On Albanese torsors and the elementary obstruction

We show that the elementary obstruction to the existence of 0-cycles of degree 1 on an arbitrary variety X (over an arbitrary field) can be expressed in terms of the Albanese 1-motives associated with dense open subsets of X. Arithmetic applications are given

KAM \`{a} la R

Recently R\"ussmann proposed a new new variant of KAM theory based on a slowly converging iteration scheme. It is the purpose of this note to make this scheme accessible in an even simpler setting, namely for analytic perturbations of constant vector fields on a torus. As a side effect the result may be the shortest complete KAM proof for perturbations of integrable vector fields available so far.Comment: 11 pages, version 2.

Galois sections for abelianized fundamental groups

Given a smooth projective curve $X$ of genus at least 2 over a number field $k$, Grothendieck's Section Conjecture predicts that the canonical projection from the \'etale fundamental group of $X$ onto the absolute Galois group of $k$ has a section if and only if the curve has a rational point. We show that there exist curves where the above map has a section over each completion of $k$ but not over $k$. In the appendix Victor Flynn gives explicit examples in genus 2. Our result is a consequence of a more general investigation of the existence of sections for the projection of the \'etale fundamental group `with abelianized geometric part' onto the Galois group. We give a criterion for the existence of sections in arbitrary dimension and over arbitrary perfect fields, and then study the case of curves over local and global fields more closely. We also point out the relation to the elementary obstruction of Colliot-Th\'el\`ene and Sansuc.Comment: This is the published version, except for a characteristic 0 assumption added in Section 5 which was unfortunately omitted there. Thanks to O. Wittenberg for noticing i

Atypical actinobacillosis in bulls in Argentina: granulomatous dermatitis and lymphadenitis

Actinobacillosis is a common cause of sporadic infection in cattle. It was mostly characterized as a pyogranulomatous inflammation of the tongue, but also soft tissues as lymph nodes, other digestive tract localization and skin. The aim of this study was to describe an episode of granulomatous dermatitis and lymphadenitis affecting a bull herd in Argentina during 2010. Actinobacillus lignieresii was isolated from samples collected from one of the affected bulls, and characteristic lesions were observed. Lesions other than 'wooden tongue' are usually uncommon; however, actinobacillosis should be included as a differential diagnosis for cutaneous diseases

