@article {10783, title = {Gadolinium tissue deposition in the periodontal ligament of mice with reduced renal function exposed to Gd-based contrast agents.}, journal = {Toxicol Lett}, volume = {301}, year = {2019}, month = {2019 Feb}, pages = {157-167}, abstract = {

Gadolinium deposition in tissue is linked to nephrogenic systemic fibrosis (NSF): a rare disorder occurring in patients with severe chronic kidney disease and associated with administration of Gd-based contrast agents (GBCAs) for Magnetic Resonance Imaging (MRI). It is suggested that the GBCAs prolonged permanence in blood in these patients may result in a Gd precipitation in peripheral or central organs, where it initiates a fibrotic process. In this study we investigated new sites of retention/precipitation of Gd in a mouse model of renal disease (5/6 nephrectomy) receiving two doses (closely after each other) of a linear GBCA. Two commercial GBCAs (Omniscan{\textregistered} and Magnevist{\textregistered}) were administered at doses slightly higher than those used in clinical practice (0.7 mmol/kg body weight, each). The animals were sacrificed one month after the last administration and the explanted organs (kidney, liver, femur, dorsal skin, teeth) were analysed by X-ray fluorescence (XRF) at two synchrotron facilities. The XRF analysis with a millimetre-sized beam at the SYRMEP beamline (Elettra, Italy) produced no detectable levels of Gd in the examined tissues, with the notable exception of the incisors of the nephrectomised mice. The XRF analyses at sub-micron resolution performed at ID21 (ESRF, France) allowed to clearly localize Gd in the periodontal ligaments of teeth both from Omniscan{\textregistered} and Magnevist{\textregistered} treated nephrectomised mice. The latter results were further confirmed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The study prompts that prolonged permanence of GBCAs in blood may result in Gd retention in this particular muscular tissue, opening possibilities for diagnostic applications at this level when investigating Gd-related toxicities.

}, keywords = {Animals, Contrast Media, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Gadolinium, Gadolinium DTPA, Magnetic Resonance Imaging, Mice, Nephrogenic Fibrosing Dermopathy, Periodontal Ligament, Renal Insufficiency, Tissue Distribution}, issn = {1879-3169}, doi = {10.1016/j.toxlet.2018.11.014}, author = {Delfino, Riccarda and Biasotto, Matteo and Candido, Riccardo and Altissimo, Matteo and Stebel, Marco and Salom{\`e}, Murielle and van Elteren, Johannes T and Vogel Miku{\v s}, Katarina and Zennaro, Cristina and {\v S}ala, Martin and Addobbati, Riccardo and Tromba, Giuliana and Pascolo, Lorella} } @article {10790, title = {Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.}, journal = {Lancet Neurol}, volume = {18}, year = {2019}, month = {2019 Jan}, pages = {56-87}, abstract = {

BACKGROUND: Traumatic brain injury (TBI) and spinal cord injury (SCI) are increasingly recognised as global health priorities in view of the preventability of most injuries and the complex and expensive medical care they necessitate. We aimed to measure the incidence, prevalence, and years of life lived with disability (YLDs) for TBI and SCI from all causes of injury in every country, to describe how these measures have changed between 1990 and 2016, and to estimate the proportion of TBI and SCI cases caused by different types of injury.

METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016 to measure the global, regional, and national burden of TBI and SCI by age and sex. We measured the incidence and prevalence of all causes of injury requiring medical care in inpatient and outpatient records, literature studies, and survey data. By use of clinical record data, we estimated the proportion of each cause of injury that required medical care that would result in TBI or SCI being considered as the nature of injury. We used literature studies to establish standardised mortality ratios and applied differential equations to convert incidence to prevalence of long-term disability. Finally, we applied GBD disability weights to calculate YLDs. We used a Bayesian meta-regression tool for epidemiological modelling, used cause-specific mortality rates for non-fatal estimation, and adjusted our results for disability experienced with comorbid conditions. We also analysed results on the basis of the Socio-demographic Index, a compound measure of income per capita, education, and fertility.

FINDINGS: In 2016, there were 27{\textperiodcentered}08 million (95\% uncertainty interval [UI] 24{\textperiodcentered}30-30{\textperiodcentered}30 million) new cases of TBI and 0{\textperiodcentered}93 million (0{\textperiodcentered}78-1{\textperiodcentered}16 million) new cases of SCI, with age-standardised incidence rates of 369 (331-412) per 100 000 population for TBI and 13 (11-16) per 100 000 for SCI. In 2016, the number of prevalent cases of TBI was 55{\textperiodcentered}50 million (53{\textperiodcentered}40-57{\textperiodcentered}62 million) and of SCI was 27{\textperiodcentered}04 million (24{\textperiodcentered}98-30{\textperiodcentered}15 million). From 1990 to 2016, the age-standardised prevalence of TBI increased by 8{\textperiodcentered}4\% (95\% UI 7{\textperiodcentered}7 to 9{\textperiodcentered}2), whereas that of SCI did not change significantly (-0{\textperiodcentered}2\% [-2{\textperiodcentered}1 to 2{\textperiodcentered}7]). Age-standardised incidence rates increased by 3{\textperiodcentered}6\% (1{\textperiodcentered}8 to 5{\textperiodcentered}5) for TBI, but did not change significantly for SCI (-3{\textperiodcentered}6\% [-7{\textperiodcentered}4 to 4{\textperiodcentered}0]). TBI caused 8{\textperiodcentered}1 million (95\% UI 6{\textperiodcentered}0-10{\textperiodcentered}4 million) YLDs and SCI caused 9{\textperiodcentered}5 million (6{\textperiodcentered}7-12{\textperiodcentered}4 million) YLDs in 2016, corresponding to age-standardised rates of 111 (82-141) per 100 000 for TBI and 130 (90-170) per 100 000 for SCI. Falls and road injuries were the leading causes of new cases of TBI and SCI in most regions.

INTERPRETATION: TBI and SCI constitute a considerable portion of the global injury burden and are caused primarily by falls and road injuries. The increase in incidence of TBI over time might continue in view of increases in population density, population ageing, and increasing use of motor vehicles, motorcycles, and bicycles. The number of individuals living with SCI is expected to increase in view of population growth, which is concerning because of the specialised care that people with SCI can require. Our study was limited by data sparsity in some regions, and it will be important to invest greater resources in collection of data for TBI and SCI to improve the accuracy of future assessments.

FUNDING: Bill \& Melinda Gates Foundation.

}, issn = {1474-4465}, doi = {10.1016/S1474-4422(18)30415-0} } @article {10784, title = {Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Aug}, pages = {1112-1121}, abstract = {

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3\% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13\% of the variance in educational attainment and 7-10\% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0147-3}, author = {Lee, James J and Wedow, Robbee and Okbay, Aysu and Kong, Edward and Maghzian, Omeed and Zacher, Meghan and Nguyen-Viet, Tuan Anh and Bowers, Peter and Sidorenko, Julia and Karlsson Linn{\'e}r, Richard and Fontana, Mark Alan and Kundu, Tushar and Lee, Chanwook and Li, Hui and Li, Ruoxi and Royer, Rebecca and Timshel, Pascal N and Walters, Raymond K and Willoughby, Emily A and Yengo, Loic and Alver, Maris and Bao, Yanchun and Clark, David W and Day, Felix R and Furlotte, Nicholas A and Joshi, Peter K and Kemper, Kathryn E and Kleinman, Aaron and Langenberg, Claudia and M{\"a}gi, Reedik and Trampush, Joey W and Verma, Shefali Setia and Wu, Yang and Lam, Max and Zhao, Jing Hua and Zheng, Zhili and Boardman, Jason D and Campbell, Harry and Freese, Jeremy and Harris, Kathleen Mullan and Hayward, Caroline and Herd, Pamela and Kumari, Meena and Lencz, Todd and Luan, Jian{\textquoteright}an and Malhotra, Anil K and Metspalu, Andres and Milani, Lili and Ong, Ken K and Perry, John R B and Porteous, David J and Ritchie, Marylyn D and Smart, Melissa C and Smith, Blair H and Tung, Joyce Y and Wareham, Nicholas J and Wilson, James F and Beauchamp, Jonathan P and Conley, Dalton C and Esko, T{\~o}nu and Lehrer, Steven F and Magnusson, Patrik K E and Oskarsson, Sven and Pers, Tune H and Robinson, Matthew R and Thom, Kevin and Watson, Chelsea and Chabris, Christopher F and Meyer, Michelle N and Laibson, David I and Yang, Jian and Johannesson, Magnus and Koellinger, Philipp D and Turley, Patrick and Visscher, Peter M and Benjamin, Daniel J and Cesarini, David} } @article {10785, title = {Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Oct}, pages = {1412-1425}, abstract = {

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0205-x}, author = {Evangelou, Evangelos and Warren, Helen R and Mosen-Ansorena, David and Mifsud, Borbala and Pazoki, Raha and Gao, He and Ntritsos, Georgios and Dimou, Niki and Cabrera, Claudia P and Karaman, Ibrahim and Ng, Fu Liang and Evangelou, Marina and Witkowska, Katarzyna and Tzanis, Evan and Hellwege, Jacklyn N and Giri, Ayush and Velez Edwards, Digna R and Sun, Yan V and Cho, Kelly and Gaziano, J Michael and Wilson, Peter W F and Tsao, Philip S and Kovesdy, Csaba P and Esko, T{\~o}nu and M{\"a}gi, Reedik and Milani, Lili and Almgren, Peter and Boutin, Thibaud and Debette, St{\'e}phanie and Ding, Jun and Giulianini, Franco and Holliday, Elizabeth G and Jackson, Anne U and Li-Gao, Ruifang and Lin, Wei-Yu and Luan, Jian{\textquoteright}an and Mangino, Massimo and Oldmeadow, Christopher and Prins, Bram Peter and Qian, Yong and Sargurupremraj, Muralidharan and Shah, Nabi and Surendran, Praveen and Th{\'e}riault, S{\'e}bastien and Verweij, Niek and Willems, Sara M and Zhao, Jing-Hua and Amouyel, Philippe and Connell, John and de Mutsert, Ren{\'e}e and Doney, Alex S F and Farrall, Martin and Menni, Cristina and Morris, Andrew D and Noordam, Raymond and Par{\'e}, Guillaume and Poulter, Neil R and Shields, Denis C and Stanton, Alice and Thom, Simon and Abecasis, Goncalo and Amin, Najaf and Arking, Dan E and Ayers, Kristin L and Barbieri, Caterina M and Batini, Chiara and Bis, Joshua C and Blake, Tineka and Bochud, Murielle and Boehnke, Michael and Boerwinkle, Eric and Boomsma, Dorret I and Bottinger, Erwin P and Braund, Peter S and Brumat, Marco and Campbell, Archie and Campbell, Harry and Chakravarti, Aravinda and Chambers, John C and Chauhan, Ganesh and Ciullo, Marina and Cocca, Massimiliano and Collins, Francis and Cordell, Heather J and Davies, Gail and de Borst, Martin H and de Geus, Eco J and Deary, Ian J and Deelen, Joris and del Greco M, Fabiola and Demirkale, Cumhur Yusuf and D{\"o}rr, Marcus and Ehret, Georg B and Elosua, Roberto and Enroth, Stefan and Erzurumluoglu, A Mesut and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Franco, Oscar H and Gandin, Ilaria and Gasparini, Paolo and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Goel, Anuj and Gow, Alan J and Gudnason, Vilmundur and Guo, Xiuqing and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Harris, Sarah E and Hartman, Catharina A and Havulinna, Aki S and Hicks, Andrew A and Hofer, Edith and Hofman, Albert and Hottenga, Jouke-Jan and Huffman, Jennifer E and Hwang, Shih-Jen and Ingelsson, Erik and James, Alan and Jansen, Rick and J{\"a}rvelin, Marjo-Riitta and Joehanes, Roby and Johansson, {\r A}sa and Johnson, Andrew D and Joshi, Peter K and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Keavney, Bernard D and Khaw, Kay-Tee and Knekt, Paul and Knight, Joanne and Kolcic, Ivana and Kooner, Jaspal S and Koskinen, Seppo and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Laan, Maris and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liewald, David C M and Lin, Li and Lind, Lars and Lindgren, Cecilia M and Liu, Yongmei and Loos, Ruth J F and Lopez, Lorna M and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Mamasoula, Chrysovalanto and Marrugat, Jaume and Marten, Jonathan and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew P and Morrison, Alanna C and Munson, Peter J and Nalls, Mike A and Nandakumar, Priyanka and Nelson, Christopher P and Niiranen, Teemu and Nolte, Ilja M and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and O{\textquoteright}Reilly, Paul F and Org, Elin and Padmanabhan, Sandosh and Palmas, Walter and Palotie, Aarno and Pattie, Alison and Penninx, Brenda W J H and Perola, Markus and Peters, Annette and Polasek, Ozren and Pramstaller, Peter P and Nguyen, Quang Tri and Raitakari, Olli T and Ren, Meixia and Rettig, Rainer and Rice, Kenneth and Ridker, Paul M and Ried, Janina S and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rose, Lynda M and Rotter, Jerome I and Rudan, Igor and Ruggiero, Daniela and Saba, Yasaman and Sala, Cinzia F and Salomaa, Veikko and Samani, Nilesh J and Sarin, Antti-Pekka and Schmidt, Reinhold and Schmidt, Helena and Shrine, Nick and Siscovick, David and Smith, Albert V and Snieder, Harold and S{\~o}ber, Siim and Sorice, Rossella and Starr, John M and Stott, David J and Strachan, David P and Strawbridge, Rona J and Sundstr{\"o}m, Johan and Swertz, Morris A and Taylor, Kent D and Teumer, Alexander and Tobin, Martin D and Tomaszewski, Maciej and Toniolo, Daniela and Traglia, Michela and Trompet, Stella and Tuomilehto, Jaakko and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and Vaez, Ahmad and van der Most, Peter J and van Duijn, Cornelia M and Vergnaud, Anne-Claire and Verwoert, Germaine C and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Vuckovic, Dragana and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Wright, Alan F and Yao, Jie and Zemunik, Tatijana and Zhang, Weihua and Attia, John R and Butterworth, Adam S and Chasman, Daniel I and Conen, David and Cucca, Francesco and Danesh, John and Hayward, Caroline and Howson, Joanna M M and Laakso, Markku and Lakatta, Edward G and Langenberg, Claudia and Melander, Olle and Mook-Kanamori, Dennis O and Palmer, Colin N A and Risch, Lorenz and Scott, Robert A and Scott, Rodney J and Sever, Peter and Spector, Tim D and van der Harst, Pim and Wareham, Nicholas J and Zeggini, Eleftheria and Levy, Daniel and Munroe, Patricia B and Newton-Cheh, Christopher and Brown, Morris J and Metspalu, Andres and Hung, Adriana M and O{\textquoteright}Donnell, Christopher J and Edwards, Todd L and Psaty, Bruce M and Tzoulaki, Ioanna and Barnes, Michael R and Wain, Louise V and Elliott, Paul and Caulfield, Mark J} } @article {10419, title = {Genetic profile of patients with early onset inflammatory bowel disease.}, journal = {Gene}, volume = {645}, year = {2018}, month = {2018 Mar 01}, pages = {18-29}, abstract = {

Inflammatory Bowel disease (IBD) is a widespread pathological condition with clinical heterogeneity and with different levels of severity. Although IBD usually occurs in young adults, onset in childhood and infancy are described in patients within the 10th and second year of age. By genome-wide association studies and meta-analysis, several genetic loci have been identified associated with an increased risk of developing IBD in Western populations with variants that may alter the normal mucosal immunity in the gastrointestinal tract. The clinical complexity and the heterogeneity of the IBD phenotype probably reflect the presence of genetic heterogeneity where different genes or combinations of them may be involved, together with environmental factors. We hypothesized that patients with early onset IBD could have either more severe genetic variants in genes associated with IBD or multiple variants in different genes. Under the multifactorial diseases is crucial to consider the small contribution of a single variant in all not only to other small variations in the same gene but also in different genes belonging to the same pathway. We performed direct gene sequencing looking for 94 variations in NOD2, ATG16L1, IL23R, IL10R, IL10 and XIAP genes previously shown as correlated with IBD both in multifactorial and in Mendelian models. All variants identified are known in literature as being associated with IBD except for three variants in the genes NOD2, IL10 and IL10RB that even though present in online databases have never been involved in association studies on IBD patients. Moreover, we coupled genetic variants identification with an accurate "in silico" analysis to verify their predictive impact on the protein structure and function. The in-silico prediction of these variants results as benign therefore even if they exhibit a very low frequency in control population being benign, they cannot be considered pathogenic as monogenic disease but fall within the multifactorial range. The variants identified in our study partially reflect the association data described in the literature but there are no significant differences with the onset of disease (VEO vs EO-IBD).

}, keywords = {Age of Onset, Autophagy-Related Proteins, Child, Child, Preschool, Computer Simulation, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Infant, Inflammatory Bowel Diseases, Interleukin-10, Male, Nod2 Signaling Adaptor Protein, Polymorphism, Single Nucleotide, Receptors, Interleukin, Receptors, Interleukin-10, Sequence Analysis, DNA, X-Linked Inhibitor of Apoptosis Protein}, issn = {1879-0038}, doi = {10.1016/j.gene.2017.12.029}, author = {Girardelli, Martina and Basaldella, Federica and Paolera, Sara Della and Vuch, Josef and Tommasini, Alberto and Martelossi, Stefano and Crovella, Sergio and Bianco, Anna Monica} } @article {10420, title = {A genetic variant of NLRP1 gene is associated with asbestos body burden in patients with malignant pleural mesothelioma.}, journal = {J Toxicol Environ Health A}, volume = {81}, year = {2018}, month = {2018}, pages = {98-105}, abstract = {

The presence of asbestos bodies (ABs) in lung parenchyma is considered a histopathologic hallmark of past exposure to asbestos fibers, of which there was a population of longer fibers. The mechanisms underlying AB formation are complex, involving inflammatory responses and iron (Fe) metabolism. Thus, the responsiveness to AB formation is variable, with some individuals appearing to be poor AB formers. The aim of this study was to disclose the possible role of genetic variants of genes encoding inflammasome and iron metabolism proteins in the ability to form ABs in a population of 81 individuals from North East Italy, who died after having developed malignant pleural mesothelioma (MPM). This study included 86 genetic variants distributed in 10 genes involved in Fe metabolism and 7 genetic variants in two genes encoding for inflammasome molecules. Genotypes/haplotypes were compared according to the number of lung ABs. Data showed that the NLRP1 rs12150220 missense variant (H155L) was significantly correlated with numbers of ABs in MPM patients. Specifically, a low number of ABs was detected in individuals carrying the NLRP1 rs12150220 A/T genotype. Our findings suggest that the NLRP1 inflammasome might contribute in the development of lung ABs. It is postulated that the NLRP1 missense variant may be considered as one of the possible host genetic factors contributing to individual variability in coating efficiency, which needs to be taken when assessing occupational exposure to asbestos.

}, issn = {1528-7394}, doi = {10.1080/15287394.2017.1416911}, author = {Crovella, S and Moura, R R and Cappellani, S and Celsi, F and Trevisan, E and Schneider, M and Brollo, A and Nicastro, E M and Vita, F and Finotto, L and Zabucchi, G and Borelli, V} } @article {10786, title = {Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 Nov 01}, pages = {691-706}, abstract = {

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5~{\texttimes} 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0\% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.09.009}, author = {Ligthart, Symen and Vaez, Ahmad and V{\~o}sa, Urmo and Stathopoulou, Maria G and de Vries, Paul S and Prins, Bram P and van der Most, Peter J and Tanaka, Toshiko and Naderi, Elnaz and Rose, Lynda M and Wu, Ying and Karlsson, Robert and Barbalic, Maja and Lin, Honghuang and Pool, Ren{\'e} and Zhu, Gu and Mac{\'e}, Aur{\'e}lien and Sidore, Carlo and Trompet, Stella and Mangino, Massimo and Sabater-Lleal, Maria and Kemp, John P and Abbasi, Ali and Kacprowski, Tim and Verweij, Niek and Smith, Albert V and Huang, Tao and Marzi, Carola and Feitosa, Mary F and Lohman, Kurt K and Kleber, Marcus E and Milaneschi, Yuri and Mueller, Christian and Huq, Mahmudul and Vlachopoulou, Efthymia and Lyytik{\"a}inen, Leo-Pekka and Oldmeadow, Christopher and Deelen, Joris and Perola, Markus and Zhao, Jing Hua and Feenstra, Bjarke and Amini, Marzyeh and Lahti, Jari and Schraut, Katharina E and Fornage, Myriam and Suktitipat, Bhoom and Chen, Wei-Min and Li, Xiaohui and Nutile, Teresa and Malerba, Giovanni and Luan, Jian{\textquoteright}an and Bak, Tom and Schork, Nicholas and del Greco M, Fabiola and Thiering, Elisabeth and Mahajan, Anubha and Marioni, Riccardo E and Mihailov, Evelin and Eriksson, Joel and Ozel, Ayse Bilge and Zhang, Weihua and Nethander, Maria and Cheng, Yu-Ching and Aslibekyan, Stella and Ang, Wei and Gandin, Ilaria and Yengo, Loic and Portas, Laura and Kooperberg, Charles and Hofer, Edith and Rajan, Kumar B and Schurmann, Claudia and den Hollander, Wouter and Ahluwalia, Tarunveer S and Zhao, Jing and Draisma, Harmen H M and Ford, Ian and Timpson, Nicholas and Teumer, Alexander and Huang, Hongyan and Wahl, Simone and Liu, Yongmei and Huang, Jie and Uh, Hae-Won and Geller, Frank and Joshi, Peter K and Yanek, Lisa R and Trabetti, Elisabetta and Lehne, Benjamin and Vozzi, Diego and Verbanck, Marie and Biino, Ginevra and Saba, Yasaman and Meulenbelt, Ingrid and O{\textquoteright}Connell, Jeff R and Laakso, Markku and Giulianini, Franco and Magnusson, Patrik K E and Ballantyne, Christie M and Hottenga, Jouke Jan and Montgomery, Grant W and Rivadineira, Fernando and Rueedi, Rico and Steri, Maristella and Herzig, Karl-Heinz and Stott, David J and Menni, Cristina and Fr{\r a}nberg, Mattias and St Pourcain, Beate and Felix, Stephan B and Pers, Tune H and Bakker, Stephan J L and Kraft, Peter and Peters, Annette and Vaidya, Dhananjay and Delgado, Graciela and Smit, Johannes H and Gro{\ss}mann, Vera and Sinisalo, Juha and Sepp{\"a}l{\"a}, Ilkka and Williams, Stephen R and Holliday, Elizabeth G and Moed, Matthijs and Langenberg, Claudia and R{\"a}ikk{\"o}nen, Katri and Ding, Jingzhong and Campbell, Harry and Sale, Michele M and Chen, Yii-Der I and James, Alan L and Ruggiero, Daniela and Soranzo, Nicole and Hartman, Catharina A and Smith, Erin N and Berenson, Gerald S and Fuchsberger, Christian and Hernandez, Dena and Tiesler, Carla M T and Giedraitis, Vilmantas and Liewald, David and Fischer, Krista and Mellstr{\"o}m, Dan and Larsson, Anders and Wang, Yunmei and Scott, William R and Lorentzon, Matthias and Beilby, John and Ryan, Kathleen A and Pennell, Craig E and Vuckovic, Dragana and Balkau, Beverly and Concas, Maria Pina and Schmidt, Reinhold and Mendes de Leon, Carlos F and Bottinger, Erwin P and Kloppenburg, Margreet and Paternoster, Lavinia and Boehnke, Michael and Musk, A W and Willemsen, Gonneke and Evans, David M and Madden, Pamela A F and K{\"a}h{\"o}nen, Mika and Kutalik, Zolt{\'a}n and Zoledziewska, Magdalena and Karhunen, Ville and Kritchevsky, Stephen B and Sattar, Naveed and LaChance, Genevieve and Clarke, Robert and Harris, Tamara B and Raitakari, Olli T and Attia, John R and van Heemst, Diana and Kajantie, Eero and Sorice, Rossella and Gambaro, Giovanni and Scott, Robert A and Hicks, Andrew A and Ferrucci, Luigi and Standl, Marie and Lindgren, Cecilia M and Starr, John M and Karlsson, Magnus and Lind, Lars and Li, Jun Z and Chambers, John C and Mori, Trevor A and de Geus, Eco J C N and Heath, Andrew C and Martin, Nicholas G and Auvinen, Juha and Buckley, Brendan M and de Craen, Anton J M and Waldenberger, Melanie and Strauch, Konstantin and Meitinger, Thomas and Scott, Rodney J and McEvoy, Mark and Beekman, Marian and Bombieri, Cristina and Ridker, Paul M and Mohlke, Karen L and Pedersen, Nancy L and Morrison, Alanna C and Boomsma, Dorret I and Whitfield, John B and Strachan, David P and Hofman, Albert and Vollenweider, Peter and Cucca, Francesco and J{\"a}rvelin, Marjo-Riitta and Jukema, J Wouter and Spector, Tim D and Hamsten, Anders and Zeller, Tanja and Uitterlinden, Andr{\'e} G and Nauck, Matthias and Gudnason, Vilmundur and Qi, Lu and Grallert, Harald and Borecki, Ingrid B and Rotter, Jerome I and M{\"a}rz, Winfried and Wild, Philipp S and Lokki, Marja-Liisa and Boyle, Michael and Salomaa, Veikko and Melbye, Mads and Eriksson, Johan G and Wilson, James F and Penninx, Brenda W J H and Becker, Diane M and Worrall, Bradford B and Gibson, Greg and Krauss, Ronald M and Ciullo, Marina and Zaza, Gianluigi and Wareham, Nicholas J and Oldehinkel, Albertine J and Palmer, Lyle J and Murray, Sarah S and Pramstaller, Peter P and Bandinelli, Stefania and Heinrich, Joachim and Ingelsson, Erik and Deary, Ian J and M{\"a}gi, Reedik and Vandenput, Liesbeth and van der Harst, Pim and Desch, Karl C and Kooner, Jaspal S and Ohlsson, Claes and Hayward, Caroline and Lehtim{\"a}ki, Terho and Shuldiner, Alan R and Arnett, Donna K and Beilin, Lawrence J and Robino, Antonietta and Froguel, Philippe and Pirastu, Mario and Jess, Tine and Koenig, Wolfgang and Loos, Ruth J F and Evans, Denis A and Schmidt, Helena and Smith, George Davey and Slagboom, P Eline and Eiriksdottir, Gudny and Morris, Andrew P and Psaty, Bruce M and Tracy, Russell P and Nolte, Ilja M and Boerwinkle, Eric and Visvikis-Siest, Sophie and Reiner, Alex P and Gross, Myron and Bis, Joshua C and Franke, Lude and Franco, Oscar H and Benjamin, Emelia J and Chasman, Daniel I and Dupuis, Jos{\'e}e and Snieder, Harold and Dehghan, Abbas and Alizadeh, Behrooz Z} } @article {10444, title = {Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Jun}, pages = {834-848}, abstract = {

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0127-7}, author = {Tedja, Milly S and Wojciechowski, Robert and Hysi, Pirro G and Eriksson, Nicholas and Furlotte, Nicholas A and Verhoeven, Virginie J M and Iglesias, Adriana I and Meester-Smoor, Magda A and Tompson, Stuart W and Fan, Qiao and Khawaja, Anthony P and Cheng, Ching-Yu and H{\"o}hn, Ren{\'e} and Yamashiro, Kenji and Wenocur, Adam and Grazal, Clare and Haller, Toomas and Metspalu, Andres and Wedenoja, Juho and Jonas, Jost B and Wang, Ya Xing and Xie, Jing and Mitchell, Paul and Foster, Paul J and Klein, Barbara E K and Klein, Ronald and Paterson, Andrew D and Hosseini, S Mohsen and Shah, Rupal L and Williams, Cathy and Teo, Yik Ying and Tham, Yih Chung and Gupta, Preeti and Zhao, Wanting and Shi, Yuan and Saw, Woei-Yuh and Tai, E-Shyong and Sim, Xue Ling and Huffman, Jennifer E and Polasek, Ozren and Hayward, Caroline and Bencic, Goran and Rudan, Igor and Wilson, James F and Joshi, Peter K and Tsujikawa, Akitaka and Matsuda, Fumihiko and Whisenhunt, Kristina N and Zeller, Tanja and van der Spek, Peter J and Haak, Roxanna and Meijers-Heijboer, Hanne and van Leeuwen, Elisabeth M and Iyengar, Sudha K and Lass, Jonathan H and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Vingerling, Johannes R and Lehtim{\"a}ki, Terho and Raitakari, Olli T and Biino, Ginevra and Concas, Maria Pina and Schwantes-An, Tae-Hwi and Igo, Robert P and Cuellar-Partida, Gabriel and Martin, Nicholas G and Craig, Jamie E and Gharahkhani, Puya and Williams, Katie M and Nag, Abhishek and Rahi, Jugnoo S and Cumberland, Phillippa M and Delcourt, C{\'e}cile and Bellenguez, C{\'e}line and Ried, Janina S and Bergen, Arthur A and Meitinger, Thomas and Gieger, Christian and Wong, Tien Yin and Hewitt, Alex W and Mackey, David A and Simpson, Claire L and Pfeiffer, Norbert and P{\"a}rssinen, Olavi and Baird, Paul N and Vitart, Veronique and Amin, Najaf and van Duijn, Cornelia M and Bailey-Wilson, Joan E and Young, Terri L and Saw, Seang-Mei and Stambolian, Dwight and MacGregor, Stuart and Guggenheim, Jeremy A and Tung, Joyce Y and Hammond, Christopher J and Klaver, Caroline C W} } @article {10430, title = {Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 May}, pages = {652-656}, abstract = {

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6\% of red hair, 24.8\% of blond hair, and 26.1\% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0100-5}, author = {Hysi, Pirro G and Valdes, Ana M and Liu, Fan and Furlotte, Nicholas A and Evans, David M and Bataille, Veronique and Visconti, Alessia and Hemani, Gibran and McMahon, George and Ring, Susan M and Smith, George Davey and Duffy, David L and Zhu, Gu and Gordon, Scott D and Medland, Sarah E and Lin, Bochao D and Willemsen, Gonneke and Jan Hottenga, Jouke and Vuckovic, Dragana and Girotto, Giorgia and Gandin, Ilaria and Sala, Cinzia and Concas, Maria Pina and Brumat, Marco and Gasparini, Paolo and Toniolo, Daniela and Cocca, Massimiliano and Robino, Antonietta and Yazar, Seyhan and Hewitt, Alex W and Chen, Yan and Zeng, Changqing and Uitterlinden, Andr{\'e} G and Ikram, M Arfan and Hamer, Merel A and van Duijn, Cornelia M and Nijsten, Tamar and Mackey, David A and Falchi, Mario and Boomsma, Dorret I and Martin, Nicholas G and Hinds, David A and Kayser, Manfred and Spector, Timothy D} } @article {10743, title = {A genome-wide association study identifies an association between variants in EFCAB4B gene and periodontal disease in an Italian isolated population.}, journal = {J Periodontal Res}, volume = {53}, year = {2018}, month = {2018 Dec}, pages = {992-998}, abstract = {

BACKGROUND AND OBJECTIVE: Periodontitis in one of the most prevalent dental diseases. Despite numerous studies have investigated its aetiopathogenetic factors, few works have focused on its genetic predisposition and most of them took into account only candidate genes. Therefore, we conducted a Genome Wide Association Study in an Italian isolated population aimed at uncovering genetic variants that predispose to this disorder.

METHODS: Diagnosis of chronic periodontitis was made following the criteria of the American Academy of Periodontology. Patients with chronic periodontitis were grouped into different categories: slight, severe, localized and generalized. A control group composed by people without signs of periodontitis or gingivitis was defined. DNA was genotyped using 370k Illumina chips. Linear mixed model regression was used to test the association between each single nucleotide polymorphism (SNP) (independent variable) and the periodontitis status (dependent variable), controlling for confounders sex, age and smoking. The genomic kinship matrix was also used as random effect.

RESULTS: Four SNPs on the gene EFCAB4B resulted significantly associated to localized periodontitis (P~<~5~{\texttimes}~10 ), with the best hit on the rs242016 SNP (P~=~1.5~{\texttimes}~10 ).

