Why do some societies fare well, and others poorly, at reducing the risk of early death? Wealth, Health, and Democracy in East Asia and Latin America finds that the public provision of basic health ...care and other inexpensive social services has reduced mortality rapidly even in tough economic circumstances, and that political democracy has contributed to the provision and utilization of such social services, in a wider range of ways than is sometimes recognized. These conclusions are based on case studies of Argentina, Brazil, Chile, Costa Rica, Indonesia, South Korea, Taiwan, and Thailand, as well as on cross-national comparisons involving these cases and others.
The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled ...replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2 (AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.
Water transit time is now a standard measure in catchment hydrological and ecohydrological research. The last comprehensive review of transit time modeling approaches was published 15+ years ago. But ...since then the field has largely expanded with new data, theory and applications. Here, we review these new developments with focus on water‐age‐balance approaches and data‐based approaches. We discuss and compare methods including StorAge‐Selection functions, well/partially mixed compartments, water age tracking through spatially distributed models, direct transit time estimates from controlled experiments, young water fractions, and ensemble hydrograph separation. We unify some of the heterogeneity in the literature that has crept in with these many new approaches, in an attempt to clarify the key differences and similarities among them. Finally, we point to open questions in transit time research, including what we still need from theory, models, field work, and community practice.
Key Points
A synthesis of 15‐years of transit time research shows progression in how lumped approaches are used at catchment scales
That synthesis reveals open questions and emerging challenges in transit time research that are summarized here
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Vascular pericytes provide critical contributions to the formation and integrity of the blood vessel wall within the microcirculation. Pericytes maintain vascular stability and homeostasis by ...promoting endothelial cell junctions and depositing extracellular matrix (ECM) components within the vascular basement membrane, among other vital functions. As their importance in sustaining microvessel health within various tissues and organs continues to emerge, so does their role in a number of pathological conditions including cancer, diabetic retinopathy, and neurological disorders. Here, we review vascular pericyte contributions to the development and remodeling of the microcirculation, with a focus on the local microenvironment during these processes. We discuss observations of their earliest involvement in vascular development and essential cues for their recruitment to the remodeling endothelium. Pericyte involvement in the angiogenic sprouting context is also considered with specific attention to crosstalk with endothelial cells such as through signaling regulation and ECM deposition. We also address specific aspects of the collective cell migration and dynamic interactions between pericytes and endothelial cells during angiogenic sprouting. Lastly, we discuss pericyte contributions to mechanisms underlying the transition from active vessel remodeling to the maturation and quiescence phase of vascular development.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
We have developed a novel real‐time quaking‐induced conversion RT‐QuIC‐based assay to detect alpha‐synuclein aggregation in brain and cerebrospinal fluid from dementia with Lewy bodies and ...Parkinson's disease patients. This assay can detect alpha‐synuclein aggregation in Dementia with Lewy bodies and Parkinson's disease cerebrospinal fluid with sensitivities of 92% and 95%, respectively, and with an overall specificity of 100% when compared to Alzheimer and control cerebrospinal fluid. Patients with neuropathologically confirmed tauopathies (progressive supranuclear palsy; corticobasal degeneration) gave negative results. These results suggest that RT‐QuiC analysis of cerebrospinal fluid is potentially useful for the early clinical assessment of patients with alpha‐synucleinopathies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Terrestrial carbon dynamics influence the contribution of dissolved organic carbon (DOC) to river networks in addition to hydrology. In this study, we use a biogeochemical process model to simulate ...the lateral transfer of DOC from land to the Arctic Ocean via riverine transport. We estimate that, over the 20th century, the pan-Arctic watershed has contributed, on average, 32 Tg C/yr of DOC to river networks emptying into the Arctic Ocean with most of the DOC coming from the extensive area of boreal deciduous needle-leaved forests and forested wetlands in Eurasian watersheds. We also estimate that the rate of terrestrial DOC loading has been increasing by 0.037 Tg C/yr
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over the 20th century primarily as a result of climate-induced increases in water yield. These increases have been offset by decreases in terrestrial DOC loading caused by wildfires. Other environmental factors (CO
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fertilization, ozone pollution, atmospheric nitrogen deposition, timber harvest, agriculture) are estimated to have relatively small effects on terrestrial DOC loading to Arctic rivers. The effects of the various environmental factors on terrestrial carbon dynamics have both offset and enhanced concurrent effects on hydrology to influence terrestrial DOC loading and may be changing the relative importance of terrestrial carbon dynamics on this carbon flux. Improvements in simulating terrestrial DOC loading to pan-Arctic rivers in the future will require better information on the production and consumption of DOC within the soil profile, the transfer of DOC from land to headwater streams, the spatial distribution of precipitation and its temporal trends, carbon dynamics of larch-dominated ecosystems in eastern Siberia, and the role of industrial organic effluents on carbon budgets of rivers in western Russia.
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BFBNIB, FZAB, GIS, IJS, INZLJ, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZRSKP
•Field research identifies obstacles to the takeup of cash transfers in Ecuador.•Survey data are analyzed to find out which obstacles are most important.•Probit analysis shows that compliance costs, ...stigma, and distrust reduce takeup.•Social assistance programs cannot help the poor if the poor do not enroll in them.
