Electrically isolated propagating streamer heads formed by strong electron attachment

Streamer discharges occur in the early stages of electric breakdown of gases in lightning, as well as in plasma and high voltage technology. They are growing filaments characterized by a curved charge layer at their tip that enhances the electric field ahead of them. In this study, we analyze the effect of strong electron attachment on the propagation of positive streamers. Strong attachment occurs in insulating gases like sulphur hexafluoride (SF6) or in air at increased density. We use the classical fluid approximation with photo-ionization for streamers in ambient air, and we artificially increase the electron attachment rate where the field is below the breakdown value. This modification approximates air pressures above 1 bar at room temperature. We find that the streamer head can keep propagating even though the ionized channel loses its conductivity closely behind the head; hence, even if it is electrically isolated. We describe how, depending on the attachment rate, the streamer propagation in a constant electric field can be accelerating, uniformly translating, or stagnating

Simulations of positive streamers in air in different electric fields: Steady motion of solitary streamer heads and the stability field

We simulate and characterize positive streamers in ambient air in homogeneous background electric fields from 4.5 to 26 kV/cm in a 4 cm gap. They can accelerate or decelerate depending on the background electric field. Many experiments have shown that a streamer keeps propagating in a stable manner in the so-called stability field of 4.5 to 5 kV/cm. Our fluid streamer simulations in STP air show that: (1) In a homogeneous field larger than 4.675 kV/cm, a single streamer accelerates, and in a lower field, it decelerates and eventually stagnates with a small radius and very high field enhancement. (2) In a field of 4.675 kV/cm, the streamer head propagates with an approximately constant velocity of 6.7 x 104 m/s and an optical radius of 55 μm over distances of several centimeters as a stable coherent structure. These values for the radius and velocity agree well with measurements of so-called minimal streamers. (3) Behind the uniformly translating streamer head, the channel conductivity decreases due to electron attachment and recombination, and the electric field returns to its background value about 1 cm behind the head. The propagation behavior of the solitary streamer agrees with the original definition of the stability field, which is the homogeneous field in which a streamer can propagate with a constant speed and shape

Simulations of positive streamers in air in different electric fields: Steady motion of solitary streamer heads and the stability field

We simulate and characterize positive streamers in ambient air in homogeneous background electric fields from 4.5 to 26 kV/cm in a 4 cm gap. They can accelerate or decelerate depending on the background electric field. Many experiments have shown that a streamer keeps propagating in a stable manner in the so-called stability field of 4.5 to 5 kV/cm. Our fluid streamer simulations in STP air show that: (1) In a homogeneous field larger than 4.675 kV/cm, a single streamer accelerates, and in a lower field, it decelerates and eventually stagnates with a small radius and very high field enhancement. (2) In a field of 4.675 kV/cm, the streamer head propagates with an approximately constant velocity of 6.7 x 104 m/s and an optical radius of 55 μm over distances of several centimeters as a stable coherent structure. These values for the radius and velocity agree well with measurements of so-called minimal streamers. (3) Behind the uniformly translating streamer head, the channel conductivity decreases due to electron attachment, and the electric field returns to its background value about 1 cm behind the head. The propaga

Sox9-Haploinsufficiency Causes Glucose Intolerance in Mice

The HMG box transcription factor Sox9 plays a critical role in progenitor cell expansion during pancreas organogenesis and is required for proper endocrine cell development in the embryo. Based on in vitro studies it has been suggested that Sox9 controls expression of a network of important developmental regulators, including Tcf2/MODY5, Hnf6, and Foxa2, in pancreatic progenitor cells. Here, we sought to: 1) determine whether Sox9 regulates this transcriptional network in vivo and 2) investigate whether reduced Sox9 gene dosage leads to impaired glucose homeostasis in adult mice. Employing two genetic models of temporally-controlled Sox9 inactivation in pancreatic progenitor cells, we demonstrate that contrary to in vitro findings, Sox9 is not required for Tcf2, Hnf6, or Foxa2 expression in vivo. Moreover, our analysis revealed a novel role for Sox9 in maintaining the expression of Pdx1/MODY4, which is an important transcriptional regulator of beta-cell development. We further show that reduced beta-cell mass in Sox9-haploinsufficient mice leads to glucose intolerance during adulthood. Sox9-haploinsufficient mice displayed 50% reduced beta-cell mass at birth, which recovered partially via a compensatory increase in beta-cell proliferation early postnatally. Endocrine islets from mice with reduced Sox9 gene dosage exhibited normal glucose stimulated insulin secretion. Our findings show Sox9 plays an important role in endocrine development by maintaining Ngn3 and Pdx1 expression. Glucose intolerance in Sox9-haploinsufficient mice suggests that mutations in Sox9 could play a role in diabetes in humans