CONCLUSION: We have identified a novel significant association between the EFCAB4B gene and localized periodontitis. These results open a new perspective in the understanding of genetic factors contributing to this common disorder.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Calcium-Binding Proteins, Chronic Periodontitis, DNA, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Italy, Male, Middle Aged, Polymorphism, Single Nucleotide, Regression Analysis, Young Adult}, issn = {1600-0765}, doi = {10.1111/jre.12598}, author = {Bevilacqua, Lorenzo and Navarra, Chiara O and Pirastu, Nicola and Lenarda, Roberto Di and Gasparini, Paolo and Robino, Antonietta} } @article {10426, title = {A genome-wide association study of corneal astigmatism: The CREAM Consortium.}, journal = {Mol Vis}, volume = {24}, year = {2018}, month = {2018}, pages = {127-142}, abstract = {

Purpose: To identify genes and genetic markers associated with corneal astigmatism.

Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression.

Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha () gene: top SNP: rs7673984, odds ratio=1.12 (95\% CI:1.08-1.16), p=5.55{\texttimes}10. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (), acid phosphatase 2, lysosomal (), and TNF alpha-induced protein 8 like 3 ().

Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the gene, gene-based analysis identified three novel candidate genes, , , and , that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

}, keywords = {Acid Phosphatase, Asian Continental Ancestry Group, Astigmatism, Claudins, Cohort Studies, Cornea, Corneal Diseases, European Continental Ancestry Group, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Odds Ratio, Polymorphism, Single Nucleotide, Receptor, Platelet-Derived Growth Factor alpha, Software}, issn = {1090-0535}, author = {Shah, Rupal L and Li, Qing and Zhao, Wanting and Tedja, Milly S and Tideman, J Willem L and Khawaja, Anthony P and Fan, Qiao and Yazar, Seyhan and Williams, Katie M and Verhoeven, Virginie J M and Xie, Jing and Wang, Ya Xing and Hess, Moritz and Nickels, Stefan and Lackner, Karl J and P{\"a}rssinen, Olavi and Wedenoja, Juho and Biino, Ginevra and Concas, Maria Pina and Uitterlinden, Andr{\'e} and Rivadeneira, Fernando and Jaddoe, Vincent W V and Hysi, Pirro G and Sim, Xueling and Tan, Nicholas and Tham, Yih-Chung and Sensaki, Sonoko and Hofman, Albert and Vingerling, Johannes R and Jonas, Jost B and Mitchell, Paul and Hammond, Christopher J and H{\"o}hn, Ren{\'e} and Baird, Paul N and Wong, Tien-Yin and Cheng, Chinfsg-Yu and Teo, Yik Ying and Mackey, David A and Williams, Cathy and Saw, Seang-Mei and Klaver, Caroline C W and Guggenheim, Jeremy A and Bailey-Wilson, Joan E} } @article {10434, title = {A Giant Ovarian Cyst in an Adolescent.}, journal = {J Pediatr}, volume = {199}, year = {2018}, month = {2018 08}, pages = {279}, keywords = {Child, Cystadenoma, Serous, Female, Humans, Ovarian Neoplasms}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2018.03.015}, author = {Corrias, Francesca and Pederiva, Federica and Cozzi, Giorgio and Ammar, Lydie and Cattaruzzi, Elisabetta and Lembo, Maria Antonietta and Barbi, Egidio} } @article {10447, title = {Girl With Chest Pain.}, journal = {Ann Emerg Med}, volume = {72}, year = {2018}, month = {2018 Aug}, pages = {e17-e18}, issn = {1097-6760}, doi = {10.1016/j.annemergmed.2018.03.010}, author = {Scarpa, Maria-Grazia and Rabach, Ingrid and Canuto, Arianna and Sanabor, Daniela and Barbi, Egidio and Schleef, Jurgen} } @article {10744, title = {A Girl with Delayed Puberty and Bumpy Lips.}, journal = {J Pediatr}, volume = {203}, year = {2018}, month = {2018 12}, pages = {454-454.e1}, keywords = {Adolescent, Exons, Female, Genes, Dominant, Humans, Lip, Multiple Endocrine Neoplasia Type 2b, Neoplasm Metastasis, Puberty, Delayed, Thyroid Neoplasms, Thyroidectomy, Tongue}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2018.05.043}, author = {Andrade, Stefanny and Sirchia, Fabio and Faleschini, Elena and Barbi, Egidio} } @article {10787, title = {Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017.}, journal = {Lancet}, volume = {392}, year = {2018}, month = {2018 11 10}, pages = {1684-1735}, abstract = {

BACKGROUND: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally.

METHODS: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950.

FINDINGS: Globally, 18{\textperiodcentered}7\% (95\% uncertainty interval 18{\textperiodcentered}4-19{\textperiodcentered}0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58{\textperiodcentered}8\% (58{\textperiodcentered}2-59{\textperiodcentered}3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48{\textperiodcentered}1 years (46{\textperiodcentered}5-49{\textperiodcentered}6) to 70{\textperiodcentered}5 years (70{\textperiodcentered}1-70{\textperiodcentered}8) for men and from 52{\textperiodcentered}9 years (51{\textperiodcentered}7-54{\textperiodcentered}0) to 75{\textperiodcentered}6 years (75{\textperiodcentered}3-75{\textperiodcentered}9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49{\textperiodcentered}1 years (46{\textperiodcentered}5-51{\textperiodcentered}7) for men in the Central African Republic to 87{\textperiodcentered}6 years (86{\textperiodcentered}9-88{\textperiodcentered}1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216{\textperiodcentered}0 deaths (196{\textperiodcentered}3-238{\textperiodcentered}1) per 1000 livebirths in 1950 to 38{\textperiodcentered}9 deaths (35{\textperiodcentered}6-42{\textperiodcentered}83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5{\textperiodcentered}4 million (5{\textperiodcentered}2-5{\textperiodcentered}6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development.

INTERPRETATION: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Adolescent, Adult, Age Distribution, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Global Burden of Disease, Global Health, Humans, Infant, Infant, Newborn, Life Expectancy, Male, Middle Aged, Mortality, Sex Distribution, Socioeconomic Factors, Young Adult}, issn = {1474-547X}, doi = {10.1016/S0140-6736(18)31891-9} } @article {10788, title = {Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.}, journal = {Lancet}, volume = {392}, year = {2018}, month = {2018 11 10}, pages = {1736-1788}, abstract = {

BACKGROUND: Global development goals increasingly rely on country-specific estimates for benchmarking a nation{\textquoteright}s progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017.

METHODS: The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries-Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODEm), to generate cause fractions and cause-specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised.

FINDINGS: At the broadest grouping of causes of death (Level 1), non-communicable diseases (NCDs) comprised the greatest fraction of deaths, contributing to 73{\textperiodcentered}4\% (95\% uncertainty interval [UI] 72{\textperiodcentered}5-74{\textperiodcentered}1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional (CMNN) causes accounted for 18{\textperiodcentered}6\% (17{\textperiodcentered}9-19{\textperiodcentered}6), and injuries 8{\textperiodcentered}0\% (7{\textperiodcentered}7-8{\textperiodcentered}2). Total numbers of deaths from NCD causes increased from 2007 to 2017 by 22{\textperiodcentered}7\% (21{\textperiodcentered}5-23{\textperiodcentered}9), representing an additional 7{\textperiodcentered}61 million (7{\textperiodcentered}20-8{\textperiodcentered}01) deaths estimated in 2017 versus 2007. The death rate from NCDs decreased globally by 7{\textperiodcentered}9\% (7{\textperiodcentered}0-8{\textperiodcentered}8). The number of deaths for CMNN causes decreased by 22{\textperiodcentered}2\% (20{\textperiodcentered}0-24{\textperiodcentered}0) and the death rate by 31{\textperiodcentered}8\% (30{\textperiodcentered}1-33{\textperiodcentered}3). Total deaths from injuries increased by 2{\textperiodcentered}3\% (0{\textperiodcentered}5-4{\textperiodcentered}0) between 2007 and 2017, and the death rate from injuries decreased by 13{\textperiodcentered}7\% (12{\textperiodcentered}2-15{\textperiodcentered}1) to 57{\textperiodcentered}9 deaths (55{\textperiodcentered}9-59{\textperiodcentered}2) per 100 000 in 2017. Deaths from substance use disorders also increased, rising from 284 000 deaths (268 000-289 000) globally in 2007 to 352 000 (334 000-363 000) in 2017. Between 2007 and 2017, total deaths from conflict and terrorism increased by 118{\textperiodcentered}0\% (88{\textperiodcentered}8-148{\textperiodcentered}6). A greater reduction in total deaths and death rates was observed for some CMNN causes among children younger than 5 years than for older adults, such as a 36{\textperiodcentered}4\% (32{\textperiodcentered}2-40{\textperiodcentered}6) reduction in deaths from lower respiratory infections for children younger than 5 years compared with a 33{\textperiodcentered}6\% (31{\textperiodcentered}2-36{\textperiodcentered}1) increase in adults older than 70 years. Globally, the number of deaths was greater for men than for women at most ages in 2017, except at ages older than 85 years. Trends in global YLLs reflect an epidemiological transition, with decreases in total YLLs from enteric infections, respiratory infections and tuberculosis, and maternal and neonatal disorders between 1990 and 2017; these were generally greater in magnitude at the lowest levels of the Socio-demographic Index (SDI). At the same time, there were large increases in YLLs from neoplasms and cardiovascular diseases. YLL rates decreased across the five leading Level 2 causes in all SDI quintiles. The leading causes of YLLs in 1990-neonatal disorders, lower respiratory infections, and diarrhoeal diseases-were ranked second, fourth, and fifth, in 2017. Meanwhile, estimated YLLs increased for ischaemic heart disease (ranked first in 2017) and stroke (ranked third), even though YLL rates decreased. Population growth contributed to increased total deaths across the 20 leading Level 2 causes of mortality between 2007 and 2017. Decreases in the cause-specific mortality rate reduced the effect of population growth for all but three causes: substance use disorders, neurological disorders, and skin and subcutaneous diseases.

INTERPRETATION: Improvements in global health have been unevenly distributed among populations. Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health. For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for NCDs, and the death rate for selected causes has increased in the past decade.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Adolescent, Adult, Age Distribution, Aged, Aged, 80 and over, Cause of Death, Child, Child, Preschool, Female, Global Burden of Disease, Global Health, Humans, Infant, Infant, Newborn, Life Expectancy, Male, Middle Aged, Sex Distribution, Socioeconomic Factors, Young Adult}, issn = {1474-547X}, doi = {10.1016/S0140-6736(18)32203-7} } @article {10789, title = {Global, regional, and national burden of meningitis, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.}, journal = {Lancet Neurol}, volume = {17}, year = {2018}, month = {2018 Dec}, pages = {1061-1082}, abstract = {

BACKGROUND: Acute meningitis has a high case-fatality rate and survivors can have severe lifelong disability. We aimed to provide a comprehensive assessment of the levels and trends of global meningitis burden that could help to guide introduction, continuation, and ongoing development of vaccines and treatment programmes.

METHODS: The Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2016 study estimated meningitis burden due to one of four types of cause: pneumococcal, meningococcal, Haemophilus influenzae type b, and a residual category of other causes. Cause-specific mortality estimates were generated via cause of death ensemble modelling of vital registration and verbal autopsy data that were subject to standardised data processing algorithms. Deaths were multiplied by the GBD standard life expectancy at age of death to estimate years of life lost, the mortality component of disability-adjusted life-years (DALYs). A systematic analysis of relevant publications and hospital and claims data was used to estimate meningitis incidence via a Bayesian meta-regression tool. Meningitis deaths and cases were split between causes with meta-regressions of aetiological proportions of mortality and incidence, respectively. Probabilities of long-term impairment by cause of meningitis were applied to survivors and used to estimate years of life lived with disability (YLDs). We assessed the relationship between burden metrics and Socio-demographic Index (SDI), a composite measure of development based on fertility, income, and education.

FINDINGS: Global meningitis deaths decreased by 21{\textperiodcentered}0\% from 1990 to 2016, from 403 012 (95\% uncertainty interval [UI] 319 426-458 514) to 318 400 (265 218-408 705). Incident cases globally increased from 2{\textperiodcentered}50 million (95\% UI 2{\textperiodcentered}19-2{\textperiodcentered}91) in 1990 to 2{\textperiodcentered}82 million (2{\textperiodcentered}46-3{\textperiodcentered}31) in 2016. Meningitis mortality and incidence were closely related to SDI. The highest mortality rates and incidence rates were found in the peri-Sahelian countries that comprise the African meningitis belt, with six of the ten countries with the largest number of cases and deaths being located within this region. Haemophilus influenzae type b was the most common cause of incident meningitis in 1990, at 780 070 cases (95\% UI 613 585-978 219) globally, but decreased the most (-49{\textperiodcentered}1\%) to become the least common cause in 2016, with 397 297 cases (291 076-533 662). Meningococcus was the leading cause of meningitis mortality in 1990 (192 833 deaths [95\% UI 153 358-221 503] globally), whereas other meningitis was the leading cause for both deaths (136 423 [112 682-178 022]) and incident cases (1{\textperiodcentered}25 million [1{\textperiodcentered}06-1{\textperiodcentered}49]) in 2016. Pneumococcus caused the largest number of YLDs (634 458 [444 787-839 749]) in 2016, owing to its more severe long-term effects on survivors. Globally in 2016, 1{\textperiodcentered}48 million (1{\textperiodcentered}04-1{\textperiodcentered}96) YLDs were due to meningitis compared with 21{\textperiodcentered}87 million (18{\textperiodcentered}20-28{\textperiodcentered}28) DALYs, indicating that the contribution of mortality to meningitis burden is far greater than the contribution of disabling outcomes.

INTERPRETATION: Meningitis burden remains high and progress lags substantially behind that of other vaccine-preventable diseases. Particular attention should be given to developing vaccines with broader coverage against the causes of meningitis, making these vaccines affordable in the most affected countries, improving vaccine uptake, improving access to low-cost diagnostics and therapeutics, and improving support for disabled survivors. Substantial uncertainty remains around pathogenic causes and risk factors for meningitis. Ongoing, active cause-specific surveillance of meningitis is crucial to continue and to improve monitoring of meningitis burdens and trends throughout the world.

FUNDING: Bill \& Melinda Gates Foundation.

}, issn = {1474-4465}, doi = {10.1016/S1474-4422(18)30387-9} } @article {10791, title = {Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Stu}, journal = {Lancet}, volume = {392}, year = {2018}, month = {2018 11 10}, pages = {1923-1994}, abstract = {

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk-outcome associations.

METHODS: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.

FINDINGS: In 2017, 34{\textperiodcentered}1 million (95\% uncertainty interval [UI] 33{\textperiodcentered}3-35{\textperiodcentered}0) deaths and 1{\textperiodcentered}21 billion (1{\textperiodcentered}14-1{\textperiodcentered}28) DALYs were attributable to GBD risk factors. Globally, 61{\textperiodcentered}0\% (59{\textperiodcentered}6-62{\textperiodcentered}4) of deaths and 48{\textperiodcentered}3\% (46{\textperiodcentered}3-50{\textperiodcentered}2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10{\textperiodcentered}4 million (9{\textperiodcentered}39-11{\textperiodcentered}5) deaths and 218 million (198-237) DALYs, followed by smoking (7{\textperiodcentered}10 million [6{\textperiodcentered}83-7{\textperiodcentered}37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6{\textperiodcentered}53 million [5{\textperiodcentered}23-8{\textperiodcentered}23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4{\textperiodcentered}72 million [2{\textperiodcentered}99-6{\textperiodcentered}70] deaths and 148 million [98{\textperiodcentered}6-202] DALYs), and short gestation for birthweight (1{\textperiodcentered}43 million [1{\textperiodcentered}36-1{\textperiodcentered}51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4{\textperiodcentered}9\% (3{\textperiodcentered}3-6{\textperiodcentered}5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23{\textperiodcentered}5\% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18{\textperiodcentered}6\% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low.

INTERPRETATION: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Adolescent, Adult, Age Distribution, Aged, Aged, 80 and over, Child, Child, Preschool, Disabled Persons, Environmental Exposure, Female, Global Burden of Disease, Global Health, Health Risk Behaviors, Humans, Infant, Infant, Newborn, Life Expectancy, Male, Metabolic Diseases, Middle Aged, Occupational Diseases, Occupational Exposure, Quality-Adjusted Life Years, Risk Assessment, Sex Distribution, Socioeconomic Factors, Young Adult}, issn = {1474-547X}, doi = {10.1016/S0140-6736(18)32225-6} } @article {10792, title = {Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.}, journal = {Lancet}, volume = {392}, year = {2018}, month = {2018 11 10}, pages = {1859-1922}, abstract = {

BACKGROUND: How long one lives, how many years of life are spent in good and poor health, and how the population{\textquoteright}s state of health and leading causes of disability change over time all have implications for policy, planning, and provision of services. We comparatively assessed the patterns and trends of healthy life expectancy (HALE), which quantifies the number of years of life expected to be lived in good health, and the complementary measure of disability-adjusted life-years (DALYs), a composite measure of disease burden capturing both premature mortality and prevalence and severity of ill health, for 359 diseases and injuries for 195 countries and territories over the past 28 years.

METHODS: We used data for age-specific mortality rates, years of life lost (YLLs) due to premature mortality, and years lived with disability (YLDs) from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to calculate HALE and DALYs from 1990 to 2017. We calculated HALE using age-specific mortality rates and YLDs per capita for each location, age, sex, and year. We calculated DALYs for 359 causes as the sum of YLLs and YLDs. We assessed how observed HALE and DALYs differed by country and sex from expected trends based on Socio-demographic Index (SDI). We also analysed HALE by decomposing years of life gained into years spent in good health and in poor health, between 1990 and 2017, and extra years lived by females compared with males.

FINDINGS: Globally, from 1990 to 2017, life expectancy at birth increased by 7{\textperiodcentered}4 years (95\% uncertainty interval 7{\textperiodcentered}1-7{\textperiodcentered}8), from 65{\textperiodcentered}6 years (65{\textperiodcentered}3-65{\textperiodcentered}8) in 1990 to 73{\textperiodcentered}0 years (72{\textperiodcentered}7-73{\textperiodcentered}3) in 2017. The increase in years of life varied from 5{\textperiodcentered}1 years (5{\textperiodcentered}0-5{\textperiodcentered}3) in high SDI countries to 12{\textperiodcentered}0 years (11{\textperiodcentered}3-12{\textperiodcentered}8) in low SDI countries. Of the additional years of life expected at birth, 26{\textperiodcentered}3\% (20{\textperiodcentered}1-33{\textperiodcentered}1) were expected to be spent in poor health in high SDI countries compared with 11{\textperiodcentered}7\% (8{\textperiodcentered}8-15{\textperiodcentered}1) in low-middle SDI countries. HALE at birth increased by 6{\textperiodcentered}3 years (5{\textperiodcentered}9-6{\textperiodcentered}7), from 57{\textperiodcentered}0 years (54{\textperiodcentered}6-59{\textperiodcentered}1) in 1990 to 63{\textperiodcentered}3 years (60{\textperiodcentered}5-65{\textperiodcentered}7) in 2017. The increase varied from 3{\textperiodcentered}8 years (3{\textperiodcentered}4-4{\textperiodcentered}1) in high SDI countries to 10{\textperiodcentered}5 years (9{\textperiodcentered}8-11{\textperiodcentered}2) in low SDI countries. Even larger variations in HALE than these were observed between countries, ranging from 1{\textperiodcentered}0 year (0{\textperiodcentered}4-1{\textperiodcentered}7) in Saint Vincent and the Grenadines (62{\textperiodcentered}4 years [59{\textperiodcentered}9-64{\textperiodcentered}7] in 1990 to 63{\textperiodcentered}5 years [60{\textperiodcentered}9-65{\textperiodcentered}8] in 2017) to 23{\textperiodcentered}7 years (21{\textperiodcentered}9-25{\textperiodcentered}6) in Eritrea (30{\textperiodcentered}7 years [28{\textperiodcentered}9-32{\textperiodcentered}2] in 1990 to 54{\textperiodcentered}4 years [51{\textperiodcentered}5-57{\textperiodcentered}1] in 2017). In most countries, the increase in HALE was smaller than the increase in overall life expectancy, indicating more years lived in poor health. In 180 of 195 countries and territories, females were expected to live longer than males in 2017, with extra years lived varying from 1{\textperiodcentered}4 years (0{\textperiodcentered}6-2{\textperiodcentered}3) in Algeria to 11{\textperiodcentered}9 years (10{\textperiodcentered}9-12{\textperiodcentered}9) in Ukraine. Of the extra years gained, the proportion spent in poor health varied largely across countries, with less than 20\% of additional years spent in poor health in Bosnia and Herzegovina, Burundi, and Slovakia, whereas in Bahrain all the extra years were spent in poor health. In 2017, the highest estimate of HALE at birth was in Singapore for both females (75{\textperiodcentered}8 years [72{\textperiodcentered}4-78{\textperiodcentered}7]) and males (72{\textperiodcentered}6 years [69{\textperiodcentered}8-75{\textperiodcentered}0]) and the lowest estimates were in Central African Republic (47{\textperiodcentered}0 years [43{\textperiodcentered}7-50{\textperiodcentered}2] for females and 42{\textperiodcentered}8 years [40{\textperiodcentered}1-45{\textperiodcentered}6] for males). Globally, in 2017, the five leading causes of DALYs were neonatal disorders, ischaemic heart disease, stroke, lower respiratory infections, and chronic obstructive pulmonary disease. Between 1990 and 2017, age-standardised DALY rates decreased by 41{\textperiodcentered}3\% (38{\textperiodcentered}8-43{\textperiodcentered}5) for communicable diseases and by 49{\textperiodcentered}8\% (47{\textperiodcentered}9-51{\textperiodcentered}6) for neonatal disorders. For non-communicable diseases, global DALYs increased by 40{\textperiodcentered}1\% (36{\textperiodcentered}8-43{\textperiodcentered}0), although age-standardised DALY rates decreased by 18{\textperiodcentered}1\% (16{\textperiodcentered}0-20{\textperiodcentered}2).

INTERPRETATION: With increasing life expectancy in most countries, the question of whether the additional years of life gained are spent in good health or poor health has been increasingly relevant because of the potential policy implications, such as health-care provisions and extending retirement ages. In some locations, a large proportion of those additional years are spent in poor health. Large inequalities in HALE and disease burden exist across countries in different SDI quintiles and between sexes. The burden of disabling conditions has serious implications for health system planning and health-related expenditures. Despite the progress made in reducing the burden of communicable diseases and neonatal disorders in low SDI countries, the speed of this progress could be increased by scaling up proven interventions. The global trends among non-communicable diseases indicate that more effort is needed to maximise HALE, such as risk prevention and attention to upstream determinants of health.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Aged, Communicable Diseases, Disabled Persons, Female, Global Burden of Disease, Health Status, Healthy Lifestyle, Humans, Life Expectancy, Male, Mortality, Mortality, Premature, Prevalence, Quality-Adjusted Life Years, Risk Factors, Socioeconomic Factors, Wounds and Injuries}, issn = {1474-547X}, doi = {10.1016/S0140-6736(18)32335-3} } @article {10793, title = {Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.}, journal = {Lancet}, volume = {392}, year = {2018}, month = {2018 11 10}, pages = {1789-1858}, abstract = {

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world{\textquoteright}s population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data.

METHODS: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting.

FINDINGS: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3{\textperiodcentered}9\% (95\% uncertainty interval [UI] 3{\textperiodcentered}1-4{\textperiodcentered}6) from 1990 to 2017; however, the all-age YLD rate increased by 7{\textperiodcentered}2\% (6{\textperiodcentered}0-8{\textperiodcentered}4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7{\textperiodcentered}9\% (6{\textperiodcentered}6-9{\textperiodcentered}2) for males and 6{\textperiodcentered}5\% (5{\textperiodcentered}4-7{\textperiodcentered}7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95\% UI 2782-3252] per 100 000 in males vs s1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]).

INTERPRETATION: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Adolescent, Adult, Age Distribution, Aged, Aged, 80 and over, Child, Child, Preschool, Disabled Persons, Female, Global Burden of Disease, Global Health, Humans, Incidence, Infant, Infant, Newborn, Life Expectancy, Male, Middle Aged, Morbidity, Prevalence, Sex Distribution, Socioeconomic Factors, Wounds and Injuries, Young Adult}, issn = {1474-547X}, doi = {10.1016/S0140-6736(18)32279-7} } @article {10794, title = {Gut microbiota characterisation in obese patients before and after bariatric surgery.}, journal = {Benef Microbes}, volume = {9}, year = {2018}, month = {2018 Apr 25}, pages = {367-373}, abstract = {

Intestinal microbiota analysis of obese patients after bariatric surgery showed that Proteobacteria decreased after laparoscopic sleeve gastrectomy (SG), while it increased after laparoscopic gastric bypass (LGB). Comparing to normal weight (NW) patients, obese patients that were selected for SG showed an almost equal amount of Firmicutes and Bacteroidetes and the ratio was not affected by the surgery. Obese patients before LGB showed a predominance of Bacteroidetes, whose amount regained a relative abundance similar to NW patients after surgery. Obese patients before LGB showed the predominance of Bacteroides, which decreased after surgery in favour of Prevotella, a bacterium associated with a healthy diet. The bacteria detected at the highest percentages belonged to biofilm forming species. In conclusion, in this study, we found that the characterization of the gut microbial communities and the modality of mucosal colonisation have a central role as markers for the clinical management of obesity and promote the maintenance of good health and the weight loss.

}, keywords = {Adult, Bariatric Surgery, Gastrointestinal Microbiome, Humans, Laparoscopy, Microbiota, Middle Aged, Obesity, Young Adult}, issn = {1876-2891}, doi = {10.3920/BM2017.0152}, author = {Campisciano, G and Palmisano, S and Cason, C and Giuricin, M and Silvestri, M and Guerra, M and Macor, D and De Manzini, N and Croc{\'e}, L S and Comar, M} } @article {10509, title = {Genetic structure in the Sherpa and neighboring Nepalese populations.}, journal = {BMC Genomics}, volume = {18}, year = {2017}, month = {2017 01 19}, pages = {102}, abstract = {

BACKGROUND: We set out to describe the fine-scale population structure across the Eastern region of Nepal. To date there is relatively little known about the genetic structure of the Sherpa residing in Nepal and their genetic relationship with the Nepalese. We assembled dense genotype data from a total of 1245 individuals representing Nepal and a variety of different populations resident across the greater Himalayan region including Tibet, China, India, Pakistan, Kazakhstan, Uzbekistan, Tajikistan and Kirghizstan. We performed analysis of principal components, admixture and homozygosity.

RESULTS: We identified clear substructure across populations resident in the Himalayan arc, with genetic structure broadly mirroring geographical features of the region. Ethnic subgroups within Nepal show distinct genetic structure, on both admixture and principal component analysis. We detected differential proportions of ancestry from northern Himalayan populations across Nepalese subgroups, with the Nepalese Rai, Magar and Tamang carrying the greatest proportions of Tibetan ancestry.

CONCLUSIONS: We show that populations dwelling on the Himalayan plateau have had a clear impact on the Northern Indian gene pool. We illustrate how the Sherpa are a remarkably isolated population, with little gene flow from surrounding Nepalese populations.

}, keywords = {Asian Continental Ancestry Group, Chromosomes, Human, Y, DNA, DNA, Mitochondrial, Ethnic Groups, Gene Flow, Genotype, Humans, Leukocytes, Likelihood Functions, Nepal, Principal Component Analysis}, issn = {1471-2164}, doi = {10.1186/s12864-016-3469-5}, author = {Cole, Amy M and Cox, Sean and Jeong, Choongwon and Petousi, Nayia and Aryal, Dhana R and Droma, Yunden and Hanaoka, Masayuki and Ota, Masao and Kobayashi, Nobumitsu and Gasparini, Paolo and Montgomery, Hugh and Robbins, Peter and Di Rienzo, Anna and Cavalleri, Gianpiero L} } @article {10511, title = {Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Mar}, pages = {403-415}, abstract = {

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

}, keywords = {Adult, Blood Pressure, Cardiovascular Diseases, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.3768}, author = {Warren, Helen R and Evangelou, Evangelos and Cabrera, Claudia P and Gao, He and Ren, Meixia and Mifsud, Borbala and Ntalla, Ioanna and Surendran, Praveen and Liu, Chunyu and Cook, James P and Kraja, Aldi T and Drenos, Fotios and Loh, Marie and Verweij, Niek and Marten, Jonathan and Karaman, Ibrahim and Lepe, Marcelo P Segura and O{\textquoteright}Reilly, Paul F and Knight, Joanne and Snieder, Harold and Kato, Norihiro and He, Jiang and Tai, E Shyong and Said, M Abdullah and Porteous, David and Alver, Maris and Poulter, Neil and Farrall, Martin and Gansevoort, Ron T and Padmanabhan, Sandosh and M{\"a}gi, Reedik and Stanton, Alice and Connell, John and Bakker, Stephan J L and Metspalu, Andres and Shields, Denis C and Thom, Simon and Brown, Morris and Sever, Peter and Esko, T{\~o}nu and Hayward, Caroline and van der Harst, Pim and Saleheen, Danish and Chowdhury, Rajiv and Chambers, John C and Chasman, Daniel I and Chakravarti, Aravinda and Newton-Cheh, Christopher and Lindgren, Cecilia M and Levy, Daniel and Kooner, Jaspal S and Keavney, Bernard and Tomaszewski, Maciej and Samani, Nilesh J and Howson, Joanna M M and Tobin, Martin D and Munroe, Patricia B and Ehret, Georg B and Wain, Louise V} } @article {10556, title = {Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Jun}, pages = {834-841}, abstract = {

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to \~{}370,000 women, we identify 389 independent signals (P < 5 {\texttimes} 10) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain \~{}7.4\% of the population variance in age at menarche, corresponding to \~{}25\% of the estimated heritability. We implicate \~{}250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

}, keywords = {Adolescent, Age Factors, Body Mass Index, Databases, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomic Imprinting, Humans, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Neoplasms, Polymorphism, Single Nucleotide, Puberty, Quantitative Trait Loci, Ribonucleoproteins, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.3841}, author = {Day, Felix R and Thompson, Deborah J and Helgason, Hannes and Chasman, Daniel I and Finucane, Hilary and Sulem, Patrick and Ruth, Katherine S and Whalen, Sean and Sarkar, Abhishek K and Albrecht, Eva and Altmaier, Elisabeth and Amini, Marzyeh and Barbieri, Caterina M and Boutin, Thibaud and Campbell, Archie and Demerath, Ellen and Giri, Ayush and He, Chunyan and Hottenga, Jouke J and Karlsson, Robert and Kolcic, Ivana and Loh, Po-Ru and Lunetta, Kathryn L and Mangino, Massimo and Marco, Brumat and McMahon, George and Medland, Sarah E and Nolte, Ilja M and Noordam, Raymond and Nutile, Teresa and Paternoster, Lavinia and Perjakova, Natalia and Porcu, Eleonora and Rose, Lynda M and Schraut, Katharina E and Segr{\`e}, Ayellet V and Smith, Albert V and Stolk, Lisette and Teumer, Alexander and Andrulis, Irene L and Bandinelli, Stefania and Beckmann, Matthias W and Benitez, Javier and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bojesen, Stig E and Bolla, Manjeet K and Brand, Judith S and Brauch, Hiltrud and Brenner, Hermann and Broer, Linda and Br{\"u}ning, Thomas and Buring, Julie E and Campbell, Harry and Catamo, Eulalia and Chanock, Stephen and Chenevix-Trench, Georgia and Corre, Tanguy and Couch, Fergus J and Cousminer, Diana L and Cox, Angela and Crisponi, Laura and Czene, Kamila and Davey Smith, George and de Geus, Eco J C N and de Mutsert, Ren{\'e}e and De Vivo, Immaculata and Dennis, Joe and Devilee, Peter and Dos-Santos-Silva, Isabel and Dunning, Alison M and Eriksson, Johan G and Fasching, Peter A and Fern{\'a}ndez-Rhodes, Lindsay and Ferrucci, Luigi and Flesch-Janys, Dieter and Franke, Lude and Gabrielson, Marike and Gandin, Ilaria and Giles, Graham G and Grallert, Harald and Gudbjartsson, Daniel F and Guenel, Pascal and Hall, Per and Hallberg, Emily and Hamann, Ute and Harris, Tamara B and Hartman, Catharina A and Heiss, Gerardo and Hooning, Maartje J and Hopper, John L and Hu, Frank and Hunter, David J and Ikram, M Arfan and Im, Hae Kyung and J{\"a}rvelin, Marjo-Riitta and Joshi, Peter K and Karasik, David and Kellis, Manolis and Kutalik, Zolt{\'a}n and LaChance, Genevieve and Lambrechts, Diether and Langenberg, Claudia and Launer, Lenore J and Laven, Joop S E and Lenarduzzi, Stefania and Li, Jingmei and Lind, Penelope A and Lindstr{\"o}m, Sara and Liu, Yongmei and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Mannermaa, Arto and Mbarek, Hamdi and McCarthy, Mark I and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Metspalu, Andres and Michailidou, Kyriaki and Milani, Lili and Milne, Roger L and Montgomery, Grant W and Mulligan, Anna M and Nalls, Mike A and Navarro, Pau and Nevanlinna, Heli and Nyholt, Dale R and Oldehinkel, Albertine J and O{\textquoteright}Mara, Tracy A and Padmanabhan, Sandosh and Palotie, Aarno and Pedersen, Nancy and Peters, Annette and Peto, Julian and Pharoah, Paul D P and Pouta, Anneli and Radice, Paolo and Rahman, Iffat and Ring, Susan M and Robino, Antonietta and Rosendaal, Frits R and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Sala, Cinzia F and Schmidt, Marjanka K and Scott, Robert A and Shah, Mitul and Sorice, Rossella and Southey, Melissa C and Sovio, Ulla and Stampfer, Meir and Steri, Maristella and Strauch, Konstantin and Tanaka, Toshiko and Tikkanen, Emmi and Timpson, Nicholas J and Traglia, Michela and Truong, Therese and Tyrer, Jonathan P and Uitterlinden, Andr{\'e} G and Edwards, Digna R Velez and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Wang, Qin and Widen, Elisabeth and van Dijk, Ko Willems and Willemsen, Gonneke and Winqvist, Robert and Wolffenbuttel, Bruce H R and Zhao, Jing Hua and Zoledziewska, Magdalena and Zygmunt, Marek and Alizadeh, Behrooz Z and Boomsma, Dorret I and Ciullo, Marina and Cucca, Francesco and Esko, T{\~o}nu and Franceschini, Nora and Gieger, Christian and Gudnason, Vilmundur and Hayward, Caroline and Kraft, Peter and Lawlor, Debbie A and Magnusson, Patrik K E and Martin, Nicholas G and Mook-Kanamori, Dennis O and Nohr, Ellen A and Polasek, Ozren and Porteous, David and Price, Alkes L and Ridker, Paul M and Snieder, Harold and Spector, Tim D and St{\"o}ckl, Doris and Toniolo, Daniela and Ulivi, Sheila and Visser, Jenny A and V{\"o}lzke, Henry and Wareham, Nicholas J and Wilson, James F and Spurdle, Amanda B and Thorsteindottir, Unnur and Pollard, Katherine S and Easton, Douglas F and Tung, Joyce Y and Chang-Claude, Jenny and Hinds, David and Murray, Anna and Murabito, Joanne M and Stefansson, Kari and Ong, Ken K and Perry, John R B} } @article {10574, title = {Gray platelet syndrome: Novel mutations of the NBEAL2 gene.}, journal = {Am J Hematol}, volume = {92}, year = {2017}, month = {2017 02}, pages = {E20-E22}, keywords = {Adult, Alleles, Blood Proteins, Child, Female, Gene Expression, Gene Frequency, Genotype, Gray Platelet Syndrome, Humans, Male, Mutation, Phenotype, Platelet Aggregation, Platelet Count, Platelet Membrane Glycoproteins}, issn = {1096-8652}, doi = {10.1002/ajh.24610}, author = {Bottega, Roberta and Nicchia, Elena and Alfano, Caterina and Glembotsky, Ana C and Pastore, Annalisa and Bertaggia-Calderara, Debora and Bisig, Bettina and Duchosal, Michel A and Arbes{\'u}, Guillermo and Alberio, Lorenzo and Heller, Paula G and Savoia, Anna} } @article {10585, title = {Guidelines of the Italian Society of Videosurgery in Infancy for the minimally invasive treatment of the esophageal atresia.}, journal = {Pediatr Med Chir}, volume = {39}, year = {2017}, month = {2017 Oct 04}, pages = {166}, abstract = {

Not available.

