Surface rupture of the Hundalee fault during the 2016 Mw 7.8 Kaikōura earthquake

The Hundalee fault is one of at least 20 faults that ruptured during the 2016 M w Mw 7.8 Kaikōura earthquake in the northeast of the South Island of New Zealand. Here, we document a 12‐km onshore section of the Hundalee fault that exhibited surface rupture from this event. To the northeast of our observations, the fault crosses the coast, and independent seabed surveys show that the 2016 rupture continued at least 2 km offshore. No surface rupture was observed across the southwestern section of the Hundalee fault, which crosses hilly vegetated terrain and poorly consolidated valley‐floor sediment. However, previous Interferometric Synthetic Aperture Radar (InSAR) analyses suggest that a 9‐km‐long section of the fault did rupture. Hence, the minimum length of the 2016 rupture along the Hundalee fault is 23 km. Field measurements indicate oblique dextral‐reverse slip along northeast‐trending Hundalee fault sections and reverse‐sinistral slip along north to north‐northeast‐trending sections. This is consistent with the regional principal horizontal shortening direction. Maximum vertical and horizontal offset measurements are 2.5±0.5 2.5±0.5 and 3.7±0.5  m 3.7±0.5  m , respectively. The discontinuous and irregular surface ruptures we observed are characteristic of a structurally immature fault, yet previous geological mapping indicates that the Hundalee fault is a regionally significant fault with >1‐km >1‐km late Cenozoic throw. Furthermore, a 60‐m‐wide sequence of fault rocks exposed by the rupture indicates that slip has localized into <10‐cm‐thick <10‐cm‐thick gouge zones, as anticipated for a mature fault. Therefore, a discrepancy exists between geological evidence of the Hundalee fault being a structurally mature fault and the characteristics of the 2016 rupture. We speculate that this signifies that the 2016 rupture was imposed on the Hundalee fault by movement across an inefficient multifault network rather than independent rupture of the Hundalee fault itself

The Endoplasmic Reticulum Stress Response in Neuroprogressive Diseases: Emerging Pathophysiological Role and Translational Implications

The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted

Genome-wide associations for birth weight and correlations with adult disease

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW ($\textit{P}$  < 5 × 10$^{-8}$). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure ($\textit{R}$ $_{g}$ = -0.22, $\textit{P}$  = 5.5 × 10$^{-13}$), T2D ($\textit{R}$ $_{g}$ = -0.27, $\textit{P}$  = 1.1 × 10$^{-6}$) and coronary artery disease ($\textit{R}$ $_{g}$ = -0.30, $\textit{P}$  = 6.5 × 10$^{-9}$). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions ($\textit{P}$ = 1.9 × 10$^{-4}$). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.For a full list of the funders pelase visit the publisher's website and look at the supplemetary material provided. Some of the funders are: British Heart Foundation, Cancer Research UK, Medical Research Council, National Institutes of Health, Royal Society and Wellcome Trust

Measurement of prompt open-charm production cross sections in proton-proton collisions at root s=13 TeV

The production cross sections for prompt open-charm mesons in proton-proton collisions at a center-of-mass energy of 13TeV are reported. The measurement is performed using a data sample collected by the CMS experiment corresponding to an integrated luminosity of 29 nb(-1). The differential production cross sections of the D*(+/-), D-+/-, and D-0 ((D) over bar (0)) mesons are presented in ranges of transverse momentum and pseudorapidity 4 < p(T) < 100 GeV and vertical bar eta vertical bar < 2.1, respectively. The results are compared to several theoretical calculations and to previous measurements.Peer reviewe

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015

Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61.7 years (95% uncertainty interval 61.4-61.9) in 1980 to 71.8 years (71.5-72.2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11.3 years (3.7-17.4), to 62.6 years (56.5-70.2). Total deaths increased by 4.1% (2.6-5.6) from 2005 to 2015, rising to 55.8 million (54.9 million to 56.6 million) in 2015, but age-standardised death rates fell by 17.0% (15.8-18.1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14.1% (12.6-16.0) to 39.8 million (39.2 million to 40.5 million) in 2015, whereas age-standardised rates decreased by 13.1% (11.9-14.3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42.1%, 39.1-44.6), malaria (43.1%, 34.7-51.8), neonatal preterm birth complications (29.8%, 24.8-34.9), and maternal disorders (29.1%, 19.3-37.1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Copyright (C) The Author(s). Published by Elsevier Ltd.Peer reviewe

