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Design of the NL-ENIGMA study: Exploring the effect of Souvenaid on cerebral glucose metabolism in early Alzheimer's disease.

Fri, 10/27/2017 - 22:48
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Design of the NL-ENIGMA study: Exploring the effect of Souvenaid on cerebral glucose metabolism in early Alzheimer's disease.

Alzheimers Dement (N Y). 2016 Nov;2(4):233-240

Authors: Scheltens NME, Kuyper IS, Boellaard R, Barkhof F, Teunissen CE, Broersen LM, Lansbergen MM, van der Flier WM, van Berckel BNM, Scheltens P

Abstract
INTRODUCTION: Alzheimer's disease is associated with early synaptic loss. Specific nutrients are known to be rate limiting for synapse formation. Studies have shown that administering specific nutrients may improve memory function, possibly by increasing synapse formation. This Dutch study explores the Effect of a specific Nutritional Intervention on cerebral Glucose Metabolism in early Alzheimer's disease (NL-ENIGMA, Dutch Trial Register NTR4718, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4718). The NL-ENIGMA study is designed to test whether the specific multinutrient combination Fortasyn Connect present in the medical food Souvenaid influences cerebral glucose metabolism as a marker for improved synapse function.
METHODS: This study is a double-blind, randomized controlled parallel-group single-center trial. Forty drug-naive patients with mild cognitive impairment or mild dementia with evidence of amyloid deposition are 1:1 randomized to receive either the multinutrient combination or placebo once daily. Main exploratory outcome parameters include absolute quantitative positron emission tomography with (18)F-fluorodeoxyglucose (including arterial sampling) and standard uptake value ratios normalized for the cerebellum or pons after 24 weeks.
DISCUSSION: We expect the NL-ENIGMA study to provide further insight in the potential of this multinutrient combination to improve synapse function.

PMID: 29067310 [PubMed]

Increased risk of pernicious anemia following scabies: a nationwide population-based matched-cohort study.

Fri, 10/27/2017 - 22:48
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Increased risk of pernicious anemia following scabies: a nationwide population-based matched-cohort study.

Ther Clin Risk Manag. 2017;13:1205-1211

Authors: Liu JM, Hsu RJ, Chang FW, Chiu FH, Yeh CL, Huang CF, Chang ST, Lee HC, Chi H, Lin CY

Abstract
OBJECTIVES: Scabies is a common and annoying disorder. Pernicious anemia (PA) is a serious disease which, when untreated, leads to death. Mounting evidence suggests that immune-mediated inflammatory processes play a role in the pathophysiology of both diseases. The relationship between these two diseases has not been investigated. We conducted this study to explore the potential relationship between scabies and PA.
MATERIALS AND METHODS: This nationwide, population-based study was conducted using the National Health Insurance Research Database of Taiwan. In total, 5,407 patients with scabies were identified as a study group and 20,089 matched patients were randomly selected as a control group. We tracked patients in both groups for a 7-year period to identify the incidence of PA. The demographic characteristics and comorbidities of the patients were analyzed, and Cox proportional hazards regression was used to calculate the hazard ratios for PA.
RESULTS: Of the 25,496 patients in this study, 183 (0.7%) patients with newly diagnosed PA were identified during the 7-year follow-up period; 71 of 5,407 (1.3%) from the scabies group and 112 of 20,089 (0.6%) from the control group. Patients with scabies had a higher risk of subsequent PA, with a crude hazard ratio of 2.368. After adjusting for covariates, the adjusted hazard ratio was 1.51 (95% confidence interval: 1.09-2.08).
CONCLUSION: This study demonstrated an increased risk of PA (adjusted hazard ratio 1.51) among patients with scabies. Immune-mediated inflammatory processes may contribute to this association. Further studies are warranted to investigate the entire pathological mechanisms between these two diseases. Physicians should pay attention to patients with history of scabies presented with anemia. Further confirmative tests of PA may contribute to correct diagnosis and initiation of vitamin B12 supplement.

PMID: 29066901 [PubMed]

Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.

Fri, 10/27/2017 - 22:48
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Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.

Lancet Respir Med. 2017 Oct 20;:

Authors: Allen RJ, Porte J, Braybrooke R, Flores C, Fingerlin TE, Oldham JM, Guillen-Guio B, Ma SF, Okamoto T, John AE, Obeidat M, Yang IV, Henry A, Hubbard RB, Navaratnam V, Saini G, Thompson N, Booth HL, Hart SP, Hill MR, Hirani N, Maher TM, McAnulty RJ, Millar AB, Molyneaux PL, Parfrey H, Rassl DM, Whyte MKB, Fahy WA, Marshall RP, Oballa E, Bossé Y, Nickle DC, Sin DD, Timens W, Shrine N, Sayers I, Hall IP, Noth I, Schwartz DA, Tobin MD, Wain LV, Jenkins RG

Abstract
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause, and few treatment options. Studies have identified a significant genetic risk associated with the development of IPF; however, mechanisms by which genetic risk factors promote IPF remain unclear. We aimed to identify genetic variants associated with IPF susceptibility and provide mechanistic insight using gene and protein expression analyses.
METHODS: We used a two-stage approach: a genome-wide association study in patients with IPF of European ancestry recruited from nine different centres in the UK and controls selected from UK Biobank (stage 1) matched for age, sex, and smoking status; and a follow-up of associated genetic variants in independent datasets of patients with IPF and controls from two independent US samples from the Chicago consortium and the Colorado consortium (stage 2). We investigated the effect of novel signals on gene expression in large transcriptomic and genomic data resources, and examined expression using lung tissue samples from patients with IPF and controls.
FINDINGS: 602 patients with IPF and 3366 controls were selected for stage 1. For stage 2, 2158 patients with IPF and 5195 controls were selected. We identified a novel genome-wide significant signal of association with IPF susceptibility near A-kinase anchoring protein 13 (AKAP13; rs62025270, odds ratio [OR] 1·27 [95% CI 1·18-1·37], p=1·32 × 10(-9)) and confirmed previously reported signals, including in mucin 5B (MUC5B; rs35705950, OR 2·89 [2·56-3·26], p=1·12 × 10(-66)) and desmoplakin (DSP; rs2076295, OR 1·44 [1·35-1·54], p=7·81 × 10(-28)). For rs62025270, the allele A associated with increased susceptibility to IPF was also associated with increased expression of AKAP13 mRNA in lung tissue from patients who had lung resection procedures (n=1111). We showed that AKAP13 is expressed in the alveolar epithelium and lymphoid follicles from patients with IPF, and AKAP13 mRNA expression was 1·42-times higher in lung tissue from patients with IPF (n=46) than that in lung tissue from controls (n=51).
INTERPRETATION: AKAP13 is a Rho guanine nucleotide exchange factor regulating activation of RhoA, which is known to be involved in profibrotic signalling pathways. The identification of AKAP13 as a susceptibility gene for IPF increases the prospect of successfully targeting RhoA pathway inhibitors in patients with IPF.
FUNDING: UK Medical Research Council, National Heart, Lung, and Blood Institute of the US National Institutes of Health, Agencia Canaria de Investigación, Innovación y Sociedad de la Información, Spain, UK National Institute for Health Research, and the British Lung Foundation.