}, keywords = {Esophageal Atresia, Humans, Infant, Minimally Invasive Surgical Procedures, Video-Assisted Surgery}, issn = {2420-7748}, doi = {10.4081/pmc.2017.166}, author = {Chiarenza, Salvatore Fabio and Conighi, Maria Luisa and Conforti, Andrea and Esposito, Ciro and Escolino, Maria and Beretta, Fabio and Cheli, Maurizio and Di Benedetto, Vincenzo and Scuderi, Maria Grazia and Casadio, Giovanni and Marzaro, Maurizio and Fascetti, Leon Francesco and Vella, Claudio and Bleve, Cosimo and Codric, Daniela and Caione, Paolo and Bagolan, Pietro} } @article {10586, title = {Guidelines of the Italian Society of Videosurgery in Infancy for the minimally invasive treatment of the ureteropelvic-junction obstruction.}, journal = {Pediatr Med Chir}, volume = {39}, year = {2017}, month = {2017 Oct 04}, pages = {174}, abstract = {

Not available.

}, keywords = {Humans, Infant, Kidney Pelvis, Minimally Invasive Surgical Procedures, Ureteral Obstruction, Video-Assisted Surgery}, issn = {2420-7748}, doi = {10.4081/pmc.2017.174}, author = {Chiarenza, Salvatore Fabio and Bleve, Cosimo and Esposito, Ciro and Escolino, Maria and Beretta, Fabio and Cheli, Maurizio and Di Benedetto, Vincenzo and Scuderi, Maria Grazia and Casadio, Giovanni and Marzaro, Maurizio and Fascetti, Leon Francesco and Bagolan, Pietro and Vella, Claudio and Conighi, Maria Luisa and Codric, Daniela and Nappo, Simona and Caione, Paolo} } @article {8304, title = {Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016}, pages = {10023}, abstract = {

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

}, keywords = {Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic}, issn = {2041-1723}, doi = {10.1038/ncomms10023}, author = {Pattaro, Cristian and Teumer, Alexander and Gorski, Mathias and Chu, Audrey Y and Li, Man and Mijatovic, Vladan and Garnaas, Maija and Tin, Adrienne and Sorice, Rossella and Li, Yong and Taliun, Daniel and Olden, Matthias and Foster, Meredith and Yang, Qiong and Chen, Ming-Huei and Pers, Tune H and Johnson, Andrew D and Ko, Yi-An and Fuchsberger, Christian and Tayo, Bamidele and Nalls, Michael and Feitosa, Mary F and Isaacs, Aaron and Dehghan, Abbas and d{\textquoteright}Adamo, Pio and Adeyemo, Adebowale and Dieffenbach, Aida Karina and Zonderman, Alan B and Nolte, Ilja M and van der Most, Peter J and Wright, Alan F and Shuldiner, Alan R and Morrison, Alanna C and Hofman, Albert and Smith, Albert V and Dreisbach, Albert W and Franke, Andre and Uitterlinden, Andr{\'e} G and Metspalu, Andres and T{\"o}njes, Anke and Lupo, Antonio and Robino, Antonietta and Johansson, {\r A}sa and Demirkan, Ayse and Kollerits, Barbara and Freedman, Barry I and Ponte, Belen and Oostra, Ben A and Paulweber, Bernhard and Kr{\"a}mer, Bernhard K and Mitchell, Braxton D and Buckley, Brendan M and Peralta, Carmen A and Hayward, Caroline and Helmer, Catherine and Rotimi, Charles N and Shaffer, Christian M and M{\"u}ller, Christian and Sala, Cinzia and van Duijn, Cornelia M and Saint-Pierre, Aude and Ackermann, Daniel and Shriner, Daniel and Ruggiero, Daniela and Toniolo, Daniela and Lu, Yingchang and Cusi, Daniele and Czamara, Darina and Ellinghaus, David and Siscovick, David S and Ruderfer, Douglas and Gieger, Christian and Grallert, Harald and Rochtchina, Elena and Atkinson, Elizabeth J and Holliday, Elizabeth G and Boerwinkle, Eric and Salvi, Erika and Bottinger, Erwin P and Murgia, Federico and Rivadeneira, Fernando and Ernst, Florian and Kronenberg, Florian and Hu, Frank B and Navis, Gerjan J and Curhan, Gary C and Ehret, George B and Homuth, Georg and Coassin, Stefan and Thun, Gian-Andri and Pistis, Giorgio and Gambaro, Giovanni and Malerba, Giovanni and Montgomery, Grant W and Eiriksdottir, Gudny and Jacobs, Gunnar and Li, Guo and Wichmann, H-Erich and Campbell, Harry and Schmidt, Helena and Wallaschofski, Henri and V{\"o}lzke, Henry and Brenner, Hermann and Kroemer, Heyo K and Kramer, Holly and Lin, Honghuang and Leach, I Mateo and Ford, Ian and Guessous, Idris and Rudan, Igor and Prokopenko, Inga and Borecki, Ingrid and Heid, Iris M and Kolcic, Ivana and Persico, Ivana and Jukema, J Wouter and Wilson, James F and Felix, Janine F and Divers, Jasmin and Lambert, Jean-Charles and Stafford, Jeanette M and Gaspoz, Jean-Michel and Smith, Jennifer A and Faul, Jessica D and Wang, Jie Jin and Ding, Jingzhong and Hirschhorn, Joel N and Attia, John and Whitfield, John B and Chalmers, John and Viikari, Jorma and Coresh, Josef and Denny, Joshua C and Karjalainen, Juha and Fernandes, Jyotika K and Endlich, Karlhans and Butterbach, Katja and Keene, Keith L and Lohman, Kurt and Portas, Laura and Launer, Lenore J and Lyytik{\"a}inen, Leo-Pekka and Yengo, Loic and Franke, Lude and Ferrucci, Luigi and Rose, Lynda M and Kedenko, Lyudmyla and Rao, Madhumathi and Struchalin, Maksim and Kleber, Marcus E and Cavalieri, Margherita and Haun, Margot and Cornelis, Marilyn C and Ciullo, Marina and Pirastu, Mario and de Andrade, Mariza and McEvoy, Mark A and Woodward, Mark and Adam, Martin and Cocca, Massimiliano and Nauck, Matthias and Imboden, Medea and Waldenberger, Melanie and Pruijm, Menno and Metzger, Marie and Stumvoll, Michael and Evans, Michele K and Sale, Michele M and K{\"a}h{\"o}nen, Mika and Boban, Mladen and Bochud, Murielle and Rheinberger, Myriam and Verweij, Niek and Bouatia-Naji, Nabila and Martin, Nicholas G and Hastie, Nick and Probst-Hensch, Nicole and Soranzo, Nicole and Devuyst, Olivier and Raitakari, Olli and Gottesman, Omri and Franco, Oscar H and Polasek, Ozren and Gasparini, Paolo and Munroe, Patricia B and Ridker, Paul M and Mitchell, Paul and Muntner, Paul and Meisinger, Christa and Smit, Johannes H and Kovacs, Peter and Wild, Philipp S and Froguel, Philippe and Rettig, Rainer and M{\"a}gi, Reedik and Biffar, Reiner and Schmidt, Reinhold and Middelberg, Rita P S and Carroll, Robert J and Penninx, Brenda W and Scott, Rodney J and Katz, Ronit and Sedaghat, Sanaz and Wild, Sarah H and Kardia, Sharon L R and Ulivi, Sheila and Hwang, Shih-Jen and Enroth, Stefan and Kloiber, Stefan and Trompet, Stella and Stengel, B{\'e}n{\'e}dicte and Hancock, Stephen J and Turner, Stephen T and Rosas, Sylvia E and Stracke, Sylvia and Harris, Tamara B and Zeller, Tanja and Zemunik, Tatijana and Lehtim{\"a}ki, Terho and Illig, Thomas and Aspelund, Thor and Nikopensius, Tiit and Esko, T{\~o}nu and Tanaka, Toshiko and Gyllensten, Ulf and V{\"o}lker, Uwe and Emilsson, Valur and Vitart, Veronique and Aalto, Ville and Gudnason, Vilmundur and Chouraki, Vincent and Chen, Wei-Min and Igl, Wilmar and M{\"a}rz, Winfried and Koenig, Wolfgang and Lieb, Wolfgang and Loos, Ruth J F and Liu, Yongmei and Snieder, Harold and Pramstaller, Peter P and Parsa, Afshin and O{\textquoteright}Connell, Jeffrey R and Susztak, Katalin and Hamet, Pavel and Tremblay, Johanne and de Boer, Ian H and B{\"o}ger, Carsten A and Goessling, Wolfram and Chasman, Daniel I and K{\"o}ttgen, Anna and Kao, W H Linda and Fox, Caroline S} } @article {8484, title = {Genome-wide association study identifies 74 loci associated with educational attainment.}, journal = {Nature}, volume = {533}, year = {2016}, month = {2016 May 26}, pages = {539-42}, abstract = {

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20\% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

}, keywords = {Alzheimer Disease, Bipolar Disorder, Brain, Cognition, Computational Biology, Educational Status, Fetus, Gene Expression Regulation, Gene-Environment Interaction, Genome-Wide Association Study, Great Britain, Humans, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Schizophrenia}, issn = {1476-4687}, doi = {10.1038/nature17671}, author = {Okbay, Aysu and Beauchamp, Jonathan P and Fontana, Mark Alan and Lee, James J and Pers, Tune H and Rietveld, Cornelius A and Turley, Patrick and Chen, Guo-Bo and Emilsson, Valur and Meddens, S Fleur W and Oskarsson, Sven and Pickrell, Joseph K and Thom, Kevin and Timshel, Pascal and de Vlaming, Ronald and Abdellaoui, Abdel and Ahluwalia, Tarunveer S and Bacelis, Jonas and Baumbach, Clemens and Bjornsdottir, Gyda and Brandsma, Johannes H and Pina Concas, Maria and Derringer, Jaime and Furlotte, Nicholas A and Galesloot, Tessel E and Girotto, Giorgia and Gupta, Richa and Hall, Leanne M and Harris, Sarah E and Hofer, Edith and Horikoshi, Momoko and Huffman, Jennifer E and Kaasik, Kadri and Kalafati, Ioanna P and Karlsson, Robert and Kong, Augustine and Lahti, Jari and van der Lee, Sven J and deLeeuw, Christiaan and Lind, Penelope A and Lindgren, Karl-Oskar and Liu, Tian and Mangino, Massimo and Marten, Jonathan and Mihailov, Evelin and Miller, Michael B and van der Most, Peter J and Oldmeadow, Christopher and Payton, Antony and Pervjakova, Natalia and Peyrot, Wouter J and Qian, Yong and Raitakari, Olli and Rueedi, Rico and Salvi, Erika and Schmidt, B{\"o}rge and Schraut, Katharina E and Shi, Jianxin and Smith, Albert V and Poot, Raymond A and St Pourcain, Beate and Teumer, Alexander and Thorleifsson, Gudmar and Verweij, Niek and Vuckovic, Dragana and Wellmann, Juergen and Westra, Harm-Jan and Yang, Jingyun and Zhao, Wei and Zhu, Zhihong and Alizadeh, Behrooz Z and Amin, Najaf and Bakshi, Andrew and Baumeister, Sebastian E and Biino, Ginevra and B{\o}nnelykke, Klaus and Boyle, Patricia A and Campbell, Harry and Cappuccio, Francesco P and Davies, Gail and De Neve, Jan-Emmanuel and Deloukas, Panos and Demuth, Ilja and Ding, Jun and Eibich, Peter and Eisele, Lewin and Eklund, Niina and Evans, David M and Faul, Jessica D and Feitosa, Mary F and Forstner, Andreas J and Gandin, Ilaria and Gunnarsson, Bjarni and Halld{\'o}rsson, Bjarni V and Harris, Tamara B and Heath, Andrew C and Hocking, Lynne J and Holliday, Elizabeth G and Homuth, Georg and Horan, Michael A and Hottenga, Jouke-Jan and de Jager, Philip L and Joshi, Peter K and Jugessur, Astanand and Kaakinen, Marika A and K{\"a}h{\"o}nen, Mika and Kanoni, Stavroula and Keltigangas-J{\"a}rvinen, Liisa and Kiemeney, Lambertus A L M and Kolcic, Ivana and Koskinen, Seppo and Kraja, Aldi T and Kroh, Martin and Kutalik, Zolt{\'a}n and Latvala, Antti and Launer, Lenore J and Lebreton, Ma{\"e}l P and Levinson, Douglas F and Lichtenstein, Paul and Lichtner, Peter and Liewald, David C M and Loukola, Anu and Madden, Pamela A and M{\"a}gi, Reedik and M{\"a}ki-Opas, Tomi and Marioni, Riccardo E and Marques-Vidal, Pedro and Meddens, Gerardus A and McMahon, George and Meisinger, Christa and Meitinger, Thomas and Milaneschi, Yusplitri and Milani, Lili and Montgomery, Grant W and Myhre, Ronny and Nelson, Christopher P and Nyholt, Dale R and Ollier, William E R and Palotie, Aarno and Paternoster, Lavinia and Pedersen, Nancy L and Petrovic, Katja E and Porteous, David J and R{\"a}ikk{\"o}nen, Katri and Ring, Susan M and Robino, Antonietta and Rostapshova, Olga and Rudan, Igor and Rustichini, Aldo and Salomaa, Veikko and Sanders, Alan R and Sarin, Antti-Pekka and Schmidt, Helena and Scott, Rodney J and Smith, Blair H and Smith, Jennifer A and Staessen, Jan A and Steinhagen-Thiessen, Elisabeth and Strauch, Konstantin and Terracciano, Antonio and Tobin, Martin D and Ulivi, Sheila and Vaccargiu, Simona and Quaye, Lydia and van Rooij, Frank J A and Venturini, Cristina and Vinkhuyzen, Anna A E and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Vonk, Judith M and Vozzi, Diego and Waage, Johannes and Ware, Erin B and Willemsen, Gonneke and Attia, John R and Bennett, David A and Berger, Klaus and Bertram, Lars and Bisgaard, Hans and Boomsma, Dorret I and Borecki, Ingrid B and B{\"u}ltmann, Ute and Chabris, Christopher F and Cucca, Francesco and Cusi, Daniele and Deary, Ian J and Dedoussis, George V and van Duijn, Cornelia M and Eriksson, Johan G and Franke, Barbara and Franke, Lude and Gasparini, Paolo and Gejman, Pablo V and Gieger, Christian and Grabe, Hans-J{\"o}rgen and Gratten, Jacob and Groenen, Patrick J F and Gudnason, Vilmundur and van der Harst, Pim and Hayward, Caroline and Hinds, David A and Hoffmann, Wolfgang and Hypp{\"o}nen, Elina and Iacono, William G and Jacobsson, Bo and J{\"a}rvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Kaprio, Jaakko and Kardia, Sharon L R and Lehtim{\"a}ki, Terho and Lehrer, Steven F and Magnusson, Patrik K E and Martin, Nicholas G and McGue, Matt and Metspalu, Andres and Pendleton, Neil and Penninx, Brenda W J H and Perola, Markus and Pirastu, Nicola and Pirastu, Mario and Polasek, Ozren and Posthuma, Danielle and Power, Christine and Province, Michael A and Samani, Nilesh J and Schlessinger, David and Schmidt, Reinhold and S{\o}rensen, Thorkild I A and Spector, Tim D and Stefansson, Kari and Thorsteinsdottir, Unnur and Thurik, A Roy and Timpson, Nicholas J and Tiemeier, Henning and Tung, Joyce Y and Uitterlinden, Andr{\'e} G and Vitart, Veronique and Vollenweider, Peter and Weir, David R and Wilson, James F and Wright, Alan F and Conley, Dalton C and Krueger, Robert F and Davey Smith, George and Hofman, Albert and Laibson, David I and Medland, Sarah E and Meyer, Michelle N and Yang, Jian and Johannesson, Magnus and Visscher, Peter M and Esko, T{\~o}nu and Koellinger, Philipp D and Cesarini, David and Benjamin, Daniel J} } @article {8345, title = {A Genome-Wide Association Study in isolated populations reveals new genes associated to common food likings.}, journal = {Rev Endocr Metab Disord}, year = {2016}, month = {2016 Apr 30}, abstract = {

Food preferences are the first factor driving food choice and thus nutrition. They involve numerous different senses such as taste and olfaction as well as various other factors such as personal experiences and hedonistic aspects. Although it is clear that several of these have a genetic basis, up to now studies have focused mostly on the effects of polymorphisms of taste receptor genes. Therefore, we have carried out one of the first large scale (4611 individuals) GWAS on food likings assessed for 20 specific food likings belonging to 4 different categories (vegetables, fatty, dairy and bitter). A two-step meta-analysis using three different isolated populations from Italy for the discovery step and two populations from The Netherlands and Central Asia for replication, revealed 15 independent genome-wide significant loci (p < 5 {\texttimes} 10(-8)) for 12 different foods. None of the identified genes coded for either taste or olfactory receptors suggesting that genetics impacts in determining food likings in a much broader way than simple differences in taste perception. These results represent a further step in uncovering the genes that underlie liking of common foods that in the end will greatly help understanding the genetics of human nutrition in general.

}, issn = {1573-2606}, doi = {10.1007/s11154-016-9354-3}, author = {Pirastu, Nicola and Kooyman, Maarten and Traglia, Michela and Robino, Antonietta and Willems, Sara M and Pistis, Giorgio and Amin, Najaf and Sala, Cinzia and Karssen, Lennart C and van Duijn, Cornelia and Toniolo, Daniela and Gasparini, Paolo} } @article {8323, title = {Geranylgeraniol and Neurological Impairment: Involvement of Apoptosis and Mitochondrial Morphology.}, journal = {Int J Mol Sci}, volume = {17}, year = {2016}, month = {2016}, pages = {365}, abstract = {

Deregulation of the cholesterol pathway is an anomaly observed in human diseases, many of which have in common neurological involvement and unknown pathogenesis. In this study we have used Mevalonate Kinase Deficiency (MKD) as a disease-model in order to investigate the link between the deregulation of the mevalonate pathway and the consequent neurodegeneration. The blocking of the mevalonate pathway in a neuronal cell line (Daoy), using statins or mevalonate, induced an increase in the expression of the inflammasome gene (NLRP3) and programmed cell death related to mitochondrial dysfunction. The morphology of the mitochondria changed, clearly showing the damage induced by oxidative stress and the decreased membrane potential associated with the alterations of the mitochondrial function. The co-administration of geranylgeraniol (GGOH) reduced the inflammatory marker and the damage of the mitochondria, maintaining its shape and components. Our data allow us to speculate about the mechanism by which isoprenoids are able to rescue the inflammatory marker in neuronal cells, independently from the block of the mevalonate pathway, and about the fact that cell death is mitochondria-related.

}, issn = {1422-0067}, doi = {10.3390/ijms17030365}, author = {Marcuzzi, Annalisa and Piscianz, Elisa and Zweyer, Marina and Bortul, Roberta and Loganes, Claudia and Girardelli, Martina and Baj, Gabriele and Monasta, Lorenzo and Celeghini, Claudio} } @article {8344, title = {Giant Cerebellar Lesion in a Patient With Purulent Ear Drainage.}, journal = {JAMA Otolaryngol Head Neck Surg}, volume = {142}, year = {2016}, month = {2016 Jun 1}, pages = {603-4}, issn = {2168-619X}, doi = {10.1001/jamaoto.2016.0014}, author = {Mandal{\`a}, Marco and Muzzi, Enrico and Trabalzini, Franco} } @article {8351, title = {Global diversity in the TAS2R38 bitter taste receptor: revisiting a classic evolutionary PROPosal.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016}, pages = {25506}, abstract = {

The ability to taste phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) is a polymorphic trait mediated by the TAS2R38 bitter taste receptor gene. It has long been hypothesized that global genetic diversity at this locus evolved under pervasive pressures from balancing natural selection. However, recent high-resolution population genetic studies of TAS2Rs suggest that demographic events have played a critical role in the evolution of these genes. We here utilized the largest TAS2R38 database yet analyzed, consisting of 5,589 individuals from 105 populations, to examine natural selection, haplotype frequencies and linkage disequilibrium to estimate the effects of both selection and demography on contemporary patterns of variation at this locus. We found signs of an ancient balancing selection acting on this gene but no post Out-Of-Africa departures from neutrality, implying that the current observed patterns of variation can be predominantly explained by demographic, rather than selective events. In addition, we found signatures of ancient selective forces acting on different African TAS2R38 haplotypes. Collectively our results provide evidence for a relaxation of recent selective forces acting on this gene and a revised hypothesis for the origins of the present-day worldwide distribution of TAS2R38 haplotypes.

}, issn = {2045-2322}, doi = {10.1038/srep25506}, author = {Risso, Davide S and Mezzavilla, Massimo and Pagani, Luca and Robino, Antonietta and Morini, Gabriella and Tofanelli, Sergio and Carrai, Maura and Campa, Daniele and Barale, Roberto and Caradonna, Fabio and Gasparini, Paolo and Luiselli, Donata and Wooding, Stephen and Drayna, Dennis} } @article {8489, title = {The Great Pretender: Pediatric Wandering Spleen: Two Case Reports and Review of the Literature.}, journal = {Pediatr Emerg Care}, year = {2016}, month = {2016 Feb 10}, abstract = {

Wandering spleen is a rare condition, typically not only due to embryological defects of the splenic ligaments, but also secondary to trauma and splenomegaly. The most common presentation is acute abdomen with a mobile abdominal mass or recurrent abdominal pain. However, the spleen may be temporary in its normal position, and patients could be asymptomatic. A familiarity, if present, strengthens the diagnostic suspect.Abdominal ultrasonography and computed tomography are the examination of choice, and the management is surgical.

}, issn = {1535-1815}, doi = {10.1097/PEC.0000000000000642}, author = {Radillo, Lucia and Taddio, Andrea and Ghirardo, Sergio and Bramuzzo, Matteo and Pederiva, Federica and Maschio, Massimo and Barbi, Egidio} } @article {8092, title = {Genetic analysis of Italian patients with congenital tufting enteropathy.}, journal = {World J Pediatr}, year = {2015}, month = {2015 Dec 18}, abstract = {

BACKGROUND: Congenital tufting enteropathy (CTE), an inherited autosomal recessive rare disease, is a severe diarrhea of infancy which is clinically characterized by absence of inflammation and presence of intestinal villous atrophy. Mutations in the EpCAM gene were identified to cause CTE. Recent cases of syndromic tufting enteropathy harboring the SPINT2 (19q13.2) mutation were described.

METHODS: Four CTE Italian patients were clinically and immunohistochemically characterized. Direct DNA sequencing of EpCAM and SPINT2 genes was performed.

RESULTS: All patients were of Italian origin. Three different mutations were detected (p.Asp219Metfs*15, Tyr186Phefs*6 and p.Ile146Asn) in the EpCAM gene; one of them is novel (p.Ile146Asn). Two patients (P1 and P2) showed compound heterozygosity revealing two mutations in separate alleles. A third patient (P3) was heterozygous for only one novel EpCAM missense mutation (p.Ile146Asn). In a syndromic patient (P4), no deleterious EpCAM mutation was found. Additional SPINT2 mutational analysis was performed. P4 showed a homozygous SPINT2 mutation (p.Y163C). No SPINT2 mutation was found in P3. CLDN7 was also evaluated as a candidate gene by mutational screening in P3 but no mutation was identified.

CONCLUSIONS: This study presented a molecular characterization of CTE Italian patients, and identified three mutations in the EpCAM gene and one in the SPINT2 gene. One of EpCAM mutations was novel, therefore increasing the mutational spectrum of allelic variants of the EpCAM gene. Molecular analysis of the SPINT2 gene also allowed us to identify a SPINT2 substitution mutation (c.488A>G) recently found to be associated with syndromic CTE subjects.

}, issn = {1867-0687}, doi = {10.1007/s12519-015-0070-y}, author = {d{\textquoteright}Apolito, Maria and Pisanelli, Daniela and Faletra, Flavio and Giardino, Ida and Gigante, Maddalena and Pettoello-Mantovani, Massimo and Goulet, Olivier and Gasparini, Paolo and Campanozzi, Angelo} } @article {7762, title = {Genetic determinants for methotrexate response in juvenile idiopathic arthritis.}, journal = {Front Pharmacol}, volume = {6}, year = {2015}, month = {2015}, pages = {52}, abstract = {

Juvenile idiopathic arthritis (JIAs) is the most common chronic rheumatic disease of childhood and is an important cause of disability. The folic acid analog methotrexate is the first choice disease-modifying anti-rheumatic drug in this disease, however, 35-45\% of patients fail to respond. Molecular elements, such as variants in genes of pharmacological relevance, influencing response to methotrexate in JIA, would be important to individualize treatment strategies. Several studies have evaluated the effects of candidate genetic variants in the complex pathway of genes involved in methotrexate pharmacodynamics and pharmacokinetics, however, results are still contrasting and no definitive genetic marker of methotrexate response useful for the clinician to tailor therapy of children with JIA has been identified. Recently, genome-wide approaches have been applied, identifying new potential biological processes involved in methotrexate response in JIA such as TGF-beta signaling and calcium channels. If these genomic results are properly validated and integrated with innovative analyses comprising deep sequencing, epigenetics, and pharmacokinetics, they will greatly contribute to personalize therapy with methotrexate in children with JIA.

}, issn = {1663-9812}, doi = {10.3389/fphar.2015.00052}, author = {Pastore, Serena and Stocco, Gabriele and Favretto, Diego and De Iudicibus, Sara and Taddio, Andrea and d{\textquoteright}Adamo, Pio and Malus{\`a}, Noelia and Addobbati, Riccardo and Decorti, Giuliana and Lepore, Loredana and Ventura, Alessandro} } @article {8069, title = {Genetic evidence for an origin of the Armenians from Bronze Age mixing of multiple populations.}, journal = {Eur J Hum Genet}, year = {2015}, month = {2015 Oct 21}, abstract = {

The Armenians are a culturally isolated population who historically inhabited a region in the Near East bounded by the Mediterranean and Black seas and the Caucasus, but remain under-represented in genetic studies and have a complex history including a major geographic displacement during World War I. Here, we analyse genome-wide variation in 173 Armenians and compare them with 78 other worldwide populations. We find that Armenians form a distinctive cluster linking the Near East, Europe, and the Caucasus. We show that Armenian diversity can be explained by several mixtures of Eurasian populations that occurred between ~3000 and ~2000 bce, a period characterized by major population migrations after the domestication of the horse, appearance of chariots, and the rise of advanced civilizations in the Near East. However, genetic signals of population mixture cease after ~1200 bce when Bronze Age civilizations in the Eastern Mediterranean world suddenly and violently collapsed. Armenians have since remained isolated and genetic structure within the population developed ~500 years ago when Armenia was divided between the Ottomans and the Safavid Empire in Iran. Finally, we show that Armenians have higher genetic affinity to Neolithic Europeans than other present-day Near Easterners, and that 29\% of Armenian ancestry may originate from an ancestral population that is best represented by Neolithic Europeans.European Journal of Human Genetics advance online publication, 21 October 2015; doi:10.1038/ejhg.2015.206.

}, issn = {1476-5438}, doi = {10.1038/ejhg.2015.206}, author = {Haber, Marc and Mezzavilla, Massimo and Xue, Yali and Comas, David and Gasparini, Paolo and Zalloua, Pierre and Tyler-Smith, Chris} } @article {7774, title = {Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study.}, journal = {Pediatr Rheumatol Online J}, volume = {13}, year = {2015}, month = {2015}, pages = {11}, abstract = {

BACKGROUND: Periodic fever syndromes (PFS) are an emerging group of autoinflammatory disorders. Clinical overlap exists and multiple genetic analyses may be needed to assist diagnosis. We evaluated the diagnostic value of a 5-gene sequencing panel (5GP) in patients with undiagnosed PFS.

METHODS: Simultaneous double strand Sanger sequencing of MEFV, MVK, TNFRSF1A, NLRP3, NLRP12 genes was performed in 42 patients with unexplained PFS. Clinical features were correlated with genetic results.

