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Mutations in multiple genes of the growth hormone/IGF-I axis have been identified in syndromes marked by growth failure. However, no pathogenic human mutations have been reported in the six high-affinity IGF-binding proteins (IGFBPs) or their regulators, such as the met alloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) that is hypothesized to increase IGF-I bioactivity by specific proteolytic cleavage of IGFBP-3 and -5. Multiple members of two unrelated families presented with progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density and elevated circulating total IGF-I, IGFBP-3, and -5, acid labile subunit, and IGF-II concentrations. Two different homozygous mutations in PAPPA2, p.D643fs25* and p.Ala1033Val, were associated with this novel syndrome of growth failure. In vitro analysis of IGFBP cleavage demonstrated that both mutations cause a complete absence of PAPP-A2 proteolytic activity. Size-exclusion chromatography showed a significant increase in IGF-I bound in its ternary complex. Free IGF-I concentrations were decreased. These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP-A2 in releasing IGF-I from its BPs. ; Research reported in this publication was supported by Fondos de Investigación Sanitaria and fondos FEDER (Grants PI100747 and PI1302195 to JA, PI1302481 to LAPJ), Ministerio de Ciencia e Innovación (Grants BFU2011–27492 and BFU2014-51836-C2-2-R to JAC), Centro de Investigación Biomédica en Red Fisiopatología de Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (JA), Fundación Endocrinología y Nutrición (JA), the Catalan Government (2014SGR1468 and ICREA Acadèmica to LAPJ), the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (Award Number K23HD07335 to AD), The Danish Council for Independent Research (FNU), and the Novo Nordisk Foundation (CO). A CIBER for Rare Diseases (CIBERER) fellowship supported CSJ

Background Transthyretin amyloidosis (also known as ATTR amyloidosis) is a systemic, life-threatening disease characterized by transthyretin (TTR) fibril deposition in organs and tissue. A definitive diagnosis of ATTR amyloidosis is often a challenge, in large part because of its heterogeneous presentation. Although ATTR amyloidosis was previously considered untreatable, disease-modifying therapies for the treatment of this disease have recently become available. This article aims to raise awareness of the initial symptoms of ATTR amyloidosis among general practitioners to facilitate identification of a patient with suspicious signs and symptoms. Methods These consensus recommendations for the suspicion and diagnosis of ATTR amyloidosis were developed through a series of development and review cycles by an international working group comprising key amyloidosis specialists. This working group met to discuss the barriers to early and accurate diagnosis of ATTR amyloidosis and develop a consensus recommendation through a thorough search of the literature performed using PubMed Central. Results The cardiac and peripheral nervous systems are most frequently involved in ATTR amyloidosis; however, many patients often also experience gastrointestinal and other systemic manifestations. Given the multisystemic nature of symptoms, ATTR amyloidosis is often misdiagnosed as a more common disorder, leading to significant delays in the initiation of treatment. Although histologic evaluation has been the gold standard to confirm ATTR amyloidosis, a range of tools are available that can facilitate early and accurate diagnosis. Of importance, genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy. Conclusions A diagnostic algorithm based on initial red flag symptoms and manifestations of cardiac or neurologic involvement will facilitate identification by the general practitioner of a patient with clinically suspicious symptoms, enabling subsequent referral of the patient to a multidisciplinary specialized medical center.

The field of social policy has a rich history but policies on the ground are undergoing intensive change. Governments around the world are responding to political, economic and financial pressures, many of them linked to the global economic crisis. National agendas typically have social policy at or close to the centre. This latest edition of Social Policy Review presents an up-to-date and diverse review of the best in social policy scholarship. It brings together research by an exciting range of internationally renowned authors and examines important debates in British and international social policy. This edition includes a special focus in the third part on work, employment and insecurity. Social Policy Review is essential reading for social policy academics and students and for anyone who is interested in the social and economic implications of government policy

Funding Information: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award "STratifying Resilience and Depression Longitudinally" (STRADL) Reference 104036/Z/14/Z). CG is supported by The Medical Research Council and The University of Edinburgh through the Precision Medicine Doctoral Training program. SRC is supported by the UK Medical Research Council [MR/R024065/1] and a National Institutes of Health (NIH) research grant R01AG054628. Acknowledgements The authors thank all of the STRADL and Generation Scotland participants for their time and effort taking part in this study. We would also like to thank all of the research assistants, clinicians and technicians for their help in the collecting this data. ; Peer reviewed ; Publisher PDF

