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Sökning: WFRF:(Srinivas A)

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  • 2019
  • Tidskriftsartikel (refereegranskat)
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  • Wang, Haidong, et al. (författare)
  • 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
  • 2016
  • Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1459-1544
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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  • Lozano, Rafael, et al. (författare)
  • Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017
  • 2018
  • Ingår i: The Lancet. - : Elsevier. - 1474-547X .- 0140-6736. ; 392:10159, s. 2091-2138
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59·4 (IQR 35·4–67·3), ranging from a low of 11·6 (95% uncertainty interval 9·6–14·0) to a high of 84·9 (83·1–86·7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030.
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  • Stanaway, Jeffrey D., et al. (författare)
  • Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017
  • 2018
  • Ingår i: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1923-1994
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk- outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.
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  • Murray, Christopher J. L., et al. (författare)
  • Population and fertility by age and sex for 195 countries and territories, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017
  • 2018
  • Ingår i: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1995-2051
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Population estimates underpin demographic and epidemiological research and are used to track progress on numerous international indicators of health and development. To date, internationally available estimates of population and fertility, although useful, have not been produced with transparent and replicable methods and do not use standardised estimates of mortality. We present single-calendar year and single-year of age estimates of fertility and population by sex with standardised and replicable methods. Methods: We estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods. We based the estimates on the demographic balancing equation, with inputs of fertility, mortality, population, and migration data. Fertility data came from 7817 location-years of vital registration data, 429 surveys reporting complete birth histories, and 977 surveys and censuses reporting summary birth histories. We estimated age-specific fertility rates (ASFRs; the annual number of livebirths to women of a specified age group per 1000 women in that age group) by use of spatiotemporal Gaussian process regression and used the ASFRs to estimate total fertility rates (TFRs; the average number of children a woman would bear if she survived through the end of the reproductive age span [age 10–54 years] and experienced at each age a particular set of ASFRs observed in the year of interest). Because of sparse data, fertility at ages 10–14 years and 50–54 years was estimated from data on fertility in women aged 15–19 years and 45–49 years, through use of linear regression. Age-specific mortality data came from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 estimates. Data on population came from 1257 censuses and 761 population registry location-years and were adjusted for underenumeration and age misreporting with standard demographic methods. Migration was estimated with the GBD Bayesian demographic balancing model, after incorporating information about refugee migration into the model prior. Final population estimates used the cohort-component method of population projection, with inputs of fertility, mortality, and migration data. Population uncertainty was estimated by use of out-of-sample predictive validity testing. With these data, we estimated the trends in population by age and sex and in fertility by age between 1950 and 2017 in 195 countries and territories. Findings: From 1950 to 2017, TFRs decreased by 49·4% (95% uncertainty interval [UI] 46·4–52·0). The TFR decreased from 4·7 livebirths (4·5–4·9) to 2·4 livebirths (2·2–2·5), and the ASFR of mothers aged 10–19 years decreased from 37 livebirths (34–40) to 22 livebirths (19–24) per 1000 women. Despite reductions in the TFR, the global population has been increasing by an average of 83·8 million people per year since 1985. The global population increased by 197·2% (193·3–200·8) since 1950, from 2·6 billion (2·5–2·6) to 7·6 billion (7·4–7·9) people in 2017; much of this increase was in the proportion of the global population in south Asia and sub-Saharan Africa. The global annual rate of population growth increased between 1950 and 1964, when it peaked at 2·0%; this rate then remained nearly constant until 1970 and then decreased to 1·1% in 2017. Population growth rates in the southeast Asia, east Asia, and Oceania GBD super-region decreased from 2·5% in 1963 to 0·7% in 2017, whereas in sub-Saharan Africa, population growth rates were almost at the highest reported levels ever in 2017, when they were at 2·7%. The global average age increased from 26·6 years in 1950 to 32·1 years in 2017, and the proportion of the population that is of working age (age 15–64 years) increased from 59·9% to 65·3%. At the national level, the TFR decreased in all countries and territories between 1950 and 2017; in 2017, TFRs ranged from a low of 1·0 livebirths (95% UI 0·9–1·2) in Cyprus to a high of 7·1 livebirths (6·8–7·4) in Niger. The TFR under age 25 years (TFU25; number of livebirths expected by age 25 years for a hypothetical woman who survived the age group and was exposed to current ASFRs) in 2017 ranged from 0·08 livebirths (0·07–0·09) in South Korea to 2·4 livebirths (2·2–2·6) in Niger, and the TFR over age 30 years (TFO30; number of livebirths expected for a hypothetical woman ageing from 30 to 54 years who survived the age group and was exposed to current ASFRs) ranged from a low of 0·3 livebirths (0·3–0·4) in Puerto Rico to a high of 3·1 livebirths (3·0–3·2) in Niger. TFO30 was higher than TFU25 in 145 countries and territories in 2017. 33 countries had a negative population growth rate from 2010 to 2017, most of which were located in central, eastern, and western Europe, whereas population growth rates of more than 2·0% were seen in 33 of 46 countries in sub-Saharan Africa. In 2017, less than 65% of the national population was of working age in 12 of 34 high-income countries, and less than 50% of the national population was of working age in Mali, Chad, and Niger. Interpretation: Population trends create demographic dividends and headwinds (ie, economic benefits and detriments) that affect national economies and determine national planning needs. Although TFRs are decreasing, the global population continues to grow as mortality declines, with diverse patterns at the national level and across age groups. To our knowledge, this is the first study to provide transparent and replicable estimates of population and fertility, which can be used to inform decision making and to monitor progress. Funding: Bill & Melinda Gates Foundation.