RESULTS: None of 42 patients analyzed displayed a causative genotype. However, single or multiple genetic variants of uncertain significance were detected in 24 subjects. Only in 5 subjects a definite diagnosis was made by taking into account both genetic and clinical data (2 TRAPS syndrome; 2 FMF; 1 FCAS). Statistical analysis showed that patients carrying genetic variants in one or more of the five selected genes displayed a significantly lower response to glucocorticoids compared with subjects who had completely negative genetic results.

CONCLUSIONS: The sequencing of multiple genes is of little help in the diagnostics of PFS and can often lead to results of uncertain interpretation, thus the clinically driven sequencing of single genes should remain the recommended approach. However, the presence of single or multiple genetic variants of uncertain significance, even if not allowing any specific diagnosis, correlated with a poorer response to glucocorticoids, possibly indicating a multifactorial subgroup of PFS with differential response to pharmacological treatment.

}, keywords = {Adolescent, Carrier Proteins, Child, Cryopyrin-Associated Periodic Syndromes, Cytoskeletal Proteins, Familial Mediterranean Fever, Female, Fever, Gene Expression Profiling, Genotype, Hereditary Autoinflammatory Diseases, Humans, Intracellular Signaling Peptides and Proteins, Logistic Models, Male, Mutation, Phosphotransferases (Alcohol Group Acceptor), Prospective Studies, Receptors, Tumor Necrosis Factor, Type I, Syndrome}, issn = {1546-0096}, doi = {10.1186/s12969-015-0006-z}, author = {De Pieri, Carlo and Vuch, Josef and De Martino, Eleonora and Bianco, Anna M and Ronfani, Luca and Athanasakis, Emmanouil and Bortot, Barbara and Crovella, Sergio and Taddio, Andrea and Severini, Giovanni M and Tommasini, Alberto} } @article {7691, title = {Genetic studies of body mass index yield new insights for obesity biology.}, journal = {Nature}, volume = {518}, year = {2015}, month = {2015 Feb 12}, pages = {197-206}, abstract = {

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P~<~5~{\texttimes}~10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for \~{}2.7\% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20\% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

}, keywords = {Adipogenesis, Adiposity, Age Factors, Body Mass Index, Continental Population Groups, Energy Metabolism, Europe, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glutamic Acid, Humans, Insulin, Male, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Synapses}, issn = {1476-4687}, doi = {10.1038/nature14177}, author = {Locke, Adam E and Kahali, Bratati and Berndt, Sonja I and Justice, Anne E and Pers, Tune H and Day, Felix R and Powell, Corey and Vedantam, Sailaja and Buchkovich, Martin L and Yang, Jian and Croteau-Chonka, Damien C and Esko, T{\~o}nu and Fall, Tove and Ferreira, Teresa and Gustafsson, Stefan and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Randall, Joshua C and Winkler, Thomas W and Wood, Andrew R and Workalemahu, Tsegaselassie and Faul, Jessica D and Smith, Jennifer A and Hua Zhao, Jing and Zhao, Wei and Chen, Jin and Fehrmann, Rudolf and Hedman, {\r A}sa K and Karjalainen, Juha and Schmidt, Ellen M and Absher, Devin and Amin, Najaf and Anderson, Denise and Beekman, Marian and Bolton, Jennifer L and Bragg-Gresham, Jennifer L and Buyske, Steven and Demirkan, Ayse and Deng, Guohong and Ehret, Georg B and Feenstra, Bjarke and Feitosa, Mary F and Fischer, Krista and Goel, Anuj and Gong, Jian and Jackson, Anne U and Kanoni, Stavroula and Kleber, Marcus E and Kristiansson, Kati and Lim, Unhee and Lotay, Vaneet and Mangino, Massimo and Mateo Leach, Irene and Medina-Gomez, Carolina and Medland, Sarah E and Nalls, Michael A and Palmer, Cameron D and Pasko, Dorota and Pechlivanis, Sonali and Peters, Marjolein J and Prokopenko, Inga and Shungin, Dmitry and Stan{\v c}{\'a}kov{\'a}, Alena and Strawbridge, Rona J and Ju Sung, Yun and Tanaka, Toshiko and Teumer, Alexander and Trompet, Stella and van der Laan, Sander W and van Setten, Jessica and Van Vliet-Ostaptchouk, Jana V and Wang, Zhaoming and Yengo, Loic and Zhang, Weihua and Isaacs, Aaron and Albrecht, Eva and Arnl{\"o}v, Johan and Arscott, Gillian M and Attwood, Antony P and Bandinelli, Stefania and Barrett, Amy and Bas, Isabelita N and Bellis, Claire and Bennett, Amanda J and Berne, Christian and Blagieva, Roza and Bl{\"u}her, Matthias and B{\"o}hringer, Stefan and Bonnycastle, Lori L and B{\"o}ttcher, Yvonne and Boyd, Heather A and Bruinenberg, Marcel and Caspersen, Ida H and Ida Chen, Yii-Der and Clarke, Robert and Daw, E Warwick and de Craen, Anton J M and Delgado, Graciela and Dimitriou, Maria and Doney, Alex S F and Eklund, Niina and Estrada, Karol and Eury, Elodie and Folkersen, Lasse and Fraser, Ross M and Garcia, Melissa E and Geller, Frank and Giedraitis, Vilmantas and Gigante, Bruna and Go, Alan S and Golay, Alain and Goodall, Alison H and Gordon, Scott D and Gorski, Mathias and Grabe, Hans-J{\"o}rgen and Grallert, Harald and Grammer, Tanja B and Gr{\"a}{\ss}ler, J{\"u}rgen and Gr{\"o}nberg, Henrik and Groves, Christopher J and Gusto, Ga{\"e}lle and Haessler, Jeffrey and Hall, Per and Haller, Toomas and Hallmans, Goran and Hartman, Catharina A and Hassinen, Maija and Hayward, Caroline and Heard-Costa, Nancy L and Helmer, Quinta and Hengstenberg, Christian and Holmen, Oddgeir and Hottenga, Jouke-Jan and James, Alan L and Jeff, Janina M and Johansson, {\r A}sa and Jolley, Jennifer and Juliusdottir, Thorhildur and Kinnunen, Leena and Koenig, Wolfgang and Koskenvuo, Markku and Kratzer, Wolfgang and Laitinen, Jaana and Lamina, Claudia and Leander, Karin and Lee, Nanette R and Lichtner, Peter and Lind, Lars and Lindstr{\"o}m, Jaana and Sin Lo, Ken and Lobbens, St{\'e}phane and Lorbeer, Roberto and Lu, Yingchang and Mach, Fran{\c c}ois and Magnusson, Patrik K E and Mahajan, Anubha and McArdle, Wendy L and McLachlan, Stela and Menni, Cristina and Merger, Sigrun and Mihailov, Evelin and Milani, Lili and Moayyeri, Alireza and Monda, Keri L and Morken, Mario A and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Musk, Arthur W and Nagaraja, Ramaiah and N{\"o}then, Markus M and Nolte, Ilja M and Pilz, Stefan and Rayner, Nigel W and Renstrom, Frida and Rettig, Rainer and Ried, Janina S and Ripke, Stephan and Robertson, Neil R and Rose, Lynda M and Sanna, Serena and Scharnagl, Hubert and Scholtens, Salome and Schumacher, Fredrick R and Scott, William R and Seufferlein, Thomas and Shi, Jianxin and Vernon Smith, Albert and Smolonska, Joanna and Stanton, Alice V and Steinthorsdottir, Valgerdur and Stirrups, Kathleen and Stringham, Heather M and Sundstr{\"o}m, Johan and Swertz, Morris A and Swift, Amy J and Syv{\"a}nen, Ann-Christine and Tan, Sian-Tsung and Tayo, Bamidele O and Thorand, Barbara and Thorleifsson, Gudmar and Tyrer, Jonathan P and Uh, Hae-Won and Vandenput, Liesbeth and Verhulst, Frank C and Vermeulen, Sita H and Verweij, Niek and Vonk, Judith M and Waite, Lindsay L and Warren, Helen R and Waterworth, Dawn and Weedon, Michael N and Wilkens, Lynne R and Willenborg, Christina and Wilsgaard, Tom and Wojczynski, Mary K and Wong, Andrew and Wright, Alan F and Zhang, Qunyuan and Brennan, Eoin P and Choi, Murim and Dastani, Zari and Drong, Alexander W and Eriksson, Per and Franco-Cereceda, Anders and G{\r a}din, Jesper R and Gharavi, Ali G and Goddard, Michael E and Handsaker, Robert E and Huang, Jinyan and Karpe, Fredrik and Kathiresan, Sekar and Keildson, Sarah and Kiryluk, Krzysztof and Kubo, Michiaki and Lee, Jong-Young and Liang, Liming and Lifton, Richard P and Ma, Baoshan and McCarroll, Steven A and McKnight, Amy J and Min, Josine L and Moffatt, Miriam F and Montgomery, Grant W and Murabito, Joanne M and Nicholson, George and Nyholt, Dale R and Okada, Yukinori and Perry, John R B and Dorajoo, Rajkumar and Reinmaa, Eva and Salem, Rany M and Sandholm, Niina and Scott, Robert A and Stolk, Lisette and Takahashi, Atsushi and Tanaka, Toshihiro and Van{\textquoteright}t Hooft, Ferdinand M and Vinkhuyzen, Anna A E and Westra, Harm-Jan and Zheng, Wei and Zondervan, Krina T and Heath, Andrew C and Arveiler, Dominique and Bakker, Stephan J L and Beilby, John and Bergman, Richard N and Blangero, John and Bovet, Pascal and Campbell, Harry and Caulfield, Mark J and Cesana, Giancarlo and Chakravarti, Aravinda and Chasman, Daniel I and Chines, Peter S and Collins, Francis S and Crawford, Dana C and Cupples, L Adrienne and Cusi, Daniele and Danesh, John and de Faire, Ulf and den Ruijter, Hester M and Dominiczak, Anna F and Erbel, Raimund and Erdmann, Jeanette and Eriksson, Johan G and Farrall, Martin and Felix, Stephan B and Ferrannini, Ele and Ferri{\`e}res, Jean and Ford, Ian and Forouhi, Nita G and Forrester, Terrence and Franco, Oscar H and Gansevoort, Ron T and Gejman, Pablo V and Gieger, Christian and Gottesman, Omri and Gudnason, Vilmundur and Gyllensten, Ulf and Hall, Alistair S and Harris, Tamara B and Hattersley, Andrew T and Hicks, Andrew A and Hindorff, Lucia A and Hingorani, Aroon D and Hofman, Albert and Homuth, Georg and Hovingh, G Kees and Humphries, Steve E and Hunt, Steven C and Hypp{\"o}nen, Elina and Illig, Thomas and Jacobs, Kevin B and J{\"a}rvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Johansen, Berit and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti M and Kaprio, Jaakko and Kastelein, John J P and Keinanen-Kiukaanniemi, Sirkka M and Kiemeney, Lambertus A and Knekt, Paul and Kooner, Jaspal S and Kooperberg, Charles and Kovacs, Peter and Kraja, Aldi T and Kumari, Meena and Kuusisto, Johanna and Lakka, Timo A and Langenberg, Claudia and Le Marchand, Loic and Lehtim{\"a}ki, Terho and Lyssenko, Valeriya and M{\"a}nnist{\"o}, Satu and Marette, Andr{\'e} and Matise, Tara C and McKenzie, Colin A and McKnight, Barbara and Moll, Frans L and Morris, Andrew D and Morris, Andrew P and Murray, Jeffrey C and Nelis, Mari and Ohlsson, Claes and Oldehinkel, Albertine J and Ong, Ken K and Madden, Pamela A F and Pasterkamp, Gerard and Peden, John F and Peters, Annette and Postma, Dirkje S and Pramstaller, Peter P and Price, Jackie F and Qi, Lu and Raitakari, Olli T and Rankinen, Tuomo and Rao, D C and Rice, Treva K and Ridker, Paul M and Rioux, John D and Ritchie, Marylyn D and Rudan, Igor and Salomaa, Veikko and Samani, Nilesh J and Saramies, Jouko and Sarzynski, Mark A and Schunkert, Heribert and Schwarz, Peter E H and Sever, Peter and Shuldiner, Alan R and Sinisalo, Juha and Stolk, Ronald P and Strauch, Konstantin and T{\"o}njes, Anke and Tr{\'e}gou{\"e}t, David-Alexandre and Tremblay, Angelo and Tremoli, Elena and Virtamo, Jarmo and Vohl, Marie-Claude and V{\"o}lker, Uwe and Waeber, Gerard and Willemsen, Gonneke and Witteman, Jacqueline C and Zillikens, M Carola and Adair, Linda S and Amouyel, Philippe and Asselbergs, Folkert W and Assimes, Themistocles L and Bochud, Murielle and Boehm, Bernhard O and Boerwinkle, Eric and Bornstein, Stefan R and Bottinger, Erwin P and Bouchard, Claude and Cauchi, St{\'e}phane and Chambers, John C and Chanock, Stephen J and Cooper, Richard S and de Bakker, Paul I W and Dedoussis, George and Ferrucci, Luigi and Franks, Paul W and Froguel, Philippe and Groop, Leif C and Haiman, Christopher A and Hamsten, Anders and Hui, Jennie and Hunter, David J and Hveem, Kristian and Kaplan, Robert C and Kivimaki, Mika and Kuh, Diana and Laakso, Markku and Liu, Yongmei and Martin, Nicholas G and M{\"a}rz, Winfried and Melbye, Mads and Metspalu, Andres and Moebus, Susanne and Munroe, Patricia B and Nj{\o}lstad, Inger and Oostra, Ben A and Palmer, Colin N A and Pedersen, Nancy L and Perola, Markus and P{\'e}russe, Louis and Peters, Ulrike and Power, Chris and Quertermous, Thomas and Rauramaa, Rainer and Rivadeneira, Fernando and Saaristo, Timo E and Saleheen, Danish and Sattar, Naveed and Schadt, Eric E and Schlessinger, David and Slagboom, P Eline and Snieder, Harold and Spector, Tim D and Thorsteinsdottir, Unnur and Stumvoll, Michael and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and van der Harst, Pim and Walker, Mark and Wallaschofski, Henri and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wichmann, H-Erich and Wilson, James F and Zanen, Pieter and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Heid, Iris M and O{\textquoteright}Connell, Jeffrey R and Strachan, David P and Stefansson, Kari and van Duijn, Cornelia M and Abecasis, Goncalo R and Franke, Lude and Frayling, Timothy M and McCarthy, Mark I and Visscher, Peter M and Scherag, Andr{\'e} and Willer, Cristen J and Boehnke, Michael and Mohlke, Karen L and Lindgren, Cecilia M and Beckmann, Jacques S and Barroso, In{\^e}s and North, Kari E and Ingelsson, Erik and Hirschhorn, Joel N and Loos, Ruth J F and Speliotes, Elizabeth K} } @article {8080, title = {Genetic testing and genomic analysis: a debate on ethical, social and legal issues in the Arab world with a focus on Qatar.}, journal = {J Transl Med}, volume = {13}, year = {2015}, month = {2015}, pages = {358}, abstract = {

In 2013 both Saudi Arabia and Qatar launched genome projects with the aim of providing information for better diagnosis, treatment and prevention of diseases and, ultimately to realize personalized medicine by sequencing hundred thousands samples. These population based genome activities raise a series of relevant ethical, legal and social issues general, related to the specific population structure as well as to the Islamic perspective on genomic analysis and genetic testing. To contribute to the debate, the Authors after reviewing the existing literature and taking advantage of their professional experience in the field and in the geographic area, discuss and provide their opinions. In particular, the Authors focus on the impact of consanguinity on population structure and disease frequency in the Arab world, on genetic testing and genomic analysis (i.e. technical aspects, impact, etc.) and on their regulations. A comparison between the Islamic perspective and the ethical, social and legal issues raised in other population contexts is also carried. In conclusion, this opinion article with an up-to-date contribution to the discussion on the relevance and impact of genomic analysis and genetic testing in the Arab world, might help in producing specific national guidelines on genetic testing and genomic analysis and help accelerate the implementation and roll out of genome projects in Muslim countries and more specifically in Qatar, and other countries of the Gulf.

}, issn = {1479-5876}, doi = {10.1186/s12967-015-0720-9}, author = {El Shanti, Hatem and Chouchane, Lotfi and Badii, Ramin and Gallouzi, Imed Eddine and Gasparini, Paolo} } @article {8083, title = {Genetics of inflammatory bowel disease from multifactorial to monogenic forms.}, journal = {World J Gastroenterol}, volume = {21}, year = {2015}, month = {2015 Nov 21}, pages = {12296-310}, abstract = {

Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn{\textquoteright}s disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in susceptibility to mycobacterium infection (IL12B). In case of early onset of IBD (VEO-IBD) within the 6(th) year of age, the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies.

}, issn = {2219-2840}, doi = {10.3748/wjg.v21.i43.12296}, author = {Bianco, Anna Monica and Girardelli, Martina and Tommasini, Alberto} } @article {8038, title = {Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Nov}, pages = {1272-81}, abstract = {

We report \~{}17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22\% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, \~{}76,000 variants common in our sample (frequency >5\%) are rare elsewhere (<0.5\% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population.

}, issn = {1546-1718}, doi = {10.1038/ng.3368}, author = {Sidore, Carlo and Busonero, Fabio and Maschio, Andrea and Porcu, Eleonora and Naitza, Silvia and Zoledziewska, Magdalena and Mulas, Antonella and Pistis, Giorgio and Steri, Maristella and Danjou, Fabrice and Kwong, Alan and Ortega Del Vecchyo, Vicente Diego and Chiang, Charleston W K and Bragg-Gresham, Jennifer and Pitzalis, Maristella and Nagaraja, Ramaiah and Tarrier, Brendan and Brennan, Christine and Uzzau, Sergio and Fuchsberger, Christian and Atzeni, Rossano and Reinier, Frederic and Berutti, Riccardo and Huang, Jie and Timpson, Nicholas J and Toniolo, Daniela and Gasparini, Paolo and Malerba, Giovanni and Dedoussis, George and Zeggini, Eleftheria and Soranzo, Nicole and Jones, Chris and Lyons, Robert and Angius, Andrea and Kang, Hyun M and Novembre, John and Sanna, Serena and Schlessinger, David and Cucca, Francesco and Abecasis, Goncalo R} } @article {7785, title = {Genome-wide association analysis on five isolated populations identifies variants of the HLA-DOA gene associated with white wine liking.}, journal = {Eur J Hum Genet}, volume = {23}, year = {2015}, month = {2015 Dec}, pages = {1717-22}, abstract = {

Wine is the most popular alcoholic beverage around the world and because of its importance in society has been widely studied. Understanding what drives its flavor has been a quest for decades but much is still unknown and will be determined at least in part by individual taste preferences. Recently studies in the genetics of taste have uncovered the role of different genes in the determination of food preferences giving new insight on its physiology. In this context we have performed a genome-wide association study on red and white wine liking using three isolated populations collected in Italy, and replicated our results on two additional populations coming from the Netherland and Central Asia for a total of 3885 samples. We have found a significant association (P=2.1 {\texttimes} 10(-8)) between white wine liking and rs9276975:C>T a polymorphism in the HLA-DOA gene encoding a non-canonical MHC II molecule, which regulates other MHC II molecules. The same association was also found with red wine liking (P=8.3 {\texttimes} 10(-6)). Sex-separated analysis have also revealed that the effect of HLA-DOA is twice as large in women as compared to men suggesting an interaction between this polymorphism and gender. Our results are one of the first examples of genome-wide association between liking of a commonly consumed food and gene variants. Moreover, our results suggest a role of the MHC system in the determination of food preferences opening new insight in this field in general.

}, issn = {1476-5438}, doi = {10.1038/ejhg.2015.34}, author = {Pirastu, Nicola and Kooyman, Maarten and Traglia, Michela and Robino, Antonietta and Willems, Sara M and Pistis, Giorgio and Amin, Najaf and Sala, Cinzia and Karssen, Lennart C and van Duijn, Cornelia M and Toniolo, Daniela and Gasparini, Paolo} } @article {7720, title = {Genome-wide association analysis on normal hearing function identifies PCDH20 and SLC28A3 as candidates for hearing function and loss.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Oct 1}, pages = {5655-64}, abstract = {

Hearing loss and individual differences in normal hearing both have a substantial genetic basis. Although many new genes contributing to deafness have been identified, very little is known about genes/variants modulating the normal range of hearing ability. To fill this gap, we performed a two-stage meta-analysis on hearing thresholds (tested at 0.25, 0.5, 1, 2, 4, 8 kHz) and on pure-tone averages (low-, medium- and high-frequency thresholds grouped) in several isolated populations from Italy and Central Asia (total N = 2636). Here, we detected two genome-wide significant loci close to PCDH20 and SLC28A3 (top hits: rs78043697, P = 4.71E-10 and rs7032430, P = 2.39E-09, respectively). For both loci, we sought replication in two independent cohorts: B58C from the UK (N = 5892) and FITSA from Finland (N = 270). Both loci were successfully replicated at a nominal level of significance (P < 0.05). In order to confirm our quantitative findings, we carried out RT-PCR and reported RNA-Seq data, which showed that both genes are expressed in mouse inner ear, especially in hair cells, further suggesting them as good candidates for modulatory genes in the auditory system. Sequencing data revealed no functional variants in the coding region of PCDH20 or SLC28A3, suggesting that variation in regulatory sequences may affect expression. Overall, these results contribute to a better understanding of the complex mechanisms underlying human hearing function.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddv279}, author = {Vuckovic, Dragana and Dawson, Sally and Scheffer, Deborah I and Rantanen, Taina and Morgan, Anna and Di Stazio, Mariateresa and Vozzi, Diego and Nutile, Teresa and Concas, Maria P and Biino, Ginevra and Nolan, Lisa and Bahl, Aileen and Loukola, Anu and Viljanen, Anne and Davis, Adrian and Ciullo, Marina and Corey, David P and Pirastu, Mario and Gasparini, Paolo and Girotto, Giorgia} } @article {7700, title = {Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 May}, pages = {535-8}, abstract = {

Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell-precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotypes identified 2 with ETV6 mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.

}, keywords = {Adult, Child, Preschool, DNA Mutational Analysis, Erythrocytes, Abnormal, Exome, Female, Genetic Association Studies, Genetic Predisposition to Disease, Germ-Line Mutation, HEK293 Cells, Hematologic Diseases, Humans, Male, Mutation, Missense, Pedigree, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogene Proteins c-ets, Repressor Proteins, Thrombocytopenia}, issn = {1546-1718}, doi = {10.1038/ng.3253}, author = {Noetzli, Leila and Lo, Richard W and Lee-Sherick, Alisa B and Callaghan, Michael and Noris, Patrizia and Savoia, Anna and Rajpurkar, Madhvi and Jones, Kenneth and Gowan, Katherine and Balduini, Carlo L and Pecci, Alessandro and Gnan, Chiara and De Rocco, Daniela and Doubek, Michael and Li, Ling and Lu, Lily and Leung, Richard and Landolt-Marticorena, Carolina and Hunger, Stephen and Heller, Paula and Gutierrez-Hartmann, Arthur and Xiayuan, Liang and Pluthero, Fred G and Rowley, Jesse W and Weyrich, Andrew S and Kahr, Walter H A and Porter, Christopher C and Di Paola, Jorge} } @article {7723, title = {The Global Burden of Cancer 2013.}, journal = {JAMA Oncol}, volume = {1}, year = {2015}, month = {2015 Jul}, pages = {505-27}, abstract = {

IMPORTANCE: Cancer is among the leading causes of death worldwide. Current estimates of cancer burden in individual countries and regions are necessary to inform local cancer control strategies.

OBJECTIVE: To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 28 cancers in 188 countries by sex from 1990 to 2013.

EVIDENCE REVIEW: The general methodology of the Global Burden of Disease (GBD) 2013 study was used. Cancer registries were the source for cancer incidence data as well as mortality incidence (MI) ratios. Sources for cause of death data include vital registration system data, verbal autopsy studies, and other sources. The MI ratios were used to transform incidence data to mortality estimates and cause of death estimates to incidence estimates. Cancer prevalence was estimated using MI ratios as surrogates for survival data; YLDs were calculated by multiplying prevalence estimates with disability weights, which were derived from population-based surveys; YLLs were computed by multiplying the number of estimated cancer deaths at each age with a reference life expectancy; and DALYs were calculated as the sum of YLDs and YLLs.

FINDINGS: In 2013 there were 14.9 million incident cancer cases, 8.2 million deaths, and 196.3 million DALYs. Prostate cancer was the leading cause for cancer incidence (1.4 million) for men and breast cancer for women (1.8 million). Tracheal, bronchus, and lung (TBL) cancer was the leading cause for cancer death in men and women, with 1.6 million deaths. For men, TBL cancer was the leading cause of DALYs (24.9 million). For women, breast cancer was the leading cause of DALYs (13.1 million). Age-standardized incidence rates (ASIRs) per 100 000 and age-standardized death rates (ASDRs) per 100 000 for both sexes in 2013 were higher in developing vs developed countries for stomach cancer (ASIR, 17 vs 14; ASDR, 15 vs 11), liver cancer (ASIR, 15 vs 7; ASDR, 16 vs 7), esophageal cancer (ASIR, 9 vs 4; ASDR, 9 vs 4), cervical cancer (ASIR, 8 vs 5; ASDR, 4 vs 2), lip and oral cavity cancer (ASIR, 7 vs 6; ASDR, 2 vs 2), and nasopharyngeal cancer (ASIR, 1.5 vs 0.4; ASDR, 1.2 vs 0.3). Between 1990 and 2013, ASIRs for all cancers combined (except nonmelanoma skin cancer and Kaposi sarcoma) increased by more than 10\% in 113 countries and decreased by more than 10\% in 12 of 188 countries.

CONCLUSIONS AND RELEVANCE: Cancer poses a major threat to public health worldwide, and incidence rates have increased in most countries since 1990. The trend is a particular threat to developing nations with health systems that are ill-equipped to deal with complex and expensive cancer treatments. The annual update on the Global Burden of Cancer will provide all stakeholders with timely estimates to guide policy efforts in cancer prevention, screening, treatment, and palliation.

}, issn = {2374-2445}, doi = {10.1001/jamaoncol.2015.0735}, author = {Fitzmaurice, Christina and Dicker, Daniel and Pain, Amanda and Hamavid, Hannah and Moradi-Lakeh, Maziar and MacIntyre, Michael F and Allen, Christine and Hansen, Gillian and Woodbrook, Rachel and Wolfe, Charles and Hamadeh, Randah R and Moore, Ami and Werdecker, Andrea and Gessner, Bradford D and Te Ao, Braden and McMahon, Brian and Karimkhani, Chante and Yu, Chuanhua and Cooke, Graham S and Schwebel, David C and Carpenter, David O and Pereira, David M and Nash, Denis and Kazi, Dhruv S and De Leo, Diego and Plass, Dietrich and Ukwaja, Kingsley N and Thurston, George D and Yun Jin, Kim and Simard, Edgar P and Mills, Edward and Park, Eun-Kee and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and deVeber, Gabrielle and Gotay, Carolyn and Khan, Gulfaraz and Hosgood, H Dean and Santos, Itamar S and Leasher, Janet L and Singh, Jasvinder and Leigh, James and Jonas, Jost and Sanabria, Juan and Beardsley, Justin and Jacobsen, Kathryn H and Takahashi, Ken and Franklin, Richard C and Ronfani, Luca and Montico, Marcella and Naldi, Luigi and Tonelli, Marcello and Geleijnse, Johanna and Petzold, Max and Shrime, Mark G and Younis, Mustafa and Yonemoto, Naohiro and Breitborde, Nicholas and Yip, Paul and Pourmalek, Farshad and Lotufo, Paulo A and Esteghamati, Alireza and Hankey, Graeme J and Ali, Raghib and Lunevicius, Raimundas and Malekzadeh, Reza and Dellavalle, Robert and Weintraub, Robert and Lucas, Robyn and Hay, Roderick and Rojas-Rueda, David and Westerman, Ronny and Sepanlou, Sadaf G and Nolte, Sandra and Patten, Scott and Weichenthal, Scott and Abera, Semaw Ferede and Fereshtehnejad, Seyed-Mohammad and Shiue, Ivy and Driscoll, Tim and Vasankari, Tommi and Alsharif, Ubai and Rahimi-Movaghar, Vafa and Vlassov, Vasiliy V and Marcenes, W S and Mekonnen, Wubegzier and Melaku, Yohannes Adama and Yano, Yuichiro and Artaman, Al and Campos, Ismael and MacLachlan, Jennifer and Mueller, Ulrich and Kim, Daniel and Trillini, Matias and Eshrati, Babak and Williams, Hywel C and Shibuya, Kenji and Dandona, Rakhi and Murthy, Kinnari and Cowie, Benjamin and Amare, Azmeraw T and Antonio, Carl Abelardo and Casta{\~n}eda-Orjuela, Carlos and van Gool, Coen H and Violante, Francesco and Oh, In-Hwan and Deribe, Kedede and Soreide, Kjetil and Knibbs, Luke and Kereselidze, Maia and Green, Mark and C{\'a}rdenas, Rosario and Roy, Nobhojit and Tillman, Taavi and Li, Yongmei and Krueger, Hans and Monasta, Lorenzo and Dey, Subhojit and Sheikhbahaei, Sara and Hafezi-Nejad, Nima and Kumar, G Anil and Sreeramareddy, Chandrashekhar T and Dandona, Lalit and Wang, Haidong and Vollset, Stein Emil and Mokdad, Ali and Salomon, Joshua A and Lozano, Rafael and Vos, Theo and Forouzanfar, Mohammad and Lopez, Alan and Murray, Christopher and Naghavi, Mohsen} } @article {3638, title = {Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.}, journal = {Lancet}, volume = {385}, year = {2015}, month = {2015 Jan 10}, pages = {117-71}, abstract = {

BACKGROUND: Up-to-date evidence on levels and trends for age-sex-specific all-cause and cause-specific mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries.

METHODS: We estimated age-sex-specific all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer{\textquoteright}s disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specific causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95\% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions.

FINDINGS: Global life expectancy for both sexes increased from 65.3 years (UI 65.0-65.6) in 1990, to 71.5 years (UI 71.0-71.9) in 2013, while the number of deaths increased from 47.5 million (UI 46.8-48.2) to 54.9 million (UI 53.6-56.3) over the same interval. Global progress masked variation by age and sex: for children, average absolute differences between countries decreased but relative differences increased. For women aged 25-39 years and older than 75 years and for men aged 20-49 years and 65 years and older, both absolute and relative differences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10.7\%, from 4.3 million deaths in 1990 to 4.8 million in 2013; but age-standardised rates declined over the same period by 21\%. For some causes of more than 100,000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions.

INTERPRETATION: For most countries, the general pattern of reductions in age-sex specific mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Cause of Death, Child, Child Mortality, Child, Preschool, Databases, Factual, Female, Global Health, Humans, Infant, Infant, Newborn, Life Expectancy, Life Tables, Male, Middle Aged, Models, Statistical, Mortality, Sex Distribution, Young Adult}, issn = {1474-547X}, doi = {10.1016/S0140-6736(14)61682-2} } @article {8043, title = {Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.}, journal = {Lancet}, volume = {386}, year = {2015}, month = {2015 Dec 5}, pages = {2287-323}, abstract = {

BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.

METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol.

FINDINGS: All risks combined account for 57{\textperiodcentered}2\% (95\% uncertainty interval [UI] 55{\textperiodcentered}8-58{\textperiodcentered}5) of deaths and 41{\textperiodcentered}6\% (40{\textperiodcentered}1-43{\textperiodcentered}0) of DALYs. Risks quantified account for 87{\textperiodcentered}9\% (86{\textperiodcentered}5-89{\textperiodcentered}3) of cardiovascular disease DALYs, ranging to a low of 0\% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5\% of DALYs: dietary risks accounting for 11{\textperiodcentered}3 million deaths and 241{\textperiodcentered}4 million DALYs, high systolic blood pressure for 10{\textperiodcentered}4 million deaths and 208{\textperiodcentered}1 million DALYs, child and maternal malnutrition for 1{\textperiodcentered}7 million deaths and 176{\textperiodcentered}9 million DALYs, tobacco smoke for 6{\textperiodcentered}1 million deaths and 143{\textperiodcentered}5 million DALYs, air pollution for 5{\textperiodcentered}5 million deaths and 141{\textperiodcentered}5 million DALYs, and high BMI for 4{\textperiodcentered}4 million deaths and 134{\textperiodcentered}0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa.

INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.

