Helicobacter pylori Infection Is Associated With Carotid Intima and Media Thickening : A Systematic Review and Meta-Analysis

Background Helicobacter pylori (H. pylori) infection affects ≈4.4 billion people worldwide. Several studies suggest that this pathogen impacts the digestive system, causing diverse and severe conditions, and results in extragastrointestinal disorders like vascular diseases. Our study aims to examine the association between H. pylori infection and carotid intima-media thickness. Methods and Results Electronic databases (MEDLINE, Embase, CENTRAL, Web of Science, and Scopus) were searched for studies, comparing the thickness of the carotid intima-media in H. pylori-infected and noninfected individuals listed until October 20, 2020. Statistical analyses were performed using the random effects meta-analysis of model of weighted mean differences with the corresponding 95% CI using the DerSimonian and Laird method. The protocol was registered in advance in PROSPERO (International Prospective Register of Systematic Reviews; CRD42021224485). Thirteen studies were found meeting inclusion criteria for our systematic review and meta-analysis, presenting data on the thickness of the carotid intima-media considering the presence of H. pylori infection. Altogether, 2298 individuals' data were included (1360 H. pylori positive, 938 negative). The overall carotid intima-media thickness was significantly larger among infected patients compared with uninfected participants (weighted mean difference: 0.07 mm; 95% CI, 0.02-0.12; P=0.004; I2=91.1%; P<0.001). In case of the right common carotid artery, the intima-media thickening was found to be significant as well (weighted mean difference, 0.08 mm; 95% CI, 0.02-0.13, P=0.007; I2=85.1%; P<0.001), while it showed no significance in the left common carotid artery (weighted mean difference, 0.12 mm; 95% CI, -0.05 to 0.28, P=0.176; I2=97.4%; P<0.001). Conclusions H. pylori infection is associated with increased carotid intima-media thickness. Therefore, the infection may indirectly contribute to the development of major vascular events

Fire hazard modulation by long-term dynamics in land cover and dominant forest type in eastern and central Europe

Wildfire occurrence is influenced by climate, vegetation and human activities. A key challenge for understanding the risk of fires is quantifying the mediating effect of vegetation on fire regimes. Here, we explore the relative importance of Holocene land cover, land use, dominant functional forest type, and climate dynamics on biomass burning in temperate and boreo-nemoral regions of central and eastern Europe over the past 12 kyr. We used an extensive data set of Holocene pollen and sedimentary charcoal records, in combination with climate simulations and statistical modelling. Biomass burning was highest during the early Holocene and lowest during the mid-Holocene in all three ecoregions (Atlantic, continental and boreo-nemoral) but was more spatially variable over the past 3–4 kyr. Although climate explained a significant variance in biomass burning during the early Holocene, tree cover was consistently the highest predictor of past biomass burning over the past 8 kyr. In temperate forests, biomass burning was high at ~ 45% tree cover and decreased to a minimum at between 60% and 70% tree cover. In needleleaf-dominated forests, biomass burning was highest at ~60 %–65%tree cover and steeply declined at > 65% tree cover. Biomass burning also increased when arable lands and grasslands reached ~15 %–20 %, although this relationship was variable depending on land use practice via ignition sources, fuel type and quantities. Higher tree cover reduced the amount of solar radiation reaching the forest floor and could provide moister, more wind-protected microclimates underneath canopies, thereby decreasing fuel flammability. Tree cover at which biomass burning increased appears to be driven by warmer and drier summer conditions during the early Holocene and by increasing human influence on land cover during the late Holocene. We suggest that longterm fire hazard may be effectively reduced through land cover management, given that land cover has controlled fire regimes under the dynamic climates of the Holocene

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

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

Helicobacter pylori Infection Is Associated With Carotid Intima and Media Thickening: A Systematic Review and Meta‐Analysis

Background Helicobacter pylori (H. pylori) infection affects ≈4.4 billion people worldwide. Several studies suggest that this pathogen impacts the digestive system, causing diverse and severe conditions, and results in extragastrointestinal disorders like vascular diseases. Our study aims to examine the association between H. pylori infection and carotid intima‐media thickness. Methods and Results Electronic databases (MEDLINE, Embase, CENTRAL, Web of Science, and Scopus) were searched for studies, comparing the thickness of the carotid intima‐media in H. pylori–infected and noninfected individuals listed until October 20, 2020. Statistical analyses were performed using the random effects meta‐analysis of model of weighted mean differences with the corresponding 95% CI using the DerSimonian and Laird method. The protocol was registered in advance in PROSPERO (International Prospective Register of Systematic Reviews; CRD42021224485). Thirteen studies were found meeting inclusion criteria for our systematic review and meta‐analysis, presenting data on the thickness of the carotid intima‐media considering the presence of H. pylori infection. Altogether, 2298 individuals’ data were included (1360 H. pylori positive, 938 negative). The overall carotid intima‐media thickness was significantly larger among infected patients compared with uninfected participants (weighted mean difference: 0.07 mm; 95% CI, 0.02–0.12; P=0.004; I2=91.1%; P<0.001). In case of the right common carotid artery, the intima‐media thickening was found to be significant as well (weighted mean difference, 0.08 mm; 95% CI, 0.02–0.13, P=0.007; I2=85.1%; P<0.001), while it showed no significance in the left common carotid artery (weighted mean difference, 0.12 mm; 95% CI, −0.05 to 0.28, P=0.176; I2=97.4%; P<0.001). Conclusions H. pylori infection is associated with increased carotid intima‐media thickness. Therefore, the infection may indirectly contribute to the development of major vascular events

