstract
Background: Handgrip strength may provide an easily-administered marker of cognitive functional status. However, further population-scale research examining relationships between grip strength and cognitive performance across multiple domains is needed. Additionally, relationships between grip strength and cognitive functioning in people with schizophrenia, who frequently experience cognitive deficits, has yet to be explored.
Methods: Baseline data from the UK Biobank (2007-2010) was analyzed; including 475397 individuals from the general population, and 1162 individuals with schizophrenia. Linear mixed models and generalized linear mixed models were used to assess the relationship between grip strength and 5 cognitive domains (visual memory, reaction time, reasoning, prospective memory, and number memory), controlling for age, gender, bodyweight, education, and geographical region.
Results: In the general population, maximal grip strength was positively and significantly related to visual memory (coefficient [coeff] = -0.1601, standard error [SE] = 0.003), reaction time (coeff = -0.0346, SE = 0.0004), reasoning (coeff = 0.2304, SE = 0.0079), number memory (coeff = 0.1616, SE = 0.0092), and prospective memory (coeff = 0.3486, SE = 0.0092: all P < .001). In the schizophrenia sample, grip strength was strongly related to visual memory (coeff = -0.155, SE = 0.042, P < .001) and reaction time (coeff = -0.049, SE = 0.009, P < .001), while prospective memory approached statistical significance (coeff = 0.233, SE = 0.132, P = .078), and no statistically significant association was found with number memory and reasoning (P > .1).
Conclusions: Grip strength is significantly associated with cognitive functioning in the general population and individuals with schizophrenia, particularly for working memory and processing speed. Future research should establish directionality, examine if grip strength also predicts functional and physical health outcomes in schizophrenia, and determine whether interventions which improve muscular strength impact on cognitive and real-world functioning.

PMID: 29684174 [PubMed - as supplied by publisher]

Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies.

Tue, 04/24/2018 - 15:07
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Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies.

J Cachexia Sarcopenia Muscle. 2018 Apr 16;:

Authors: Spitali P, Hettne K, Tsonaka R, Charrout M, van den Bergen J, Koeks Z, Kan HE, Hooijmans MT, Roos A, Straub V, Muntoni F, Al-Khalili-Szigyarto C, Koel-Simmelink MJA, Teunissen CE, Lochmüller H, Niks EH, Aartsma-Rus A

Abstract
BACKGROUND: Analysis of muscle biopsies allowed to characterize the pathophysiological changes of Duchenne and Becker muscular dystrophies (D/BMD) leading to the clinical phenotype. Muscle tissue is often investigated during interventional dose finding studies to show in situ proof of concept and pharmacodynamics effect of the tested drug. Less invasive readouts are needed to objectively monitor patients' health status, muscle quality, and response to treatment. The identification of serum biomarkers correlating with clinical function and able to anticipate functional scales is particularly needed for personalized patient management and to support drug development programs.
METHODS: A large-scale proteomic approach was used to identify serum biomarkers describing pathophysiological changes (e.g. loss of muscle mass), association with clinical function, prediction of disease milestones, association with in vivo 31 P magnetic resonance spectroscopy data and dystrophin levels in muscles. Cross-sectional comparisons were performed to compare DMD patients, BMD patients, and healthy controls. A group of DMD patients was followed up for a median of 4.4 years to allow monitoring of individual disease trajectories based on yearly visits.
RESULTS: Cross-sectional comparison enabled to identify 10 proteins discriminating between healthy controls, DMD and BMD patients. Several proteins (285) were able to separate DMD from healthy, while 121 proteins differentiated between BMD and DMD; only 13 proteins separated BMD and healthy individuals. The concentration of specific proteins in serum was significantly associated with patients' performance (e.g. BMP6 serum levels and elbow flexion) or dystrophin levels (e.g. TIMP2) in BMD patients. Analysis of longitudinal trajectories allowed to identify 427 proteins affected over time indicating loss of muscle mass, replacement of muscle by adipose tissue, and cardiac involvement. Over-representation analysis of longitudinal data allowed to highlight proteins that could be used as pharmacodynamic biomarkers for drugs currently in clinical development.
CONCLUSIONS: Serum proteomic analysis allowed to not only discriminate among DMD, BMD, and healthy subjects, but it enabled to detect significant associations with clinical function, dystrophin levels, and disease progression.