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9.
  • Klionsky, Daniel J., et al. (författare)
  • Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
  • 2008
  • Ingår i: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
  • Forskningsöversikt (refereegranskat)abstract
    • Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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  • Micah, Angela E., et al. (författare)
  • Tracking development assistance for health and for COVID-19 : a review of development assistance, government, out-of-pocket, and other private spending on health for 204 countries and territories, 1990-2050
  • 2021
  • Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 398:10308, s. 1317-1343
  • Forskningsöversikt (refereegranskat)abstract
    • Background The rapid spread of COVID-19 renewed the focus on how health systems across the globe are financed, especially during public health emergencies. Development assistance is an important source of health financing in many low-income countries, yet little is known about how much of this funding was disbursed for COVID-19. We aimed to put development assistance for health for COVID-19 in the context of broader trends in global health financing, and to estimate total health spending from 1995 to 2050 and development assistance for COVID-19 in 2020. Methods We estimated domestic health spending and development assistance for health to generate total health-sector spending estimates for 204 countries and territories. We leveraged data from the WHO Global Health Expenditure Database to produce estimates of domestic health spending. To generate estimates for development assistance for health, we relied on project-level disbursement data from the major international development agencies' online databases and annual financial statements and reports for information on income sources. To adjust our estimates for 2020 to include disbursements related to COVID-19, we extracted project data on commitments and disbursements from a broader set of databases (because not all of the data sources used to estimate the historical series extend to 2020), including the UN Office of Humanitarian Assistance Financial Tracking Service and the International Aid Transparency Initiative. We reported all the historic and future spending estimates in inflation-adjusted 2020 US$, 2020 US$ per capita, purchasing-power parity-adjusted US$ per capita, and as a proportion of gross domestic product. We used various models to generate future health spending to 2050. Findings In 2019, health spending globally reached $8. 8 trillion (95% uncertainty interval [UI] 8.7-8.8) or $1132 (1119-1143) per person. Spending on health varied within and across income groups and geographical regions. Of this total, $40.4 billion (0.5%, 95% UI 0.5-0.5) was development assistance for health provided to low-income and middle-income countries, which made up 24.6% (UI 24.0-25.1) of total spending in low-income countries. We estimate that $54.8 billion in development assistance for health was disbursed in 2020. Of this, $13.7 billion was targeted toward the COVID-19 health response. $12.3 billion was newly committed and $1.4 billion was repurposed from existing health projects. $3.1 billion (22.4%) of the funds focused on country-level coordination and $2.4 billion (17.9%) was for supply chain and logistics. Only $714.4 million (7.7%) of COVID-19 development assistance for health went to Latin America, despite this region reporting 34.3% of total recorded COVID-19 deaths in low-income or middle-income countries in 2020. Spending on health is expected to rise to $1519 (1448-1591) per person in 2050, although spending across countries is expected to remain varied. Interpretation Global health spending is expected to continue to grow, but remain unequally distributed between countries. We estimate that development organisations substantially increased the amount of development assistance for health provided in 2020. Continued efforts are needed to raise sufficient resources to mitigate the pandemic for the most vulnerable, and to help curtail the pandemic for all. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.
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11.