We report the first APOGEE metallicities and alpha-element abundances measured for 3600 red giant stars spanning a large radial range of both the Large (LMC) and Small Magellanic Clouds, the largest Milky Way (MW) dwarf galaxies. Our sample is an order of magnitude larger than that of previous studies and extends to much larger radial distances. These are the first results presented that make use of the newly installed southern APOGEE instrument on the du Pont telescope at Las Campanas Observatory. Our unbiased sample of the LMC spans a large range in metallicity, from [Fe/H] = -0.2 to very metal-poor stars with [Fe/H] -2.5, the most metal-poor Magellanic Cloud (MC) stars detected to date. The LMC [alpha/Fe]-[Fe/H] distribution is very flat over a large metallicity range but rises by similar to 0.1 dex at -1.0 < [Fe/H] less than or similar to -0.5. We interpret this as a sign of the known recent increase in MC star formation activity and are able to reproduce the pattern with a chemical evolution model that includes a recent "starburst." At the metal-poor end, we capture the increase of [alpha/Fe] with decreasing [Fe/H] and constrain the "alpha-knee" to [Fe/H] less than or similar to -2.2 in both MCs, implying a low star formation efficiency of similar to 0.01 Gyr(-1). The MC knees are more metal-poor than those of less massive MW dwarf galaxies such as Fornax, Sculptor, or Sagittarius. One possible interpretation is that the MCs formed in a lower-density environment than the MW, a hypothesis that is consistent with the paradigm that the MCs fell into the MW's gravitational potential only recently. ; State Research Agency (AEI) of the Spanish Ministry of Science, Innovation and Universities (MCIU) European Union (EU) AYA2017-88254-P National Science Foundation (NSF) AST-1801940 Crafoord Foundation Swedish Research Council Ruth och Nils-Erik Stenbacks stiftelse Physics Frontier Center/JINA Center for the Evolution of the Elements (JINA-CEE) - US National Science Foundation PHY 14-30152 Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) CONICYT FONDECYT 3180210 1170364 Becas Iberoamerica Investigador 2019, Banco Santander Chile Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) CONICYT PIA/BASAL AFB-170002 Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT) Universidad Nacional Autónoma de México IN109919 Alfred P. Sloan Foundation United States Department of Energy (DOE) Center for High-Performance Computing at the University of Utah

Since its initial publication, Critical Digital Studies has proven an indispensable guide to understanding digitally mediated culture. Bringing together the leading scholars in this growing field, internationally renowned scholars Arthur and Marilouise Kroker present an innovative and interdisciplinary survey of the relationship between humanity and technology. The reader offers a study of our digital future, a means of understanding the world with new analytic tools and means of communication that are defining the twenty-first century.The second edition includes new essays on the impact of social networking technologies and new media. A new section – "New Digital Media" – presents important, new articles on topics including hacktivism in the age of digital power and the relationship between gaming and capitalism. The extraordinary range and depth of the first edition has been maintained in this new edition. Critical Digital Studies will continue to provide the leading edge to readers wanting to understand the complex intersection of digital culture and human knowledge

As many social inequalities widen, this is a crucial survey of local authorities' evolving role in health, social care and wellbeing. Health and social and public policy experts review structural changes in provision and procurement, and explore social determinants of health including intergenerational needs and housing. With detailed assessments of regional disparities and case studies of effective strategies and interventions from local authorities, this collaborative study addresses complex issues (Wicked Issues), considers where responsibility for wellbeing lies and points the way to future policy-making. The Centre for Partnering (CfP) is a key outcome of this innovative review along with Bonner's previous work Social Determinants of Health (2017)

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files ; INTRODUCTION: We investigate the risks of subsequent primary bone cancers after childhood and adolescent cancer in 12 European countries. For the first time, we satisfactorily address the risks beyond 40 years from diagnosis and beyond 40 years of age among all survivors. METHODS: This largest-ever assembled cohort comprises 69 460 five-year survivors of cancer diagnosed before age 20 years. Standardized incidence ratios, absolute excess risks, and multivariable-adjusted relative risks and relative excess risks were calculated. All statistical tests were two-sided. RESULTS: Overall, survivors were 21.65 times (95% confidence interval = 18.97 to 24.60 times) more likely to be diagnosed with a subsequent primary bone cancer than expected from the general population. The greatest excess numbers of bone cancers were observed after retinoblastoma, bone sarcoma, and soft tissue sarcoma. The excess number of bone cancers declined linearly with both years since diagnosis and attained age (all P < .05). Beyond 40 years from diagnosis and age 40 years, there were at most 0.45 excess bone cancers among all survivors per 10 000 person-years at risk; beyond 30 years from diagnosis and age 30 years, there were at most 5.02 excess bone cancers after each of retinoblastoma, bone sarcoma, and soft tissue sarcoma, per 10 000 person-years at risk. CONCLUSIONS: For all survivors combined and the cancer groups with the greatest excess number of bone cancers, the excess numbers observed declined with both age and years from diagnosis. These results provide novel, reliable, and unbiased information about risks and risk factors among long-term survivors of childhood and adolescent cancer. ; European Union Italian Association for Cancer Research Compagnia San Paolo Fondo Chiara Rama OLUS Swedish Childhood Cancer Foundation Norwegian Childhood Cancer Foundation ...