PMID: 29682908 [PubMed - as supplied by publisher]

Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function.

Tue, 04/24/2018 - 15:07
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Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function.

Wellcome Open Res. 2018;3:13

Authors: Adewoye AB, Shrine N, Odenthal-Hesse L, Welsh S, Malarstig A, Jelinsky S, Kilty I, Tobin MD, Hollox EJ, Wain LV

Abstract
Background: The CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. Small molecule CCR5 antagonists exist, including the approved antiretroviral drug maraviroc, and therapeutic monoclonal antibodies are in development. Repositioning of drugs and targets into new disease areas can accelerate the availability of new therapies and substantially reduce costs. As it has been shown that drug targets with genetic evidence supporting their involvement in the disease are more likely to be successful in clinical development, using genetic association studies to identify new target repurposing opportunities could be fruitful. Here we investigate the potential of perturbation of the CCL3L1-CCR5 axis as treatment for respiratory disease. Europeans typically carry between 0 and 5 copies of CCL3L1 and this multi-allelic variation is not detected by widely used genome-wide single nucleotide polymorphism studies.  Methods: We directly measured the complex structural variation of CCL3L1 using the Paralogue Ratio Test and imputed (with validation) CCR5del32 genotypes in 5,000 individuals from UK Biobank, selected from the extremes of the lung function distribution, and analysed DNA and RNAseq data for CCL3L1 from the 1000 Genomes Project. Results: We confirmed the gene dosage effect of CCL3L1 copy number on CCL3L1 mRNA expression levels.  We found no evidence for association of CCL3L1 copy number or CCR5del32 genotype with lung function. Conclusions: These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.

PMID: 29682616 [PubMed]

Egg consumption and the risk of cardiovascular disease and all-cause mortality: Guangzhou Biobank Cohort Study and meta-analyses.

Tue, 04/24/2018 - 15:07
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Egg consumption and the risk of cardiovascular disease and all-cause mortality: Guangzhou Biobank Cohort Study and meta-analyses.

Eur J Nutr. 2018 Apr 21;:

Authors: Xu L, Lam TH, Jiang CQ, Zhang WS, Zhu F, Jin YL, Woo J, Cheng KK, Thomas GN

Abstract
PURPOSE: Eggs are highly nutritious but concerns over their cholesterol content have led to dietary avoidance among many. There are also important international differences in relevant dietary guidance. We conducted the first prospective study in China investigating the association of egg consumption, cardiovascular disease (CVD) mortality, and a meta-analysis.
METHODS: We included 28,024 participants without CVD at baseline (2003-8) in Guangzhou Biobank Cohort Study. All-cause and CVD mortality were identified through record linkage. We used Cox proportional hazards regression. We followed the Meta-analysis Of Observational Studies in Epidemiology reporting guidelines.
RESULTS: During 275,343 person-years follow-up (average 9.8 years), we found 2685 all-cause and 873 CVD deaths. We found no significant difference in all-cause mortality between higher (7+ eggs/week) and low consumption (< 1 egg/week) [adjusted hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.93-1.24], and mortality from CVD (0.99, 95% CI 0.76-1.27), ischemic heart disease (IHD) (0.92, 95% CI 0.63-1.36), or stroke (0.88, 95% CI 0.57-1.35). The updated meta-analyses including our results showed that 7+ eggs/week was not associated with all-cause mortality (HR 1.09, 95% CI 0.997-1.200) or IHD (HR 0.97, 95% CI 0.90-1.05), but associated with a small reduction in stroke (HR 0.91. 95% CI 0.85-0.98).
CONCLUSIONS: Eating one egg daily is not associated with increase in CVD or all-cause mortality. The small observed reduction in stroke risk needs to be confirmed. Our findings support current guidelines recommending eggs as part of a healthy diet, and should be considered in other dietary recommendations.