  • Axfors, Cathrine, et al. (författare)
  • Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
  • 2021
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I-2=0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I-2=0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities. Hydroxychloroquine and chloroquine have been investigated as a potential treatment for Covid-19 in several clinical trials. Here the authors report a meta-analysis of published and unpublished trials, and show that treatment with hydroxychloroquine for patients with Covid-19 was associated with increased mortality, and there was no benefit from chloroquine.
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12.
  • Lohoff, T., et al. (författare)
  • Integration of spatial and single-cell transcriptomic data elucidates mouse organogenesis
  • 2022
  • Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 40, s. 74-85
  • Tidskriftsartikel (refereegranskat)abstract
    • Molecular profiling of single cells has advanced our knowledge of the molecular basis of development. However, current approaches mostly rely on dissociating cells from tissues, thereby losing the crucial spatial context of regulatory processes. Here, we apply an image-based single-cell transcriptomics method, sequential fluorescence in situ hybridization (seqFISH), to detect mRNAs for 387 target genes in tissue sections of mouse embryos at the 8–12 somite stage. By integrating spatial context and multiplexed transcriptional measurements with two single-cell transcriptome atlases, we characterize cell types across the embryo and demonstrate that spatially resolved expression of genes not profiled by seqFISH can be imputed. We use this high-resolution spatial map to characterize fundamental steps in the patterning of the midbrain–hindbrain boundary (MHB) and the developing gut tube. We uncover axes of cell differentiation that are not apparent from single-cell RNA-sequencing (scRNA-seq) data, such as early dorsal–ventral separation of esophageal and tracheal progenitor populations in the gut tube. Our method provides an approach for studying cell fate decisions in complex tissues and development. © 2021, The Author(s).
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13.
  • Zabriskie, Matthew S., et al. (författare)
  • BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia
  • 2014
  • Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 26:3, s. 428-442
  • Tidskriftsartikel (refereegranskat)abstract
    • Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph+) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph+ leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.
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14.
  • Alhalaweh, Amjad, et al. (författare)
  • Pharmaceutical cocrystals of nitrofurantoin: screening, characterization and crystal structure analysis
  • 2012
  • Ingår i: CrystEngComm. - : Royal Society of Chemistry (RSC). - 1466-8033. ; 14:15, s. 5078-5088
  • Tidskriftsartikel (refereegranskat)abstract
    • The objective of this study was to screen and prepare cocrystals of the poorly soluble drug nitrofurantoin (NTF) with the aim of increasing its solubility. Screening for cocrystals of NTF using 47 coformers was performed by high-throughput (HT) screening using liquid assisted grinding (LAG) methods. Raman spectroscopy and powder X-ray diffraction (PXRD) were used as the primary analytical tools to identify the new crystalline solid forms. Manual LAG and reaction crystallization (RC) experiments were carried out to confirm and scale-up the hits. Seven hits were confirmed to be cocrystals. The cocrystals were characterized by PXRD, Raman and IR spectroscopy, thermal analysis (DSC and TGA) and liquid-state NMR or elemental analysis. The solution stability of the scaled-up cocrystals in water was tested by slurrying the cocrystals at 25 °C for one week. NTF forms cocrystals with a 1:1 stoichiometric ratio with urea (1), 4-hydroxybenzoic acid (2), nicotinamide (3), citric acid (4), l-proline (5) and vanillic acid (6). In addition, NTF forms a 1:2 cocrystal with vanillin (7). All but one of the NTF cocrystals transformed (dissociated) in water, resulting in NTF hydrate crystalline material or NTF hydrate plus the coformer, which indicates that the transforming cocrystals have a higher solubility than the NTF hydrate under these conditions. The crystal structures of 1:1 NTF-citric acid (4) and 1:2 NTF-vanillin (7) were solved by single-crystal X-ray diffraction. The crystal structures of these two cocrystals were analyzed in terms of their supramolecular synthons.
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15.
  • Fuller, Franklin D, et al. (författare)
  • Drop-on-demand sample delivery for studying biocatalysts in action at X-ray free-electron lasers
  • 2017
  • Ingår i: Nature Methods. - : Macmillan Publishers Ltd.. - 1548-7091 .- 1548-7105. ; 14, s. 443-449
  • Tidskriftsartikel (refereegranskat)abstract
    • X-ray crystallography at X-ray free-electron laser sources is a powerful method for studying macromolecules at biologically relevant temperatures. Moreover, when combined with complementary techniques like X-ray emission spectroscopy, both global structures and chemical properties of metalloenzymes can be obtained concurrently, providing insights into the interplay between the protein structure and dynamics and the chemistry at an active site. The implementation of such a multimodal approach can be compromised by conflicting requirements to optimize each individual method. In particular, the method used for sample delivery greatly affects the data quality. We present here a robust way of delivering controlled sample amounts on demand using acoustic droplet ejection coupled with a conveyor belt drive that is optimized for crystallography and spectroscopy measurements of photochemical and chemical reactions over a wide range of time scales. Studies with photosystem II, the phytochrome photoreceptor, and ribonucleotide reductase R2 illustrate the power and versatility of this method.