PMID: 29066090 [PubMed - as supplied by publisher]

Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study.

Fri, 10/27/2017 - 22:48
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Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study.

J Neurol Neurosurg Psychiatry. 2017 Aug;88(8):621-625

Authors: Lunde HMB, Assmus J, Myhr KM, Bø L, Grytten N

Abstract
OBJECTIVE: Survival and causes of death (COD) in multiple sclerosis (MS) provide ultimate endpoints. We aimed to investigate survival and COD in a 60-year population-based MS cohort compared with the general population.
METHODS: All patients with incident multiple sclerosis (MS) (N=1388) with onset during 1953-2012 in Hordaland County, Western Norway, were included. Data were obtained from patient records at Haukeland University Hospital and linked to the Norwegian COD registry. Survival adjusted for sex, age and disease course were estimated by Kaplan-Meier analyses from birth and from disease onset. Mortality and COD in MS relative to the general population were examined by standardised mortality ratio (SMR).
RESULTS: Of 1388 patients, 291 had deceased, mainly of MS (56.4%). Median life expectancy was 74.7 years for MS and 81.8 years for the general population (p<0.001); 77.2 years for women with MS and 72.2 years for men with MS (p<0.001). Life expectancy for patients with relapsing remitting MS (RRMS) was 77.8 years and -71.4 years for primary progressive MS (PPMS) (p<0.001). Overall SMR was 2.7 (p>0.0001); 2.9 in women and 2.5 in men (p=0.0009). SMR was 2.4 in RRMS and 3.9 in PPMS (p<0.0001). SMR from disease onset during 1953-1974 was 3.1; 2.6 during 1975-1996 and 0.7 during 1997-2012 (p<0.0083). No difference in cause-specific deaths were found (p=0.0871).
CONCLUSION: We found a 7-year shorter life expectancy and almost threefold higher mortality in MS compared with the general population. A rise in survival in MS was observed during the entire observation period.

PMID: 28365589 [PubMed - indexed for MEDLINE]

Correlations between lncRNA-SOX2OT polymorphism and susceptibility to breast cancer in a Chinese population.

Fri, 10/27/2017 - 22:48
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Correlations between lncRNA-SOX2OT polymorphism and susceptibility to breast cancer in a Chinese population.

Biomark Med. 2017 Mar;11(3):277-284

Authors: Tang X, Gao Y, Yu L, Lu Y, Zhou G, Cheng L, Sun K, Zhu B, Xu M, Liu J

Abstract
AIM: We evaluated the effect of lncRNA SOX2OT expression and its SNP in tumorigenesis and development of breast cancer (BC) in a case-control study.
METHODS: A total of 1106 individuals, 505 newly diagnosed BC patients and 601 age-matched controls (±2 years) were testified. Real-time PCR was adopted for testing tissues' SOX2OT expression. Genotyping of rs9839776 were conducted by using SNaPshot assays.
RESULTS: SOX2OT were overexpressed in BC tissues (p < 0.001). SOX2OT SNP rs9839776 was strongly associated with the higher expression of SOX2OT and an increased risk of BC in Chinese women (odds ratio: 1.42; 95% CI: 1.06-1.90; p = 0.018).
CONCLUSION: These results confirmed that BC was conspicuously associated with higher SOX2OT expression. SOX2OT SNP rs9839776 was significantly associated with the onset of BC possibly via influencing the expression of SOX2OT.

PMID: 28240100 [PubMed - indexed for MEDLINE]

The effect of polyethylene glycol-modified lipids on the interaction of HIV-1 derived peptide-dendrimer complexes with lipid membranes.

Fri, 10/27/2017 - 22:48
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The effect of polyethylene glycol-modified lipids on the interaction of HIV-1 derived peptide-dendrimer complexes with lipid membranes.

Biochim Biophys Acta. 2016 12;1858(12):3005-3016

Authors: Melikishvili S, Poturnayova A, Ionov M, Bryszewska M, Vary T, Cirak J, Muñoz-Fernández MÁ, Gomez-Ramirez R, de la Mata FJ, Hianik T

Abstract
In this study, dendrimers have been purposed as an alternative approach for delivery of HIV peptides to dendritic cells. We have investigated the interaction of dendriplexes formed from polyanionic HIV peptide Nef and cationic carbosilane dendrimer (CBD) with model lipid membranes - large unilamellar vesicles (LUVs), Langmuir monolayers and supported lipid membranes (sBLMs) containing various molar ratio of zwitterionic 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG2000). In our experiments, the lipid membranes represented the model of the plasma membrane of the cell. PEGylated lipids were used in order to model glycocalyx which constitutes the outer leaflet of cellular membranes. The presence of PEGylated lipids resulted in an increase of the phase transition temperature of the lipid bilayer of LUVs, in a decrease of specific volume and adiabatic compressibility. Fluorescence anisotropy study suggests that PEGylated LUVs possessed higher lipid order and decreased fluidity when compared to zwitterionic DMPC vesicles. The interaction of dendriplexes with monolayers was accompanied by the formation of the aggregates as revealed by BAM experiments. This conclusion has been confirmed also by AFM imaging of sBLMs. We have demonstrated that dendriplexes interact with lipid membranes for all types of lipid composition. Moreover, the stronger interaction of cationic dendrimer/peptide complexes with lipid monolayers, vesicles and sBLMs was observed for membranes composed of zwitterionic lipids than for PEGylated lipid membranes. Increased concentration of PEGylated lipids made this interaction weaker.

PMID: 27620331 [PubMed - indexed for MEDLINE]

Safety and vaccine-induced HIV-1 immune responses in healthy volunteers following a late MVA-B boost 4 years after the last immunization.

