Improved spatial resolution of elemental maps through inversion of LA-ICP-MS data

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) provides the spatial distribution of elements within crystals and therefore can constrain the rates of geological processes. Spatial resolution of LA-ICP-MS is limited by the requirement to ablate sufficient material to surpass the detection limit of the instrument: too little material and the concentration cannot be measured; too much material from the same spatial location and the possibility of depth dependent variations in concentration increases. Because of this requirement and typical analytical setup, this commonly places a lower bound on the diameter of an ablation ‘spot’ size of approximately 20 μm for elements with ppm concentration. Here we present a means to achieve sub-spot size resolution using inverse methods. We discretize the space sampled in an analysis into pixels and note that the average concentration of the pixels sampled by a spot equals the measured concentration. As multiple overlapping spots sample some of the same pixels, we can combine discrete expressions for each spot as a system of linear equations. Through linear inversion with smoothness constraints we can solve for unknown pixel concentrations. We highlight this approach with two natural examples in which diffusive processes are important: magmatic ascent speeds and (U-Th)/He noble gas thermochronometry. In these examples, accurate results require that the true concentration gradients can be recovered from LA-ICP-MS data. We show that the ability to infer rapid rates of magma ascent is improved from months to weeks and that we are able to interpret previously un-interpretable thermochronometric data

Late Cenozoic deepening of Yosemite Valley, USA

Although Yosemite Valley, USA, catalyzed the modern environmental movement and fueled foundational debates in geomorphology, a century of investigation has failed to definitively determine when it formed. The non-depositional nature of the landscape and homogeneous bedrock have prevented direct geological assessments. Indirect assumptions about the age of downcutting have ranged from pre-Eocene to Pleistocene. Clarity on this issue would not only satisfy public interest but also provide a new constraint for contentious debates about the Cenozoic tectonic and geomorphologic history of the Sierra Nevada in California. Here we use thermochronometric analysis of radiogenic helium in apatite crystals, coupled with numerical models of crustal temperatures beneath evolving topography, to demonstrate significant late Cenozoic deepening of Tenaya Canyon, Yosemite’s northeastern branch. Approximately 40%–90% of the current relief has developed since 10 Ma and most likely since 5 Ma. This coincides with renewed regional tectonism, which is a long-hypothesized but much debated driver of Sierran canyon development. Pleistocene glaciation caused spatially variable incision and valley widening in Yosemite Valley, whereas little contemporaneous erosion occurred in the adjacent upper Tuolumne watershed. Such variations probably arise from glacial erosion’s dependence on topographic focusing of ice discharge into zones of rapid flow, and on the abundance of pre-existing fractures in the substrate. All available data, including those from our study, are consistent with a moderately high and slowly eroding mid-Cenozoic Sierra Nevada followed by significant late Cenozoic incision of some, but not all, west-side canyon

Westernmost Grand Canyon incision: Testing thermochronometric resolution

The timing of carving of Grand Canyon has been debated for over 100 years with competing endmember hypotheses advocating for either a 70 Ma (“old”) or <6 Ma (“young”) Grand Canyon. Several geological constraints appear to support a “young” canyon model, but thermochronometric measures of cooling history and corresponding estimates of landscape evolution have been in debate. In particular, 4He/3He thermochronometric data record the distribution of radiogenic 4He (from the 238U, 235U and 232Th decay series) within an individual apatite crystal and thus are highly sensitive to the thermal history corresponding to landscape evolution. However, there are several complicating factors that make interpreting such data challenging in geologic scenarios involving reheating. Here, we analyze new data that provide measures of the cooling of basement rocks at the base of westernmost Grand Canyon, and use these data as a testbed for exploring the resolving power and limitations of 4He/3He data in general. We explore a range of thermal histories and find that these data are most consistent with a “young” Grand Canyon. A problem with the recovered thermal history, however, is that burial temperatures are under predicted based on sedimentological evidence. A solution to this problem is to increase the resistance of alpha recoil damage to annealing, thus modifying He diffusion kinetics, allowing for higher temperatures throughout the thermal history. This limitation in quantifying radiation damage (and hence crystal retentivity) introduces non-uniqueness to interpreting time–temperature paths in rocks that resided in the apatite helium partial retention zone for long durations. Another source of non-uniqueness, is due to unknown U and Th distributions within crystals. We show that for highly zoned with a decrease in effective U of 20 ppm over the outer 80% of the radius of the crystal, the 4He/3He data could be consistent with an “old” canyon model. To reduce this non-uniqueness, we obtain U and Th zonation information for separate crystals from the same rock sample through LA-ICP-MS analysis. The observed U and Th distributions are relatively uniform and not strongly zoned, thus supporting a “young” canyon model interpretation of the 4He/3He data. Furthermore, we show that for the mapped zonation, the difference between predicted 4He/3He data for a uniform crystal and a 3D model of the crystal are minimal, highlighting that zonation is unlikely to lead us to falsely infer an “old” Grand Canyon