FUNDING: Bill \& Melinda Gates Foundation.

}, issn = {1474-547X}, doi = {10.1016/S0140-6736(15)00128-2}, author = {Forouzanfar, Mohammad H and Alexander, Lily and Anderson, H Ross and Bachman, Victoria F and Biryukov, Stan and Brauer, Michael and Burnett, Richard and Casey, Daniel and Coates, Matthew M and Cohen, Aaron and Delwiche, Kristen and Estep, Kara and Frostad, Joseph J and Astha, K C and Kyu, Hmwe H and Moradi-Lakeh, Maziar and Ng, Marie and Slepak, Erica Leigh and Thomas, Bernadette A and Wagner, Joseph and Aasvang, Gunn Marit and Abbafati, Cristiana and Abbasoglu Ozgoren, Ayse and Abd-Allah, Foad and Abera, Semaw F and Aboyans, Victor and Abraham, Biju and Abraham, Jerry Puthenpurakal and Abubakar, Ibrahim and Abu-Rmeileh, Niveen M E and Aburto, Tania C and Achoki, Tom and Adelekan, Ademola and Adofo, Koranteng and Adou, Ars{\`e}ne K and Adsuar, Jos{\'e} C and Afshin, Ashkan and Agardh, Emilie E and Al Khabouri, Mazin J and Al Lami, Faris H and Alam, Sayed Saidul and Alasfoor, Deena and Albittar, Mohammed I and Alegretti, Miguel A and Aleman, Alicia V and Alemu, Zewdie A and Alfonso-Cristancho, Rafael and Alhabib, Samia and Ali, Raghib and Ali, Mohammed K and Alla, Fran{\c c}ois and Allebeck, Peter and Allen, Peter J and Alsharif, Ubai and Alvarez, Elena and Alvis-Guzm{\'a}n, Nelson and Amankwaa, Adansi A and Amare, Azmeraw T and Ameh, Emmanuel A and Ameli, Omid and Amini, Heresh and Ammar, Walid and Anderson, Benjamin O and Antonio, Carl Abelardo T and Anwari, Palwasha and Argeseanu Cunningham, Solveig and Arnl{\"o}v, Johan and Arsenijevic, Valentina S Arsic and Artaman, Al and Asghar, Rana J and Assadi, Reza and Atkins, Lydia S and Atkinson, Charles and Avila, Marco A and Awuah, Baffour and Badawi, Alaa and Bahit, Maria C and Bakfalouni, Talal and Balakrishnan, Kalpana and Balalla, Shivanthi and Balu, Ravi Kumar and Banerjee, Amitava and Barber, Ryan M and Barker-Collo, Suzanne L and Barquera, Simon and Barregard, Lars and Barrero, Lope H and Barrientos-Gutierrez, Tonatiuh and Basto-Abreu, Ana C and Basu, Arindam and Basu, Sanjay and Basulaiman, Mohammed O and Batis Ruvalcaba, Carolina and Beardsley, Justin and Bedi, Neeraj and Bekele, Tolesa and Bell, Michelle L and Benjet, Corina and Bennett, Derrick A and Benzian, Habib and Bernabe, Eduardo and Beyene, Tariku J and Bhala, Neeraj and Bhalla, Ashish and Bhutta, Zulfiqar A and Bikbov, Boris and Bin Abdulhak, Aref A and Blore, Jed D and Blyth, Fiona M and Bohensky, Megan A and Bora Ba{\c s}ara, Berrak and Borges, Guilherme and Bornstein, Natan M and Bose, Dipan and Boufous, Soufiane and Bourne, Rupert R and Brainin, Michael and Brazinova, Alexandra and Breitborde, Nicholas J and Brenner, Hermann and Briggs, Adam D M and Broday, David M and Brooks, Peter M and Bruce, Nigel G and Brugha, Traolach S and Brunekreef, Bert and Buchbinder, Rachelle and Bui, Linh N and Bukhman, Gene and Bulloch, Andrew G and Burch, Michael and Burney, Peter G J and Campos-Nonato, Ismael R and Campuzano, Julio C and Cantoral, Alejandra J and Caravanos, Jack and C{\'a}rdenas, Rosario and Cardis, Elisabeth and Carpenter, David O and Caso, Valeria and Casta{\~n}eda-Orjuela, Carlos A and Castro, Ruben E and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and Cavalleri, Fiorella and Cavlin, Alanur and Chadha, Vineet K and Chang, Jung-Chen and Charlson, Fiona J and Chen, Honglei and Chen, Wanqing and Chen, Zhengming and Chiang, Peggy P and Chimed-Ochir, Odgerel and Chowdhury, Rajiv and Christophi, Costas A and Chuang, Ting-Wu and Chugh, Sumeet S and Cirillo, Massimo and Cla{\ss}en, Thomas K D and Colistro, Valentina and Colomar, Mercedes and Colquhoun, Samantha M and Contreras, Alejandra G and Cooper, Cyrus and Cooperrider, Kimberly and Cooper, Leslie T and Coresh, Josef and Courville, Karen J and Criqui, Michael H and Cuevas-Nasu, Lucia and Damsere-Derry, James and Danawi, Hadi and Dandona, Lalit and Dandona, Rakhi and Dargan, Paul I and Davis, Adrian and Davitoiu, Dragos V and Dayama, Anand and de Castro, E Filipa and De la Cruz-G{\'o}ngora, Vanessa and De Leo, Diego and de Lima, Gra{\c c}a and Degenhardt, Louisa and del Pozo-Cruz, Borja and Dellavalle, Robert P and Deribe, Kebede and Derrett, Sarah and Des Jarlais, Don C and Dessalegn, Muluken and deVeber, Gabrielle A and Devries, Karen M and Dharmaratne, Samath D and Dherani, Mukesh K and Dicker, Daniel and Ding, Eric L and Dokova, Klara and Dorsey, E Ray and Driscoll, Tim R and Duan, Leilei and Durrani, Adnan M and Ebel, Beth E and Ellenbogen, Richard G and Elshrek, Yousef M and Endres, Matthias and Ermakov, Sergey P and Erskine, Holly E and Eshrati, Babak and Esteghamati, Alireza and Fahimi, Saman and Faraon, Emerito Jose A and Farzadfar, Farshad and Fay, Derek F J and Feigin, Valery L and Feigl, Andrea B and Fereshtehnejad, Seyed-Mohammad and Ferrari, Alize J and Ferri, Cleusa P and Flaxman, Abraham D and Fleming, Thomas D and Foigt, Nataliya and Foreman, Kyle J and Paleo, Urbano Fra and Franklin, Richard C and Gabbe, Belinda and Gaffikin, Lynne and Gakidou, Emmanuela and Gamkrelidze, Amiran and Gankp{\'e}, Fortun{\'e} G and Gansevoort, Ron T and Garc{\'\i}a-Guerra, Francisco A and Gasana, Evariste and Geleijnse, Johanna M and Gessner, Bradford D and Gething, Pete and Gibney, Katherine B and Gillum, Richard F and Ginawi, Ibrahim A M and Giroud, Maurice and Giussani, Giorgia and Goenka, Shifalika and Goginashvili, Ketevan and Gomez Dantes, Hector and Gona, Philimon and Gonzalez de Cosio, Teresita and Gonz{\'a}lez-Castell, Dinorah and Gotay, Carolyn C and Goto, Atsushi and Gouda, Hebe N and Guerrant, Richard L and Gugnani, Harish C and Guillemin, Francis and Gunnell, David and Gupta, Rahul and Gupta, Rajeev and Guti{\'e}rrez, Reyna A and Hafezi-Nejad, Nima and Hagan, Holly and Hagstromer, Maria and Halasa, Yara A and Hamadeh, Randah R and Hammami, Mouhanad and Hankey, Graeme J and Hao, Yuantao and Harb, Hilda L and Haregu, Tilahun Nigatu and Haro, Josep Maria and Havmoeller, Rasmus and Hay, Simon I and Hedayati, Mohammad T and Heredia-Pi, Ileana B and Hernandez, Lucia and Heuton, Kyle R and Heydarpour, Pouria and Hijar, Martha and Hoek, Hans W and Hoffman, Howard J and Hornberger, John C and Hosgood, H Dean and Hoy, Damian G and Hsairi, Mohamed and Hu, Guoqing and Hu, Howard and Huang, Cheng and Huang, John J and Hubbell, Bryan J and Huiart, Laetitia and Husseini, Abdullatif and Iannarone, Marissa L and Iburg, Kim M and Idrisov, Bulat T and Ikeda, Nayu and Innos, Kaire and Inoue, Manami and Islami, Farhad and Ismayilova, Samaya and Jacobsen, Kathryn H and Jansen, Henrica A and Jarvis, Deborah L and Jassal, Simerjot K and Jauregui, Alejandra and Jayaraman, Sudha and Jeemon, Panniyammakal and Jensen, Paul N and Jha, Vivekanand and Jiang, Fan and Jiang, Guohong and Jiang, Ying and Jonas, Jost B and Juel, Knud and Kan, Haidong and Kany Roseline, Sidibe S and Karam, Nadim E and Karch, Andr{\'e} and Karema, Corine K and Karthikeyan, Ganesan and Kaul, Anil and Kawakami, Norito and Kazi, Dhruv S and Kemp, Andrew H and Kengne, Andre P and Keren, Andre and Khader, Yousef S and Khalifa, Shams Eldin Ali Hassan and Khan, Ejaz A and Khang, Young-Ho and Khatibzadeh, Shahab and Khonelidze, Irma and Kieling, Christian and Kim, Daniel and Kim, Sungroul and Kim, Yunjin and Kimokoti, Ruth W and Kinfu, Yohannes and Kinge, Jonas M and Kissela, Brett M and Kivipelto, Miia and Knibbs, Luke D and Knudsen, Ann Kristin and Kokubo, Yoshihiro and Kose, M Rifat and Kosen, Soewarta and Kraemer, Alexander and Kravchenko, Michael and Krishnaswami, Sanjay and Kromhout, Hans and Ku, Tiffany and Kuate Defo, Barthelemy and Kucuk Bicer, Burcu and Kuipers, Ernst J and Kulkarni, Chanda and Kulkarni, Veena S and Kumar, G Anil and Kwan, Gene F and Lai, Taavi and Lakshmana Balaji, Arjun and Lalloo, Ratilal and Lallukka, Tea and Lam, Hilton and Lan, Qing and Lansingh, Van C and Larson, Heidi J and Larsson, Anders and Laryea, Dennis O and Lavados, Pablo M and Lawrynowicz, Alicia E and Leasher, Janet L and Lee, Jong-Tae and Leigh, James and Leung, Ricky and Levi, Miriam and Li, Yichong and Li, Yongmei and Liang, Juan and Liang, Xiaofeng and Lim, Stephen S and Lindsay, M Patrice and Lipshultz, Steven E and Liu, Shiwei and Liu, Yang and Lloyd, Belinda K and Logroscino, Giancarlo and London, Stephanie J and Lopez, Nancy and Lortet-Tieulent, Joannie and Lotufo, Paulo A and Lozano, Rafael and Lunevicius, Raimundas and Ma, Jixiang and Ma, Stefan and Machado, Vasco M P and MacIntyre, Michael F and Magis-Rodriguez, Carlos and Mahdi, Abbas A and Majdan, Marek and Malekzadeh, Reza and Mangalam, Srikanth and Mapoma, Christopher C and Marape, Marape and Marcenes, Wagner and Margolis, David J and Margono, Christopher and Marks, Guy B and Martin, Randall V and Marzan, Melvin B and Mashal, Mohammad T and Masiye, Felix and Mason-Jones, Amanda J and Matsushita, Kunihiro and Matzopoulos, Richard and Mayosi, Bongani M and Mazorodze, Tasara T and McKay, Abigail C and McKee, Martin and McLain, Abigail and Meaney, Peter A and Medina, Catalina and Mehndiratta, Man Mohan and Mejia-Rodriguez, Fabiola and Mekonnen, Wubegzier and Melaku, Yohannes A and Meltzer, Michele and Memish, Ziad A and Mendoza, Walter and Mensah, George A and Meretoja, Atte and Mhimbira, Francis Apolinary and Micha, Renata and Miller, Ted R and Mills, Edward J and Misganaw, Awoke and Mishra, Santosh and Mohamed Ibrahim, Norlinah and Mohammad, Karzan A and Mokdad, Ali H and Mola, Glen L and Monasta, Lorenzo and Monta{\~n}ez Hernandez, Julio C and Montico, Marcella and Moore, Ami R and Morawska, Lidia and Mori, Rintaro and Moschandreas, Joanna and Moturi, Wilkister N and Mozaffarian, Dariush and Mueller, Ulrich O and Mukaigawara, Mitsuru and Mullany, Erin C and Murthy, Kinnari S and Naghavi, Mohsen and Nahas, Ziad and Naheed, Aliya and Naidoo, Kovin S and Naldi, Luigi and Nand, Devina and Nangia, Vinay and Narayan, K M Venkat and Nash, Denis and Neal, Bruce and Nejjari, Chakib and Neupane, Sudan P and Newton, Charles R and Ngalesoni, Frida N and Ngirabega, Jean de Dieu and Nguyen, Grant and Nguyen, Nhung T and Nieuwenhuijsen, Mark J and Nisar, Muhammad I and Nogueira, Jos{\'e} R and Nolla, Joan M and Nolte, Sandra and Norheim, Ole F and Norman, Rosana E and Norrving, Bo and Nyakarahuka, Luke and Oh, In-Hwan and Ohkubo, Takayoshi and Olusanya, Bolajoko O and Omer, Saad B and Opio, John Nelson and Orozco, Ricardo and Pagcatipunan, Rodolfo S and Pain, Amanda W and Pandian, Jeyaraj D and Panelo, Carlo Irwin A and Papachristou, Christina and Park, Eun-Kee and Parry, Charles D and Paternina Caicedo, Angel J and Patten, Scott B and Paul, Vinod K and Pavlin, Boris I and Pearce, Neil and Pedraza, Lilia S and Pedroza, Andrea and Pejin Stokic, Ljiljana and Pekericli, Ayfer and Pereira, David M and Perez-Padilla, Rogelio and Perez-Ruiz, Fernando and Perico, Norberto and Perry, Samuel A L and Pervaiz, Aslam and Pesudovs, Konrad and Peterson, Carrie B and Petzold, Max and Phillips, Michael R and Phua, Hwee Pin and Plass, Dietrich and Poenaru, Dan and Polanczyk, Guilherme V and Polinder, Suzanne and Pond, Constance D and Pope, C Arden and Pope, Daniel and Popova, Svetlana and Pourmalek, Farshad and Powles, John and Prabhakaran, Dorairaj and Prasad, Noela M and Qato, Dima M and Quezada, Amado D and Quistberg, D Alex A and Racap{\'e}, Lionel and Rafay, Anwar and Rahimi, Kazem and Rahimi-Movaghar, Vafa and Rahman, Sajjad Ur and Raju, Murugesan and Rakovac, Ivo and Rana, Saleem M and Rao, Mayuree and Razavi, Homie and Reddy, K Srinath and Refaat, Amany H and Rehm, J{\"u}rgen and Remuzzi, Giuseppe and Ribeiro, Antonio L and Riccio, Patricia M and Richardson, Lee and Riederer, Anne and Robinson, Margaret and Roca, Anna and Rodriguez, Alina and Rojas-Rueda, David and Romieu, Isabelle and Ronfani, Luca and Room, Robin and Roy, Nobhojit and Ruhago, George M and Rushton, Lesley and Sabin, Nsanzimana and Sacco, Ralph L and Saha, Sukanta and Sahathevan, Ramesh and Sahraian, Mohammad Ali and Salomon, Joshua A and Salvo, Deborah and Sampson, Uchechukwu K and Sanabria, Juan R and Sanchez, Luz Maria and S{\'a}nchez-Pimienta, Tania G and Sanchez-Riera, Lidia and Sandar, Logan and Santos, Itamar S and Sapkota, Amir and Satpathy, Maheswar and Saunders, James E and Sawhney, Monika and Saylan, Mete I and Scarborough, Peter and Schmidt, J{\"u}rgen C and Schneider, Ione J C and Sch{\"o}ttker, Ben and Schwebel, David C and Scott, James G and Seedat, Soraya and Sepanlou, Sadaf G and Serdar, Berrin and Servan-Mori, Edson E and Shaddick, Gavin and Shahraz, Saeid and Levy, Teresa Shamah and Shangguan, Siyi and She, Jun and Sheikhbahaei, Sara and Shibuya, Kenji and Shin, Hwashin H and Shinohara, Yukito and Shiri, Rahman and Shishani, Kawkab and Shiue, Ivy and Sigfusdottir, Inga D and Silberberg, Donald H and Simard, Edgar P and Sindi, Shireen and Singh, Abhishek and Singh, Gitanjali M and Singh, Jasvinder A and Skirbekk, Vegard and Sliwa, Karen and Soljak, Michael and Soneji, Samir and S{\o}reide, Kjetil and Soshnikov, Sergey and Sposato, Luciano A and Sreeramareddy, Chandrashekhar T and Stapelberg, Nicolas J C and Stathopoulou, Vasiliki and Steckling, Nadine and Stein, Dan J and Stein, Murray B and Stephens, Natalie and St{\"o}ckl, Heidi and Straif, Kurt and Stroumpoulis, Konstantinos and Sturua, Lela and Sunguya, Bruno F and Swaminathan, Soumya and Swaroop, Mamta and Sykes, Bryan L and Tabb, Karen M and Takahashi, Ken and Talongwa, Roberto T and Tandon, Nikhil and Tanne, David and Tanner, Marcel and Tavakkoli, Mohammad and Te Ao, Braden J and Teixeira, Carolina M and T{\'e}llez Rojo, Martha M and Terkawi, Abdullah S and Texcalac-Sangrador, Jos{\'e} Luis and Thackway, Sarah V and Thomson, Blake and Thorne-Lyman, Andrew L and Thrift, Amanda G and Thurston, George D and Tillmann, Taavi and Tobollik, Myriam and Tonelli, Marcello and Topouzis, Fotis and Towbin, Jeffrey A and Toyoshima, Hideaki and Traebert, Jefferson and Tran, Bach X and Trasande, Leonardo and Trillini, Matias and Trujillo, Ulises and Dimbuene, Zacharie Tsala and Tsilimbaris, Miltiadis and Tuzcu, Emin Murat and Uchendu, Uche S and Ukwaja, Kingsley N and Uzun, Selen B and van de Vijver, Steven and Van Dingenen, Rita and van Gool, Coen H and van Os, Jim and Varakin, Yuri Y and Vasankari, Tommi J and Vasconcelos, Ana Maria N and Vavilala, Monica S and Veerman, Lennert J and Velasquez-Melendez, Gustavo and Venketasubramanian, N and Vijayakumar, Lakshmi and Villalpando, Salvador and Violante, Francesco S and Vlassov, Vasiliy Victorovich and Vollset, Stein Emil and Wagner, Gregory R and Waller, Stephen G and Wallin, Mitchell T and Wan, Xia and Wang, Haidong and Wang, JianLi and Wang, Linhong and Wang, Wenzhi and Wang, Yanping and Warouw, Tati S and Watts, Charlotte H and Weichenthal, Scott and Weiderpass, Elisabete and Weintraub, Robert G and Werdecker, Andrea and Wessells, K Ryan and Westerman, Ronny and Whiteford, Harvey A and Wilkinson, James D and Williams, Hywel C and Williams, Thomas N and Woldeyohannes, Solomon M and Wolfe, Charles D A and Wong, John Q and Woolf, Anthony D and Wright, Jonathan L and Wurtz, Brittany and Xu, Gelin and Yan, Lijing L and Yang, Gonghuan and Yano, Yuichiro and Ye, Pengpeng and Yenesew, Muluken and Yent{\"u}r, G{\"o}kalp K and Yip, Paul and Yonemoto, Naohiro and Yoon, Seok-Jun and Younis, Mustafa Z and Younoussi, Zourkaleini and Yu, Chuanhua and Zaki, Maysaa E and Zhao, Yong and Zheng, Yingfeng and Zhou, Maigeng and Zhu, Jun and Zhu, Shankuan and Zou, Xiaonong and Zunt, Joseph R and Lopez, Alan D and Vos, Theo and Murray, Christopher J} } @article {8044, title = {Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition.}, journal = {Lancet}, volume = {386}, year = {2015}, month = {2015 Nov 28}, pages = {2145-91}, abstract = {

BACKGROUND: The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age-sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development.

METHODS: We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95\% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95\% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time.

FINDINGS: Worldwide, from 1990 to 2013, life expectancy at birth rose by 6{\textperiodcentered}2 years (95\% UI 5{\textperiodcentered}6-6{\textperiodcentered}6), from 65{\textperiodcentered}3 years (65{\textperiodcentered}0-65{\textperiodcentered}6) in 1990 to 71{\textperiodcentered}5 years (71{\textperiodcentered}0-71{\textperiodcentered}9) in 2013, HALE at birth rose by 5{\textperiodcentered}4 years (4{\textperiodcentered}9-5{\textperiodcentered}8), from 56{\textperiodcentered}9 years (54{\textperiodcentered}5-59{\textperiodcentered}1) to 62{\textperiodcentered}3 years (59{\textperiodcentered}7-64{\textperiodcentered}8), total DALYs fell by 3{\textperiodcentered}6\% (0{\textperiodcentered}3-7{\textperiodcentered}4), and age-standardised DALY rates per 100 000 people fell by 26{\textperiodcentered}7\% (24{\textperiodcentered}6-29{\textperiodcentered}1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non-communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50\% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10\% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries.

INTERPRETATION: Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition--in which increasing sociodemographic status brings structured change in disease burden--is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Aged, Chronic Disease, Communicable Diseases, Female, Global Health, Health Transition, Humans, Life Expectancy, Male, Middle Aged, Mortality, Premature, Quality-Adjusted Life Years, Socioeconomic Factors, Wounds and Injuries}, issn = {1474-547X}, doi = {10.1016/S0140-6736(15)61340-X}, author = {Murray, Christopher J L and Barber, Ryan M and Foreman, Kyle J and Abbasoglu Ozgoren, Ayse and Abd-Allah, Foad and Abera, Semaw F and Aboyans, Victor and Abraham, Jerry P and Abubakar, Ibrahim and Abu-Raddad, Laith J and Abu-Rmeileh, Niveen M and Achoki, Tom and Ackerman, Ilana N and Ademi, Zanfina and Adou, Ars{\`e}ne K and Adsuar, Jos{\'e} C and Afshin, Ashkan and Agardh, Emilie E and Alam, Sayed Saidul and Alasfoor, Deena and Albittar, Mohammed I and Alegretti, Miguel A and Alemu, Zewdie A and Alfonso-Cristancho, Rafael and Alhabib, Samia and Ali, Raghib and Alla, Fran{\c c}ois and Allebeck, Peter and AlMazroa, Mohammad A and Alsharif, Ubai and Alvarez, Elena and Alvis-Guzm{\'a}n, Nelson and Amare, Azmeraw T and Ameh, Emmanuel A and Amini, Heresh and Ammar, Walid and Anderson, H Ross and Anderson, Benjamin O and Antonio, Carl Abelardo T and Anwari, Palwasha and Arnl{\"o}v, Johan and Arsic Arsenijevic, Valentina S and Artaman, Al and Asghar, Rana J and Assadi, Reza and Atkins, Lydia S and Avila, Marco A and Awuah, Baffour and Bachman, Victoria F and Badawi, Alaa and Bahit, Maria C and Balakrishnan, Kalpana and Banerjee, Amitava and Barker-Collo, Suzanne L and Barquera, Simon and Barregard, Lars and Barrero, Lope H and Basu, Arindam and Basu, Sanjay and Basulaiman, Mohammed O and Beardsley, Justin and Bedi, Neeraj and Beghi, Ettore and Bekele, Tolesa and Bell, Michelle L and Benjet, Corina and Bennett, Derrick A and Bensenor, Isabela M and Benzian, Habib and Bernabe, Eduardo and Bertozzi-Villa, Amelia and Beyene, Tariku J and Bhala, Neeraj and Bhalla, Ashish and Bhutta, Zulfiqar A and Bienhoff, Kelly and Bikbov, Boris and Biryukov, Stan and Blore, Jed D and Blosser, Christopher D and Blyth, Fiona M and Bohensky, Megan A and Bolliger, Ian W and Bora Ba{\c s}ara, Berrak and Bornstein, Natan M and Bose, Dipan and Boufous, Soufiane and Bourne, Rupert R A and Boyers, Lindsay N and Brainin, Michael and Brayne, Carol E and Brazinova, Alexandra and Breitborde, Nicholas J K and Brenner, Hermann and Briggs, Adam D and Brooks, Peter M and Brown, Jonathan C and Brugha, Traolach S and Buchbinder, Rachelle and Buckle, Geoffrey C and Budke, Christine M and Bulchis, Anne and Bulloch, Andrew G and Campos-Nonato, Ismael R and Carabin, H{\'e}l{\`e}ne and Carapetis, Jonathan R and C{\'a}rdenas, Rosario and Carpenter, David O and Caso, Valeria and Casta{\~n}eda-Orjuela, Carlos A and Castro, Ruben E and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and Cavalleri, Fiorella and Cavlin, Alanur and Chadha, Vineet K and Chang, Jung-Chen and Charlson, Fiona J and Chen, Honglei and Chen, Wanqing and Chiang, Peggy P and Chimed-Ochir, Odgerel and Chowdhury, Rajiv and Christensen, Hanne and Christophi, Costas A and Cirillo, Massimo and Coates, Matthew M and Coffeng, Luc E and Coggeshall, Megan S and Colistro, Valentina and Colquhoun, Samantha M and Cooke, Graham S and Cooper, Cyrus and Cooper, Leslie T and Coppola, Luis M and Cortinovis, Monica and Criqui, Michael H and Crump, John A and Cuevas-Nasu, Lucia and Danawi, Hadi and Dandona, Lalit and Dandona, Rakhi and Dansereau, Emily and Dargan, Paul I and Davey, Gail and Davis, Adrian and Davitoiu, Dragos V and Dayama, Anand and De Leo, Diego and Degenhardt, Louisa and del Pozo-Cruz, Borja and Dellavalle, Robert P and Deribe, Kebede and Derrett, Sarah and Des Jarlais, Don C and Dessalegn, Muluken and Dharmaratne, Samath D and Dherani, Mukesh K and Diaz-Torn{\'e}, Cesar and Dicker, Daniel and Ding, Eric L and Dokova, Klara and Dorsey, E Ray and Driscoll, Tim R and Duan, Leilei and Duber, Herbert C and Ebel, Beth E and Edmond, Karen M and Elshrek, Yousef M and Endres, Matthias and Ermakov, Sergey P and Erskine, Holly E and Eshrati, Babak and Esteghamati, Alireza and Estep, Kara and Faraon, Emerito Jose A and Farzadfar, Farshad and Fay, Derek F and Feigin, Valery L and Felson, David T and Fereshtehnejad, Seyed-Mohammad and Fernandes, Jefferson G and Ferrari, Alize J and Fitzmaurice, Christina and Flaxman, Abraham D and Fleming, Thomas D and Foigt, Nataliya and Forouzanfar, Mohammad H and Fowkes, F Gerry R and Paleo, Urbano Fra and Franklin, Richard C and F{\"u}rst, Thomas and Gabbe, Belinda and Gaffikin, Lynne and Gankp{\'e}, Fortun{\'e} G and Geleijnse, Johanna M and Gessner, Bradford D and Gething, Peter and Gibney, Katherine B and Giroud, Maurice and Giussani, Giorgia and Gomez Dantes, Hector and Gona, Philimon and Gonzalez-Medina, Diego and Gosselin, Richard A and Gotay, Carolyn C and Goto, Atsushi and Gouda, Hebe N and Graetz, Nicholas and Gugnani, Harish C and Gupta, Rahul and Gupta, Rajeev and Guti{\'e}rrez, Reyna A and Haagsma, Juanita and Hafezi-Nejad, Nima and Hagan, Holly and Halasa, Yara A and Hamadeh, Randah R and Hamavid, Hannah and Hammami, Mouhanad and Hancock, Jamie and Hankey, Graeme J and Hansen, Gillian M and Hao, Yuantao and Harb, Hilda L and Haro, Josep Maria and Havmoeller, Rasmus and Hay, Simon I and Hay, Roderick J and Heredia-Pi, Ileana B and Heuton, Kyle R and Heydarpour, Pouria and Higashi, Hideki and Hijar, Martha and Hoek, Hans W and Hoffman, Howard J and Hosgood, H Dean and Hossain, Mazeda and Hotez, Peter J and Hoy, Damian G and Hsairi, Mohamed and Hu, Guoqing and Huang, Cheng and Huang, John J and Husseini, Abdullatif and Huynh, Chantal and Iannarone, Marissa L and Iburg, Kim M and Innos, Kaire and Inoue, Manami and Islami, Farhad and Jacobsen, Kathryn H and Jarvis, Deborah L and Jassal, Simerjot K and Jee, Sun Ha and Jeemon, Panniyammakal and Jensen, Paul N and Jha, Vivekanand and Jiang, Guohong and Jiang, Ying and Jonas, Jost B and Juel, Knud and Kan, Haidong and Karch, Andr{\'e} and Karema, Corine K and Karimkhani, Chante and Karthikeyan, Ganesan and Kassebaum, Nicholas J and Kaul, Anil and Kawakami, Norito and Kazanjan, Konstantin and Kemp, Andrew H and Kengne, Andre P and Keren, Andre and Khader, Yousef S and Khalifa, Shams Eldin A and Khan, Ejaz A and Khan, Gulfaraz and Khang, Young-Ho and Kieling, Christian and Kim, Daniel and Kim, Sungroul and Kim, Yunjin and Kinfu, Yohannes and Kinge, Jonas M and Kivipelto, Miia and Knibbs, Luke D and Knudsen, Ann Kristin and Kokubo, Yoshihiro and Kosen, Soewarta and Krishnaswami, Sanjay and Kuate Defo, Barthelemy and Kucuk Bicer, Burcu and Kuipers, Ernst J and Kulkarni, Chanda and Kulkarni, Veena S and Kumar, G Anil and Kyu, Hmwe H and Lai, Taavi and Lalloo, Ratilal and Lallukka, Tea and Lam, Hilton and Lan, Qing and Lansingh, Van C and Larsson, Anders and Lawrynowicz, Alicia E B and Leasher, Janet L and Leigh, James and Leung, Ricky and Levitz, Carly E and Li, Bin and Li, Yichong and Li, Yongmei and Lim, Stephen S and Lind, Maggie and Lipshultz, Steven E and Liu, Shiwei and Liu, Yang and Lloyd, Belinda K and Lofgren, Katherine T and Logroscino, Giancarlo and Looker, Katharine J and Lortet-Tieulent, Joannie and Lotufo, Paulo A and Lozano, Rafael and Lucas, Robyn M and Lunevicius, Raimundas and Lyons, Ronan A and Ma, Stefan and MacIntyre, Michael F and Mackay, Mark T and Majdan, Marek and Malekzadeh, Reza and Marcenes, Wagner and Margolis, David J and Margono, Christopher and Marzan, Melvin B and Masci, Joseph R and Mashal, Mohammad T and Matzopoulos, Richard and Mayosi, Bongani M and Mazorodze, Tasara T and Mcgill, Neil W and McGrath, John J and McKee, Martin and McLain, Abigail and Meaney, Peter A and Medina, Catalina and Mehndiratta, Man Mohan and Mekonnen, Wubegzier and Melaku, Yohannes A and Meltzer, Michele and Memish, Ziad A and Mensah, George A and Meretoja, Atte and Mhimbira, Francis A and Micha, Renata and Miller, Ted R and Mills, Edward J and Mitchell, Philip B and Mock, Charles N and Mohamed Ibrahim, Norlinah and Mohammad, Karzan A and Mokdad, Ali H and Mola, Glen L D and Monasta, Lorenzo and Monta{\~n}ez Hernandez, Julio C and Montico, Marcella and Montine, Thomas J and Mooney, Meghan D and Moore, Ami R and Moradi-Lakeh, Maziar and Moran, Andrew E and Mori, Rintaro and Moschandreas, Joanna and Moturi, Wilkister N and Moyer, Madeline L and Mozaffarian, Dariush and Msemburi, William T and Mueller, Ulrich O and Mukaigawara, Mitsuru and Mullany, Erin C and Murdoch, Michele E and Murray, Joseph and Murthy, Kinnari S and Naghavi, Mohsen and Naheed, Aliya and Naidoo, Kovin S and Naldi, Luigi and Nand, Devina and Nangia, Vinay and Narayan, K M Venkat and Nejjari, Chakib and Neupane, Sudan P and Newton, Charles R and Ng, Marie and Ngalesoni, Frida N and Nguyen, Grant and Nisar, Muhammad I and Nolte, Sandra and Norheim, Ole F and Norman, Rosana E and Norrving, Bo and Nyakarahuka, Luke and Oh, In-Hwan and Ohkubo, Takayoshi and Ohno, Summer L and Olusanya, Bolajoko O and Opio, John Nelson and Ortblad, Katrina and Ortiz, Alberto and Pain, Amanda W and Pandian, Jeyaraj D and Panelo, Carlo Irwin A and Papachristou, Christina and Park, Eun-Kee and Park, Jae-Hyun and Patten, Scott B and Patton, George C and Paul, Vinod K and Pavlin, Boris I and Pearce, Neil and Pereira, David M and Perez-Padilla, Rogelio and Perez-Ruiz, Fernando and Perico, Norberto and Pervaiz, Aslam and Pesudovs, Konrad and Peterson, Carrie B and Petzold, Max and Phillips, Michael R and Phillips, Bryan K and Phillips, David E and Piel, Fr{\'e}d{\'e}ric B and Plass, Dietrich and Poenaru, Dan and Polinder, Suzanne and Pope, Daniel and Popova, Svetlana and Poulton, Richie G and Pourmalek, Farshad and Prabhakaran, Dorairaj and Prasad, Noela M and Pullan, Rachel L and Qato, Dima M and Quistberg, D Alex and Rafay, Anwar and Rahimi, Kazem and Rahman, Sajjad U and Raju, Murugesan and Rana, Saleem M and Razavi, Homie and Reddy, K Srinath and Refaat, Amany and Remuzzi, Giuseppe and Resnikoff, Serge and Ribeiro, Antonio L and Richardson, Lee and Richardus, Jan Hendrik and Roberts, D Allen and Rojas-Rueda, David and Ronfani, Luca and Roth, Gregory A and Rothenbacher, Dietrich and Rothstein, David H and Rowley, Jane T and Roy, Nobhojit and Ruhago, George M and Saeedi, Mohammad Y and Saha, Sukanta and Sahraian, Mohammad Ali and Sampson, Uchechukwu K A and Sanabria, Juan R and Sandar, Logan and Santos, Itamar S and Satpathy, Maheswar and Sawhney, Monika and Scarborough, Peter and Schneider, Ione J and Sch{\"o}ttker, Ben and Schumacher, Austin E and Schwebel, David C and Scott, James G and Seedat, Soraya and Sepanlou, Sadaf G and Serina, Peter T and Servan-Mori, Edson E and Shackelford, Katya A and Shaheen, Amira and Shahraz, Saeid and Shamah Levy, Teresa and Shangguan, Siyi and She, Jun and Sheikhbahaei, Sara and Shi, Peilin and Shibuya, Kenji and Shinohara, Yukito and Shiri, Rahman and Shishani, Kawkab and Shiue, Ivy and Shrime, Mark G and Sigfusdottir, Inga D and Silberberg, Donald H and Simard, Edgar P and Sindi, Shireen and Singh, Abhishek and Singh, Jasvinder A and Singh, Lavanya and Skirbekk, Vegard and Slepak, Erica Leigh and Sliwa, Karen and Soneji, Samir and S{\o}reide, Kjetil and Soshnikov, Sergey and Sposato, Luciano A and Sreeramareddy, Chandrashekhar T and Stanaway, Jeffrey D and Stathopoulou, Vasiliki and Stein, Dan J and Stein, Murray B and Steiner, Caitlyn and Steiner, Timothy J and Stevens, Antony and Stewart, Andrea and Stovner, Lars J and Stroumpoulis, Konstantinos and Sunguya, Bruno F and Swaminathan, Soumya and Swaroop, Mamta and Sykes, Bryan L and Tabb, Karen M and Takahashi, Ken and Tandon, Nikhil and Tanne, David and Tanner, Marcel and Tavakkoli, Mohammad and Taylor, Hugh R and Te Ao, Braden J and Tediosi, Fabrizio and Temesgen, Awoke M and Templin, Tara and Ten Have, Margreet and Tenkorang, Eric Y and Terkawi, Abdullah S and Thomson, Blake and Thorne-Lyman, Andrew L and Thrift, Amanda G and Thurston, George D and Tillmann, Taavi and Tonelli, Marcello and Topouzis, Fotis and Toyoshima, Hideaki and Traebert, Jefferson and Tran, Bach X and Trillini, Matias and Truelsen, Thomas and Tsilimbaris, Miltiadis and Tuzcu, Emin M and Uchendu, Uche S and Ukwaja, Kingsley N and Undurraga, Eduardo A and Uzun, Selen B and Van Brakel, Wim H and van de Vijver, Steven and van Gool, Coen H and van Os, Jim and Vasankari, Tommi J and Venketasubramanian, N and Violante, Francesco S and Vlassov, Vasiliy V and Vollset, Stein Emil and Wagner, Gregory R and Wagner, Joseph and Waller, Stephen G and Wan, Xia and Wang, Haidong and Wang, JianLi and Wang, Linhong and Warouw, Tati S and Weichenthal, Scott and Weiderpass, Elisabete and Weintraub, Robert G and Wenzhi, Wang and Werdecker, Andrea and Westerman, Ronny and Whiteford, Harvey A and Wilkinson, James D and Williams, Thomas N and Wolfe, Charles D and Wolock, Timothy M and Woolf, Anthony D and Wulf, Sarah and Wurtz, Brittany and Xu, Gelin and Yan, Lijing L and Yano, Yuichiro and Ye, Pengpeng and Yent{\"u}r, G{\"o}kalp K and Yip, Paul and Yonemoto, Naohiro and Yoon, Seok-Jun and Younis, Mustafa Z and Yu, Chuanhua and Zaki, Maysaa E and Zhao, Yong and Zheng, Yingfeng and Zonies, David and Zou, Xiaonong and Salomon, Joshua A and Lopez, Alan D and Vos, Theo} } @article {8045, title = {Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.}, journal = {Lancet}, volume = {386}, year = {2015}, month = {2015 Aug 22}, pages = {743-800}, abstract = {