Wed, 10/25/2017 - 14:24
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Safety and vaccine-induced HIV-1 immune responses in healthy volunteers following a late MVA-B boost 4 years after the last immunization.

PLoS One. 2017;12(10):e0186602

Authors: C Guardo A, Gómez CE, Díaz-Brito V, Pich J, Arnaiz JA, Perdiguero B, García-Arriaza J, González N, Sorzano COS, Jiménez L, Jiménez JL, Muñoz-Fernández MÁ, Gatell JM, Alcamí J, Esteban M, López Bernaldo de Quirós JC, García F, Plana M, RISVAC02boost study

Abstract
BACKGROUND: We have previously shown that an HIV vaccine regimen including three doses of HIV-modified vaccinia virus Ankara vector expressing HIV-1 antigens from clade B (MVA-B) was safe and elicited moderate and durable (1 year) T-cell and antibody responses in 75% and 95% of HIV-negative volunteers (n = 24), respectively (RISVAC02 study). Here, we describe the long-term durability of vaccine-induced responses and the safety and immunogenicity of an additional MVA-B boost.
METHODS: 13 volunteers from the RISVAC02 trial were recruited to receive a fourth dose of MVA-B 4 years after the last immunization. End-points were safety, cellular and humoral immune responses to HIV-1 and vector antigens assessed by ELISPOT, intracellular cytokine staining (ICS) and ELISA performed before and 2, 4 and 12 weeks after receiving the boost.
RESULTS: Volunteers reported 64 adverse events (AEs), although none was a vaccine-related serious AE. After 4 years from the 1st dose of the vaccine, only 2 volunteers maintained low HIV-specific T-cell responses. After the late MVA-B boost, a modest increase in IFN-γ T-cell responses, mainly directed against Env, was detected by ELISPOT in 5/13 (38%) volunteers. ICS confirmed similar results with 45% of volunteers showing that CD4+ T-cell responses were mainly directed against Env, whereas CD8+ T cell-responses were similarly distributed against Env, Gag and GPN. In terms of antibody responses, 23.1% of the vaccinees had detectable Env-specific binding antibodies 4 years after the last MVA-B immunization with a mean titer of 96.5. The late MVA-B boost significantly improved both the response rate (92.3%) and the magnitude of the systemic binding antibodies to gp120 (mean titer of 11460). HIV-1 neutralizing antibodies were also enhanced and detected in 77% of volunteers. Moreover, MVA vector-specific T cell and antibody responses were boosted in 80% and 100% of volunteers respectively.
CONCLUSIONS: One boost of MVA-B four years after receiving 3 doses of the same vaccine was safe, induced moderate increases in HIV-specific T cell responses in 38% of volunteers but significantly boosted the binding and neutralizing antibody responses to HIV-1 and to the MVA vector.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01923610.

PMID: 29065142 [PubMed - in process]

'It is an entrustment': Broad consent for genomic research and biobanks in Sub-Saharan Africa.

Wed, 10/25/2017 - 14:24
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'It is an entrustment': Broad consent for genomic research and biobanks in Sub-Saharan Africa.

Dev World Bioeth. 2017 Oct 23;:

Authors: Tindana P, Molyneux S, Bull S, Parker M

Abstract
In recent years, there has been an increase in the establishment of biobanks for genetic and genomic studies around the globe. One example of this is the Human Heredity and Health in Africa Initiative (H3Africa), which has established biobanks in the sub-region to facilitate future indigenous genomic studies. The concept of 'broad consent' has been proposed as a mechanism to enable potential research participants in biobanks to give permission for their samples to be used in future research studies. However, questions remain about the acceptability of this model of consent. Drawing on findings from empirical research about the role of trust in decision-making, we argue that an account of entrustment may be an appropriate way of addressing current challenges of seeking consent for biobank research in Africa. We propose a set of key points to consider that can support the proposed entrustment framework.

PMID: 29063669 [PubMed - as supplied by publisher]

High participation rate among 25 721 patients with broad age range in a hospital-based research project involving whole-genome sequencing - the Lausanne Institutional Biobank.

Wed, 10/25/2017 - 14:24
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High participation rate among 25 721 patients with broad age range in a hospital-based research project involving whole-genome sequencing - the Lausanne Institutional Biobank.

Swiss Med Wkly. 2017 Oct 24;147:w14528

Authors: Bochud M, Currat C, Chapatte L, Roth C, Mooser V

Abstract
AIMS: We aimed to evaluate the interest of adult inpatients and selected outpatients in engaging in a large, real-life, hospital-based, genomic medicine research project and in receiving clinically actionable incidental findings.
METHODS: Within the framework of the cross-sectional Institutional Biobank of Lausanne, Switzerland, a total of 25721 patients of the CHUV University Hospital were systematically invited to grant researchers access to their biomedical data and to donate blood for future analyses, including whole-genome sequencing. Multivariable logistic regression analysis was used to identify personal factors, including age, gender, religion, ethnicity, citizenship, education level and mode of admission, associated with willingness to participate in this genomic research project and with interest in receiving clinically actionable incidental findings.
RESULTS: The overall participation rate was 79% (20343/25721). Participation rate declined progressively with age, averaging 83%, 75%, 67% and 62% in patients aged <64 years (n = 13108), ≥64 years (n = 12613), ≥80 years (n = 4557) and ≥90 years (n = 1050), respectively. Factors associated with participation substantially differed between age strata. Patients less likely to participate included women (odds ratio 0.86, [95% confidence interval 0.79-0.95] and 0.78 [0.71-0.85] before and after age 64, respectively), non-Swiss (0.81 [0.74-0.90] and 0.58 [0.52-0.65]) and those admitted through the emergency ward (0.88 [0.79-0.98] and 0.66 [0.60-0.73]). Religion and marital status were associated with participation among patients aged <64 years. A total of 19 018 (93%) participants were willing to be re-contacted for incidental findings. A high education level was associated with higher participation rate, but not with higher willingness to receive incidental findings within the population who had agreed to participate.
CONCLUSION: A large proportion of adult patients, even among the elderly, are willing to actively participate and receive incidental findings in this systematic hospital-based precision and genomic medicine research program with broad consent.

PMID: 29063527 [PubMed - in process]

Obstacles to Widening Biosample Research.

Wed, 10/25/2017 - 14:24
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Obstacles to Widening Biosample Research.