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16.
  • Gkoutzamanis, V. G., et al. (författare)
  • Conceptual design and energy storage positioning aspects for a hybrid-electric light aircraft
  • 2020
  • Ingår i: Proceedings of the ASME Turbo Expo. - : American Society of Mechanical Engineers (ASME). - 9780791884140
  • Konferensbidrag (refereegranskat)abstract
    • This work focuses on the feasibility of a 19-passenger hybrid-electric aircraft, to serve the short-haul segment within the 200-600 nautical miles. Its ambition is to answer some dominating research questions, during the evaluation and design of aircraft based on electric propulsion architectures. The potential entry into service of such aircraft is foreseen in 2030. A literature review is performed, to identify similar concepts that are under research and development. After the requirements definition, the first level of conceptual design is employed. Based on a set of assumptions, a methodology for the sizing of the hybrid-electric aircraft is described to explore the basis of the design space. Additionally, a methodology for the energy storage positioning is provided, to highlight the multidisciplinary aspects between the sizing of an aircraft, the selected architecture (series/parallel partial hybrid) and the energy storage operational characteristics. The design choices are driven by the aim to reduce CO2 emissions and accommodate boundary layer ingestion engines, with aircraft electrification. The results show that it is not possible to fulfill the initial design requirements (600 nmi) with a fully-electric aircraft configuration, due to the farfetched battery necessities. It is also highlighted that compliance with airworthiness certifications is favored by switching to hybrid-electric aircraft configurations and relaxing the design requirements (targeted range, payload, battery technology). Finally, the lower degree of hybridization (40%) is observed to have a higher energy efficiency (12% lower energy consumption and larger CO2 reduction), compared to the higher degree of hybridization (50%), with respect to the conventional configuration.
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17.
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18.
  • O Reese, Matthew, et al. (författare)
  • Consensus stability testing protocols for organic photovoltaic materials and devices
  • 2011
  • Ingår i: SOLAR ENERGY MATERIALS AND SOLAR CELLS. - : Elsevier Science B.V., Amsterdam.. - 0927-0248. ; 95:5, s. 1253-1267
  • Tidskriftsartikel (refereegranskat)abstract
    • Procedures for testing organic solar cell devices and modules with respect to stability and operational lifetime are described. The descriptions represent a consensus of the discussion and conclusions reached during the first 3 years of the international summit on OPV stability (ISOS). The procedures include directions for shelf life testing, outdoor testing, laboratory weathering testing and thermal cycling testing, as well as guidelines for reporting data. These procedures are not meant to be qualification tests, but rather generally agreed test conditions and practices to allow ready comparison between laboratories and to help improving the reliability of reported values. Failure mechanisms and detailed degradation mechanisms are not covered in this report.
  •  
19.
  • Pablos, Isabel, et al. (författare)
  • Mechanistic insights into COVID-19 by global analysis of the SARS-CoV-2 3CL(pro) substrate degradome
  • 2021
  • Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 37:4
  • Tidskriftsartikel (refereegranskat)abstract
    • The main viral protease (3CL(pro)) is indispensable for SARS-CoV-2 replication. We delineate the human protein substrate landscape of 3CL(pro) by TAILS substrate-targeted N-terminomics. We identify more than 100 substrates in human lung and kidney cells supported by analyses of SARS-CoV-2-infected cells. Enzyme kinetics and molecular docking simulations of 3CL(pro) engaging substrates reveal how noncanonical cleavage sites, which diverge from SARS-CoV, guide substrate specificity. Cleaving the interactors of essential effector proteins, effectively stranding them from their binding partners, amplifies the consequences of proteolysis. We show that 3CL(pro) targets the Hippo pathway, including inactivation of MAP4K5, and key effectors of transcription, mRNA processing, and translation. We demonstrate that Spike glycoprotein directly binds galectin-8, with galectin-8 cleavage disengaging CALCOCO2/NDP52 to decouple antiviral-autophagy. Indeed, in post-mortem COVID-19 lung samples, NDP52 rarely colocalizes with galectin-8, unlike in healthy lungs. The 3CL(pro) substrate degradome establishes a foundational substrate atlas to accelerate exploration of SARSCoV-2 pathology and drug design.