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

Search for dark matter particles produced in association with a Higgs boson in proton-proton collisions at √s = 13 TeV

© 2020, The Author(s). A search for dark matter (DM) particles is performed using events with a Higgs boson candidate and large missing transverse momentum. The analysis is based on proton- proton collision data at a center-of-mass energy of 13 TeV collected by the CMS experiment at the LHC in 2016, corresponding to an integrated luminosity of 35.9 fb−1. The search is performed in five Higgs boson decay channels: h → b b ¯ , γγ, τ+τ−, W+W−, and ZZ. The results from the individual channels are combined to maximize the sensitivity of the analysis. No significant excess over the expected standard model background is observed in any of the five channels or in their combination. Limits are set on DM production in the context of two simplified models. The results are also interpreted in terms of a spin-independent DM-nucleon scattering cross section and compared to those from direct-detection DM experiments. This is the first search for DM particles produced in association with a Higgs boson decaying to a pair of W or Z bosons, and the first statistical combination based on five Higgs boson decay channels. [Figure not available: see fulltext.].SCOAP

High levels, partitioning and fish consumption based water guidelines of perfluoroalkyl acids downstream of a former firefighting training facility in Canada

High levels of perfluoroalkyl acids (PFAAs), especially perfluorooctane sulfonic acid (PFOS), have been observed at locations in/around/downstream of the sites where PFOS-based firefighting foam was used repeatedly for a prolonged period. In this study, we conducted a detailed investigation of PFAA contamination in the Lake Niapenco area in Ontario, Canada, where among the highest ever reported levels of PFOS were recently measured in amphipods, fish and snapping turtle plasma. Levels and distribution of PFAAs in water, sediment and fish samples collected from the area varied widely. An upstream pond beside a former firefighting training area (FFTA) was confirmed as the source of PFAAs even 20 years after the last use of the foam at the FFTA. Recent PFOS concentration in water (~ 60 ng/L) at Lake Niapenco, about 14 km downstream of the pond, was still 3–7 × higher than the background levels. For PFOS, Log KD ranged 1.3–2.5 (mean ± SE: 1.7 ± 0.1), Log BAFs ranged 2.4–4.7 (3.4 ± 0.05), and Log BSAFs ranged 0.7–2.9 (1.7 ± 0.05). Some fish species-specific differences in BAF and BSAF were observed. At Log BAF of 4.7, fish PFOS levels at Lake Niapenco could reach 15,000 ng/g, 100 × greater than a “do not eat” advisory benchmark, without exceeding the current drinking water guideline of 300 ng/L. A fish consumption based water guideline was estimated at 1–15 ng/L, which is likely applicable worldwide given that the Log BAFs observed in this study were comparable to those previously reported in the literature. It appears that PFAA in the downstream waters increased between 2011 and 2015; however, further monitoring is required to confirm this trend. © 201

Machine learning reveals multimodal MRI patterns predictive of isocitrate dehydrogenase and 1p/19q status in diffuse low- and high-grade gliomas

PurposeIsocitrate dehydrogenase (IDH) and 1p19q codeletion status are importantin providing prognostic information as well as prediction of treatment response in gliomas. Accurate determination of the IDH mutation status and 1p19q co-deletion prior to surgery may complement invasive tissue sampling and guide treatment decisions.MethodsPreoperative MRIs of 538 glioma patients from three institutions were used as a training cohort. Histogram, shape, and texture features were extracted from preoperative MRIs of T1 contrast enhanced and T2-FLAIR sequences. The extracted features were then integrated with age using a random forest algorithm to generate a model predictive of IDH mutation status and 1p19q codeletion. The model was then validated using MRIs from glioma patients in the Cancer Imaging Archive.ResultsOur model predictive of IDH achieved an area under the receiver operating characteristic curve (AUC) of 0.921 in the training cohort and 0.919 in the validation cohort. Age offered the highest predictive value, followed by shape features. Based on the top 15 features, the AUC was 0.917 and 0.916 for the training and validation cohort, respectively. The overall accuracy for 3 group prediction (IDH-wild type, IDH-mutant and 1p19q co-deletion, IDH-mutant and 1p19q non-codeletion) was 78.2% (155 correctly predicted out of 198).ConclusionUsing machine-learning algorithms, high accuracy was achieved in the prediction of IDH genotype in gliomas and moderate accuracy in a three-group prediction including IDH genotype and 1p19q codeletion