Sci Eng Ethics. 2017 Oct 23;:

Authors: Colledge F, Passweg J, Elger B

Abstract
Switzerland has an excellent culture of medical research and is a melting pot for medical experts with international expertise. Nevertheless, as in other countries, the resources available to medical researchers are not being fully used. Biological samples, which enable a host of medical research studies to be carried out without invasive methods involving patients, are frequently left unused or forgotten. The aim of this study is to examine the experiences of biobank stakeholders regarding the use or underuse of biosamples, in order to develop paths to optimize biosample research. Interviews were carried out with 36 biobank stakeholders in Switzerland concerning their experiences with biosample use, and the possible obstacles at each stage of the process. Interviews revealed that standard operating procedures were the most frequently cited obstacle, although these were not judged to be severe hindrances. Despite a stated desire to develop biosample research, skepticism of sharing networks and wariness of new partnerships were strong themes. Biobanking still functions as an emerging field, in which exchange practices have yet to be established at the national and international levels. Sample exchange continues to function largely based on personal contacts; while this is an inherent feature of competitive medical research, opportunities for large-scale studies may be lost due to excessive caution.

PMID: 29063372 [PubMed - as supplied by publisher]

Electronic health record and genome-wide genetic data in Generation Scotland participants.

Wed, 10/25/2017 - 14:24
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Electronic health record and genome-wide genetic data in Generation Scotland participants.

Wellcome Open Res. 2017;2:85

Authors: Kerr SM, Campbell A, Marten J, Vitart V, McIntosh AM, Porteous DJ, Hayward C

Abstract
This article provides the first detailed demonstration of the research value of the Electronic Health Record (EHR) linked to research data in Generation Scotland Scottish Family Health Study (GS:SFHS) participants, together with how to access this data. The structured, coded variables in the routine biochemistry, prescribing and morbidity records, in particular, represent highly valuable phenotypic data for a genomics research resource. Access to a wealth of other specialized datasets, including cancer, mental health and maternity inpatient information, is also possible through the same straightforward and transparent application process. The EHR linked dataset is a key component of GS:SFHS, a biobank conceived in 1999 for the purpose of studying the genetics of health areas of current and projected public health importance. Over 24,000 adults were recruited from 2006 to 2011, with broad and enduring written informed consent for biomedical research. Consent was obtained from 23,603 participants for GS:SFHS study data to be linked to their Scottish National Health Service (NHS) records, using their Community Health Index number. This identifying number is used for NHS Scotland procedures (registrations, attendances, samples, prescribing and investigations) and allows healthcare records for individuals to be linked across time and location. Here, we describe the NHS EHR dataset on the sub-cohort of 20,032 GS:SFHS participants with consent and mechanism for record linkage plus extensive genetic data. Together with existing study phenotypes, including family history and environmental exposures, such as smoking, the EHR is a rich resource of real world data that can be used in research to characterise the health trajectory of participants, available at low cost and a high degree of timeliness, matched to DNA, urine and serum samples and genome-wide genetic information.

PMID: 29062915 [PubMed]

A birth cohort study in the Middle East: the Qatari birth cohort study (QBiC) phase I.

Wed, 10/25/2017 - 14:24
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A birth cohort study in the Middle East: the Qatari birth cohort study (QBiC) phase I.

BMC Public Health. 2017 Oct 23;17(1):836

Authors: Sadoun E, Leventakou V, Casas M, Ahmed HF, Kogevinas M, Fthenou E

Abstract
BACKGROUND: The latest scientific reports raise concerns about the rapidly increasing burden of chronic diseases in the state of Qatar. Pregnant Qatari women often confront complications during pregnancy including gestational diabetes, hypertension, abortion and stillbirth. The investigation of early life environmental, genetic, nutritional and social factors that may affect lifelong health is of great importance. Birth cohort studies offer a great opportunity to address early life hazards and their possible long lasting effects on health.
METHODS/DESIGN: The Qatari Birth Cohort study is the first mother-child cohort study in the Middle East Area that aims to assess the synergetic role of environmental exposure and genetic factors in the development of chronic disease and monitor woman and child health and/or obstetric characteristics with high prevalence. The present manuscript describes the recruitment phase of the study (duration: 2 years; expected number: 3000 families), where the pregnant Qatari women and their husbands are being contacted before the 15th week of gestation at the Primary Health Care Centers. The consented participants are interviewed to obtain information on several factors (sociodemographic characteristics, dietary habits, occupational/environmental exposure) and maternal characteristics are assessed based on anthropometric measurements, spirometry, and blood pressure. Pregnant women are invited to provide biological samples (blood and urine) in each trimester of their pregnancy, as well as cord blood at delivery. Fathers are also asked to provide biological samples.
DISCUSSION: The present study provides invaluable insights into a wide range of early life factors affecting human health. With a geographical focus on the Middle East, it will be a resource for information to the wider scientific community and will allow the formulation of effective policies with a primary focus on public health interventions for maternal and child health.

PMID: 29061134 [PubMed - in process]

The Influence of Family History Risk Levels of Diabetes on Disease Prevalence in a High-Risk Diabetic Chinese Population.

Wed, 10/25/2017 - 14:24
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The Influence of Family History Risk Levels of Diabetes on Disease Prevalence in a High-Risk Diabetic Chinese Population.

Diabetes Technol Ther. 2016 Aug;18(8):494-8

Authors: Du X, Zhang Y, Gao F, Lu H, Shen Y, Chen R, Fang P, Bao Y, Wang C, Jia W

Abstract
BACKGROUND: Diabetes is associated with genetic susceptibility, and family history is a risk factor. The study investigated the association between different family history risk levels and the prevalence of diabetes in a multi high-risk cohort and evaluated the impact of family history of diabetes on insulin secretion and insulin sensitivity.
MATERIALS AND METHODS: We analyzed data from 9754 adults who participated in the Shanghai High-Risk Diabetic Screen Project between 2002 and 2012. The association among three family history risk levels (mild, moderate, and high) with the prevalence of diabetes, insulin secretion, and insulin sensitivity was evaluated in the multi high-risk cohort.
RESULTS: Overall, 69.6%, 24.8%, and 5.6% of participants were categorized as having mild, moderate, and high familial risk, respectively. The standardized prevalence was higher in the high family history risk group (43.1%) than in the moderate group (37.3%) and in the mild group (23.5%) (P < 0.001). The odds ratios (ORs) were significantly increased in the moderate group (OR 1.27, 95% confidence interval [CI] 1.15-1.40, P < 0.05) and in the high group (OR 1.69, 95% CI 1.41-2.02, P < 0.05). Among the 3245 normal glucose tolerance participants, insulin secretion significantly declined with increasing levels of family history risk, but there were no significant differences in insulin sensitivity among the three groups.
CONCLUSION: The prevalence of diabetes was independently associated with an increasing family history risk level among multi high-risk Chinese populations. Subjects with moderate and high familial history of diabetes displayed a significant decrease in insulin secretion.