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20.
  • Proletov, Ian, et al. (författare)
  • Primary and secondary glomerulonephritides 1.
  • 2014
  • Ingår i: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385. ; 29 Suppl 3:May, s. 186-200
  • Tidskriftsartikel (refereegranskat)
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21.
  • Rapp, Östen, et al. (författare)
  • Electronic and atomic disorder in icosahedral AlPdRe
  • 2008
  • Ingår i: Journal of Physics. - : IOP Publishing. - 0953-8984 .- 1361-648X. ; 20:11, s. 114120-
  • Tidskriftsartikel (refereegranskat)abstract
    • Relations between electronic and atomic disorder of i-AlPdRe have been investigated by studies of neutron irradiated and annealed samples. The advantage with this technique is that a single sample can be monitored over a significant range of varying electronic properties, without concern for any influence of varying impurities. X-ray diffraction, the electrical resistivity and its temperature dependence, and the magnetoresistance are studied. The results show that annealings of an irradiated sample lead to improvement of the atomic order, as reflected in increased intensities of the x-ray diffraction peaks, while electronic properties change in the direction of increasing electronic disorder towards a metal-insulator transition. The observed relation in quasicrystals that improved atomic structure is associated with stronger anomalies in transport properties is thus also seen in i-AlPdRe. In particular, the variation of the diffusion constant in the region of small values of the resistivity is found to be similar for annealed polygrain samples and for single grain samples with varying Pd concentration, as evaluated from literature data, indicating a similar development of electronic disorder in both sets of samples. However, the problem remains as to why the resistivity is small in single grain samples which are atomically well-ordered. The possibility of a strong sensitivity to concentration differences is pointed out.
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22.
  • Alderman, J. McKee, et al. (författare)
  • Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice
  • 2009
  • Ingår i: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 44:1-2, s. 26-33
  • Tidskriftsartikel (refereegranskat)abstract
    • Pit1 null (Snell dwarf) and Proph1 null (Ames dwarf) mutant mice lack GH, PRL and TSH. Snell and Ames dwarf mice also exhibit reduced IGF-I, resistance to cancer and a longer lifespan than control mice. Endogenous glucose production during fasting is reduced in Snell dwarf mice compared to fasting control mice. In view of cancer cell dependence on glucose for energy, low endogenous glucose production may provide Snell dwarf mice with resistance to cancer. We investigated whether endogenous glucose production is lower in Snell dwarf mice during feeding. Inhibition of endogenous glucose production by glucose injection was enhanced in 12 to 14 month-old female Snell dwarf mice. Thus, we hypothesize that lower endogenous glucose production during feeding and fasting reduces cancer cell glucose utilization providing Snell dwarf mice with resistance to cancer. The elevation of circulating adiponectin, a hormone produced by adipose tissue, may contribute to the suppression of endogenous glucose production in 12 to 14 month-old Snell dwarf mice. We compared the incidence of cancer at time of death between old Snell dwarf and control mice. Only 18% of old Snell dwarf mice had malignant lesions at the time of death compared to 82% of control mice. The median ages at death for old Snell dwarf and control mice were 33 and 26 months, respectively. By contrast, previous studies showed a high incidence of cancer in old Ames dwarf mice at the time of death. Hence, resistance to cancer in old Snell dwarf mice may be mediated by neuroendocrine factors that reduce glucose utilization besides elevated adiponectin, reduced IGF-I and a lack of GH, PRL and TSH, seen in both Snell and Ames dwarf mice. Proteomics analysis of pituitary secretions from Snell dwarf mice confirmed the absence of GH and PRL, the secretion of ACTH and elevated secretion of Chromogranin B and Secretogranin II. Radioimmune assays confirmed that circulating Chromogranin B and Secretogranin II were elevated in 12 to 14 month-old Snell dwarf mice. In summary, our results in Snell dwarf mice suggest that the pituitary gland and adipose tissue are part of a neuroendocrine loop that lowers the risk of cancer during aging by reducing the availability of glucose.
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23.