PMID: 29680985 [PubMed - as supplied by publisher]

The economic impact of multiple sclerosis to the patients and their families in Norway.

Tue, 04/24/2018 - 15:07
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The economic impact of multiple sclerosis to the patients and their families in Norway.

Eur J Health Econ. 2018 Apr 21;:

Authors: Svendsen B, Grytten N, Bø L, Aarseth H, Smedal T, Myhr KM

Abstract
BACKGROUND: Multiple sclerosis (MS) imposes high economic costs on society, but the patients and their families have to bear some of these costs.
OBJECTIVE: We aimed to estimate the magnitude of these economic costs in Norway.
METHOD: We collected data through a postal questionnaire survey targeting 922 MS patients in Hordaland County, western Norway, in 2013-2014; 546 agreed to participate and were included. The questionnaire included clinical and demographic characteristics, volume and cost of MS-related resource use, work participation, income, government financial support, and disability status.
RESULTS: The mean annual total economic costs for the patients and their families were €11,603. Indirect costs accounted for 66% and were lower for women than for men. The direct costs were nearly identical for men and women. The costs increased up to Expanded Disability Status Scale score 6 except for steps between 3 and 4 where it remained nearly constant. The costs reduced from EDSS 6 to 8, and increased from 8 to 9. Lifetime costs ranged from €24,897 to €70,021 for patients with late disease onset and slow progression, and between €441,934 and €574,860 for patients with early onset and rapid progression.
CONCLUSION: The economic costs of MS impose a heavy burden on the patients and their families. Supplementing the information on the cost of MS to society, our finding should be included as background information in decisions on reimbursing and allocating public resources for the well-being of MS patients and their families.

PMID: 29680926 [PubMed - as supplied by publisher]

Rapid Detection of the mt3243A > G Mutation Using Urine Sediment in Elderly Chinese Type 2 Diabetic Patients.

Tue, 04/24/2018 - 15:07
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Rapid Detection of the mt3243A > G Mutation Using Urine Sediment in Elderly Chinese Type 2 Diabetic Patients.

J Diabetes Res. 2017;2017:4683857

Authors: Zhang Y, Du X, Geng X, Chu C, Lu H, Shen Y, Chen R, Fang P, Feng Y, Zhang X, Chen Y, Zhou Y, Wang C, Jia W

Abstract
OBJECTIVE: In this study, we aimed to identify mt3243A > G mutation carriers in a group of Chinese elderly type 2 diabetic patients by a rapid and noninvasive diagnostic system.
METHODS: DNA was extracted from blood, saliva, and urine sediment samples. The mutation screening and quantitation of heteroplasmy were performed by high-resolution melting (HRM) curve and pyrosequencing, respectively. Patients with mt3243A > G mutation underwent a detailed audiometric, ophthalmologic, neurological, and cardiac examination.
RESULTS: Two patients (2/1041) carrying the mt3243A > G mutation were detected among all type 2 diabetic patients. In patient 1, the heteroplasmy was 0.8%, 2.8%, and 14.7% in peripheral blood leukocytes, saliva, and urine sediment, respectively. In patient 2, the heteroplasmy was 5.3%, 8.4%, and 37.7% in peripheral blood leukocytes, saliva, and urine sediment, respectively. Both of the two patients showed hearing impairment. Abnormal ophthalmologic conditions and hyperintensity on T2-weighted magnetic resonance images were showed in patient 1.
CONCLUSION: The occurrence of mt3243 A > G mutation was 0.2% in Chinese elderly type 2 diabetic patients. Moreover, detection of mt3243 A > G mutation in urine sediment with high-resolution melting (HRM) curve and pyrosequencing is feasible in molecular genetic diagnosis.