PMID: 27227381 [PubMed - indexed for MEDLINE]

Association analysis identifies 65 new breast cancer risk loci.

Tue, 10/24/2017 - 13:18

Association analysis identifies 65 new breast cancer risk loci.

Nature. 2017 Oct 23;:

Authors: Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, Kar S, Lemaçon A, Soucy P, Glubb D, Rostamianfar A, Bolla MK, Wang Q, Tyrer J, Dicks E, Lee A, Wang Z, Allen J, Keeman R, Eilber U, French JD, Qing Chen X, Fachal L, McCue K, McCart Reed AE, Ghoussaini M, Carroll JS, Jiang X, Finucane H, Adams M, Adank MA, Ahsan H, Aittomäki K, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Arun B, Auer PL, Bacot F, Barrdahl M, Baynes C, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bernstein L, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Børresen-Dale AL, Brand JS, Brauch H, Brennan P, Brenner H, Brinton L, Broberg P, Brock IW, Broeks A, Brooks-Wilson A, Brucker SY, Brüning T, Burwinkel B, Butterbach K, Cai Q, Cai H, Caldés T, Canzian F, Carracedo A, Carter BD, Castelao JE, Chan TL, David Cheng TY, Seng Chia K, Choi JY, Christiansen H, Clarke CL, NBCS Collaborators, Collée M, Conroy DM, Cordina-Duverger E, Cornelissen S, Cox DG, Cox A, Cross SS, Cunningham JM, Czene K, Daly MB, Devilee P, Doheny KF, Dörk T, Dos-Santos-Silva I, Dumont M, Durcan L, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Ellberg C, Elvira M, Engel C, Eriksson M, Fasching PA, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fritschi L, Gaborieau V, Gabrielson M, Gago-Dominguez M, Gao YT, Gapstur SM, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Glendon G, Goldberg MS, Goldgar DE, González-Neira A, Grenaker Alnæs GI, Grip M, Gronwald J, Grundy A, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hamel N, Hankinson S, Harrington P, Hart SN, Hartikainen JM, Hartman M, Hein A, Heyworth J, Hicks B, Hillemanns P, Ho DN, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Hou MF, Hsiung CN, Huang G, Humphreys K, Ishiguro J, Ito H, Iwasaki M, Iwata H, Jakubowska A, Janni W, John EM, Johnson N, Jones K, Jones M, Jukkola-Vuorinen A, Kaaks R, Kabisch M, Kaczmarek K, Kang D, Kasuga Y, Kerin MJ, Khan S, Khusnutdinova E, Kiiski JI, Kim SW, Knight JA, Kosma VM, Kristensen VN, Krüger U, Kwong A, Lambrechts D, Le Marchand L, Lee E, Lee MH, Lee JW, Neng Lee C, Lejbkowicz F, Li J, Lilyquist J, Lindblom A, Lissowska J, Lo WY, Loibl S, Long J, Lophatananon A, Lubinski J, Luccarini C, Lux MP, Ma ESK, MacInnis RJ, Maishman T, Makalic E, Malone KE, Kostovska IM, Mannermaa A, Manoukian S, Manson JE, Margolin S, Mariapun S, Martinez ME, Matsuo K, Mavroudis D, McKay J, McLean C, Meijers-Heijboer H, Meindl A, Menéndez P, Menon U, Meyer J, Miao H, Miller N, Taib NAM, Muir K, Mulligan AM, Mulot C, Neuhausen SL, Nevanlinna H, Neven P, Nielsen SF, Noh DY, Nordestgaard BG, Norman A, Olopade OI, Olson JE, Olsson H, Olswold C, Orr N, Pankratz VS, Park SK, Park-Simon TW, Lloyd R, Perez JIA, Peterlongo P, Peto J, Phillips KA, Pinchev M, Plaseska-Karanfilska D, Prentice R, Presneau N, Prokofyeva D, Pugh E, Pylkäs K, Rack B, Radice P, Rahman N, Rennert G, Rennert HS, Rhenius V, Romero A, Romm J, Ruddy KJ, Rüdiger T, Rudolph A, Ruebner M, Rutgers EJT, Saloustros E, Sandler DP, Sangrajrang S, Sawyer EJ, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schumacher F, Schürmann P, Scott RJ, Scott C, Seal S, Seynaeve C, Shah M, Sharma P, Shen CY, Sheng G, Sherman ME, Shrubsole MJ, Shu XO, Smeets A, Sohn C, Southey MC, Spinelli JJ, Stegmaier C, Stewart-Brown S, Stone J, Stram DO, Surowy H, Swerdlow A, Tamimi R, Taylor JA, Tengström M, Teo SH, Beth Terry M, Tessier DC, Thanasitthichai S, Thöne K, Tollenaar RAEM, Tomlinson I, Tong L, Torres D, Truong T, Tseng CC, Tsugane S, Ulmer HU, Ursin G, Untch M, Vachon C, van Asperen CJ, Van Den Berg D, van den Ouweland AMW, van der Kolk L, van der Luijt RB, Vincent D, Vollenweider J, Waisfisz Q, Wang-Gohrke S, Weinberg CR, Wendt C, Whittemore AS, Wildiers H, Willett W, Winqvist R, Wolk A, Wu AH, Xia L, Yamaji T, Yang XR, Har Yip C, Yoo KY, Yu JC, Zheng W, Zheng Y, Zhu B, Ziogas A, Ziv E, ABCTB Investigators, ConFab/AOCS Investigators, Lakhani SR, Antoniou AC, Droit A, Andrulis IL, Amos CI, Couch FJ, Pharoah PDP, Chang-Claude J, Hall P, Hunter DJ, Milne RL, García-Closas M, Schmidt MK, Chanock SJ, Dunning AM, Edwards SL, Bader GD, Chenevix-Trench G, Simard J, Kraft P, Easton DF

Abstract
Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10(-8). The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

PMID: 29059683 [PubMed - as supplied by publisher]

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Tue, 10/24/2017 - 13:18

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Nat Genet. 2017 Oct 23;:

Authors: Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, Hui S, Lemaçon A, Soucy P, Dennis J, Jiang X, Rostamianfar A, Finucane H, Bolla MK, McGuffog L, Wang Q, Aalfs CM, ABCTB Investigators, Adams M, Adlard J, Agata S, Ahmed S, Ahsan H, Aittomäki K, Al-Ejeh F, Allen J, Ambrosone CB, Amos CI, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Arnold N, Aronson KJ, Auber B, Auer PL, Ausems MGEM, Azzollini J, Bacot F, Balmaña J, Barile M, Barjhoux L, Barkardottir RB, Barrdahl M, Barnes D, Barrowdale D, Baynes C, Beckmann MW, Benitez J, Bermisheva M, Bernstein L, Bignon YJ, Blazer KR, Blok MJ, Blomqvist C, Blot W, Bobolis K, Boeckx B, Bogdanova NV, Bojesen A, Bojesen SE, Bonanni B, Børresen-Dale AL, Bozsik A, Bradbury AR, Brand JS, Brauch H, Brenner H, Bressac-de Paillerets B, Brewer C, Brinton L, Broberg P, Brooks-Wilson A, Brunet J, Brüning T, Burwinkel B, Buys SS, Byun J, Cai Q, Caldés T, Caligo MA, Campbell I, Canzian F, Caron O, Carracedo A, Carter BD, Castelao JE, Castera L, Caux-Moncoutier V, Chan SB, Chang-Claude J, Chanock SJ, Chen X, Cheng TD, Chiquette J, Christiansen H, Claes KBM, Clarke CL, Conner T, Conroy DM, Cook J, Cordina-Duverger E, Cornelissen S, Coupier I, Cox A, Cox DG, Cross SS, Cuk K, Cunningham JM, Czene K, Daly MB, Damiola F, Darabi H, Davidson R, De Leeneer K, Devilee P, Dicks E, Diez O, Ding YC, Ditsch N, Doheny KF, Domchek SM, Dorfling CM, Dörk T, Dos-Santos-Silva I, Dubois S, Dugué PA, Dumont M, Dunning AM, Durcan L, Dwek M, Dworniczak B, Eccles D, Eeles R, Ehrencrona H, Eilber U, Ejlertsen B, Ekici AB, Eliassen AH, EMBRACE, Engel C, Eriksson M, Fachal L, Faivre L, Fasching PA, Faust U, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Foulkes WD, Friedman E, Fritschi L, Frost D, Gabrielson M, Gaddam P, Gammon MD, Ganz PA, Gapstur SM, Garber J, Garcia-Barberan V, García-Sáenz JA, Gaudet MM, Gauthier-Villars M, Gehrig A, GEMO Study Collaborators, Georgoulias V, Gerdes AM, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Goodfellow P, Greene MH, Alnæs GIG, Grip M, Gronwald J, Grundy A, Gschwantler-Kaulich D, Guénel P, Guo Q, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hallberg E, Hamann U, Hamel N, Hankinson S, Hansen TVO, Harrington P, Hart SN, Hartikainen JM, Healey CS, HEBON, Hein A, Helbig S, Henderson A, Heyworth J, Hicks B, Hillemanns P, Hodgson S, Hogervorst FB, Hollestelle A, Hooning MJ, Hoover B, Hopper JL, Hu C, Huang G, Hulick PJ, Humphreys K, Hunter DJ, Imyanitov EN, Isaacs C, Iwasaki M, Izatt L, Jakubowska A, James P, Janavicius R, Janni W, Jensen UB, John EM, Johnson N, Jones K, Jones M, Jukkola-Vuorinen A, Kaaks R, Kabisch M, Kaczmarek K, Kang D, Kast K, kConFab/AOCS Investigators, Keeman R, Kerin MJ, Kets CM, Keupers M, Khan S, Khusnutdinova E, Kiiski JI, Kim SW, Knight JA, Konstantopoulou I, Kosma VM, Kristensen VN, Kruse TA, Kwong A, Lænkholm AV, Laitman Y, Lalloo F, Lambrechts D, Landsman K, Lasset C, Lazaro C, Le Marchand L, Lecarpentier J, Lee A, Lee E, Lee JW, Lee MH, Lejbkowicz F, Lesueur F, Li J, Lilyquist J, Lincoln A, Lindblom A, Lissowska J, Lo WY, Loibl S, Long J, Loud JT, Lubinski J, Luccarini C, Lush M, MacInnis RJ, Maishman T, Makalic E, Kostovska IM, Malone KE, Manoukian S, Manson JE, Margolin S, Martens JWM, Martinez ME, Matsuo K, Mavroudis D, Mazoyer S, McLean C, Meijers-Heijboer H, Menéndez P, Meyer J, Miao H, Miller A, Miller N, Mitchell G, Montagna M, Muir K, Mulligan AM, Mulot C, Nadesan S, Nathanson KL, NBSC Collaborators, Neuhausen SL, Nevanlinna H, Nevelsteen I, Niederacher D, Nielsen SF, Nordestgaard BG, Norman A, Nussbaum RL, Olah E, Olopade OI, Olson JE, Olswold C, Ong KR, Oosterwijk JC, Orr N, Osorio A, Pankratz VS, Papi L, Park-Simon TW, Paulsson-Karlsson Y, Lloyd R, Pedersen IS, Peissel B, Peixoto A, Perez JIA, Peterlongo P, Peto J, Pfeiler G, Phelan CM, Pinchev M, Plaseska-Karanfilska D, Poppe B, Porteous ME, Prentice R, Presneau N, Prokofieva D, Pugh E, Pujana MA, Pylkäs K, Rack B, Radice P, Rahman N, Rantala J, Rappaport-Fuerhauser C, Rennert G, Rennert HS, Rhenius V, Rhiem K, Richardson A, Rodriguez GC, Romero A, Romm J, Rookus MA, Rudolph A, Ruediger T, Saloustros E, Sanders J, Sandler DP, Sangrajrang S, Sawyer EJ, Schmidt DF, Schoemaker MJ, Schumacher F, Schürmann P, Schwentner L, Scott C, Scott RJ, Seal S, Senter L, Seynaeve C, Shah M, Sharma P, Shen CY, Sheng X, Shimelis H, Shrubsole MJ, Shu XO, Side LE, Singer CF, Sohn C, Southey MC, Spinelli JJ, Spurdle AB, Stegmaier C, Stoppa-Lyonnet D, Sukiennicki G, Surowy H, Sutter C, Swerdlow A, Szabo CI, Tamimi RM, Tan YY, Taylor JA, Tejada MI, Tengström M, Teo SH, Terry MB, Tessier DC, Teulé A, Thöne K, Thull DL, Tibiletti MG, Tihomirova L, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Tong L, Torres D, Tranchant M, Truong T, Tucker K, Tung N, Tyrer J, Ulmer HU, Vachon C, van Asperen CJ, Van Den Berg D, van den Ouweland AMW, van Rensburg EJ, Varesco L, Varon-Mateeva R, Vega A, Viel A, Vijai J, Vincent D, Vollenweider J, Walker L, Wang Z, Wang-Gohrke S, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wesseling J, Whittemore AS, Wijnen JT, Willett W, Winqvist R, Wolk A, Wu AH, Xia L, Yang XR, Yannoukakos D, Zaffaroni D, Zheng W, Zhu B, Ziogas A, Ziv E, Zorn KK, Gago-Dominguez M, Mannermaa A, Olsson H, Teixeira MR, Stone J, Offit K, Ottini L, Park SK, Thomassen M, Hall P, Meindl A, Schmutzler RK, Droit A, Bader GD, Pharoah PDP, Couch FJ, Easton DF, Kraft P, Chenevix-Trench G, García-Closas M, Schmidt MK, Antoniou AC, Simard J