BACKGROUND: Up-to-date evidence about levels and trends in disease and injury incidence, prevalence, and years lived with disability (YLDs) is an essential input into global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013), we estimated these quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013.

METHODS: Estimates were calculated for disease and injury incidence, prevalence, and YLDs using GBD 2010 methods with some important refinements. Results for incidence of acute disorders and prevalence of chronic disorders are new additions to the analysis. Key improvements include expansion to the cause and sequelae list, updated systematic reviews, use of detailed injury codes, improvements to the Bayesian meta-regression method (DisMod-MR), and use of severity splits for various causes. An index of data representativeness, showing data availability, was calculated for each cause and impairment during three periods globally and at the country level for 2013. In total, 35 620 distinct sources of data were used and documented to calculated estimates for 301 diseases and injuries and 2337 sequelae. The comorbidity simulation provides estimates for the number of sequelae, concurrently, by individuals by country, year, age, and sex. Disability weights were updated with the addition of new population-based survey data from four countries.

FINDINGS: Disease and injury were highly prevalent; only a small fraction of individuals had no sequelae. Comorbidity rose substantially with age and in absolute terms from 1990 to 2013. Incidence of acute sequelae were predominantly infectious diseases and short-term injuries, with over 2 billion cases of upper respiratory infections and diarrhoeal disease episodes in 2013, with the notable exception of tooth pain due to permanent caries with more than 200 million incident cases in 2013. Conversely, leading chronic sequelae were largely attributable to non-communicable diseases, with prevalence estimates for asymptomatic permanent caries and tension-type headache of 2{\textperiodcentered}4 billion and 1{\textperiodcentered}6 billion, respectively. The distribution of the number of sequelae in populations varied widely across regions, with an expected relation between age and disease prevalence. YLDs for both sexes increased from 537{\textperiodcentered}6 million in 1990 to 764{\textperiodcentered}8 million in 2013 due to population growth and ageing, whereas the age-standardised rate decreased little from 114{\textperiodcentered}87 per 1000 people to 110{\textperiodcentered}31 per 1000 people between 1990 and 2013. Leading causes of YLDs included low back pain and major depressive disorder among the top ten causes of YLDs in every country. YLD rates per person, by major cause groups, indicated the main drivers of increases were due to musculoskeletal, mental, and substance use disorders, neurological disorders, and chronic respiratory diseases; however HIV/AIDS was a notable driver of increasing YLDs in sub-Saharan Africa. Also, the proportion of disability-adjusted life years due to YLDs increased globally from 21{\textperiodcentered}1\% in 1990 to 31{\textperiodcentered}2\% in 2013.

INTERPRETATION: Ageing of the world{\textquoteright}s population is leading to a substantial increase in the numbers of individuals with sequelae of diseases and injuries. Rates of YLDs are declining much more slowly than mortality rates. The non-fatal dimensions of disease and injury will require more and more attention from health systems. The transition to non-fatal outcomes as the dominant source of burden of disease is occurring rapidly outside of sub-Saharan Africa. Our results can guide future health initiatives through examination of epidemiological trends and a better understanding of variation across countries.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Acute Disease, Adolescent, Adult, Age Distribution, Aged, Aged, 80 and over, Child, Child, Preschool, Chronic Disease, Cost of Illness, Developed Countries, Developing Countries, Disabled Persons, Female, Global Health, Humans, Incidence, Infant, Infant, Newborn, Male, Middle Aged, Neglected Diseases, Prevalence, Residence Characteristics, Sex Distribution, Wounds and Injuries, Young Adult}, issn = {1474-547X}, doi = {10.1016/S0140-6736(15)60692-4} } @article {8065, title = {Glucocorticoid pharmacogenetics in pediatric idiopathic nephrotic syndrome.}, journal = {Pharmacogenomics}, volume = {16}, year = {2015}, month = {2015 Sep}, pages = {1631-48}, abstract = {

Idiopathic nephrotic syndrome represents the most common type of primary glomerular disease in children: glucocorticoids (GCs) are the first-line therapy, even if considerable interindividual differences in thepir efficacy and side effects have been reported. Immunosuppressive and anti-inflammatory effects of these drugs are mainly due to the GC-mediated transcription regulation of pro- and anti-inflammatory genes. This mechanism of action is the result of a complex multistep pathway that involves the glucocorticoid receptor and several other proteins, encoded by polymorphic genes. Aim of this review is to highlight the current knowledge on genetic variants that could affect GC response, particularly focusing on children with idiopathic nephrotic syndrome.

}, issn = {1744-8042}, doi = {10.2217/pgs.15.101}, author = {Cuzzoni, Eva and De Iudicibus, Sara and Franca, Raffaella and Stocco, Gabriele and Lucaf{\`o}, Marianna and Pelin, Marco and Favretto, Diego and Pasini, Andrea and Montini, Giovanni and Decorti, Giuliana} } @article {3588, title = {GRID2 a novel gene possibly associated with mevalonate kinase deficiency.}, journal = {Rheumatol Int}, volume = {35}, year = {2015}, month = {2015 Apr}, pages = {657-9}, abstract = {

Mevalonate kinase deficiency (MKD) is a rare autosomal disease caused by mutations in the mevalonate kinase gene (MVK). The genotype-phenotype correlation is sometimes problematic due to the great genetic and clinical heterogeneity; so we hypothesize that genes other than MVK are able to modulate MKD clinical phenotypes. This hypothesis was tested by analyzing the exome of 22 patients with MKD all carrying MVK gene mutations, and 20 patients with recurrent fevers (RF) not carrying MVK mutations. Our preliminary findings suggest a possible role of GRID2 in the susceptibility to develop MKD. GRID2 gene (4q22.2), encoding for human glutamate receptor delta-2, associated with MKD: The rs1450500 SNP was differently distributed in patients with MKD with respect to those with RF. Being aware of the small number of patients analyzed, we hypothesized a possible role for GRID2 as possible phenotype modifier in MKD patients, especially in those with severe phenotypes.

}, issn = {1437-160X}, doi = {10.1007/s00296-014-3115-y}, author = {Moura, Ronald and Tricarico, Paola Maura and Campos Coelho, Antonio Victor and Crovella, Sergio} } @article {3520, title = {A general approach for haplotype phasing across the full spectrum of relatedness.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Apr}, pages = {e1004234}, abstract = {

Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally {\textquoteright}unrelated{\textquoteright} individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.

}, keywords = {Chromosome Mapping, Cohort Effect, Family, Genotype, Haplotypes, Humans, Models, Genetic, Pedigree, Phenotype, Recombination, Genetic}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004234}, author = {O{\textquoteright}Connell, Jared and Gurdasani, Deepti and Delaneau, Olivier and Pirastu, Nicola and Ulivi, Sheila and Cocca, Massimiliano and Traglia, Michela and Huang, Jie and Huffman, Jennifer E and Rudan, Igor and McQuillan, Ruth and Fraser, Ross M and Campbell, Harry and Polasek, Ozren and Asiki, Gershim and Ekoru, Kenneth and Hayward, Caroline and Wright, Alan F and Vitart, Veronique and Navarro, Pau and Zagury, Jean-Francois and Wilson, James F and Toniolo, Daniela and Gasparini, Paolo and Soranzo, Nicole and Sandhu, Manjinder S and Marchini, Jonathan} } @article {3568, title = {Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Aug}, pages = {826-36}, abstract = {

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain \~{}8-10\% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

}, keywords = {Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.3014}, author = {Arking, Dan E and Pulit, Sara L and Crotti, Lia and van der Harst, Pim and Munroe, Patricia B and Koopmann, Tamara T and Sotoodehnia, Nona and Rossin, Elizabeth J and Morley, Michael and Wang, Xinchen and Johnson, Andrew D and Lundby, Alicia and Gudbjartsson, Daniel F and Noseworthy, Peter A and Eijgelsheim, Mark and Bradford, Yuki and Tarasov, Kirill V and D{\"o}rr, Marcus and M{\"u}ller-Nurasyid, Martina and Lahtinen, Annukka M and Nolte, Ilja M and Smith, Albert Vernon and Bis, Joshua C and Isaacs, Aaron and Newhouse, Stephen J and Evans, Daniel S and Post, Wendy S and Waggott, Daryl and Lyytik{\"a}inen, Leo-Pekka and Hicks, Andrew A and Eisele, Lewin and Ellinghaus, David and Hayward, Caroline and Navarro, Pau and Ulivi, Sheila and Tanaka, Toshiko and Tester, David J and Chatel, St{\'e}phanie and Gustafsson, Stefan and Kumari, Meena and Morris, Richard W and Naluai, {\r A}sa T and Padmanabhan, Sandosh and Kluttig, Alexander and Strohmer, Bernhard and Panayiotou, Andrie G and Torres, Maria and Knoflach, Michael and Hubacek, Jaroslav A and Slowikowski, Kamil and Raychaudhuri, Soumya and Kumar, Runjun D and Harris, Tamara B and Launer, Lenore J and Shuldiner, Alan R and Alonso, Alvaro and Bader, Joel S and Ehret, Georg and Huang, Hailiang and Kao, W H Linda and Strait, James B and Macfarlane, Peter W and Brown, Morris and Caulfield, Mark J and Samani, Nilesh J and Kronenberg, Florian and Willeit, Johann and Smith, J Gustav and Greiser, Karin H and Meyer Zu Schwabedissen, Henriette and Werdan, Karl and Carella, Massimo and Zelante, Leopoldo and Heckbert, Susan R and Psaty, Bruce M and Rotter, Jerome I and Kolcic, Ivana and Polasek, Ozren and Wright, Alan F and Griffin, Maura and Daly, Mark J and Arnar, David O and Holm, Hilma and Thorsteinsdottir, Unnur and Denny, Joshua C and Roden, Dan M and Zuvich, Rebecca L and Emilsson, Valur and Plump, Andrew S and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Yin, Xiaoyan and Bobbo, Marco and d{\textquoteright}Adamo, Adamo P and Iorio, Annamaria and Sinagra, Gianfranco and Carracedo, Angel and Cummings, Steven R and Nalls, Michael A and Jula, Antti and Kontula, Kimmo K and Marjamaa, Annukka and Oikarinen, Lasse and Perola, Markus and Porthan, Kimmo and Erbel, Raimund and Hoffmann, Per and J{\"o}ckel, Karl-Heinz and K{\"a}lsch, Hagen and N{\"o}then, Markus M and den Hoed, Marcel and Loos, Ruth J F and Thelle, Dag S and Gieger, Christian and Meitinger, Thomas and Perz, Siegfried and Peters, Annette and Prucha, Hanna and Sinner, Moritz F and Waldenberger, Melanie and de Boer, Rudolf A and Franke, Lude and van der Vleuten, Pieter A and Beckmann, Britt Maria and Martens, Eimo and Bardai, Abdennasser and Hofman, Nynke and Wilde, Arthur A M and Behr, Elijah R and Dalageorgou, Chrysoula and Giudicessi, John R and Medeiros-Domingo, Argelia and Barc, Julien and Kyndt, Florence and Probst, Vincent and Ghidoni, Alice and Insolia, Roberto and Hamilton, Robert M and Scherer, Stephen W and Brandimarto, Jeffrey and Margulies, Kenneth and Moravec, Christine E and del Greco M, Fabiola and Fuchsberger, Christian and O{\textquoteright}Connell, Jeffrey R and Lee, Wai K and Watt, Graham C M and Campbell, Harry and Wild, Sarah H and El Mokhtari, Nour E and Frey, Norbert and Asselbergs, Folkert W and Mateo Leach, Irene and Navis, Gerjan and van den Berg, Maarten P and van Veldhuisen, Dirk J and Kellis, Manolis and Krijthe, Bouwe P and Franco, Oscar H and Hofman, Albert and Kors, Jan A and Uitterlinden, Andr{\'e} G and Witteman, Jacqueline C M and Kedenko, Lyudmyla and Lamina, Claudia and Oostra, Ben A and Abecasis, Goncalo R and Lakatta, Edward G and Mulas, Antonella and Orru, Marco and Schlessinger, David and Uda, Manuela and Markus, Marcello R P and V{\"o}lker, Uwe and Snieder, Harold and Spector, Timothy D and Arnl{\"o}v, Johan and Lind, Lars and Sundstr{\"o}m, Johan and Syv{\"a}nen, Ann-Christine and Kivimaki, Mika and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Raitakari, Olli T and Viikari, Jorma S and Adamkova, Vera and Kiechl, Stefan and Brion, Maria and Nicolaides, Andrew N and Paulweber, Bernhard and Haerting, Johannes and Dominiczak, Anna F and Nyberg, Fredrik and Whincup, Peter H and Hingorani, Aroon D and Schott, Jean-Jacques and Bezzina, Connie R and Ingelsson, Erik and Ferrucci, Luigi and Gasparini, Paolo and Wilson, James F and Rudan, Igor and Franke, Andre and M{\"u}hleisen, Thomas W and Pramstaller, Peter P and Lehtim{\"a}ki, Terho J and Paterson, Andrew D and Parsa, Afshin and Liu, Yongmei and van Duijn, Cornelia M and Siscovick, David S and Gudnason, Vilmundur and Jamshidi, Yalda and Salomaa, Veikko and Felix, Stephan B and Sanna, Serena and Ritchie, Marylyn D and Stricker, Bruno H and Stefansson, Kari and Boyer, Laurie A and Cappola, Thomas P and Olsen, Jesper V and Lage, Kasper and Schwartz, Peter J and K{\"a}{\"a}b, Stefan and Chakravarti, Aravinda and Ackerman, Michael J and Pfeufer, Arne and de Bakker, Paul I W and Newton-Cheh, Christopher} } @article {3622, title = {Genetic landscape of populations along the Silk Road: admixture and migration patterns.}, journal = {BMC Genet}, volume = {15}, year = {2014}, month = {2014}, pages = {131}, abstract = {

BACKGROUND: The ancient Silk Road has been a trading route between Europe and Central Asia from the 2(nd) century BCE to the 15(th) century CE. While most populations on this route have been characterized, the genetic background of others remains poorly understood, and little is known about past migration patterns. The scientific expedition "Marco Polo" has recently collected genetic and phenotypic data in six regions (Georgia, Armenia, Azerbaijan, Uzbekistan, Kazakhstan, Tajikistan) along the Silk Road to study the genetics of a number of phenotypes.

RESULTS: We characterized the genetic structure of these populations within a worldwide context. We observed a West-East subdivision albeit the existence of a genetic component shared within Central Asia and nearby populations from Europe and Near East. We observed a contribution of up to 50\% from Europe and Asia to most of the populations that have been analyzed. The contribution from Asia dates back to ~25 generations and is limited to the Eastern Silk Road. Time and direction of this contribution are consistent with the Mongolian expansion era.

CONCLUSIONS: We clarified the genetic structure of six populations from Central Asia and suggested a complex pattern of gene flow among them. We provided a map of migration events in time and space and we quantified exchanges among populations. Altogether these novel findings will support the future studies aimed at understanding the genetics of the phenotypes that have been collected during the Marco Polo campaign, they will provide insights into the history of these populations, and they will be useful to reconstruct the developments and events that have shaped modern Eurasians genomes.

}, keywords = {Asian Continental Ancestry Group, Commonwealth of Independent States, European Continental Ancestry Group, Gene Flow, Homozygote, Human Migration, Humans, Phenotype, Polymorphism, Single Nucleotide, Principal Component Analysis, Sequence Analysis, DNA}, issn = {1471-2156}, doi = {10.1186/s12863-014-0131-6}, author = {Mezzavilla, Massimo and Vozzi, Diego and Pirastu, Nicola and Girotto, Giorgia and d{\textquoteright}Adamo, Pio and Gasparini, Paolo and Colonna, Vincenza} } @article {3639, title = {Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Aug 15}, pages = {4452-64}, abstract = {

Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants{\textquoteright} relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 {\texttimes} 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 {\texttimes} 10(-5)) and short adult stature (p = 7.5 {\texttimes} 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddu150}, author = {Cousminer, Diana L and Stergiakouli, Evangelia and Berry, Diane J and Ang, Wei and Groen-Blokhuis, Maria M and K{\"o}rner, Antje and Siitonen, Niina and Ntalla, Ioanna and Marinelli, Marcella and Perry, John R B and Kettunen, Johannes and Jansen, Rick and Surakka, Ida and Timpson, Nicholas J and Ring, Susan and McMahon, George and Power, Chris and Wang, Carol and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Lehtim{\"a}ki, Terho and Middeldorp, Christel M and Hulshoff Pol, Hilleke E and Neef, Madlen and Weise, Sebastian and Pahkala, Katja and Niinikoski, Harri and Zeggini, Eleftheria and Panoutsopoulou, Kalliope and Bustamante, Mariona and Penninx, Brenda W J H and Murabito, Joanne and Torrent, Maties and Dedoussis, George V and Kiess, Wieland and Boomsma, Dorret I and Pennell, Craig E and Raitakari, Olli T and Hypp{\"o}nen, Elina and Davey Smith, George and Ripatti, Samuli and McCarthy, Mark I and Widen, Elisabeth} } @article {3517, title = {A girl with photosensitivity and hepatic steatosis.}, journal = {J Pediatr}, volume = {165}, year = {2014}, month = {2014 Jul}, pages = {201-201.e1}, keywords = {Child, Diagnosis, Differential, Fatty Liver, Female, Humans, Photosensitivity Disorders, Protoporphyria, Erythropoietic}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2014.02.056}, author = {Pavan, Matteo and Gortani, Giulia and Rubinato, Elisa and Faletra, Flavio and Pastore, Serena and Ventura, Alessandro} } @article {3576, title = {Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.}, journal = {Lancet}, volume = {384}, year = {2014}, month = {2014 Sep 13}, pages = {1005-70}, abstract = {

BACKGROUND: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration.

METHODS: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets.

FINDINGS: Globally in 2013, there were 1{\textperiodcentered}8 million new HIV infections (95\% uncertainty interval 1{\textperiodcentered}7 million to 2{\textperiodcentered}1 million), 29{\textperiodcentered}2 million prevalent HIV cases (28{\textperiodcentered}1 to 31{\textperiodcentered}7), and 1{\textperiodcentered}3 million HIV deaths (1{\textperiodcentered}3 to 1{\textperiodcentered}5). At the peak of the epidemic in 2005, HIV caused 1{\textperiodcentered}7 million deaths (1{\textperiodcentered}6 million to 1{\textperiodcentered}9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19{\textperiodcentered}1 million life-years (16{\textperiodcentered}6 million to 21{\textperiodcentered}5 million) have been saved, 70{\textperiodcentered}3\% (65{\textperiodcentered}4 to 76{\textperiodcentered}1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7{\textperiodcentered}5 million (7{\textperiodcentered}4 million to 7{\textperiodcentered}7 million), prevalence was 11{\textperiodcentered}9 million (11{\textperiodcentered}6 million to 12{\textperiodcentered}2 million), and number of deaths was 1{\textperiodcentered}4 million (1{\textperiodcentered}3 million to 1{\textperiodcentered}5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7{\textperiodcentered}1 million (6{\textperiodcentered}9 million to 7{\textperiodcentered}3 million), prevalence was 11{\textperiodcentered}2 million (10{\textperiodcentered}8 million to 11{\textperiodcentered}6 million), and number of deaths was 1{\textperiodcentered}3 million (1{\textperiodcentered}2 million to 1{\textperiodcentered}4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64{\textperiodcentered}0\% of cases (63{\textperiodcentered}6 to 64{\textperiodcentered}3) and 64{\textperiodcentered}7\% of deaths (60{\textperiodcentered}8 to 70{\textperiodcentered}3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1{\textperiodcentered}2 million deaths (1{\textperiodcentered}1 million to 1{\textperiodcentered}4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31{\textperiodcentered}5\% (15{\textperiodcentered}7 to 44{\textperiodcentered}1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.

INTERPRETATION: Our estimates of the number of people living with HIV are 18{\textperiodcentered}7\% smaller than UNAIDS{\textquoteright}s estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Age Distribution, Epidemics, Female, Global Health, HIV Infections, Humans, Incidence, Malaria, Male, Mortality, Organizational Objectives, Sex Distribution, Tuberculosis}, issn = {1474-547X}, doi = {10.1016/S0140-6736(14)60844-8}, author = {Murray, Christopher J L and Ortblad, Katrina F and Guinovart, Caterina and Lim, Stephen S and Wolock, Timothy M and Roberts, D Allen and Dansereau, Emily A and Graetz, Nicholas and Barber, Ryan M and Brown, Jonathan C and Wang, Haidong and Duber, Herbert C and Naghavi, Mohsen and Dicker, Daniel and Dandona, Lalit and Salomon, Joshua A and Heuton, Kyle R and Foreman, Kyle and Phillips, David E and Fleming, Thomas D and Flaxman, Abraham D and Phillips, Bryan K and Johnson, Elizabeth K and Coggeshall, Megan S and Abd-Allah, Foad and Abera, Semaw Ferede and Abraham, Jerry P and Abubakar, Ibrahim and Abu-Raddad, Laith J and Abu-Rmeileh, Niveen Me and Achoki, Tom and Adeyemo, Austine Olufemi and Adou, Ars{\`e}ne Kouablan and Adsuar, Jos{\'e} C and Agardh, Emilie Elisabet and Akena, Dickens and Al Kahbouri, Mazin J and Alasfoor, Deena and Albittar, Mohammed I and Alcal{\'a}-Cerra, Gabriel and Alegretti, Miguel Angel and Alemu, Zewdie Aderaw and Alfonso-Cristancho, Rafael and Alhabib, Samia and Ali, Raghib and Alla, Fran{\c c}ois and Allen, Peter J and Alsharif, Ubai and Alvarez, Elena and Alvis-Guzm{\'a}n, Nelson and Amankwaa, Adansi A and Amare, Azmeraw T and Amini, Hassan and Ammar, Walid and Anderson, Benjamin O and Antonio, Carl Abelardo T and Anwari, Palwasha and Arnl{\"o}v, Johan and Arsenijevic, Valentina S Arsic and Artaman, Ali and Asghar, Rana J and Assadi, Reza and Atkins, Lydia S and Badawi, Alaa and Balakrishnan, Kalpana and Banerjee, Amitava and Basu, Sanjay and Beardsley, Justin and Bekele, Tolesa and Bell, Michelle L and Bernabe, Eduardo and Beyene, Tariku Jibat and Bhala, Neeraj and Bhalla, Ashish and Bhutta, Zulfiqar A and Abdulhak, Aref Bin and Binagwaho, Agnes and Blore, Jed D and Basara, Berrak Bora and Bose, Dipan and Brainin, Michael and Breitborde, Nicholas and Casta{\~n}eda-Orjuela, Carlos A and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and Chadha, Vineet K and Chang, Jung-Chen and Chiang, Peggy Pei-Chia and Chuang, Ting-Wu and Colomar, Mercedes and Cooper, Leslie Trumbull and Cooper, Cyrus and Courville, Karen J and Cowie, Benjamin C and Criqui, Michael H and Dandona, Rakhi and Dayama, Anand and De Leo, Diego and Degenhardt, Louisa and del Pozo-Cruz, Borja and Deribe, Kebede and Des Jarlais, Don C and Dessalegn, Muluken and Dharmaratne, Samath D and Dilmen, U{\u g}ur and Ding, Eric L and Driscoll, Tim R and Durrani, Adnan M and Ellenbogen, Richard G and Ermakov, Sergey Petrovich and Esteghamati, Alireza and Faraon, Emerito Jose A and Farzadfar, Farshad and Fereshtehnejad, Seyed-Mohammad and Fijabi, Daniel Obadare and Forouzanfar, Mohammad H and Fra Paleo, Urbano and Gaffikin, Lynne and Gamkrelidze, Amiran and Gankp{\'e}, Fortun{\'e} Gb{\`e}toho and Geleijnse, Johanna M and Gessner, Bradford D and Gibney, Katherine B and Ginawi, Ibrahim Abdelmageem Mohamed and Glaser, Elizabeth L and Gona, Philimon and Goto, Atsushi and Gouda, Hebe N and Gugnani, Harish Chander and Gupta, Rajeev and Gupta, Rahul and Hafezi-Nejad, Nima and Hamadeh, Randah Ribhi and Hammami, Mouhanad and Hankey, Graeme J and Harb, Hilda L and Haro, Josep Maria and Havmoeller, Rasmus and Hay, Simon I and Hedayati, Mohammad T and Pi, Ileana B Heredia and Hoek, Hans W and Hornberger, John C and Hosgood, H Dean and Hotez, Peter J and Hoy, Damian G and Huang, John J and Iburg, Kim M and Idrisov, Bulat T and Innos, Kaire and Jacobsen, Kathryn H and Jeemon, Panniyammakal and Jensen, Paul N and Jha, Vivekanand and Jiang, Guohong and Jonas, Jost B and Juel, Knud and Kan, Haidong and Kankindi, Ida and Karam, Nadim E and Karch, Andr{\'e} and Karema, Corine Kakizi and Kaul, Anil and Kawakami, Norito and Kazi, Dhruv S and Kemp, Andrew H and Kengne, Andre Pascal and Keren, Andre and Kereselidze, Maia and Khader, Yousef Saleh and Khalifa, Shams Eldin Ali Hassan and Khan, Ejaz Ahmed and Khang, Young-Ho and Khonelidze, Irma and Kinfu, Yohannes and Kinge, Jonas M and Knibbs, Luke and Kokubo, Yoshihiro and Kosen, S and Defo, Barthelemy Kuate and Kulkarni, Veena S and Kulkarni, Chanda and Kumar, Kaushalendra and Kumar, Ravi B and Kumar, G Anil and Kwan, Gene F and Lai, Taavi and Balaji, Arjun Lakshmana and Lam, Hilton and Lan, Qing and Lansingh, Van C and Larson, Heidi J and Larsson, Anders and Lee, Jong-Tae and Leigh, James and Leinsalu, Mall and Leung, Ricky and Li, Yichong and Li, Yongmei and de Lima, Gra{\c c}a Maria Ferreira and Lin, Hsien-Ho and Lipshultz, Steven E and Liu, Shiwei and Liu, Yang and Lloyd, Belinda K and Lotufo, Paulo A and Machado, Vasco Manuel Pedro and Maclachlan, Jennifer H and Magis-Rodriguez, Carlos and Majdan, Marek and Mapoma, Christopher Chabila and Marcenes, Wagner and Marzan, Melvin Barrientos and Masci, Joseph R and Mashal, Mohammad Taufiq and Mason-Jones, Amanda J and Mayosi, Bongani M and Mazorodze, Tasara T and Mckay, Abigail Cecilia and Meaney, Peter A and Mehndiratta, Man Mohan and Mejia-Rodriguez, Fabiola and Melaku, Yohannes Adama and Memish, Ziad A and Mendoza, Walter and Miller, Ted R and Mills, Edward J and Mohammad, Karzan Abdulmuhsin and Mokdad, Ali H and Mola, Glen Liddell and Monasta, Lorenzo and Montico, Marcella and Moore, Ami R and Mori, Rintaro and Moturi, Wilkister Nyaora and Mukaigawara, Mitsuru and Murthy, Kinnari S and Naheed, Aliya and Naidoo, Kovin S and Naldi, Luigi and Nangia, Vinay and Narayan, K M Venkat and Nash, Denis and Nejjari, Chakib and Nelson, Robert G and Neupane, Sudan Prasad and Newton, Charles R and Ng, Marie and Nisar, Muhammad Imran and Nolte, Sandra and Norheim, Ole F and Nowaseb, Vincent and Nyakarahuka, Luke and Oh, In-Hwan and Ohkubo, Takayoshi and Olusanya, Bolajoko O and Omer, Saad B and Opio, John Nelson and Orisakwe, Orish Ebere and Pandian, Jeyaraj D and Papachristou, Christina and Caicedo, Angel J Paternina and Patten, Scott B and Paul, Vinod K and Pavlin, Boris Igor and Pearce, Neil and Pereira, David M and Pervaiz, Aslam and Pesudovs, Konrad and Petzold, Max and Pourmalek, Farshad and Qato, Dima and Quezada, Amado D and Quistberg, D Alex and Rafay, Anwar and Rahimi, Kazem and Rahimi-Movaghar, Vafa and ur Rahman, Sajjad and Raju, Murugesan and Rana, Saleem M and Razavi, Homie and Reilly, Robert Quentin and Remuzzi, Giuseppe and Richardus, Jan Hendrik and Ronfani, Luca and Roy, Nobhojit and Sabin, Nsanzimana and Saeedi, Mohammad Yahya and Sahraian, Mohammad Ali and Samonte, Genesis May J and Sawhney, Monika and Schneider, Ione J C and Schwebel, David C and Seedat, Soraya and Sepanlou, Sadaf G and Servan-Mori, Edson E and Sheikhbahaei, Sara and Shibuya, Kenji and Shin, Hwashin Hyun and Shiue, Ivy and Shivakoti, Rupak and Sigfusdottir, Inga Dora and Silberberg, Donald H and Silva, Andrea P and Simard, Edgar P and Singh, Jasvinder A and Skirbekk, Vegard and Sliwa, Karen and Soneji, Samir and Soshnikov, Sergey S and Sreeramareddy, Chandrashekhar T and Stathopoulou, Vasiliki Kalliopi and Stroumpoulis, Konstantinos and Swaminathan, Soumya and Sykes, Bryan L and Tabb, Karen M and Talongwa, Roberto Tchio and Tenkorang, Eric Yeboah and Terkawi, Abdullah Sulieman and Thomson, Alan J and Thorne-Lyman, Andrew L and Towbin, Jeffrey A and Traebert, Jefferson and Tran, Bach X and Dimbuene, Zacharie Tsala and Tsilimbaris, Miltiadis and Uchendu, Uche S and Ukwaja, Kingsley N and Uzun, Selen Beg{\"u}m and Vallely, Andrew J and Vasankari, Tommi J and Venketasubramanian, N and Violante, Francesco S and Vlassov, Vasiliy Victorovich and Vollset, Stein Emil and Waller, Stephen and Wallin, Mitchell T and Wang, Linhong and Wang, XiaoRong and Wang, Yanping and Weichenthal, Scott and Weiderpass, Elisabete and Weintraub, Robert G and Westerman, Ronny and White, Richard A and Wilkinson, James D and Williams, Thomas Neil and Woldeyohannes, Solomon Meseret and Wong, John Q and Xu, Gelin and Yang, Yang C and Yano, Yuichiro and Yentur, Gokalp Kadri and Yip, Paul and Yonemoto, Naohiro and Yoon, Seok-Jun and Younis, Mustafa and Yu, Chuanhua and Jin, Kim Yun and El Sayed Zaki, Maysaa and Zhao, Yong and Zheng, Yingfeng and Zhou, Maigeng and Zhu, Jun and Zou, Xiao Nong and Lopez, Alan D and Vos, Theo} } @article {3531, title = {Global, regional, and national levels and causes of maternal mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.}, journal = {Lancet}, volume = {384}, year = {2014}, month = {2014 Sep 13}, pages = {980-1004}, abstract = {

BACKGROUND: The fifth Millennium Development Goal (MDG 5) established the goal of a 75\% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100,000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.