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950–2019: a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2•72 (95% uncertainty interval [UI] 2•66–2•79) in 2000 to 2•31 (2•17–2•46) in 2019. Global annual livebirths increased from 134•5 million (131•5–137•8) in 2000 to a peak of 139•6 million (133•0–146•9) in 2016. Global livebirths then declined to 135•3 million (127•2–144•1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2•1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27•1% (95% UI 26•4–27•8) of global livebirths. Global life expectancy at birth increased from 67•2 years (95% UI 66•8–67•6) in 2000 to 73•5 years (72•8–74•3) in 2019. The total number of deaths increased from 50•7 million (49•5–51•9) in 2000 to 56•5 million (53•7–59•2) in 2019. Under-5 deaths declined from 9•6 million (9•1–10•3) in 2000 to 5•0 million (4•3–6•0) in 2019. Global population increased by 25•7%, from 6•2 billion (6•0–6•3) in 2000 to 7•7 billion (7•5–8•0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58•6 years (56•1–60•8) in 2000 to 63•5 years (60•8–66•1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. Interpretation: Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global burden of 87 risk factors in 204 countries and territories, 1990�2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Rigorous analysis of levels and trends in exposure to leading risk factors and quantification of their effect on human health are important to identify where public health is making progress and in which cases current efforts are inadequate. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a standardised and comprehensive assessment of the magnitude of risk factor exposure, relative risk, and attributable burden of disease. Methods: GBD 2019 estimated attributable mortality, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 87 risk factors and combinations of risk factors, at the global level, regionally, and for 204 countries and territories. GBD uses a hierarchical list of risk factors so that specific risk factors (eg, sodium intake), and related aggregates (eg, diet quality), are both evaluated. This method has six analytical steps. (1) We included 560 risk�outcome pairs that met criteria for convincing or probable evidence on the basis of research studies. 12 risk�outcome pairs included in GBD 2017 no longer met inclusion criteria and 47 risk�outcome pairs for risks already included in GBD 2017 were added based on new evidence. (2) Relative risks were estimated as a function of exposure based on published systematic reviews, 81 systematic reviews done for GBD 2019, and meta-regression. (3) Levels of exposure in each age-sex-location-year included in the study were estimated based on all available data sources using spatiotemporal Gaussian process regression, DisMod-MR 2.1, a Bayesian meta-regression method, or alternative methods. (4) We determined, from published trials or cohort studies, the level of exposure associated with minimum risk, called the theoretical minimum risk exposure level. (5) Attributable deaths, YLLs, YLDs, and DALYs were computed by multiplying population attributable fractions (PAFs) by the relevant outcome quantity for each age-sex-location-year. (6) PAFs and attributable burden for combinations of risk factors were estimated taking into account mediation of different risk factors through other risk factors. Across all six analytical steps, 30 652 distinct data sources were used in the analysis. Uncertainty in each step of the analysis was propagated into the final estimates of attributable burden. Exposure levels for dichotomous, polytomous, and continuous risk factors were summarised with use of the summary exposure value to facilitate comparisons over time, across location, and across risks. Because the entire time series from 1990 to 2019 has been re-estimated with use of consistent data and methods, these results supersede previously published GBD estimates of attributable burden. Findings: The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure. Global declines also occurred for tobacco smoking and lead exposure. The largest increases in risk exposure were for ambient particulate matter pollution, drug use, high fasting plasma glucose, and high body-mass index. In 2019, the leading Level 2 risk factor globally for attributable deaths was high systolic blood pressure, which accounted for 10·8 million (95 uncertainty interval UI 9·51�12·1) deaths (19·2% 16·9�21·3 of all deaths in 2019), followed by tobacco (smoked, second-hand, and chewing), which accounted for 8·71 million (8·12�9·31) deaths (15·4% 14·6�16·2 of all deaths in 2019). The leading Level 2 risk factor for attributable DALYs globally in 2019 was child and maternal malnutrition, which largely affects health in the youngest age groups and accounted for 295 million (253�350) DALYs (11·6% 10·3�13·1 of all global DALYs that year). The risk factor burden varied considerably in 2019 between age groups and locations. Among children aged 0�9 years, the three leading detailed risk factors for attributable DALYs were all related to malnutrition. Iron deficiency was the leading risk factor for those aged 10�24 years, alcohol use for those aged 25�49 years, and high systolic blood pressure for those aged 50�74 years and 75 years and older. Interpretation: Overall, the record for reducing exposure to harmful risks over the past three decades is poor. Success with reducing smoking and lead exposure through regulatory policy might point the way for a stronger role for public policy on other risks in addition to continued efforts to provide information on risk factor harm to the general public. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Early onset gastric cancer: on the road to unravelling gastric carcinogenesis

Gastric cancer is the fourth most common malignancy in the world and ranks second in terms of cancer-related death. It is thought to result from a combination of environmental factors and the accumulation of alterations due to increasing genetic instability, and consequently affects mainly older patients, often after a long period of atrophic gastritis. Tumorigenesis is considered a multistep process involving generalized and specific genetic alterations that drive the progressive transformation of cells into cancer. Central to this transformation are genetic or epigenetic changes in the genome which specifically activate oncogenes with a dominant gain of function, and produce alterations in tumor suppressor genes which cause loss of function. There is however by no means a clear-cut pattern of mutations in gastric cancers, and the genetic research can often be hampered by the diversity of changes that are induced by Helicobacter pylori infection, diet, ageing and other environmental factors. Tumors are unquestionably riddled with genetic changes yet we are faced with an unsolvable puzzle with respect to a temporal relationship. In order to solve this problem, one approach is to investigate tumors that are less influenced by these environmental factors. Gastric cancers occurring in young patients, known as early-onset gastric cancers, the main subject of this thesis, provide an ideal background on which to try and uncover the initiating stages in gastric carcinogenesis, as the role of genetics is presumably greater than in older patients, with less of an impact from environmental carcinogens. Ultimately they may provide vital information about molecular genetic pathways in sporadic cancers and may aid in the unraveling of gastric carcinogenesis as discussed in chapter 2. In chapter 3 microsatellite instability, is consistently absent in young patients. In chapter 4 we exclude the role of RUNX3 as a tumour suppressor gene in EOGC. In chapter 5 we find that the molecular expression profile of EOGC and conventional gastric cancers differ with EOGCs having a COX-2 Low, TFF-1 expressing phenotype. In chapter 6 we see that the-765 G/C promoter polymorphism in COX-2 is significantly associated with gastric cancer. The expression of low molecular weight isoforms of cyclin E are found to differ in EOGC in chapter 7 and are shown to be a positive prognostic indicator. In chapter 8 we find frequent loss of the putative tumor suppressor gene cdc4/FBXW7 in EOGC and in chapter 9 using representational difference analysis to characterize genetic changes particular to diffuse gastric cancer, a novel amplification at 11p 12-13 was found and was associated with overexpression of CD44v6 especially in EOGC. In Chapter 10, we report the molecular characterization of eight primary gastric carcinomas, corresponding xenografts, and two novel gastric carcinoma cell lines using MS-MLPA, IHC and mutation analysis. In chapter 11 we look at the phenomenon of collision tumors of the gastro-esophageal junction from the molecular genetic prospective and in chapter 12 we describe an inflammatory myofibroblastic tumor with an ALK/TPM3 fusion, a rare tumor which is also found in young people and children