Abstract
Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10(-8) with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

PMID: 29058716 [PubMed - as supplied by publisher]

Association of Vitamin E Levels with Metabolic Syndrome, and MRI-Derived Body Fat Volumes and Liver Fat Content.

Tue, 10/24/2017 - 13:18

Association of Vitamin E Levels with Metabolic Syndrome, and MRI-Derived Body Fat Volumes and Liver Fat Content.

Nutrients. 2017 Oct 18;9(10):

Authors: Waniek S, Giuseppe RD, Plachta-Danielzik S, Ratjen I, Jacobs G, Koch M, Borggrefe J, Both M, Müller HP, Kassubek J, Nöthlings U, Esatbeyoglu T, Schlesinger S, Rimbach G, Lieb W

Abstract
We aimed to relate circulating α- and γ-tocopherol levels to a broad spectrum of adiposityrelated traits in a cross-sectional Northern German study. Anthropometric measures were obtained, and adipose tissue volumes and liver fat were quantified by magnetic resonance imaging in 641 individuals (mean age 61 years; 40.6% women). Concentrations of α- and γ-tocopherol were measured using high performance liquid chromatography. Multivariable-adjusted linear and logistic regression were used to assess associations of circulating α- and γ-tocopherol/cholesterol ratio levels with visceral (VAT) and subcutaneous adipose tissue (SAT), liver signal intensity (LSI), fatty liver disease (FLD), metabolic syndrome (MetS), and its individual components. The α- tocopherol/cholesterol ratio was positively associated with VAT (β scaled by interquartile range (IQR): 0.036; 95%Confidence Interval (CI): 0.0003; 0.071) and MetS (Odds Ratio (OR): 1.83; 95% CI: 1.21-2.76 for 3rd vs. 1st tertile), and the γ-tocopherol/cholesterol ratio was positively associated with VAT (β scaled by IQR: 0.066; 95% CI: 0.027; 0.104), SAT (β scaled by IQR: 0.048; 95% CI: 0.010; 0.087) and MetS (OR: 1.87; 95% CI: 1.23-2.84 for 3rd vs. 1st tertile). α- and γ-tocopherol levels were positively associated with high triglycerides and low high density lipoprotein cholesterol levels (all Ptrend < 0.05). No association of α- and γ-tocopherol/cholesterol ratio with LSI/FLD was observed. Circulating vitamin E levels displayed strong associations with VAT and MetS. These observations lay the ground for further investigation in longitudinal studies.

PMID: 29057829 [PubMed - in process]

Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism and Eating Disorders: Data From a New Biobank and Meta-Analysis of Previously Published Studies.

Tue, 10/24/2017 - 13:18
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Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism and Eating Disorders: Data From a New Biobank and Meta-Analysis of Previously Published Studies.

Eur Eat Disord Rev. 2017 Nov;25(6):524-532

Authors: Collantoni E, Solmi M, Gallicchio D, Santonastaso P, Meneguzzo P, Carvalho AF, Stubbs B, Clementi M, Pinato C, Forzan M, Cassina M, Fontana F, Piva I, Siani R, Salvo P, Tenconi E, Veronese N, Correll CU, Favaro A

Abstract
OBJECTIVES: We investigated whether catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with eating disorders (EDs).
METHODS: We conducted a systematic literature search of studies published until 15 January 2017 and added data from the Italian 'Biobanca Veneta per i Disturbi Alimentari' biobank, performing a meta-analysis comparing COMT Val158Met genotype and allele frequencies in EDs and anorexia nervosa (AN) or bulimia nervosa (BN) patients versus controls.
RESULTS: Ten studies plus Biobanca Veneta per i Disturbi Alimentari (ED: n = 920, controls: n = 261 controls) with 3541 ED patients (AN = 2388; BN = 233) and 3684 controls were included. There were no significant group differences in COMT Val158Met alleles and genotype frequencies between patients and controls, for all EDs pooled together [range of odds ratios (ORs): 0.96-1.04, p-values: 0.46-0.97, I(2)  = 0%] and when analysing separately patients with AN (ORs: 0.94-1.04, p-values: 0.31-0.61, I(2)  = 0%) or BN (ORs: 0.80-1.09, p-values: 0.28-0.64, I(2)  = 0-44%).
CONCLUSIONS: Meta-analysing data results from 11 studies and 7225 subjects show that COMT Val158Met polymorphism is not associated with EDs. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

PMID: 29057600 [PubMed - in process]

International management platform for children's interstitial lung disease (chILD-EU).

Tue, 10/24/2017 - 13:18
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International management platform for children's interstitial lung disease (chILD-EU).