Social assistance programs cannot help the poor if the poor do not enroll in them. Obstacles to the takeup of social assistance in industrialized countries include information costs, compliance costs, and psychological costs. Using qualitative field research and quantitative analysis of data from a nationwide survey in 2013–14, we explore the impact of these costs on the takeup of the Bono de Desarrollo Humano (BDH), a US $50 monthly cash transfer in Ecuador. Drawing on interviews with Ecuadorians whose households are eligible for the BDH, as well as on findings about social assistance takeup in industrialized countries, we hypothesize that particular information costs, compliance costs, and psychological costs, along with program design and household poverty, will influence the probability of BDH takeup. We then use probit regression to estimate the statistical effect of these factors on the probability of takeup, using data on 11,449 BDH-eligible households sampled by Ecuador's 2013–14 Encuesta Condiciones de Vida (Living Standards Measurement Survey). Controlling for program design and household poverty, we find that compliance costs and psychological costs each have a significant deterrent effect on BDH takeup. The purpose of social assistance is to help the poor, but if social assistance is to achieve this goal, the poor must actually receive it. This study helps to identify the forces and circumstances that influence the takeup of an important social assistance program in a middle-income Latin American country.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background Shock is a prime inciting event for postinjury multiple organ failure (MOF), believed to induce a state of injurious systemic inflammation. In animal models of hemorrhagic shock, early (< ...24 hours) changes in cytokine production are an index of the systemic inflammatory response syndrome. However, their predictive value in trauma patients remains to be fully elucidated. Study Design In a prospective observational pilot study of > 1 year at an urban Level I trauma center, serial (every 4 hours) serum cytokine levels were determined during a 24-hour period using multiplex suspension immunoassay in patients with major torso trauma (excluding severe brain injury) who met criteria for standardized shock resuscitation. Temporal cytokine expression was assessed during shock resuscitation in severe trauma patients to predict risk for MOF. MOF was assessed with the Denver score. Results Of 48 study patients (mean age 39 ± 3 years, 67% men, 88% blunt mechanism, mean Injury Severity Score 25 ± 2), MOF developed in 11 (23%). MOF patients had a considerably higher mortality (64% versus 3%) and fewer ICU-free days (3.5 ± 2 versus 17.8 ± 1.3 days) compared with non-MOF patients. Traditional predictors of MOF, including age (45 ± 7 versus 38 ± 3 years; p=0.21), Injury Severity Score (26 ± 3 versus 25 ± 2; p=0.67), admission hemoglobin (11.4 ± 0.9 versus 12.1 ± 0.5 g/dL; p=0.22), international normalized ratio (1.6 ± 0.2 versus 1.4 ± 0.06; p=0.17), and base deficit (9.0 ± 2 versus 7.1 ± 0.8; p=0.19), were not significantly different between MOF and non-MOF patients. Statistical analysis identified six candidate predictors of MOF: inducible protein 10, macrophage inflammatory protein-1β, interleukin-10, interleukin-6, interleukin-1Ra, and eotaxin. Conclusions These data provide insight into cytokine expression during traumatic shock that can enable earlier identification of patients at risk for development of MOF.
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GEOZS, NUK, OILJ, SBCE, SBJE, UL, UPUK
Real-time quaking-induced conversion (RT-QuIC) is an assay in which disease-associated prion protein (PrP) initiates a rapid conformational transition in recombinant PrP (recPrP), resulting in the ...formation of amyloid that can be monitored in real time using the dye thioflavin T. It therefore has potential advantages over analogous cell-free PrP conversion assays such as protein misfolding cyclic amplification (PMCA). The QuIC assay and the related amyloid seeding assay have been developed largely using rodent-passaged sheep scrapie strains. Given the potential RT-QuIC has for Creutzfeldt-Jakob disease (CJD) research and human prion test development, this study characterized the behaviour of a range of CJD brain specimens with hamster and human recPrP in the RT-QuIC assay. The results showed that RT-QuIC is a rapid, sensitive and specific test for the form of abnormal PrP found in the most commonly occurring forms of sporadic CJD. The assay appeared to be largely independent of species-related sequence differences between human and hamster recPrP and of the methionine/valine polymorphism at codon 129 of the human PrP gene. However, with the same conditions and substrate, the assay was less efficient in detecting the abnormal PrP that characterizes variant CJD brain. Comparison of these QuIC results with those previously obtained using PMCA suggested that these two seemingly similar assays differ in important respects.
The association between political regime form and social performance, measured by the infant mortality rate, is explored using time-series cross-sectional regression analysis of 155-180 countries ...observed annually from 1972 to 2007. Controlling for other factors likely to affect infant mortality, democracies are found to have lower infant mortality than authoritarian regimes, and long-term democratic experience is found to matter more than short-term democratic practice. Among authoritarian regime types, one-party regimes have lower infant mortality than military or limited multiparty regimes, which have lower infant mortality than monarchies.
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BFBNIB, DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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