Early-onset gastric cancer: Learning lessons from the young.

There is by no means a clear-cut pattern of mutations contributing to gastric cancers, and gastric cancer research can be hampered by the diversity of factors that can induce gastric cancer, such as Helicobacter pylori infection, diet, ageing and other environmental factors. Tumours are unquestionably riddled with genetic changes yet we are faced with an unsolvable puzzle with respect to a temporal relationship. It is postulated that inherited genetic factors may be more important in early-onset gastric cancer (EOGC) than in gastric cancers found in older patients as they have less exposure to environmental carcinogens. EOGC, therefore, could provide a key to unravelling the genetic changes in gastric carcinogenesis. Gastric cancers occurring in young patients provide an ideal background on which to try and uncover the initiating stages of gastric carcinogenesis. This review summarizes the literature regarding EOGC and also presents evidence that these cancers have a unique molecular-genetic phenotype, distinct from conventional gastric cancer

Molecular analysis of primary gastric cancer, corresponding xenografts, and 2 novel gastric carcinoma cell lines reveals novel alterations in gastric carcinogenesis.

Contains fulltext : 52642.pdf (publisher's version ) (Closed access)We report the molecular characterization of 8 primary gastric carcinomas, corresponding xenografts, and 2 novel gastric carcinoma cell lines. We compared the tumors and cell lines, with respect to histology, immunohistochemistry, copy number, and hypermethylation of up to 38 genes using methylation-specific multiplex ligation-dependent probe amplification, and TP53 and CDH1 mutation analysis where relevant. The primary tumors and xenografts were histologically comparable and shared expression of 11 of 14 immunohistochemical markers (E-cadherin, beta-catenin, COX-2, p53, p16, TFF1, cyclin E, MLH1, SMAD4, p27, KLK3, CASR, CHFR, and DAPK1). Gains of CASR, DAPK1, and KLK3--not yet described in gastric cancer--were present in the primary tumors, xenografts, and cell lines. The most prominent losses occurred at CDKN2A (p16), CDKN2B (p15), CDKN1B (p27/KIP1), and ATM. Except for ATM, these losses were found only in the cell line or xenograft, suggesting an association with tumor progression. However, examination of p16 and p27 in 174 gastric cancers using tissue microarrays revealed no significant correlation with tumor stage or lymph node status. Further losses and hypermethylation were detected for MLH1, CHFR, RASSF1, and ESR, and were also seen in primary tumors. Loss of CHFR expression correlated significantly with the diffuse phenotype. Interestingly, we found the highest rate of methylation in primary tumors which gave rise to cell lines. In addition, both cell lines harbored mutations in CDH1, encoding E-cadherin. Xenografts and gastric cancer cell lines remain an invaluable research tool in the uncovering of the multistep progression of cancer. The frequent gains, losses, and hypermethylation reported in this study indicate that the involved genes or chromosomal regions may be relevant to gastric carcinogenesis