  • Bikkina, Srinivas, et al. (författare)
  • Air quality in megacity Delhi affected by countryside biomass burning
  • 2019
  • Ingår i: Nature Sustainability. - : Springer Science and Business Media LLC. - 2398-9629. ; 2:3, s. 200-205
  • Tidskriftsartikel (refereegranskat)abstract
    • South Asian megacities are strong sources of regional air pollution. Delhi is a key hotspot of health-and climate-impacting black carbon (BC) emissions, affecting environmental sustainability in densely populated northern India. Effective mitigation of BC impact is hampered by highly uncertain emission source estimates. Here, we use dual-carbon isotope fingerprints (delta C-13/Delta C-14) of BC to constrain the seasonal source variability in Delhi. These measurements show that lower BC concentrations in summer are predominantly from fossil fuel sources (similar to 83%). However, large-scale open burning of post-harvest crop residue/wood in nearby rural regions is contributing to severe haze pollution in Delhi during winter and autumn (similar to 42 +/- 17%). Hence, the common conception that megacities affect their surroundings is here amended or seasonally reversed. Therefore, to combat the severe air pollution problems in Delhi and the environmental quality of northern India, current urban efforts need to be complemented with countryside regional mitigation.
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24.
  • Bikkina, Srinivas, et al. (författare)
  • Carbon isotope-constrained seasonality of carbonaceous aerosol sources from an urban location (Kanpur) in the Indo-Gangetic Plain
  • 2017
  • Ingår i: Journal of Geophysical Research - Atmospheres. - 2169-897X .- 2169-8996. ; 122:9, s. 4903-4923
  • Tidskriftsartikel (refereegranskat)abstract
    • The Indo-Gangetic Plain (IGP) in northern India, Pakistan, and Bangladesh is a major source of carbonaceous aerosols in South Asia. However, poorly constrained seasonality of their sources over the IGP leads to large uncertainty in climate and health effects. Here we present a first data set for year-round radiocarbon (C-14) and stable carbon (C-13)-based source apportionment of total carbon (TC) in ambient PM10 (n = 17) collected from an urban site (Kanpur: 26.5 degrees N, 80.3 degrees E) in the IGP during January 2007 to January 2008. The year-round C-14-based fraction biomass (f(bio-TC)) estimate at Kanpur averages 777% and emphasizes an impact of biomass burning emissions (BBEs). The highest f(bio-TC) (%) is observed in fall season (October-November, 856%) followed by winter (December-February, 804%) and spring (March-May, 758%), while lowest values are found in summer (June-September, 69 +/- 2%). Since biomass/coal combustion and vehicular emissions mostly contribute to carbonaceous aerosols over the IGP, we predict C-13(TC) (C-13(pred)) over Kanpur using known C-13 source signatures and the measured C-14 value of each sample. The seasonal variability of C-13(obs)-C-13(pred) versus C-14(TC) together with air mass back trajectories and Moderate Resolution Imaging Spectroradiometer fire count data reveal that carbonaceous aerosols in winter/fall are significantly influenced by atmospheric aging (downwind transport of crop residue burning/wood combustion emissions in the northern IGP), while local sources (wheat residue combustion/vehicular emissions) dominate in spring/summer. Given the large temporal and seasonal variability in sources and emission strength of TC over the IGP, C-14-based constraints are, thus, crucial for reducing their uncertainties in carbonaceous aerosol budgets in climate models.
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25.
  • Bikkina, Srinivas, et al. (författare)
  • Dual carbon isotope characterization of total organic carbon in wintertime carbonaceous aerosols from northern India
  • 2016
  • Ingår i: Journal of Geophysical Research - Atmospheres. - 2169-897X .- 2169-8996. ; 121:9, s. 4797-4809
  • Tidskriftsartikel (refereegranskat)abstract
    • Large-scale emissions of carbonaceous aerosols (CA) from South Asia impact both regional climate and air quality, yet their sources are not well constrained. Here we use source-diagnostic stable and radiocarbon isotopes (delta C-13 and Delta C-14) to characterize CA sources at a semiurban site (Hisar: 29.2 degrees N, 75.2 degrees E) in the NW Indo-Gangetic Plain (IGP) and a remote high-altitude location in the Himalayan foothills (Manora Peak: 29.4 degrees N, 79.5 degrees E, 1950 m above sea level) in northern India during winter. The Delta C-14 of total aerosol organic carbon (TOC) varied from -178% to -63% at Hisar and from -198% to -1% at Manora Peak. The absence of significant differences in the C-14-based fraction biomass of TOC between Hisar (0.81 +/- 0.03) and Manora Peak (0.82 +/- 0.07) reveals that biomass burning/biogenic emissions (BBEs) are the dominant sources of CA at both sites. Combining this information with d13C, other chemical tracers (K+/OC and SO42-/EC) and air mass back trajectory analyses indicate similar source regions in the IGP (e.g., Punjab and Haryana). These results highlight that CA from BBEs in the IGP are not only confined to the atmospheric boundary layer but also extend to higher elevations of the troposphere, where the synoptic-scale circulations could substantially influence their abundances both to the Himalayas and over the downwind oceanic regions such as the Indian Ocean. Given the vast emissions of CA from postharvest crop residue combustion practices in the IGP during early Northeast Monsoon, this information is important for both improved process and model understanding of climate and health effects, as well as in guiding policy decision aiming at reducing emissions.