Circulating Tumor Cell Transcriptomics as Biopsy Surrogates in Metastatic Breast Cancer

BACKGROUND Metastatic breast cancer (MBC) and the circulating tumor cells (CTCs) leading to macrometastases are inherently different than primary breast cancer. We evaluated whether whole transcriptome RNA-Seq of CTCs isolated via an epitope-independent approach may serve as a surrogate for biopsies of macrometastases. METHODS We performed RNA-Seq on fresh metastatic tumor biopsies, CTCs, and peripheral blood (PB) from 19 newly diagnosed MBC patients. CTCs were harvested using the ANGLE Parsortix microfluidics system to isolate cells based on size and deformability, independent of a priori knowledge of cell surface marker expression. RESULTS Gene expression separated CTCs, metastatic biopsies, and PB into distinct groups despite heterogeneity between patients and sample types. CTCs showed higher expression of immune oncology targets compared with corresponding metastases and PB. Predictive biomarker (n = 64) expression was highly concordant for CTCs and metastases. Repeat observation data post-treatment demonstrated changes in the activation of different biological pathways. Somatic single nucleotide variant analysis showed increasing mutational complexity over time. CONCLUSION We demonstrate that RNA-Seq of CTCs could serve as a surrogate biomarker for breast cancer macrometastasis and yield clinically relevant insights into disease biology and clinically actionable targets

Influence of effective stress on swelling pressure of expansive soils

The volume change and shear strength behaviour of soils are controlled by the effective stress. Recent advances in unsaturated soil mechanics have shown that the effective stress as applicable to unsaturated soils is equal to the difference between the externally applied stress and the suction stress. The latter can be established based on the soil-water characteristic curve (SWCC) of the soil. In the present study, the evolution of swelling pressure in compacted bentonite-sand mixtures was investigated. Comparisons were made between magnitudes of applied suction, suction stress, and swelling pressure

Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: A systematic analysis from the Global Burden of Disease Study 2016

Background: A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. Methods Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. Findings In 2016, HAQ Index performance spanned from a high of 97\ub71 (95% UI 95\ub78-98\ub71) in Iceland, followed by 96\ub76 (94\ub79-97\ub79) in Norway and 96\ub71 (94\ub75-97\ub73) in the Netherlands, to values as low as 18\ub76 (13\ub71-24\ub74) in the Central African Republic, 19\ub70 (14\ub73-23\ub77) in Somalia, and 23\ub74 (20\ub72-26\ub78) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91\ub75 (89\ub71-93\ub76) in Beijing to 48\ub70 (43\ub74-53\ub72) in Tibet (a 43\ub75-point difference), while India saw a 30\ub78-point disparity, from 64\ub78 (59\ub76-68\ub78) in Goa to 34\ub70 (30\ub73-38\ub71) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4\ub78-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20\ub79-point to 17\ub70-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17\ub72-point to 20\ub74-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. Interpretation GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle- SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage hinges upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view-and subsequent provision-of quality health care for all populations

Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: A systematic analysis from the Global Burden of Disease Study 2016

Copyright © 2018 The Author(s). Published by Elsevier Ltd. Background A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. Methods Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. Findings In 2016, HAQ Index performance spanned from a high of 97·1 (95% UI 95·8-98·1) in Iceland, followed by 96·6 (94·9-97·9) in Norway and 96·1 (94·5-97·3) in the Netherlands, to values as low as 18·6 (13·1-24·4) in the Central African Republic, 19·0 (14·3-23·7) in Somalia, and 23·4 (20·2-26·8) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91·5 (89·1-93·6) in Beijing to 48·0 (43·4-53·2) in Tibet (a 43·5-point difference), while India saw a 30·8-point disparity, from 64·8 (59·6-68·8) in Goa to 34·0 (30·3-38·1) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4·8-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20·9-point to 17·0-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17·2-point to 20·4-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. Interpretation GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle- SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage hinges upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view - and subsequent provision - of quality health care for all populations