METHODS: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95\% uncertainty intervals (UIs) for all values.

FINDINGS: 292,982 (95\% UI 261,017-327,792) maternal deaths occurred in 2013, compared with 376,034 (343,483-407,574) in 1990. The global annual rate of change in the MMR was -0{\textperiodcentered}3\% (-1{\textperiodcentered}1 to 0{\textperiodcentered}6) from 1990 to 2003, and -2{\textperiodcentered}7\% (-3{\textperiodcentered}9 to -1{\textperiodcentered}5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0{\textperiodcentered}4\% (0{\textperiodcentered}2-0{\textperiodcentered}6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956{\textperiodcentered}8 (685{\textperiodcentered}1-1262{\textperiodcentered}8) in South Sudan to 2{\textperiodcentered}4 (1{\textperiodcentered}6-3{\textperiodcentered}6) in Iceland.

INTERPRETATION: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.

FUNDING: Bill \& Melinda Gates Foundation.

}, keywords = {Age Distribution, Cause of Death, Female, Global Health, HIV Infections, Humans, Maternal Mortality, Models, Statistical, Organizational Objectives, Pregnancy, Pregnancy Complications, Infectious, Risk Factors, Socioeconomic Factors, Time Factors}, issn = {1474-547X}, doi = {10.1016/S0140-6736(14)60696-6}, author = {Kassebaum, Nicholas J and Bertozzi-Villa, Amelia and Coggeshall, Megan S and Shackelford, Katya A and Steiner, Caitlyn and Heuton, Kyle R and Gonzalez-Medina, Diego and Barber, Ryan and Huynh, Chantal and Dicker, Daniel and Templin, Tara and Wolock, Timothy M and Ozgoren, Ayse Abbasoglu and Abd-Allah, Foad and Abera, Semaw Ferede and Abubakar, Ibrahim and Achoki, Tom and Adelekan, Ademola and Ademi, Zanfina and Adou, Ars{\`e}ne Kouablan and Adsuar, Jos{\'e} C and Agardh, Emilie E and Akena, Dickens and Alasfoor, Deena and Alemu, Zewdie Aderaw and Alfonso-Cristancho, Rafael and Alhabib, Samia and Ali, Raghib and Al Kahbouri, Mazin J and Alla, Fran{\c c}ois and Allen, Peter J and AlMazroa, Mohammad A and Alsharif, Ubai and Alvarez, Elena and Alvis-Guzm{\'a}n, Nelson and Amankwaa, Adansi A and Amare, Azmeraw T and Amini, Hassan and Ammar, Walid and Antonio, Carl A T and Anwari, Palwasha and Arnl{\"o}v, Johan and Arsenijevic, Valentina S Arsic and Artaman, Ali and Asad, Majed Masoud and Asghar, Rana J and Assadi, Reza and Atkins, Lydia S and Badawi, Alaa and Balakrishnan, Kalpana and Basu, Arindam and Basu, Sanjay and Beardsley, Justin and Bedi, Neeraj and Bekele, Tolesa and Bell, Michelle L and Bernabe, Eduardo and Beyene, Tariku J and Bhutta, Zulfiqar and Bin Abdulhak, Aref and Blore, Jed D and Basara, Berrak Bora and Bose, Dipan and Breitborde, Nicholas and C{\'a}rdenas, Rosario and Casta{\~n}eda-Orjuela, Carlos A and Castro, Ruben Estanislao and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and Cavlin, Alanur and Chang, Jung-Chen and Che, Xuan and Christophi, Costas A and Chugh, Sumeet S and Cirillo, Massimo and Colquhoun, Samantha M and Cooper, Leslie Trumbull and Cooper, Cyrus and da Costa Leite, Iuri and Dandona, Lalit and Dandona, Rakhi and Davis, Adrian and Dayama, Anand and Degenhardt, Louisa and De Leo, Diego and del Pozo-Cruz, Borja and Deribe, Kebede and Dessalegn, Muluken and deVeber, Gabrielle A and Dharmaratne, Samath D and Dilmen, U{\u g}ur and Ding, Eric L and Dorrington, Rob E and Driscoll, Tim R and Ermakov, Sergei Petrovich and Esteghamati, Alireza and Faraon, Emerito Jose A and Farzadfar, Farshad and Felicio, Manuela Mendonca and Fereshtehnejad, Seyed-Mohammad and de Lima, Gra{\c c}a Maria Ferreira and Forouzanfar, Mohammad H and Fran{\c c}a, Elisabeth B and Gaffikin, Lynne and Gambashidze, Ketevan and Gankp{\'e}, Fortun{\'e} Gb{\`e}toho and Garcia, Ana C and Geleijnse, Johanna M and Gibney, Katherine B and Giroud, Maurice and Glaser, Elizabeth L and Goginashvili, Ketevan and Gona, Philimon and Gonz{\'a}lez-Castell, Dinorah and Goto, Atsushi and Gouda, Hebe N and Gugnani, Harish Chander and Gupta, Rahul and Gupta, Rajeev and Hafezi-Nejad, Nima and Hamadeh, Randah Ribhi and Hammami, Mouhanad and Hankey, Graeme J and Harb, Hilda L and Havmoeller, Rasmus and Hay, Simon I and Pi, Ileana B Heredia and Hoek, Hans W and Hosgood, H Dean and Hoy, Damian G and Husseini, Abdullatif and Idrisov, Bulat T and Innos, Kaire and Inoue, Manami and Jacobsen, Kathryn H and Jahangir, Eiman and Jee, Sun Ha and Jensen, Paul N and Jha, Vivekanand and Jiang, Guohong and Jonas, Jost B and Juel, Knud and Kabagambe, Edmond Kato and Kan, Haidong and Karam, Nadim E and Karch, Andr{\'e} and Karema, Corine Kakizi and Kaul, Anil and Kawakami, Norito and Kazanjan, Konstantin and Kazi, Dhruv S and Kemp, Andrew H and Kengne, Andre Pascal and Kereselidze, Maia and Khader, Yousef Saleh and Khalifa, Shams Eldin Ali Hassan and Khan, Ejaz Ahmed and Khang, Young-Ho and Knibbs, Luke and Kokubo, Yoshihiro and Kosen, Soewarta and Defo, Barthelemy Kuate and Kulkarni, Chanda and Kulkarni, Veena S and Kumar, G Anil and Kumar, Kaushalendra and Kumar, Ravi B and Kwan, Gene and Lai, Taavi and Lalloo, Ratilal and Lam, Hilton and Lansingh, Van C and Larsson, Anders and Lee, Jong-Tae and Leigh, James and Leinsalu, Mall and Leung, Ricky and Li, Xiaohong and Li, Yichong and Li, Yongmei and Liang, Juan and Liang, Xiaofeng and Lim, Stephen S and Lin, Hsien-Ho and Lipshultz, Steven E and Liu, Shiwei and Liu, Yang and Lloyd, Belinda K and London, Stephanie J and Lotufo, Paulo A and Ma, Jixiang and Ma, Stefan and Machado, Vasco Manuel Pedro and Mainoo, Nana Kwaku and Majdan, Marek and Mapoma, Christopher Chabila and Marcenes, Wagner and Marzan, Melvin Barrientos and Mason-Jones, Amanda J and Mehndiratta, Man Mohan and Mejia-Rodriguez, Fabiola and Memish, Ziad A and Mendoza, Walter and Miller, Ted R and Mills, Edward J and Mokdad, Ali H and Mola, Glen Liddell and Monasta, Lorenzo and de la Cruz Monis, Jonathan and Hernandez, Julio Cesar Monta{\~n}ez and Moore, Ami R and Moradi-Lakeh, Maziar and Mori, Rintaro and Mueller, Ulrich O and Mukaigawara, Mitsuru and Naheed, Aliya and Naidoo, Kovin S and Nand, Devina and Nangia, Vinay and Nash, Denis and Nejjari, Chakib and Nelson, Robert G and Neupane, Sudan Prasad and Newton, Charles R and Ng, Marie and Nieuwenhuijsen, Mark J and Nisar, Muhammad Imran and Nolte, Sandra and Norheim, Ole F and Nyakarahuka, Luke and Oh, In-Hwan and Ohkubo, Takayoshi and Olusanya, Bolajoko O and Omer, Saad B and Opio, John Nelson and Orisakwe, Orish Ebere and Pandian, Jeyaraj D and Papachristou, Christina and Park, Jae-Hyun and Caicedo, Angel J Paternina and Patten, Scott B and Paul, Vinod K and Pavlin, Boris Igor and Pearce, Neil and Pereira, David M and Pesudovs, Konrad and Petzold, Max and Poenaru, Dan and Polanczyk, Guilherme V and Polinder, Suzanne and Pope, Dan and Pourmalek, Farshad and Qato, Dima and Quistberg, D Alex and Rafay, Anwar and Rahimi, Kazem and Rahimi-Movaghar, Vafa and ur Rahman, Sajjad and Raju, Murugesan and Rana, Saleem M and Refaat, Amany and Ronfani, Luca and Roy, Nobhojit and Pimienta, Tania Georgina S{\'a}nchez and Sahraian, Mohammad Ali and Salomon, Joshua A and Sampson, Uchechukwu and Santos, Itamar S and Sawhney, Monika and Sayinzoga, Felix and Schneider, Ione J C and Schumacher, Austin and Schwebel, David C and Seedat, Soraya and Sepanlou, Sadaf G and Servan-Mori, Edson E and Shakh-Nazarova, Marina and Sheikhbahaei, Sara and Shibuya, Kenji and Shin, Hwashin Hyun and Shiue, Ivy and Sigfusdottir, Inga Dora and Silberberg, Donald H and Silva, Andrea P and Singh, Jasvinder A and Skirbekk, Vegard and Sliwa, Karen and Soshnikov, Sergey S and Sposato, Luciano A and Sreeramareddy, Chandrashekhar T and Stroumpoulis, Konstantinos and Sturua, Lela and Sykes, Bryan L and Tabb, Karen M and Talongwa, Roberto Tchio and Tan, Feng and Teixeira, Carolina Maria and Tenkorang, Eric Yeboah and Terkawi, Abdullah Sulieman and Thorne-Lyman, Andrew L and Tirschwell, David L and Towbin, Jeffrey A and Tran, Bach X and Tsilimbaris, Miltiadis and Uchendu, Uche S and Ukwaja, Kingsley N and Undurraga, Eduardo A and Uzun, Selen Beg{\"u}m and Vallely, Andrew J and van Gool, Coen H and Vasankari, Tommi J and Vavilala, Monica S and Venketasubramanian, N and Villalpando, Salvador and Violante, Francesco S and Vlassov, Vasiliy Victorovich and Vos, Theo and Waller, Stephen and Wang, Haidong and Wang, Linhong and Wang, XiaoRong and Wang, Yanping and Weichenthal, Scott and Weiderpass, Elisabete and Weintraub, Robert G and Westerman, Ronny and Wilkinson, James D and Woldeyohannes, Solomon Meseret and Wong, John Q and Wordofa, Muluemebet Abera and Xu, Gelin and Yang, Yang C and Yano, Yuichiro and Yentur, Gokalp Kadri and Yip, Paul and Yonemoto, Naohiro and Yoon, Seok-Jun and Younis, Mustafa Z and Yu, Chuanhua and Jin, Kim Yun and El Sayed Zaki, Maysaa and Zhao, Yong and Zheng, Yingfeng and Zhou, Maigeng and Zhu, Jun and Zou, Xiao Nong and Lopez, Alan D and Naghavi, Mohsen and Murray, Christopher J L and Lozano, Rafael} } @article {3532, title = {Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.}, journal = {Lancet}, volume = {384}, year = {2014}, month = {2014 Sep 13}, pages = {957-79}, abstract = {

BACKGROUND: Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success.

METHODS: We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29,000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.

FINDINGS: We estimated that 6{\textperiodcentered}3 million (95\% UI 6{\textperiodcentered}0-6{\textperiodcentered}6) children under-5 died in 2013, a 64\% reduction from 17{\textperiodcentered}6 million (17{\textperiodcentered}1-18{\textperiodcentered}1) in 1970. In 2013, child mortality rates ranged from 152{\textperiodcentered}5 per 1000 livebirths (130{\textperiodcentered}6-177{\textperiodcentered}4) in Guinea-Bissau to 2{\textperiodcentered}3 (1{\textperiodcentered}8-2{\textperiodcentered}9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6{\textperiodcentered}8\% to 0{\textperiodcentered}1\%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41{\textperiodcentered}6\% of under-5 deaths compared with 37{\textperiodcentered}4\% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1{\textperiodcentered}4 million more child deaths, and rising income per person and maternal education led to 0{\textperiodcentered}9 million and 2{\textperiodcentered}2 million fewer deaths, respectively. Changes in secular trends led to 4{\textperiodcentered}2 million fewer deaths. Unexplained factors accounted for only -1\% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.

INTERPRETATION: Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.

FUNDING: Bill \& Melinda Gates Foundation, US Agency for International Development.

}, keywords = {Child Mortality, Child, Preschool, Global Health, Humans, Infant, Infant Mortality, Infant, Newborn, Organizational Objectives, Risk Factors, Socioeconomic Factors}, issn = {1474-547X}, doi = {10.1016/S0140-6736(14)60497-9}, author = {Wang, Haidong and Liddell, Chelsea A and Coates, Matthew M and Mooney, Meghan D and Levitz, Carly E and Schumacher, Austin E and Apfel, Henry and Iannarone, Marissa and Phillips, Bryan and Lofgren, Katherine T and Sandar, Logan and Dorrington, Rob E and Rakovac, Ivo and Jacobs, Troy A and Liang, Xiaofeng and Zhou, Maigeng and Zhu, Jun and Yang, Gonghuan and Wang, Yanping and Liu, Shiwei and Li, Yichong and Ozgoren, Ayse Abbasoglu and Abera, Semaw Ferede and Abubakar, Ibrahim and Achoki, Tom and Adelekan, Ademola and Ademi, Zanfina and Alemu, Zewdie Aderaw and Allen, Peter J and AlMazroa, Mohammad AbdulAziz and Alvarez, Elena and Amankwaa, Adansi A and Amare, Azmeraw T and Ammar, Walid and Anwari, Palwasha and Cunningham, Solveig Argeseanu and Asad, Majed Masoud and Assadi, Reza and Banerjee, Amitava and Basu, Sanjay and Bedi, Neeraj and Bekele, Tolesa and Bell, Michelle L and Bhutta, Zulfiqar and Blore, Jed D and Basara, Berrak Bora and Boufous, Soufiane and Breitborde, Nicholas and Bruce, Nigel G and Bui, Linh Ngoc and Carapetis, Jonathan R and C{\'a}rdenas, Rosario and Carpenter, David O and Caso, Valeria and Castro, Ruben Estanislao and Catal{\'a}-L{\'o}pez, Ferr{\'a}n and Cavlin, Alanur and Che, Xuan and Chiang, Peggy Pei-Chia and Chowdhury, Rajiv and Christophi, Costas A and Chuang, Ting-Wu and Cirillo, Massimo and da Costa Leite, Iuri and Courville, Karen J and Dandona, Lalit and Dandona, Rakhi and Davis, Adrian and Dayama, Anand and Deribe, Kebede and Dharmaratne, Samath D and Dherani, Mukesh K and Dilmen, U{\u g}ur and Ding, Eric L and Edmond, Karen M and Ermakov, Sergei Petrovich and Farzadfar, Farshad and Fereshtehnejad, Seyed-Mohammad and Fijabi, Daniel Obadare and Foigt, Nataliya and Forouzanfar, Mohammad H and Garcia, Ana C and Geleijnse, Johanna M and Gessner, Bradford D and Goginashvili, Ketevan and Gona, Philimon and Goto, Atsushi and Gouda, Hebe N and Green, Mark A and Greenwell, Karen Fern and Gugnani, Harish Chander and Gupta, Rahul and Hamadeh, Randah Ribhi and Hammami, Mouhanad and Harb, Hilda L and Hay, Simon and Hedayati, Mohammad T and Hosgood, H Dean and Hoy, Damian G and Idrisov, Bulat T and Islami, Farhad and Ismayilova, Samaya and Jha, Vivekanand and Jiang, Guohong and Jonas, Jost B and Juel, Knud and Kabagambe, Edmond Kato and Kazi, Dhruv S and Kengne, Andre Pascal and Kereselidze, Maia and Khader, Yousef Saleh and Khalifa, Shams Eldin Ali Hassan and Khang, Young-Ho and Kim, Daniel and Kinfu, Yohannes and Kinge, Jonas M and Kokubo, Yoshihiro and Kosen, Soewarta and Defo, Barthelemy Kuate and Kumar, G Anil and Kumar, Kaushalendra and Kumar, Ravi B and Lai, Taavi and Lan, Qing and Larsson, Anders and Lee, Jong-Tae and Leinsalu, Mall and Lim, Stephen S and Lipshultz, Steven E and Logroscino, Giancarlo and Lotufo, Paulo A and Lunevicius, Raimundas and Lyons, Ronan Anthony and Ma, Stefan and Mahdi, Abbas Ali and Marzan, Melvin Barrientos and Mashal, Mohammad Taufiq and Mazorodze, Tasara T and McGrath, John J and Memish, Ziad A and Mendoza, Walter and Mensah, George A and Meretoja, Atte and Miller, Ted R and Mills, Edward J and Mohammad, Karzan Abdulmuhsin and Mokdad, Ali H and Monasta, Lorenzo and Montico, Marcella and Moore, Ami R and Moschandreas, Joanna and Msemburi, William T and Mueller, Ulrich O and Muszynska, Magdalena M and Naghavi, Mohsen and Naidoo, Kovin S and Narayan, K M Venkat and Nejjari, Chakib and Ng, Marie and de Dieu Ngirabega, Jean and Nieuwenhuijsen, Mark J and Nyakarahuka, Luke and Ohkubo, Takayoshi and Omer, Saad B and Caicedo, Angel J Paternina and Pillay-van Wyk, Victoria and Pope, Dan and Pourmalek, Farshad and Prabhakaran, Dorairaj and Rahman, Sajjad U R and Rana, Saleem M and Reilly, Robert Quentin and Rojas-Rueda, David and Ronfani, Luca and Rushton, Lesley and Saeedi, Mohammad Yahya and Salomon, Joshua A and Sampson, Uchechukwu and Santos, Itamar S and Sawhney, Monika and Schmidt, J{\"u}rgen C and Shakh-Nazarova, Marina and She, Jun and Sheikhbahaei, Sara and Shibuya, Kenji and Shin, Hwashin Hyun and Shishani, Kawkab and Shiue, Ivy and Sigfusdottir, Inga Dora and Singh, Jasvinder A and Skirbekk, Vegard and Sliwa, Karen and Soshnikov, Sergey S and Sposato, Luciano A and Stathopoulou, Vasiliki Kalliopi and Stroumpoulis, Konstantinos and Tabb, Karen M and Talongwa, Roberto Tchio and Teixeira, Carolina Maria and Terkawi, Abdullah Sulieman and Thomson, Alan J and Thorne-Lyman, Andrew L and Toyoshima, Hideaki and Dimbuene, Zacharie Tsala and Uwaliraye, Parfait and Uzun, Selen Beg{\"u}m and Vasankari, Tommi J and Vasconcelos, Ana Maria Nogales and Vlassov, Vasiliy Victorovich and Vollset, Stein Emil and Waller, Stephen and Wan, Xia and Weichenthal, Scott and Weiderpass, Elisabete and Weintraub, Robert G and Westerman, Ronny and Wilkinson, James D and Williams, Hywel C and Yang, Yang C and Yentur, Gokalp Kadri and Yip, Paul and Yonemoto, Naohiro and Younis, Mustafa and Yu, Chuanhua and Jin, Kim Yun and El Sayed Zaki, Maysaa and Zhu, Shankuan and Vos, Theo and Lopez, Alan D and Murray, Christopher J L} } @article {3474, title = {Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Feb}, pages = {145-54}, abstract = {

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

}, keywords = {Analysis of Variance, European Continental Ancestry Group, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Glucose, Gout, Humans, Inhibins, Polymorphism, Single Nucleotide, Signal Transduction, Uric Acid}, issn = {1546-1718}, doi = {10.1038/ng.2500}, author = {K{\"o}ttgen, Anna and Albrecht, Eva and Teumer, Alexander and Vitart, Veronique and Krumsiek, Jan and Hundertmark, Claudia and Pistis, Giorgio and Ruggiero, Daniela and O{\textquoteright}Seaghdha, Conall M and Haller, Toomas and Yang, Qiong and Tanaka, Toshiko and Johnson, Andrew D and Kutalik, Zolt{\'a}n and Smith, Albert V and Shi, Julia and Struchalin, Maksim and Middelberg, Rita P S and Brown, Morris J and Gaffo, Angelo L and Pirastu, Nicola and Li, Guo and Hayward, Caroline and Zemunik, Tatijana and Huffman, Jennifer and Yengo, Loic and Zhao, Jing Hua and Demirkan, Ayse and Feitosa, Mary F and Liu, Xuan and Malerba, Giovanni and Lopez, Lorna M and van der Harst, Pim and Li, Xinzhong and Kleber, Marcus E and Hicks, Andrew A and Nolte, Ilja M and Johansson, {\r A}sa and Murgia, Federico and Wild, Sarah H and Bakker, Stephan J L and Peden, John F and Dehghan, Abbas and Steri, Maristella and Tenesa, Albert and Lagou, Vasiliki and Salo, Perttu and Mangino, Massimo and Rose, Lynda M and Lehtim{\"a}ki, Terho and Woodward, Owen M and Okada, Yukinori and Tin, Adrienne and M{\"u}ller, Christian and Oldmeadow, Christopher and Putku, Margus and Czamara, Darina and Kraft, Peter and Frogheri, Laura and Thun, Gian Andri and Grotevendt, Anne and Gislason, Gauti Kjartan and Harris, Tamara B and Launer, Lenore J and McArdle, Patrick and Shuldiner, Alan R and Boerwinkle, Eric and Coresh, Josef and Schmidt, Helena and Schallert, Michael and Martin, Nicholas G and Montgomery, Grant W and Kubo, Michiaki and Nakamura, Yusuke and Tanaka, Toshihiro and Munroe, Patricia B and Samani, Nilesh J and Jacobs, David R and Liu, Kiang and d{\textquoteright}Adamo, Pio and Ulivi, Sheila and Rotter, Jerome I and Psaty, Bruce M and Vollenweider, Peter and Waeber, Gerard and Campbell, Susan and Devuyst, Olivier and Navarro, Pau and Kolcic, Ivana and Hastie, Nicholas and Balkau, Beverley and Froguel, Philippe and Esko, T{\~o}nu and Salumets, Andres and Khaw, Kay Tee and Langenberg, Claudia and Wareham, Nicholas J and Isaacs, Aaron and Kraja, Aldi and Zhang, Qunyuan and Wild, Philipp S and Scott, Rodney J and Holliday, Elizabeth G and Org, Elin and Viigimaa, Margus and Bandinelli, Stefania and Metter, Jeffrey E and Lupo, Antonio and Trabetti, Elisabetta and Sorice, Rossella and D{\"o}ring, Angela and Lattka, Eva and Strauch, Konstantin and Theis, Fabian and Waldenberger, Melanie and Wichmann, H-Erich and Davies, Gail and Gow, Alan J and Bruinenberg, Marcel and Stolk, Ronald P and Kooner, Jaspal S and Zhang, Weihua and Winkelmann, Bernhard R and Boehm, Bernhard O and Lucae, Susanne and Penninx, Brenda W and Smit, Johannes H and Curhan, Gary and Mudgal, Poorva and Plenge, Robert M and Portas, Laura and Persico, Ivana and Kirin, Mirna and Wilson, James F and Mateo Leach, Irene and van Gilst, Wiek H and Goel, Anuj and Ongen, Halit and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Imboden, Medea and von Eckardstein, Arnold and Cucca, Francesco and Nagaraja, Ramaiah and Piras, Maria Grazia and Nauck, Matthias and Schurmann, Claudia and Budde, Kathrin and Ernst, Florian and Farrington, Susan M and Theodoratou, Evropi and Prokopenko, Inga and Stumvoll, Michael and Jula, Antti and Perola, Markus and Salomaa, Veikko and Shin, So-Youn and Spector, Tim D and Sala, Cinzia and Ridker, Paul M and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Hengstenberg, Christian and Nelson, Christopher P and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Singleton, Andrew B and Kamatani, Naoyuki and Zeller, Tanja and Burnier, Michel and Attia, John and Laan, Maris and Klopp, Norman and Hillege, Hans L and Kloiber, Stefan and Choi, Hyon and Pirastu, Mario and Tore, Silvia and Probst-Hensch, Nicole M and V{\"o}lzke, Henry and Gudnason, Vilmundur and Parsa, Afshin and Schmidt, Reinhold and Whitfield, John B and Fornage, Myriam and Gasparini, Paolo and Siscovick, David S and Polasek, Ozren and Campbell, Harry and Rudan, Igor and Bouatia-Naji, Nabila and Metspalu, Andres and Loos, Ruth J F and van Duijn, Cornelia M and Borecki, Ingrid B and Ferrucci, Luigi and Gambaro, Giovanni and Deary, Ian J and Wolffenbuttel, Bruce H R and Chambers, John C and M{\"a}rz, Winfried and Pramstaller, Peter P and Snieder, Harold and Gyllensten, Ulf and Wright, Alan F and Navis, Gerjan and Watkins, Hugh and Witteman, Jacqueline C M and Sanna, Serena and Schipf, Sabine and Dunlop, Malcolm G and T{\"o}njes, Anke and Ripatti, Samuli and Soranzo, Nicole and Toniolo, Daniela and Chasman, Daniel I and Raitakari, Olli and Kao, W H Linda and Ciullo, Marina and Fox, Caroline S and Caulfield, Mark and Bochud, Murielle and Gieger, Christian} } @article {1960, title = {Genetics of food preferences: a first view from silk road populations.}, journal = {J Food Sci}, volume = {77}, year = {2012}, month = {2012 Dec}, pages = {S413-8}, abstract = {

Food preferences are the main factor driving food intake and choice. There are good reasons to suspect some genetic influence on food acceptance, not least because genetic factors are implicated in a number of factors that are likely to be related to food choice. In addition, some food dislikes show themselves early in life, before there is any evidence for aversive experiences. Although taste has been widely studied in regards of pure tastes such as bitter or sweet perception, the relationship between taste-related genes and food preferences has seldom been explored. In this work we investigated relationship of 37 taste-related genes with food preferences. The study was carried out during a scientific expedition through Caucasus and Central Asia (Silk Road) analyzing more than 400 samples from 5 different countries. A food preference questionnaire was administered to each participant and a DNA sample was obtained. Other information, such as age, sex, life style and anthropometrical measures, were also collected. We found significant associations with variants of: (1) TAS1R2 [Correction added after initial online publication on 27 Aug 2012. TAS1R3 was changed to TAS1R2.] gene and liking of Vodka (P= 1.6 {\texttimes} 10(-3)), white wine (P= 4.0 {\texttimes} 10(-4)) and lamb meat (P= 1.6 {\texttimes} 10(-3)); (2) PCLB2 gene and preference for Hot Tea (P= 8.0 {\texttimes} 10(-4)); (3) TPRV1 gene and beet liking (P= 3.8 {\texttimes} 10(-5)); and (4) ITPR3 gene and liking of both lamb meat (5.8 {\texttimes} 10(-4)) and sheep cheese (8.9{\texttimes}10(-4)). These findings give a new insight on a better understanding, of genetic factors influencing food preferences which is critical to the development of effective dietary interventions, especially for people that may be genetically not predisposed for liking specific nutrients.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Azerbaijan, Child, Choice Behavior, Cohort Studies, Female, Food Habits, Food Preferences, Gene Frequency, Genotype, Georgia, Humans, Kazakhstan, Linear Models, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Questionnaires, Tajikistan, Taste, Uzbekistan, Young Adult}, issn = {1750-3841}, doi = {10.1111/j.1750-3841.2012.02852.x}, author = {Pirastu, Nicola and Robino, Antonietta and Lanzara, Carmela and Athanasakis, Emmanouil and Esposito, Laura and Tepper, Beverly J and Gasparini, Paolo} } @article {1907, title = {Genome-wide association and functional follow-up reveals new loci for kidney function.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002584}, abstract = {

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

}, keywords = {African Americans, Aged, Animals, Caspase 9, Cyclin-Dependent Kinases, DEAD-box RNA Helicases, DNA Helicases, European Continental Ancestry Group, Female, Follow-Up Studies, Gene Knockdown Techniques, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Male, Middle Aged, Phosphoric Diester Hydrolases, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002584}, author = {Pattaro, Cristian and K{\"o}ttgen, Anna and Teumer, Alexander and Garnaas, Maija and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Taliun, Daniel and Li, Man and Gao, Xiaoyi and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and O{\textquoteright}Seaghdha, Conall M and Glazer, Nicole and Isaacs, Aaron and Liu, Ching-Ti and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Johnson, Andrew D and Gierman, Hinco J and Feitosa, Mary and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, {\r A}sa and T{\"o}njes, Anke and Dehghan, Abbas and Chouraki, Vincent and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Kollerits, Barbara and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Cavalieri, Margherita and Rao, Madhumathi and Hu, Frank B and Demirkan, Ayse and Oostra, Ben A and de Andrade, Mariza and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Koenig, Wolfgang and Illig, Thomas and D{\"o}ring, Angela and Wichmann, H-Erich and Kolcic, Ivana and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Endlich, Karlhans and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Ketkar, Shamika and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Giulianini, Franco and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Metzger, Marie and Mitchell, Paul and Ciullo, Marina and Kim, Stuart K and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Siscovick, David S and van Duijn, Cornelia M and Borecki, Ingrid and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline C M and Hayward, Caroline and Ridker, Paul and Parsa, Afshin and Bochud, Murielle and Heid, Iris M and Goessling, Wolfram and Chasman, Daniel I and Kao, W H Linda and Fox, Caroline S} } @article {1919, title = {Genomic profiling by whole-genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse.}, journal = {Genes Chromosomes Cancer}, volume = {51}, year = {2012}, month = {2012 Jul}, pages = {644-53}, abstract = {

Despite the excellent survival rate of Wilms tumor (WT) patients, only approximately one-half of children who suffer tumor recurrence reach second durable remission. This underlines the need for novel markers to optimize initial treatment. We investigated 77 tumors using Illumina 370CNV-QUAD genotyping BeadChip arrays and compared their genomic profiles to detect copy number (CN) abnormalities and allelic ratio anomalies associated with the following clinicopathological variables: relapse (yes vs. no), age at diagnosis (<= 24 months vs. >24 months), and disease stage (low stage, I and II, vs. high stage, III and IV). We found that CN gains at chromosome region 1q21.1-q31.3 were significantly associated with relapse. Additional genetic events, including allelic imbalances at chromosome arms 1p, 1q, 3p, 3q, and 14q were also found to occur at higher frequency in relapsing tumors. Interestingly, allelic imbalances at 1p and 14q also showed a borderline association with higher tumor stages. No genetic events were found to be associated with age at diagnosis. This is the first genome wide analysis with single nucleotide polymorphism (SNP) arrays specifically investigating the role of genetic anomalies in predicting WT relapse on cases prospectively enrolled in the same clinical trial. Our study, besides confirming the role of 1q gains, identified a number of additional candidate genetic markers, warranting further molecular investigations.