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26.
  • Elfawy, Hasnaa A., et al. (författare)
  • Molecular toxicity of Benzo(a)pyrene mediated by elicited oxidative stress infer skeletal deformities and apoptosis in embryonic zebrafish
  • 2021
  • Ingår i: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. ; 789
  • Tidskriftsartikel (refereegranskat)abstract
    • Benzo(a)pyrene (BaP) has become an integral component of disposed of plastic waste, organic pollutants, and remnants of combustible materials in the aquatic environment due to their persistent nature. The accumulation and integration of these polycyclic aromatic hydrocarbons (PAHs) have raised concern to human health and ecological safety. This study assessed the BaP-induced in vivo molecular toxicity with embryonic zebrafish inferred by oxidative stress and apoptosis. BaP was found to induce morphological and physiological abnormalities like delayed hatching (p < 0.05). Computational analysis demonstrated the high-affinity interaction of BaP with the zebrafish hatching enzyme (ZHE1) with Arg, Cys, Ala, Tyr, and Phe located at the active site revealing the influence of BaP on delayed hatching due to alteration of the enzyme structure. RT-PCR analysis revealed significant down-regulation of the skeletal genes Sox9a, SPP1/OPN, and Col1a1 (p < 0.05) genes. The cellular investigations unraveled that the toxicity of BaP extends to the skeletal regions of zebrafish (head, backbone, and tail) because of the elicited oxidative stress leading to apoptosis. The study extended the horizon of understanding of BaP toxicity at the molecular level which will enhance the indulgent and designing of techniques for better ecological sustainability.
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27.
  • Holmqvist, Annica, et al. (författare)
  • Urologic, lymphedema, pelvic pain and gastrointestinal symptoms increase after radiotherapy in patients with primary uterine tumors : a prospective longitudinal Swedish cohort study
  • 2021
  • Ingår i: Clinical and Translational Oncology. - : SPRINGER INTERNATIONAL PUBLISHING AG. - 1699-048X .- 1699-3055. ; 23:9, s. 1752-1760
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose Radiotherapy (RT) causes an inflammatory reaction of the tissue which leads to fibrosis and reduced functioning of the pelvic organs. Few studies have shown significant relationships between side effects and RT in uterine tumors. Here, the urological, lymphedema, pelvic pain and gastrointestinal (GI) symptoms were studied before and after RT in patients with primary uterine tumors using the EORTC QLQ-EN24, specifically designed for uterine cancer patients. Methods This prospective cohort study comprised patients with primary uterine tumors who received pelvic radiotherapy (RT). A total of 43 patients were included from May 2014 to February 2019. Patients completed the questionnaires for global health status and functioning before the start of RT and at 3 and 12 months after RT. Results We found a significant worsening of the urological symptoms 3 months after RT which persisted up to 12 months after RT compared to baseline values prior to start of RT (p = 0.007). An exacerbation of the urinary symptoms was seen in patients with vaginal brachytherapy/boost compared to patients with pelvic RT at 12 months after RT (p = 0.053). The severity of lymphedema symptoms increased from RT start to 12 months after RT (p = 0.019) and the pelvic pain were higher at 3 months after RT compared to before RT (p = 0.004). Also, the level of GI symptoms was significantly higher 12 months after RT compared to the RT start (p < 0.001). Conclusions The urologic, lymphedema, pelvic pain and GI symptoms all increase after RT.
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28.