The Parkinson Progression Marker Initiative (PPMI) is a comprehensive observational, international, multicenter study designed to identify PD progression biomarkers both to improve understanding of disease etiology and course and to provide crucial tools to enhance the likelihood of success of PD modifying therapeutic trials. The PPMI cohort will comprise 400 recently diagnosed PD and 200 healthy subjects followed longitudinally for clinical, imaging and biospecimen biomarker assessment using standardized data acquisition protocols at twenty-one clinical sites. All study data will be integrated in the PPMI study database and will be rapidly and publically available through the PPMI web site- www.ppmi-info.org. Biological samples including longitudinal collection of blood, cerebrospinal fluid (CSF) and urine will be available to scientists by application to an independent PPMI biospecimen review committee also through the PPMI web site. PPMI will rely on a partnership of government, PD foundations, industry and academics working cooperatively. This approach is crucial to enhance the potential for success of this ambitious strategy to develop PD progression biomarkers that will accelerate research in disease modifying therapeutics.

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available. ; This investigation was supported in part by the following sources: NIH/NINDS awards R01NS088155 and 1R01NS099240, the Valhalla Charitable Foundation, and the Heidrich Family and Friends Foundation (Sergio E. Baranzini). US National Multiple Sclerosis Society (TA 3056-A-2), the Harvard NeuroDiscovery Center and an Intel Parallel Computing Center award (Nikolaos A. Patsopoulos). Swedish Medical Research Council; Swedish Research Council for Health, Working Life and Welfare, Knut and Alice Wallenberg Foundation, AFA insurance, Swedish Brain Foundation, the Swedish Association for Persons with Neurological Disabilities. Cambridge NIHR Biomedical Research Centre, UK Medical Research Council (G1100125) and the UK MS society (861/07). NIH/NINDS: R01 NS049477, NIH/NIAID: R01 AI059829, NIH/NIEHS: R01 ES0495103. Research Council of Norway grant 196776 and 240102. NINDS/NIH R01NS088155. Oslo MS association. Research Council KU Leuven, Research Foundation Flanders. AFM, AFM-Généthon, CIC, ARSEP, ANR-10-INBS-01 and ANR-10-IAIHU-06. Research Council KU Leuven, Research Foundation Flanders. Inserm ATIP-Avenir Fellowship and Connect-Talents Award. German Ministry for Education and Research, German Competence Network MS (BMBF KKNMS). Oslo MS association, Research Council of Norway grant 196776 and 240102. Dutch MS Research Foundation. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. German Ministry for Education and Research, German Competence Network MS (BMBF KKNMS). Italian Foundation of Multiple Sclerosis (FISM). NMSS (RG 4680A1/1). German Ministry for Education and Research, German Competence Network MS (BMBF KKNMS). Lundbeck Foundation and Benzon Foundation. ; updatedVersion

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intraindividual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available. ; This investigation was supported in part by the following sources: NIH/NINDS awards R01NS088155 and 1R01NS099240, the Valhalla Charitable Foundation, and the Heidrich Family and Friends Foundation (Sergio E. Baranzini). US National Multiple Sclerosis Society (TA 3056-A-2), the Harvard NeuroDiscovery Center and an Intel Parallel Computing Center award (Nikolaos A. Patsopoulos). Swedish Medical Research Council; Swedish Research Council for Health, Working Life and Welfare, Knut and Alice Wallenberg Foundation, AFA insurance, Swedish Brain Foundation, the Swedish Association for Persons with Neurological Disabilities. Cambridge NIHR Biomedical Research Centre, UK Medical Research Council (G1100125) and the UK MS society (861/07). NIH/NINDS: R01 NS049477, NIH/NIAID: R01 AI059829, NIH/NIEHS: R01 ES0495103. Research Council of Norway grant 196776 and 240102. NINDS/NIH R01NS088155. Oslo MS association. Research Council KU Leuven, Research Foundation Flanders. AFM, AFM-Généthon, CIC, ARSEP, ANR-10-INBS-01 and ANR-10-IAIHU-06. Research Council KU Leuven, Research Foundation Flanders. Inserm ATIP-Avenir Fellowship and Connect-Talents Award. German Ministry for Education and Research, German Competence Network MS (BMBF KKNMS). Oslo MS association, Research Council of Norway grant 196776 and 240102. Dutch MS Research Foundation. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. German Ministry for Education and Research, German Competence Network MS (BMBF KKNMS). Italian Foundation of Multiple Sclerosis (FISM). NMSS (RG 4680A1/1). German Ministry for Education and Research, German Competence Network MS (BMBF KKNMS). Lundbeck Foundation and Benzon Foundation. ; publishedVersion