Advanced Multilevel Node Separator Algorithms

A node separator of a graph is a subset S of the nodes such that removing S and its incident edges divides the graph into two disconnected components of about equal size. In this work, we introduce novel algorithms to find small node separators in large graphs. With focus on solution quality, we introduce novel flow-based local search algorithms which are integrated in a multilevel framework. In addition, we transfer techniques successfully used in the graph partitioning field. This includes the usage of edge ratings tailored to our problem to guide the graph coarsening algorithm as well as highly localized local search and iterated multilevel cycles to improve solution quality even further. Experiments indicate that flow-based local search algorithms on its own in a multilevel framework are already highly competitive in terms of separator quality. Adding additional local search algorithms further improves solution quality. Our strongest configuration almost always outperforms competing systems while on average computing 10% and 62% smaller separators than Metis and Scotch, respectively

GPIIb/IIIa Receptor Antagonism Using Small Molecules Provides no Additive Long-Term Protection after Percutaneous Coronary Intervention as Compared to Clopidogrel Plus Aspirin

Background: There is some controversy as to whether tirofiban or eptifibatide, two small anti-aggregating drugs (AAD), may reduce the incidence of composite ischemic events within one year in patients undergoing percutaneous coronary intervention (PCI) in the real clinical world. Methods: We compared consecutive patients on oral double AAD (with clopidogrel and aspirin) who underwent PCI (n=207) and patients who were on single AAD and received a second AAD, just prior to PCI, and either high-dose tirofiban or double-bolus eptifibatide (double AAD plus small molecules group, n=666). The primary end point (incidence of composite ischemic events within one year) included death, acute myocardial infarction, unstable angina, stent thrombosis or repeat PCI or coronary bypass surgery (related to the target vessel PCI failure) and was modelled by Cox's regression. Results: There were 89 composite ischemic events: 24 (11.6%) in double AAD alone and 65 (9.8%) in double AAD plus small molecules groups (log-rank test: p=0.36). Incidences by type of ischemic events were similar between the 2 groups. Based on 21 potential covariates fitted simultaneously, adjusted hazard ratios (HR and 95% confidence intervals) showed that age (HR 1.03, 1.01-1.06, p=0.01), diabetes (HR 1.68, 1.01-2.79, p=0.05) and intra aortic balloon pump (HR 5.12, 2.36-11.10, p=0.0001) were significant risk factors whereas thrombolysis by tenecteplase (HR 0.35, 0.13-0.98, p=0.05) and having had hypertension or anti-hypertensive treatment (HR 0.58, 0.36-0.93, p=0.03) were significant protectors for events. Whether small molecules were present provided a non significant additional benefit as compared to double AAD alone (HR 0.83, 0.51-1.36, p=0.46). Pre-PCI CK-MB were not useful to predict events (HR 1.01, 0.99-1.01, p=0.17). Conclusions: In clinical world patients undergoing PCI (rescue plus primary <13%) while on double AAD, based on clopidogrel plus aspirin, small molecules (tirofiban or eptifibatide) provided no additive long-term protection against the occurrence of composite ischemic events whereas thrombolysis by tenecteplase did. © Schiariti et al

Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England

The SARS-CoV-2 lineage B.1.1.7, designated variant of concern (VOC) 202012/01 by Public Health England1, was first identified in the UK in late summer to early autumn 20202. Whole-genome SARS-CoV-2 sequence data collected from community-based diagnostic testing for COVID-19 show an extremely rapid expansion of the B.1.1.7 lineage during autumn 2020, suggesting that it has a selective advantage. Here we show that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S gene target failures (SGTF) in community-based diagnostic PCR testing. Analysis of trends in SGTF and non-SGTF case numbers in local areas across England shows that B.1.1.7 has higher transmissibility than non-VOC lineages, even if it has a different latent period or generation time. The SGTF data indicate a transient shift in the age composition of reported cases, with cases of B.1.1.7 including a larger share of under 20-year-olds than non-VOC cases. We estimated time-varying reproduction numbers for B.1.1.7 and co-circulating lineages using SGTF and genomic data. The best-supported models did not indicate a substantial difference in VOC transmissibility among different age groups, but all analyses agreed that B.1.1.7 has a substantial transmission advantage over other lineages, with a 50% to 100% higher reproduction number

Identification of biomarkers for the antiangiogenic and antitumour activity of the superoxide dismutase 1 (SOD1) inhibitor tetrathiomolybdate (ATN-224)

Tetrathiomolybdate (choline salt; ATN-224), a specific, high-affinity copper binder, is currently being evaluated in several phase II cancer trials. ATN-224 inhibits CuZn superoxide dismutase 1 (SOD1) leading to antiangiogenic and antitumour effects. The pharmacodynamics of tetrathiomolybdate has been followed by tracking ceruloplasmin (Cp), a biomarker for systemic copper. However, at least in mice, the inhibition of angiogenesis occurs before a measurable decrease in systemic copper is observed. Thus, the identification and characterisation of other biomarkers to follow the activity of ATN-224 in the clinic is of great interest. Here, we present the preclinical evaluation of two potential biomarkers for the activity of ATN-224: (i) SOD activity measurements in blood cells in mice and (ii) levels of endothelial progenitor cells (EPCs) in bonnet macaques treated with ATN-224. The superoxide dismutase activity in blood cells in mice is rapidly inhibited by ATN-224 treatment at doses at which angiogenesis is maximally inhibited. Furthermore, ATN-224 dosing in bonnet macaques causes a profound and reversible decrease in EPCs without significant toxicity. Thus, both SOD activity measurements and levels of EPCs may be useful biomarkers of the antiangiogenic activity of ATN-224 to be used in its clinical development