Thorax. 2017 Oct 22;:

Authors: Griese M, Seidl E, Hengst M, Reu S, Rock H, Anthony G, Kiper N, Emiralioğlu N, Snijders D, Goldbeck L, Leidl R, Ley-Zaporozhan J, Krüger-Stollfuss I, Kammer B, Wesselak T, Eismann C, Schams A, Neuner D, MacLean M, Nicholson AG, Lauren M, Clement A, Epaud R, de Blic J, Ashworth M, Aurora P, Calder A, Wetzke M, Kappler M, Cunningham S, Schwerk N, Bush A, and the other chILD-EU collaborators

Abstract
BACKGROUND: Children's interstitial lung diseases (chILD) cover many rare entities, frequently not diagnosed or studied in detail. There is a great need for specialised advice and for internationally agreed subclassification of entities collected in a register.Our objective was to implement an international management platform with independent multidisciplinary review of cases at presentation for long-term follow-up and to test if this would allow for more accurate diagnosis. Also, quality and reproducibility of a diagnostic subclassification system were assessed using a collection of 25 complex chILD cases.
METHODS: A web-based chILD management platform with a registry and biobank was successfully designed and implemented.
RESULTS: Over a 3-year period, 575 patients were included for observation spanning a wide spectrum of chILD. In 346 patients, multidisciplinary reviews were completed by teams at five international sites (Munich 51%, London 12%, Hannover 31%, Ankara 1% and Paris 5%). In 13%, the diagnosis reached by the referring team was not confirmed by peer review. Among these, the diagnosis initially given was wrong (27%), imprecise (50%) or significant information was added (23%).The ability of nine expert clinicians to subcategorise the final diagnosis into the chILD-EU register classification had an overall exact inter-rater agreement of 59% on first assessment and after training, 64%. Only 10% of the 'wrong' answers resulted in allocation to an incorrect category. Subcategorisation proved useful but training is needed for optimal implementation.
CONCLUSIONS: We have shown that chILD-EU has generated a platform to help the clinical assessment of chILD.
TRIAL REGISTRATION NUMBER: Results, NCT02852928.

PMID: 29056600 [PubMed - as supplied by publisher]

Adjuvant Chemotherapy After Radical Cystectomy for Urothelial Bladder Cancer: Outcome and Prognostic Factors for Survival in a French Multicenter, Contemporary Cohort.

Tue, 10/24/2017 - 13:18
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Adjuvant Chemotherapy After Radical Cystectomy for Urothelial Bladder Cancer: Outcome and Prognostic Factors for Survival in a French Multicenter, Contemporary Cohort.

Clin Genitourin Cancer. 2017 Feb;15(1):e45-e52

Authors: Pouessel D, Bastuji-Garin S, Houédé N, Vordos D, Loriot Y, Chevreau C, Sevin E, Beuzeboc P, Taille A, Le Thuaut A, Allory Y, Culine S

Abstract
BACKGROUND: In the past decade, adjuvant chemotherapy (AC) after radical cystectomy (RC) was preferred worldwide for patients with muscle-invasive urothelial bladder cancer. In this study we aimed to determine the outcome of patients who received AC and evaluated prognostic factors associated with survival.
PATIENTS AND METHODS: We retrospectively analyzed 226 consecutive patients treated in 6 academic hospitals between 2000 and 2009. Multivariate Cox proportional hazards regression adjusted for center to estimate adjusted hazard ratios (HRs) with 95% confidence intervals were used.
RESULTS: The median age was 62.4 (range, 35-82) years. Patients had pT3/pT4 and/or pN+ in 180 (79.6%) and 168 patients (74.3%), respectively. Median lymph node (LN) density was 25% (range, 3.1-100). Median time between RC and AC was 61.5 (range, 18-162) days. Gemcitabine with cisplatin, gemcitabine with carboplatin, and MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimens were delivered in 161 (71.2%), 49 (21.7%), and 12 patients (5.3%) of patients, respectively. The median number of cycles was 4 (range, 1-6). Thirteen patients (5.7%) with LN metastases also received adjuvant pelvic radiotherapy (ART). After a median follow-up of 4.2 years, 5-year overall survival (OS) was 40.7%. In multivariate analysis, pT ≥3 stage (HR, 1.73; P = .05), LN density >50% (HR, 1.94; P = .03), and number of AC cycles <4 (HR, 4.26; P = .001) were adverse prognostic factors for OS. ART (HR, 0.30; P = .05) tended to provide survival benefit.
CONCLUSION: Classical prognostic features associated with survival are not modified by the use of AC. Patients who derived benefit from AC had a low LN density and received at least 4 cycles of treatment.

PMID: 27554584 [PubMed - indexed for MEDLINE]

IgG glycosylation and DNA methylation are interconnected with smoking.

Mon, 10/23/2017 - 17:57

IgG glycosylation and DNA methylation are interconnected with smoking.

Biochim Biophys Acta. 2017 Oct 18;:

Authors: Wahl A, Kasela S, Monotoro EC, van Iterson M, Štambuk J, Sharma S, van den Akker E, Klaric L, Benedetti E, Razdorov G, Trbojević-Akmačić I, Vučković F, Ugrina I, Beekman M, Deelen J, van Heemst D, Heijmans BT, Consortium BIOS, Wuhrer M, Plomp R, Keser T, Šimurina M, Pavić T, Gudelj I, Krištić J, Grallert H, Kunze S, Peters A, Bell JT, Spector TD, Milani L, Eline Slagboom P, Lauc G, Gieger C

Abstract
BACKGROUND: Glycosylation is one of the most common post-translation modifications with large influences on protein structure and function. The effector function of immunoglobulin G (IgG) alters between pro- and anti-inflammatory, based on its glycosylation. IgG glycan synthesis is highly complex and dynamic.
METHODS: With the use of two different analytical methods for assessing IgG glycosylation, we aim to elucidate the link between DNA methylation and glycosylation of IgG by means of epigenome-wide association studies. In total, 3000 individuals from 4 cohorts were analyzed.
RESULTS: The overlap of the results from the two glycan measurement panels yielded DNA methylation of 7 CpG-sites on 5 genomic locations to be associated with IgG glycosylation: cg25189904 (chr.1, GNG12); cg05951221, cg21566642 and cg01940273 (chr.2, ALPPL2); cg05575921 (chr.5, AHRR); cg06126421 (6p21.33); and cg03636183 (chr.19, F2RL3). Mediation analyses with respect to smoking revealed that the effect of smoking on IgG glycosylation may be at least partially mediated via DNA methylation levels at these 7 CpG-sites.
CONCLUSION: Our results suggest the presence of an indirect link between DNA methylation and IgG glycosylation that may in part capture environmental exposures.
GENERAL SIGNIFICANCE: An epigenome-wide analysis conducted in four population-based cohorts revealed an association between DNA methylation and IgG glycosylation patterns. Presumably, DNA methylation mediates the effect of smoking on IgG glycosylation.

PMID: 29055820 [PubMed - as supplied by publisher]