PMID: 28713835 [PubMed - indexed for MEDLINE]

Implantation and extravillous trophoblast invasion: From rare archival specimens to modern biobanking.

Tue, 04/24/2018 - 15:07
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Implantation and extravillous trophoblast invasion: From rare archival specimens to modern biobanking.

Placenta. 2017 Aug;56:19-26

Authors: Moser G, Huppertz B

Abstract
Extravillous trophoblast invasion serves to attach the placenta to the uterus and to enable access to nutrients for the embryo throughout pregnancy - secretions of the uterine glands in the first trimester, maternal blood in the second and third trimester. For assessing extravillous trophoblast invasion, histology (in combination with immunohistochemistry) still plays a major role in placental research. This is especially true for the re-assessment of rare archival specimens from early human implantation sites or placenta in utero with the background of recent knowledge which may help to strengthen current hypotheses. This review summarizes the recently expanded picture of extravillous trophoblast invasion, gives an overview about fundamental archival specimens in placental research, presents new images of archival specimens, gives insights into the latest developments in the field of biobanking and provides insight into the current situation on sample usage in the absence of biobanks. Modern techniques allow expanding our hitherto believed concept of extravillous trophoblast invasion, which is not restricted to spiral arteries: Extravillous trophoblasts also invade into uterine glands and uterine veins and thereby connect all these luminal structures with the intervillous space. All biomedical research dramatically depends on the quality of the assessed biological samples. Hence, researchers should be aware that the time between collection of a sample from a body and the beginning of analysis (pre-analytical phase) may have more impact on the outcome of a study than previously assumed.

PMID: 28202182 [PubMed - indexed for MEDLINE]

Eleven loci with new reproducible genetic associations with allergic disease risk.

Sun, 04/22/2018 - 12:38
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Eleven loci with new reproducible genetic associations with allergic disease risk.

J Allergy Clin Immunol. 2018 Apr 18;:

Authors: Ferreira MA, Vonk JM, Baurecht H, Marenholz I, Tian C, Hoffman JD, Helmer Q, Tillander A, Ullemar V, Lu Y, Rüschendorf F, 23andMe Research Team, collaborators of the SHARE study, Hinds DA, Hübner N, Weidinger S, Magnusson PK, Jorgenson E, Lee YA, Boomsma DI, Karlsson R, Almqvist C, Koppelman GH, Paternoster L

Abstract
BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities.
OBJECTIVE: To identify novel risk loci shared between asthma, hay fever and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 individuals.
METHODS: We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analysed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 individuals from the UK Biobank study.
RESULTS: Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P-value of 2.5x10-6. Of these, 20 were also significantly associated (P<0.05/30=0.0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWAS. Amongst these were nine genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L and LAT. For four genes (e.g. ATXN2L), a genetically-determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress Th2 responses.
CONCLUSION: Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWAS. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.

PMID: 29679657 [PubMed - as supplied by publisher]

A six-gene-based prognostic signature for hepatocellular carcinoma overall survival prediction.

Sun, 04/22/2018 - 12:38
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A six-gene-based prognostic signature for hepatocellular carcinoma overall survival prediction.

Life Sci. 2018 Apr 17;:

Authors: Wang Z, Teng D, Li Y, Hu Z, Liu L, Zheng H

Abstract
AIMS: The purpose of this study was to propose a pipeline to identify prognostic signature for HCC overall survival (OS) prediction based on HCC gene expression datasets from The Cancer Genome Atlas (TCGA).
RESULTS: Differential expression analysis identified 3573 genes aberrantly expressed (DEGs) in HCC samples. Univariate cox regression analysis obtained 1605 and 1067 HCC OS and relapse free survival (RFS) related genes, which are abbreviated as OS-Gene and RFS-Gene respectively. Besides, there are 55 overlaps among DEGs, OS-Genes and RFS-Genes. Further prioritization of the 55 overlapping genes through Sure Independence Screening (SIS) resulted in 6 genes, including SRL, TTC26, CPSF2, TAF3, C16orf46 and CSN1S1, and the prognostic signature is the weighted combination of their expression values. Kaplan-Meier analysis based on the prognostic score (PS) of every sample indicates higher PS is associated with better HCC OS. Robustness of the prognostic signature was evaluated through another HCC gene expression datasets from the Gene Expression Omnibus (GEO). What's more, univariate and multivariate cox regression analysis indicate significant associations between stage/PS and HCC OS.
CONCLUSIONS: Our study provides a pipeline for the identification of prognostic signature for HCC OS prediction, which should also be suit for other types of cancers.