}, keywords = {Adolescent, Allelic Imbalance, Child, Child, Preschool, Chromosome Aberrations, DNA Copy Number Variations, Female, Genetic Markers, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Infant, Kaplan-Meier Estimate, Male, Polymorphism, Single Nucleotide, Prospective Studies, Recurrence, Wilms Tumor}, issn = {1098-2264}, doi = {10.1002/gcc.21951}, author = {Perotti, Daniela and Spreafico, Filippo and Torri, Federica and Gamba, Beatrice and d{\textquoteright}Adamo, Pio and Pizzamiglio, Sara and Terenziani, Monica and Catania, Serena and Collini, Paola and Nantron, Marilina and Pession, Andrea and Bianchi, Maurizio and Indolfi, Paolo and D{\textquoteright}Angelo, Paolo and Fossati-Bellani, Franca and Verderio, Paolo and Macciardi, Fabio and Radice, Paolo} } @article {1931, title = {Gluten-dependent intestinal autoimmune response.}, journal = {Curr Pharm Des}, volume = {18}, year = {2012}, month = {2012}, pages = {5753-8}, abstract = {

Celiac disease is a multi-systemic autoimmune disease of the small bowel induced by gluten in genetically predisposed subjects. Highly specific and gluten-dependent production of auto-antibodies targeting self-proteins of the transglutaminase family occurs in the intestinal mucosa. These anti-transglutaminase antibodies are found deposited in intestinal and extra-intestinal tissue where they might exert biological effects, together with the intestinal mucosal gliadin-specific T lymphocytes. We conducted a brief review on antitransglutaminase antibodies effects, discussing their roles in the pathogenesis of several clinical manifestations of celiac disease.

}, keywords = {Animals, Autoantibodies, Celiac Disease, Genetic Predisposition to Disease, Gliadin, Glutens, Humans, Intestinal Mucosa, T-Lymphocytes, Transglutaminases}, issn = {1873-4286}, author = {Korponay-Szab{\'o}, Ilma Rita and Simon-Vecsei, Zsafia and De Leo, Luigina and Not, Tarcisio} } @article {1724, title = {Gastroesophageal reflux disease at any cost: a dangerous paediatric attitude.}, journal = {Acta Paediatr}, volume = {100}, year = {2011}, month = {2011 Oct}, pages = {e178-80}, keywords = {Diagnostic Errors, Gastroesophageal Reflux, Humans, Inappropriate Prescribing, Infant, Infant, Newborn, Male, Proton Pump Inhibitors, Spasms, Infantile}, issn = {1651-2227}, doi = {10.1111/j.1651-2227.2011.02315.x}, author = {Taddio, Andrea and Bersanini, Chiara and Basile, Lucio and Fontana, Massimo and Ventura, Alessandro} } @article {1610, title = {Gastrointestinal Foxp3 expression in normal, inflammatory and neoplastic conditions.}, journal = {Pathology}, volume = {43}, year = {2011}, month = {2011 Aug}, pages = {465-71}, abstract = {

BACKGROUND: Foxp3(+) regulatory T lymphocytes (T-regs) represent an important regulatory cell subset in inflammatory, preneoplastic and neoplastic conditions of the gastrointestinal tract.

METHODS: Inflammatory, preneoplastic and neoplastic conditions of the gastrointestinal tract (189 cases) were studied with the evaluation of Foxp3 regulatory T cells based on immunohistochemistry.

RESULTS: Few Foxp3(+) cells were found in controls and inflammatory conditions (oesophagitis, gastritis, coeliac disease, inflammatory bowel disease); in preneoplastic and neoplastic conditions the number of Foxp3(+) cells was significatively increased.

CONCLUSIONS: In normal conditions the number of mucosal lymphocytes is very low throughout the gastro-intestinal tract; in active coeliac disease patients or on a gluten-free diet, only a slight increase in Foxp3(+) cells may be found. Gastrointestinal cancers are associated with higher Foxp3(+) cell proportion, compared with microscopically normal tissue and with precancerous conditions. However, it is uncertain whether the increase in these regulatory cells is a cause or a consequence of tumour progression.

}, keywords = {Adult, Aged, Celiac Disease, Cell Count, Disease Progression, Esophagitis, Female, Forkhead Transcription Factors, Gastric Mucosa, Gastritis, Humans, Inflammatory Bowel Diseases, Lymphocytes, Male, Middle Aged, Precancerous Conditions, Stomach Diseases, Stomach Neoplasms, Young Adult}, issn = {1465-3931}, doi = {10.1097/PAT.0b013e3283485e37}, author = {Villanacci, Vincenzo and Not, Tarcisio and Nascimbeni, Riccardo and Ferrara, Fortunato and Tommasini, Alberto and Manenti, Stefania and Antonelli, Elisabetta and Bassotti, Gabrio} } @article {1652, title = {Genetic predictors of glucocorticoid response in pediatric patients with inflammatory bowel diseases.}, journal = {J Clin Gastroenterol}, volume = {45}, year = {2011}, month = {2011 Jan}, pages = {e1-7}, abstract = {

BACKGROUND: Glucocorticoids (GCs) are used in moderate-to-severe inflammatory bowel diseases (IBD) but their effect is often unpredictable.

AIM: To determine the influence of 4 polymorphisms in the GC receptor [nuclear receptor subfamily 3, group C, member 1 (NR3C1)], interleukin-1β (IL-1β), and NACHT leucine-rich-repeat protein 1 (NALP1) genes, on the clinical response to steroids in pediatric patients with IBD.

METHODS: One hundred fifty-four young IBD patients treated with GCs for at least 30 days and with a minimum follow-up of 1 year were genotyped. The polymorphisms considered are the BclI in the NR3C1 gene, C-511T in IL-1β gene, and Leu155His and rs2670660/C in NALP1 gene. Patients were grouped as responder, dependant, and resistant to GCs. The relation between GC response and the genetic polymorphisms considered was examined using univariate, multivariate, and Classification and Regression Tree (CART) analysis.

RESULTS: Univariate analysis showed that BclI polymorphism was more frequent in responders compared with dependant patients (P=0.03) and with the combined dependant and resistant groups (P=0.02). Moreover, the NALP1 Leu155His polymorphism was less frequent in the GC responsive group compared with resistant (P=0.0059) and nonresponder (P=0.02) groups. Multivariate analysis comparing responders and nonresponders confirmed an association between BclI mutated genotype and steroid response (P=0.030), and between NALP1 Leu155His mutant variant and nonresponders (P=0.033). An association between steroid response and male sex was also observed (P=0.034). In addition, Leu155His mutated genotype was associated with steroid resistance (P=0.034). Two CART analyses supported these findings by showing that BclI and Leu155His polymorphisms had the greatest effect on steroid response (permutation P value=0.046). The second CART analysis also identified age of disease onset and male sex as important variables affecting response.

CONCLUSIONS: These results confirm that genetic and demographic factors may affect the response to GCs in young patients with IBD and strengthen the importance of studying high-order interactions for predicting response.

}, keywords = {Adolescent, Child, Drug Resistance, Female, Follow-Up Studies, Genotype, Glucocorticoids, Humans, Inflammatory Bowel Diseases, Male, Multivariate Analysis, Polymorphism, Genetic, Receptors, Glucocorticoid, Regression Analysis, Retrospective Studies, Sex Factors, Treatment Outcome}, issn = {1539-2031}, doi = {10.1097/MCG.0b013e3181e8ae93}, author = {De Iudicibus, Sara and Stocco, Gabriele and Martelossi, Stefano and Londero, Margherita and Ebner, Egle and Pontillo, Alessandra and Lionetti, Paolo and Barabino, Arrigo and Bartoli, Fiora and Ventura, Alessandro and Decorti, Giuliana} } @article {1760, title = {A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity.}, journal = {Leukemia}, volume = {25}, year = {2011}, month = {2011 Jan}, pages = {66-74}, abstract = {

Asparaginase is an important component for treatment of childhood acute lymphoblastic leukemia (ALL). The basis for interindividual differences in asparaginase sensitivity remains unclear. To comprehensively identify genetic variants important in the cytotoxicity of asparaginase, we used a genome-wide association approach using the HapMap lymphoblastoid cell lines (87 CEU trio members) and 54 primary ALL leukemic blast samples at diagnosis. Asparaginase sensitivity was assessed as the drug concentration necessary to inhibit 50\% of growth (inhibitory concentration (IC)(50)). In CEU lines, we tested 2,390,203 single-nucleotide polymorphism (SNP) genotypes at the individual SNP (P<0.001) and gene level (P<0.05), and identified 329 SNPs representing 94 genes that were associated with asparaginase IC(50). The aspartate metabolism pathway was the most overrepresented among 199 pathways evaluated (P=8.1 {\texttimes} 10(-3)), with primary involvement of adenylosuccinate lyase and aspartyl-tRNA synthetase genes. We validated that SNPs in the aspartate metabolism pathway were also associated with asparaginase sensitivity in primary ALL leukemic blast samples (P=5.5 {\texttimes} 10(-5)). Our genome-wide interrogation of CEU cell lines and primary ALL blasts revealed that inherited genomic interindividual variation in a plausible candidate pathway can contribute to asparaginase sensitivity.

}, keywords = {Antineoplastic Agents, Asparaginase, Aspartic Acid, Cell Line, Genome-Wide Association Study, Humans, Multivariate Analysis, Polymorphism, Single Nucleotide, Precursor Cell Lymphoblastic Leukemia-Lymphoma}, issn = {1476-5551}, doi = {10.1038/leu.2010.256}, author = {Chen, S-H and Yang, W and Fan, Y and Stocco, G and Crews, K R and Yang, J J and Paugh, S W and Pui, C-H and Evans, W E and Relling, M V} } @article {1840, title = {Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Oct}, pages = {1005-11}, abstract = {

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 {\texttimes} 10(-8) to P = 2.3 {\texttimes} 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

}, keywords = {Arteries, Blood Pressure, Case-Control Studies, Follow-Up Studies, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Linkage Disequilibrium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.922}, author = {Wain, Louise V and Verwoert, Germaine C and O{\textquoteright}Reilly, Paul F and Shi, Gang and Johnson, Toby and Johnson, Andrew D and Bochud, Murielle and Rice, Kenneth M and Henneman, Peter and Smith, Albert V and Ehret, Georg B and Amin, Najaf and Larson, Martin G and Mooser, Vincent and Hadley, David and D{\"o}rr, Marcus and Bis, Joshua C and Aspelund, Thor and Esko, T{\~o}nu and Janssens, A Cecile J W and Zhao, Jing Hua and Heath, Simon and Laan, Maris and Fu, Jingyuan and Pistis, Giorgio and Luan, Jian{\textquoteright}an and Arora, Pankaj and Lucas, Gavin and Pirastu, Nicola and Pichler, Irene and Jackson, Anne U and Webster, Rebecca J and Zhang, Feng and Peden, John F and Schmidt, Helena and Tanaka, Toshiko and Campbell, Harry and Igl, Wilmar and Milaneschi, Yuri and Hottenga, Jouke-Jan and Vitart, Veronique and Chasman, Daniel I and Trompet, Stella and Bragg-Gresham, Jennifer L and Alizadeh, Behrooz Z and Chambers, John C and Guo, Xiuqing and Lehtim{\"a}ki, Terho and Kuhnel, Brigitte and Lopez, Lorna M and Polasek, Ozren and Boban, Mladen and Nelson, Christopher P and Morrison, Alanna C and Pihur, Vasyl and Ganesh, Santhi K and Hofman, Albert and Kundu, Suman and Mattace-Raso, Francesco U S and Rivadeneira, Fernando and Sijbrands, Eric J G and Uitterlinden, Andr{\'e} G and Hwang, Shih-Jen and Vasan, Ramachandran S and Wang, Thomas J and Bergmann, Sven and Vollenweider, Peter and Waeber, Gerard and Laitinen, Jaana and Pouta, Anneli and Zitting, Paavo and McArdle, Wendy L and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Glazer, Nicole L and Taylor, Kent D and Harris, Tamara B and Alavere, Helene and Haller, Toomas and Keis, Aime and Tammesoo, Mari-Liis and Aulchenko, Yurii and Barroso, In{\^e}s and Khaw, Kay-Tee and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Eyheramendy, Susana and Org, Elin and S{\~o}ber, Siim and Lu, Xiaowen and Nolte, Ilja M and Penninx, Brenda W and Corre, Tanguy and Masciullo, Corrado and Sala, Cinzia and Groop, Leif and Voight, Benjamin F and Melander, Olle and O{\textquoteright}Donnell, Christopher J and Salomaa, Veikko and d{\textquoteright}Adamo, Adamo Pio and Fabretto, Antonella and Faletra, Flavio and Ulivi, Sheila and Del Greco, Fabiola M and Facheris, Maurizio and Collins, Francis S and Bergman, Richard N and Beilby, John P and Hung, Joseph and Musk, A William and Mangino, Massimo and Shin, So-Youn and Soranzo, Nicole and Watkins, Hugh and Goel, Anuj and Hamsten, Anders and Gider, Pierre and Loitfelder, Marisa and Zeginigg, Marion and Hernandez, Dena and Najjar, Samer S and Navarro, Pau and Wild, Sarah H and Corsi, Anna Maria and Singleton, Andrew and de Geus, Eco J C and Willemsen, Gonneke and Parker, Alex N and Rose, Lynda M and Buckley, Brendan and Stott, David and Orru, Marco and Uda, Manuela and van der Klauw, Melanie M and Zhang, Weihua and Li, Xinzhong and Scott, James and Chen, Yii-Der Ida and Burke, Gregory L and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and D{\"o}ring, Angela and Meitinger, Thomas and Davies, Gail and Starr, John M and Emilsson, Valur and Plump, Andrew and Lindeman, Jan H and Hoen, Peter A C {\textquoteright}t and K{\"o}nig, Inke R and Felix, Janine F and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Breteler, Monique and Debette, St{\'e}phanie and Destefano, Anita L and Fornage, Myriam and Mitchell, Gary F and Smith, Nicholas L and Holm, Hilma and Stefansson, Kari and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Samani, Nilesh J and Preuss, Michael and Rudan, Igor and Hayward, Caroline and Deary, Ian J and Wichmann, H-Erich and Raitakari, Olli T and Palmas, Walter and Kooner, Jaspal S and Stolk, Ronald P and Jukema, J Wouter and Wright, Alan F and Boomsma, Dorret I and Bandinelli, Stefania and Gyllensten, Ulf B and Wilson, James F and Ferrucci, Luigi and Schmidt, Reinhold and Farrall, Martin and Spector, Tim D and Palmer, Lyle J and Tuomilehto, Jaakko and Pfeufer, Arne and Gasparini, Paolo and Siscovick, David and Altshuler, David and Loos, Ruth J F and Toniolo, Daniela and Snieder, Harold and Gieger, Christian and Meneton, Pierre and Wareham, Nicholas J and Oostra, Ben A and Metspalu, Andres and Launer, Lenore and Rettig, Rainer and Strachan, David P and Beckmann, Jacques S and Witteman, Jacqueline C M and Erdmann, Jeanette and van Dijk, Ko Willems and Boerwinkle, Eric and Boehnke, Michael and Ridker, Paul M and J{\"a}rvelin, Marjo-Riitta and Chakravarti, Aravinda and Abecasis, Goncalo R and Gudnason, Vilmundur and Newton-Cheh, Christopher and Levy, Daniel and Munroe, Patricia B and Psaty, Bruce M and Caulfield, Mark J and Rao, Dabeeru C and Tobin, Martin D and Elliott, Paul and van Duijn, Cornelia M} } @article {1672, title = {Geraniol rescues inflammation in cellular and animal models of mevalonate kinase deficiency.}, journal = {In Vivo}, volume = {25}, year = {2011}, month = {2011 Jan-Feb}, pages = {87-92}, abstract = {

BACKGROUND/AIM: The inhibition of the mevalonate pathway through genetic defects such as mevalonate kinase deficiency (MKD) or pharmacological drugs such as aminobisphosphonates causes a shortage of intermediate compounds, in particular geranylgeranyl-pyrophosphate (GGPP), which is associated with the consequent augmented IL-1β release in monocytes. Considering that, due to its biochemical structure, isoprenoid geraniol enters the mevalonate pathway and may revert the genetic or pharmacological inhibition, the present study tested isoprenoid geraniol in cellular and animal MKD models obtained through the use of aminobisphosphonate pamidronate.

MATERIALS AND METHODS: The effect of natural isoprenoid geraniol on bacterial induced-inflammation was evaluated in a monocytic cell line (Raw 264.7) and in Balb/c mice treated with pamidronate.

RESULTS: Geraniol diminished the levels of inflammatory markers induced by pamidronate stimuli in vitro and in vivo.

CONCLUSION: Geraniol may be proposed as a novel therapeutic approach for the orphan disease MKD, and may also be considered for the evaluation of possible inflammatory side-effects of aminobisphosphonates.

}, keywords = {Animals, Anti-Inflammatory Agents, Cell Line, Diphosphonates, Disease Models, Animal, Inflammation, Lipopolysaccharides, Mevalonate Kinase Deficiency, Mice, Mice, Inbred BALB C, Monocytes, Nitric Oxide, Terpenes}, issn = {1791-7549}, author = {Marcuzzi, Annalisa and Crovella, Sergio and Pontillo, Alessandra} } @article {1765, title = {"GINEXMAL RCT: Induction of labour versus expectant management in gestational diabetes pregnancies".}, journal = {BMC Pregnancy Childbirth}, volume = {11}, year = {2011}, month = {2011}, pages = {31}, abstract = {

BACKGROUND: Gestational diabetes (GDM) is one of the most common complications of pregnancies affecting around 7\% of women. This clinical condition is associated with an increased risk of developing fetal macrosomia and is related to a higher incidence of caesarean section in comparison to the general population. Strong evidence indicating the best management between induction of labour at term and expectant monitoring are missing.

METHODS/DESIGN: Pregnant women with singleton pregnancy in vertex presentation previously diagnosed with gestational diabetes will be asked to participate in a multicenter open-label randomized controlled trial between 38+0 and 39+0 gestational weeks. Women will be recruited in the third trimester in the outpatient clinic or in the Day Assessment Unit according to local protocols. Women who opt to take part will be randomized according to induction of labour or expectant management for spontaneous delivery. Patients allocated to the induction group will be admitted to the obstetric ward and offered induction of labour via use of prostaglandins, Foley catheter or oxytocin (depending on clinical conditions). Women assigned to the expectant arm will be sent to their domicile where they will be followed up until delivery, through maternal and fetal wellbeing monitoring twice weekly. The primary study outcome is the Caesarean section (C-section) rate, whilst secondary measurements are maternal and neonatal outcomes. A total sample of 1760 women (880 each arm) will be recruited to identify a relative difference between the two arms equal to 20\% in favour of induction, with concerns to C-section rate. Data will be collected until mothers and newborns discharge from the hospital. Analysis of the outcome measures will be carried out by intention to treat.

DISCUSSION: The present trial will provide evidence as to whether or not, in women affected by gestational diabetes, induction of labour between 38+0 and 39+0 weeks is an effective management to ameliorate maternal and neonatal outcomes. The primary objective is to determine whether caesarean section rate could be reduced among women undergoing induction of labour, in comparison to patients allocated to expectant monitoring. The secondary objective consists of the assessment and comparison of maternal and neonatal outcomes in the two study arms. .

}, keywords = {Adolescent, Adult, Cesarean Section, Diabetes, Gestational, Female, Gestational Age, Humans, Intention to Treat Analysis, Labor, Induced, Patient Selection, Pregnancy, Pregnancy Outcome, Research Design, Watchful Waiting, Young Adult}, issn = {1471-2393}, doi = {10.1186/1471-2393-11-31}, author = {Maso, Gianpaolo and Alberico, Salvatore and Wiesenfeld, Uri and Ronfani, Luca and Erenbourg, Anna and Hadar, Eran and Yogev, Yariv and Hod, Moshe} } @article {1834, title = {Glutamine-enriched nutrition does not reduce mucosal morbidity or complications after stem-cell transplantation for childhood malignancies: a prospective randomized study.}, journal = {Transplantation}, volume = {91}, year = {2011}, month = {2011 Jun 27}, pages = {1321-5}, abstract = {

BACKGROUND: Intravenous glutamine-enriched solution seems to be effective in posttransplant period in decreasing the severity and duration of mucositis. The aim of this randomized study was to determine the benefit of glutamine supplementation both on mucosal morbidity and in posttransplant associated complications.

METHODS: Children undergoing allogeneic hematopoietic stem-cell transplantation (HSCT) for malignant hematological diseases were randomly assigned to standard total parenteral nutrition (S-TPN) or glutamine-enriched (GE)-TPN solution consisting of 0.4 g/kg/day of l-alanine-glutamine dipeptide. This treatment started on the day of HSCT and ended when the patients could orally cover more than 50\% of their daily energy requirements. The severity and the rate of post-HSCT mucositis were based on World Health Organization criteria. All the analyses were conducted on intention-to-treat principle.

RESULTS: One hundred twenty consecutive patients (83 men; median age, 8.1 years) were enrolled. The mean duration of treatment was 23.5 and 23 days in the two treatment arms. The mean calorie intake was 1538 kcal/d in the S-TPN group and 1512 kcal/d in GE-TPN group. All patients were well nourished before and after HSCT. Mucositis occurred in 91.4\% and 91.7\% of patients in S-TPN and GE-TPN arm, respectively (P=0.98). Odds ratio adjusted by type of HSCT was 0.98 (95\% confidence interval, 0.26-2.63). Type and duration of analgesic treatment, clinical outcome (engraftment, graft versus host disease, early morbidity, and mortality, relapse rate up to 180 days post-HSCT) were not significantly different in the two treatment arms.

CONCLUSION: GE-TPN solution does not affect mucositis and outcome in well-nourished HSCT allogeneic patients.

}, keywords = {Adolescent, Analgesia, Child, Child, Preschool, Double-Blind Method, Female, Glutamine, Hematopoietic Stem Cell Transplantation, Humans, Infant, Male, Mucositis, Mucous Membrane, Neoplasms, Odds Ratio, Parenteral Nutrition, Prospective Studies, Recurrence, Stem Cells, Treatment Outcome}, issn = {1534-6080}, doi = {10.1097/TP.0b013e31821ab959}, author = {Uderzo, Cornelio and Rebora, Paola and Marrocco, Emanuela and Varotto, Stefania and Cichello, Francesca and Bonetti, Maurizio and Maximova, Natalia and Zanon, Davide and Fagioli, Franca and Nesi, Francesca and Masetti, Riccardo and Masetti, Roberto and Rovelli, Attilio and Rondelli, Roberto and Valsecchi, Maria Grazia and Cesaro, Simone} } @article {1712, title = {A G to C transversion at the last nucleotide of exon 25 of the MYH9 gene results in a missense mutation rather than in a splicing defect.}, journal = {Eur J Med Genet}, volume = {53}, year = {2010}, month = {2010 Sep-Oct}, pages = {256-60}, abstract = {

MYH9-related disease (MYH9-RD) is a rare autosomal dominant disorder caused by mutations in MYH9, the gene encoding the heavy chain of non-muscle myosin IIA. Patients present with congenital macrothrombocytopenia and inclusion bodies in neutrophils and might develop sensorineural deafness, presenile cataract, and/or progressive nephropathy leading to end-stage renal failure. In two families with macrothrombocytopenia we identified a novel c.3485G~>~C mutation in the last nucleotide of exon 25. Bioinformatic tools for splice site prediction and minigene functional test predicted splicing anomalies of exon 25. However, analysis of RNA purified from patient{\textquoteright}s peripheral blood did not allowed us to detect any anomalies, suggesting that RNA processing is correct at least in this tissue. Therefore, we concluded that c.3485G~>~C leads to a novel missense mutation (p.Arg1162Thr) of myosin-9, which resulted to be slightly degraded in patient platelets. A precise definition of the effect of mutations is fundamental to improve our knowledge into the pathogenetic mechanisms responsible for the disease.

}, keywords = {Adolescent, Adult, Blood Platelets, Computational Biology, Exons, Female, Humans, Inclusion Bodies, Kidney Failure, Chronic, Molecular Motor Proteins, Mutation, Missense, Myosin Heavy Chains, Neutrophils, Nonmuscle Myosin Type IIA, Nucleotides, RNA Splicing, Thrombocytopenia}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2010.06.010}, author = {Vettore, Silvia and De Rocco, Daniela and Gerber, Bernhard and Scandellari, Raffaella and Bianco, Anna Monica and Balduini, Carlo L and Pecci, Alessandro and Fabris, Fabrizio and Savoia, Anna} } @article {1705, title = {Genetic polymorphism of inosine-triphosphate-pyrophosphatase influences mercaptopurine metabolism and toxicity during treatment of acute lymphoblastic leukemia individualized for thiopurine-S-methyl-transferase status.}, journal = {Expert Opin Drug Saf}, volume = {9}, year = {2010}, month = {2010 Jan}, pages = {23-37}, abstract = {

IMPORTANCE OF THE FIELD: Although genetic polymorphisms in the gene encoding human thiopurine methyltransferase (TPMT) are known to have a marked effect on mercaptopurine metabolism and toxicity, there are many patients with wild-type TPMT who develop toxicity. Furthermore, when mercaptopurine dosages are adjusted in patients who are heterozygous at the TPMT locus, there are still some patients who develop toxicity for reasons that are not fully understood. Therefore, we recently studied the effects of a common polymorphism in another gene encoding an enzyme involved in mercaptopurine metabolism (SNP rs1127354 in inosine-triphospate-pyrophosphatase, ITPA), showing that genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of febrile neutropenia following combination chemotherapy of acute lymphoblastic leukemia (ALL) in which mercaptopurine doses are individualized based on TPMT genotype.

AREA COVERED IN THIS REVIEW: In this review, we summarize the knowledge available about the effect and clinical relevance of TPMT and ITPA on mercaptopurine pharmacogenomics, with a particular focus on the use of this medication in pediatric patients with ALL.

WHAT THE READER WILL GAIN: Reader will gain insights into: i) the effects of pharmacogenomic traits on mercaptopurine toxicity and efficacy for the treatment of ALL and ii) individualization strategies that can be used to mitigate toxicity without compromising efficacy in pediatric patients with ALL.

TAKE HOME MESSAGE: Mercaptopurine dose can be adjusted on the basis of TPMT genotype to mitigate toxicity in pediatric patients with ALL. As treatment is individualized in this way for the most relevant genetic determinant of drug response (i.e., for mercaptopurine, TPMT), the importance of other genetic polymorphisms emerges (e.g., ITPA).

}, keywords = {6-Mercaptopurine, Antineoplastic Combined Chemotherapy Protocols, Child, Humans, Individualized Medicine, Methyltransferases, Models, Biological, Neutropenia, Nucleotide Transport Proteins, Polymorphism, Genetic, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Pyrophosphatases}, issn = {1744-764X}, doi = {10.1517/14740330903426151}, author = {Stocco, Gabriele and Crews, Kristine R and Evans, William E} } @article {1616, title = {Gestational diabetes and fetal growth acceleration: induction of labour versus expectant management.}, journal = {Minerva Ginecol}, volume = {62}, year = {2010}, month = {2010 Dec}, pages = {533-9}, abstract = {

AIM: The aim of the study was to compare elective induction of labour at 38 weeks versus expectant management in A1 and A2 gestational diabetes (GDM) pregnancies with fetal growth acceleration. Primary outcome of the study was C-section (CS) rate, while secondary outcomes were macrosomia incidence and adverse perinatal outcomes.

METHODS: A retrospective cohort study was carried out. Data were collected between 1996 and 2006 and evaluated through patients{\textquoteright} records analysis. Differences between the two study groups were investigated using non-parametric tests for continuous variables and χ2 test for categorical ones.

RESULTS: There was no significant difference between induction and expectant management in terms of caesarean section rate. A trend favoring women in the induction group in terms of incidence of macrosomia and neonatal outcomes was identified, but results were not statistically significant.

CONCLUSION: Labour induction at 38 weeks in GDM patients with fetal growth acceleration does not seem to determine an increased incidence of C-section in comparison to expectant management, particularly in case of maternal obesity.

}, keywords = {Adult, Body Mass Index, Cesarean Section, Diabetes, Gestational, Elective Surgical Procedures, Female, Fetal Development, Fetal Macrosomia, Gestational Age, Humans, Incidence, Infant, Newborn, Italy, Labor, Induced, Medical Records, Obesity, Pregnancy, Pregnancy Outcome, Retrospective Studies, Risk Factors, Statistics, Nonparametric, Watchful Waiting}, issn = {0026-4784}, author = {Alberico, S and Businelli, C and Wiesenfeld, U and Erenbourg, A and Maso, G and Piccoli, M and Ronfani, L} }