Livelihood and vulnerability in the wake of Typhoon Yolanda: lessons of community and resilience

Livelihood strategies that are crafted in ‘extra-ordinary’ post-disaster conditions should also be able to function once some semblance of normalcy has resumed. This article aims to show that the vulnerability experienced in relation to Typhoon Yolanda was, and continues to be, directly linked to inadequate livelihood assets and opportunities. We examine the extent to which various livelihood strategies lessened vulnerability post-Typhoon Yolanda and argue that creating conditions under which disaster survivors have the freedom to pursue sustainable livelihood is essential in order to foster resilience and reduce vulnerability against future disasters. We offer suggestions to improve future relief efforts, including suggestions made by the survivors themselves. We caution against rehabilitation strategies that knowingly or unknowingly, resurrect pre-disaster vulnerability. Strategies that foster dependency, fail to appreciate local political or ecological conditions or undermine cooperation and cohesion in already vulnerable communities will be bound to fail. Some of the livelihood strategies that we observed post-Typhoon Yolanda failed on some or all of these points. It is important for future policy that these failings are addressed

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

High-Resolution Positional Tracking for Long-Term Analysis of Drosophila Sleep and Locomotion Using the “Tracker” Program

Drosophila melanogaster has been used for decades in the study of circadian behavior, and more recently has become a popular model for the study of sleep. The classic method for monitoring fly activity involves counting the number of infrared beam crosses in individual small glass tubes. Incident recording methods such as this can measure gross locomotor activity, but they are unable to provide details about where the fly is located in space and do not detect small movements (i.e. anything less than half the enclosure size), which could lead to an overestimation of sleep and an inaccurate report of the behavior of the fly. This is especially problematic if the fly is awake, but is not moving distances that span the enclosure. Similarly, locomotor deficiencies could be incorrectly classified as sleep phenotypes. To address these issues, we have developed a locomotor tracking technique (the “Tracker” program) that records the exact location of a fly in real time. This allows for the detection of very small movements at any location within the tube. In addition to circadian locomotor activity, we are able to collect other information, such as distance, speed, food proximity, place preference, and multiple additional parameters that relate to sleep structure. Direct comparisons of incident recording and our motion tracking application using wild type and locomotor-deficient (CASK-β null) flies show that the increased temporal resolution in the data from the Tracker program can greatly affect the interpretation of the state of the fly. This is especially evident when a particular condition or genotype has strong effects on the behavior, and can provide a wealth of information previously unavailable to the investigator. The interaction of sleep with other behaviors can also be assessed directly in many cases with this method

Plasmodium vivax lineages: geographical distribution, tandem repeat polymorphism, and phylogenetic relationship

<p>Abstract</p> <p>Background</p> <p>Multi-drug resistance and severe/complicated cases are the emerging phenotypes of vivax malaria, which may deteriorate current anti-malarial control measures. The emergence of these phenotypes could be associated with either of the two <it>Plasmodium vivax </it>lineages. The two lineages had been categorized as Old World and New World, based on geographical sub-division and genetic and phenotypical markers. This study revisited the lineage hypothesis of <it>P. vivax </it>by typing the distribution of lineages among global isolates and evaluated their genetic relatedness using a panel of new mini-satellite markers.</p> <p>Methods</p> <p><it>18S SSU rRNA S-type </it>gene was amplified from 420 <it>Plasmodium vivax </it>field isolates collected from different geographical regions of India, Thailand and Colombia as well as four strains each of <it>P. vivax </it>originating from Nicaragua, Panama, Thailand (Pak Chang), and Vietnam (ONG). A mini-satellite marker panel was then developed to understand the population genetic parameters and tested on a sample subset of both lineages.</p> <p>Results</p> <p><it>18S SSU rRNA S-type </it>gene typing revealed the distribution of both lineages (Old World and New World) in all geographical regions. However, distribution of <it>Plasmodium vivax </it>lineages was highly variable in every geographical region. The lack of geographical sub-division between lineages suggests that both lineages are globally distributed. Ten mini-satellites were scanned from the <it>P. vivax </it>genome sequence; these tandem repeats were located in eight of the chromosomes. Mini-satellites revealed substantial allelic diversity (7-21, <it>AE </it>= 14.6 ± 2.0) and heterozygosity (<it>He </it>= 0.697-0.924, <it>AE </it>= 0.857 ± 0.033) per locus. Mini-satellite comparison between the two lineages revealed high but similar pattern of genetic diversity, allele frequency, and high degree of allele sharing. A Neighbour-Joining phylogenetic tree derived from genetic distance data obtained from ten mini-satellites also placed both lineages together in every cluster.</p> <p>Conclusions</p> <p>The global lineage distribution, lack of genetic distance, similar pattern of genetic diversity, and allele sharing strongly suggested that both lineages are a single species and thus new emerging phenotypes associated with vivax malaria could not be clearly classified as belonging to a particular lineage on basis of their geographical origin.</p