PMID: 29678742 [PubMed - as supplied by publisher]

Integrating Biobank Data into a Clinical Data Research Network: The IBCB Project.

Sun, 04/22/2018 - 12:38
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Integrating Biobank Data into a Clinical Data Research Network: The IBCB Project.

Stud Health Technol Inform. 2018;247:16-20

Authors: Bouzille G, Jouhet V, Turlin B, Clement B, Desille M, Riou C, Hajjar M, Delamarre D, Le Quilleuc D, Thiessard F, Cuggia M

Abstract
Development of biobanks is still hampered by difficulty to collect high quality sample annotations using patient clinical information. The IBCB project evaluated the feasibility of a nationwide clinical data research network for this purpose.
METHOD: the infrastructure, based on eHOP and I2B2 technologies, was interfaced with the legacy IT components of 3 hospitals. The evaluation focused on the data management process and tested 5 expert queries in Hepatocarcinoma.
RESULTS: the integration of biobank data was comprehensive and easy. Five out of 5 queries were successfully performed and shown consistent results with the data sources excepted one query which required to search in unstructured data. The platform was designed to be scalable and showed that with few effort biobank data and clinical data can be integrated and leveraged between hospitals. Clinical or phenotyping concepts extraction techniques from free text could significantly improve the samples annotation with fine granularity information.

PMID: 29677914 [PubMed - in process]

Ondansetron Blocks Wildtype and p.F503L Variant Small Conductance Calcium Activated Potassium Channels.

Sat, 04/21/2018 - 13:17
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Ondansetron Blocks Wildtype and p.F503L Variant Small Conductance Calcium Activated Potassium Channels.

Am J Physiol Heart Circ Physiol. 2018 Apr 20;:

Authors: Ko JS, Guo S, Hassel J, Celestino-Soper P, Lynnes TC, Tisdale JE, Zheng JJ, Taylor SE, Foroud T, Murray MD, Kovacs RJ, Li X, Lin SF, Chen Z, Vatta M, Chen PS, Rubart M

Abstract
The apamin-sensitive, small conductance, calcium-activated potassium (SK) current ( IKAS) is encoded by KCNN genes. IKAS importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that IKAS inhibition contributes to drug-induced long QT (diLQT) syndrome, we (1) screened for KCNN variants among patients with diLQT, (2) determined the properties of heterologously expressed wildtype and variant KCNN channels, and (3) determined if the 5-HT3 receptor antagonist ondansetron blocks IKAS. We searched 2,306,335 records in the Indiana Network for Patient Care and found 11 patients with diLQT who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-year-old woman presenting with QTc interval prolongation at baseline (473 ms) and further QTc interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNE1 and ANK2, respectively. Patch-clamp studies revealed that the p.F503L KCNN2 variant heterologously expressed in human embryonic kidney (HEK)293 cells augmented Ca2+ sensitivity, increasing IKAS density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of wildtype KCNN2 protein. Ondansetron at nanomolar concentrations inhibited wildtype and p.F503L SK2 channels expressed in HEK293 cells as well native SK channels in ventricular cardiomyocytes. Ondansetron-induced IKAS inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, heterozygous p.F503L KCNN2 variant increases Ca2+ sensitivity and IKAS density in transfected HEK293 cells. Ondansetron at therapeutic, i.e., nanomolar, concentrations is a potent IKAS blocker.

PMID: 29677462 [PubMed - as supplied by publisher]