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Genomic and functional characteristics of DNA copy number variants associated with developmental abnormalities

Small gains and losses of chromosomal DNA, called copy number variants (CNVs), are the cause of many human developmental abnormalities detected before or after birth. Clinically-significant CNVs are found in 2-6% of developmentally arrested embryos and fetuses (termed miscarriage) and in ~15% of children with postnatal developmental abnormalities, typically including abnormal brain function and leading to neuro-developmental delay (NDD). The overall goal of my PhD project was to characterize CNVs found in both miscarriages and in children with NDD in order to identify candidate genes that cause these two aspects of abnormal development. I used a multi-faceted approach consisting of bioinformatics, human cell-line analysis and transgenic animal model investigations. I characterized CNVs reported in miscarriages from literature as well as from our laboratory by using bioinformatics approaches to determine the CNVs size, gene content, gene density and function, known gene knockout murine phenotype, and biological pathway enrichment for all miscarriage CNV genes. My analysis identified several genes from miscarriage CNVs with important functions during prenatal development and pregnancy (e.g. CDKN1C and TIMP2) and enrichment of genes from miscarriage CNVs in biological pathways and processes relevant to embryo/fetal development and feto-maternal interaction (e.g. immune response). For discovery of candidate genes responsible for childhood NDD, I characterized CNVs mapping to a chromosome region, 2p15p16.1, which are known to be associated with multiple postnatal developmental abnormalities and NDD (termed 2p15p16.1 microdeletion syndrome). I performed detailed phenotype and CNV analysis of 33 patients with 2p15p16.1 microdeletions and identified 3 candidate genes (XPO1, REL, and BCL11A) for the developmental problems. By studying their expression in patient cell-lines as well as phenotypic consequences of the loss or gain of their expression in zebrafish, I confirmed their role in developmental abnormalities associated with this syndrome. I have also explored the role of non-coding sequences from this CNV in regulation of one of the candidate genes, BCL11A. The results of my study provide a blueprint for identification of genes with a role in abnormal development by characterizing CNVs. Understanding the cause of the developmental abnormalities opens paths for exploring possibilities for their improved diagnosis, prevention, and potential cure.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

Signet ring carcinoma of ampulla of vater

Signet ring carcinoma is a common type of adenocarcinoma of stomach but its occurrence in ampulla of Vater is extremely rare. There are only a few previous reported cases of signet ring carcinoma of ampulla of Vater. Here we reported a 61-year-old woman with obstructive jaundice. Ultrasonography and computed tomography (CT scan) examination showed intra- and extrahepatic bile duct dilatation. Endoscopic examination with biopsies revealed a small-size mass in ampulla of Vater with diagnosis of signet ring carcinoma. On consequent pancreatoduodenectomy the tumor was diagnosed as T2N0M0, stage IB. Because of the specific site of signet ring carcinoma of ampulla of Vater, the tumor seems to present itself at an early stage of disease. We review in the literature to suggest our idea

Intratumoral and Peritumoral Mast Cells in Malignant Melanoma: An Immunohistochemical Study

Background: The aim of the current study was to determine mast cell infiltration in malignant melanoma by immunohistochemistry method and its relationship with some of the cancer prognostic factors, including age, sex, and depth of the tumor. Materials and Methods: In this retrospective analytic cross-sectional study, paraffin-embedded tissue blocks of patients with cutaneous malignant melanoma who had undergone excisional biopsy were studied. Mast cells count in studied cases in different stages of the tumor depth was evaluated by mast cell tryptase immunohistochemistry method. Mast cells infiltration was evaluated both inside the tumor and peritumoral area. Tumor infiltrating lymphocytes (TILs) was also determined. Distribution of intratumoral and peritumoral mast cells and TILs was compared in different stages tof tumor depth. Results: In this study, 51 cases with melanoma were studied. Mean ± standard deviation (SD) of intratumoral mast cells in stages 1, 2, and 3 was 9.4 ± 4.2, 10.8 ± 5.1, and 2.1 ± 2.3, respectively (P = 0.000). Mean ± SD of peritumoral mast cells in stages 1, 2 and 3 was 13.4 ± 2.4, 16.6 ± 2.4 and 8.2 ± 4.6, respectively (P = 0.000). There was a significant direct relationship between depth of the tumor and TIL (P = 0.000) and distribution of intratumoral (P = 0.000) and peritumoral mast cells (P = 0.000). Conclusion: Lower distribution of intratumoral and peritumoral mast cells and TILs in higher stages of tumor depth in malignant melanoma suggests a possible inhibitory effect of infiltrating mast cells and lymphocytes on the progression of this tumor