Invasion patterns in brain metastases of solid cancers

Background Brain metastases are generally considered to be well demarcated from the surrounding brain parenchyma, although infiltrative growth patterns have been observed. We systemically investigated infiltration patterns and expression of adhesion molecules in a large and well-defined series of autopsy cases of brain metastases. Methods Ninety-seven autopsy specimens from 57 brain metastasis patients (primary tumor: 27 lung cancer, 6 breast cancer, 8 melanoma, 2 colorectal cancer, 1 kidney cancer, and 13 other) were evaluated for patterns of invasion into surrounding brain parenchyma. Expression of integrins αv; cytoplasmic β3, αvβ3, αvβ5, αvβ6, and αvβ8; and of E and N cadherin were evaluated using immunohistochemistry. Results Three main invasion patterns were seen: well-demarcated growth (29/57, 51%), vascular co-option (10/57, 18%), and diffuse infiltration (18/57, 32%). There was no statistically significant association of invasion pattern with primary tumor type, although vascular co-option was most common in melanoma brain metastases (4/10). Invasion patterns of different brain metastases of the same patient were highly concordant (P < .001, chi-square test). Distance of infiltration from the main tumor mass ranged from 12.5 µm to 450 µm (median 56.2 µm) and was not significantly different between the vascular co-option and the diffuse infiltration groups. Levels of αvβ6 were significantly higher in the well-demarcated group than in the vascular co-option and the diffuse infiltration groups (P = .033, Kruskal-Wallis test). Expression of αvβ5 in tumor cells was higher in brain metastasis lesions previously treated with stereotactic radiosurgery (P = .034, chi-square test). Conclusions Distinct invasion patterns of brain metastases into the brain parenchyma are not specific for primary tumor types, seem to be influenced by expression of αv integrin complexes, and may help to guide clinical decision-making

Fire risk modulation by long-term dynamics in land cover and dominant forest type in Eastern and Central Europe

International audienceWildfire occurrence is influenced by climate, vegetation and human activities. A key challenge forunderstanding fire-climate-vegetation interactions is to quantify the effect vegetation has in mediating fire regime. Here, we explore the relative importance of Holocene land cover and dominant functional forest type, and climate dynamics on biomass burned in temperate and boreo-nemoral regions of Central and Eastern Europe over the past 12 ka BP years. We used an extensive data set of Holocene pollen and sedimentary charcoal records, in combination with climate simulations and novel statistical modelling. Biomass burned was highest during the early Holocene and lowest during the mid Holocene in all three ecoregions, but diverged more markedly over the past 3-4 ka BP. Although the climate was an important driver of fire hazard during the warm and dry early Holocene, tree cover was consistently the strongest predictor of past biomass burning. In temperate forests, biomass burned was high at ~ 45% tree cover and decreased strongly towards 60% tree cover. In needleleaf dominated forests, biomass burned was highest at ~60-65% tree cover and abruptly declined at >65% tree cover. Biomass burned also increased when arable lands and grasslands reached ~15-20%, although this relationship was highly dynamic depending on land use intensity throughout ignition and fuel type and availability. Our observations cover the full range of Holocene climate variability and land cover changes and illustrates that percentages of land cover is a key predictor of the probability of fire occurrence over timescales of centuries to millennia. We suggest that long-term fire risk may be effectively reduced through land cover management, given that land cover has controlled fire regimes under the dynamic climates of theHolocene

Fire hazard modulation by long-term dynamics in land cover and dominant forest type in eastern and central Europe

Wildfire occurrence is influenced by climate, vegetation and human activities. A key challenge for understanding the risk of fires is quantifying the mediating effect of vegetation on fire regimes. Here, we explore the relative importance of Holocene land cover, land use, dominant functional forest type, and climate dynamics on biomass burning in temperate and boreo-nemoral regions of central and eastern Europe over the past 12 kyr. We used an extensive data set of Holocene pollen and sedimentary charcoal records, in combination with climate simulations and statistical modelling. Biomass burning was highest during the early Holocene and lowest during the mid-Holocene in all three ecoregions (Atlantic, continental and boreo-nemoral) but was more spatially variable over the past 3-4 kyr. Although climate explained a significant variance in biomass burning during the early Holocene, tree cover was consistently the highest predictor of past biomass burning over the past 8 kyr. In temperate forests, biomass burning was high at ∼ 45% tree cover and decreased to a minimum at between 60% and 70% tree cover. In needleleaf-dominated forests, biomass burning was highest at ∼60 %-65%tree cover and steeply declined at > 65% tree cover. Biomass burning also increased when arable lands and grasslands reached ∼15 %-20 %, although this relationship was variable depending on land use practice via ignition sources, fuel type and quantities. Higher tree cover reduced the amount of solar radiation reaching the forest floor and could provide moister, more wind-protected microclimates underneath canopies, thereby decreasing fuel flammability. Tree cover at which biomass burning increased appears to be driven by warmer and drier summer conditions during the early Holocene and by increasing human influence on land cover during the late Holocene. We suggest that longterm fire hazard may be effectively reduced through land cover management, given that land cover has controlled fire regimes under the dynamic climates of the Holocene