  • Insulander, J., et al. (författare)
  • Prognosis following surgical bypass compared with laparotomy alone in unresectable pancreatic adenocarcinoma
  • 2016
  • Ingår i: British Journal of Surgery. - : John Wiley & Sons. - 0007-1323 .- 1365-2168. ; 103:9, s. 1200-1208
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Resection with curative intent has been shown to prolong survival of patients with locoregional pancreatic ductal adenocarcinoma (PDAC). However, up to 33 per cent of patients are deemed unresectable at exploratory laparotomy owing to unanticipated locally advanced or metastatic disease. In these patients, prophylactic double bypass (PDB) procedures have been considered the standard of care. The aim of this study was to compare PDB with exploratory laparotomy alone in terms of impact on postoperative course, chemotherapy and overall survival.Methods: This retrospective observational cohort study (2004-2013) was conducted using a prospective institutional database. Patients with histologically confirmed, unresectable PDAC were included. Relationships between PDB procedures, exploratory laparotomy alone, postoperative chemotherapy and best supportive care were investigated by means of Cox regression. Overall survival was compared using Kaplan-Meier estimations and log rank test.Results: Of 503 patients with PDAC scheduled for resection with curative intent, 104 were deemed unresectable at laparotomy (resection rate 79·3 per cent). Seventy-four patients underwent PDB procedures and 30 had exploratory laparotomy alone. PDB and exploratory laparotomy were similar in terms of perioperative mortality, initiation of chemotherapy and overall survival. Compared with best supportive care, postoperative chemotherapy prolonged survival (8·0 versus 14·4 months in locally advanced PDAC, P = 0·007; 2·3 versus 8·0 months in metastatic PDAC, P < 0·001). Patients undergoing chemotherapy following exploratory laparotomy alone had longer median overall survival than patients undergoing chemotherapy following PDB procedures (16·3 versus 10·3 months; P = 0·040).Conclusion: Patients with pancreatic cancer deemed unresectable at laparotomy may derive survival benefit from subsequent chemotherapy as opposed to supportive care alone. At laparotomy, proceeding with a bypass procedure for prophylactic symptom control may be prognostically unfavourable.
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29.
  • Karkin, A. E., et al. (författare)
  • Monitoring an insulator-metal transition in icosahedral AlPdRe by neutron irradiation
  • 2002
  • Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 66:9
  • Tidskriftsartikel (refereegranskat)abstract
    • The intrinsic disorder effect on the electrical resistivity and magnetoresistance (MR) of icosahedral AlPdRe is studied by use of high-energy neutron irradiation. The icosahedral phase is preserved under irradiation with a decrease of x-ray peak intensity and volume of the coherent icosahedral phase. An insulator-metal transition, as observed in the MR, can be driven by the irradiation and is monitored by the resistance ratio R[=rho(4.2 K)/rho(295 K)]. The relation of MR vs R was found to be similar for samples of a widely different history.
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30.
  • Kuru, Erkin, et al. (författare)
  • In Situ probing of newly synthesized peptidoglycan in live bacteria with fluorescent D-amino acids
  • 2012
  • Ingår i: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 51:50, s. 12519-12523
  • Tidskriftsartikel (refereegranskat)abstract
    • Tracking a bug's life: Peptidoglycan (PG) of diverse bacteria is labeled by exploiting the tolerance of cells for incorporating different non-natural D-amino acids. These nontoxic D-amino acids preferably label the sites of active PG synthesis, thereby enabling fine spatiotemporal tracking of cell-wall dynamics in phylogenetically and morphologically diverse bacteria. HCC = 7-hydroxycoumarin, NBD = 7-nitrobenzofurazan, TAMRA = carboxytetramethylrhodamine.
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31.
  • Lindahl, Johanna, et al. (författare)
  • Brucellosis in India : results of a collaborative workshop to define One Health priorities
  • 2020
  • Ingår i: Tropical Animal Health and Production. - : Springer Science and Business Media LLC. - 0049-4747 .- 1573-7438. ; 52, s. 387-396
  • Tidskriftsartikel (refereegranskat)abstract
    • Brucellosis is an important zoonosis worldwide. In livestock, it frequently causes chronic disease with reproductive failures that contribute to production losses, and in humans, it causes an often-chronic febrile illness that is frequently underdiagnosed in many low- and middle-income countries, including India. India has one of the largest ruminant populations in the world, and brucellosis is endemic in the country in both humans and animals. In November 2017, the International Livestock Research Institute invited experts from government, national research institutes, universities, and different international organizations to a one-day meeting to set priorities towards a "One Health" control strategy for brucellosis in India. Using a risk prioritization exercise followed by discussions, the meeting agreed on the following priorities: collaboration (transboundary and transdisciplinary); collection of more epidemiological evidence in humans, cattle, and in small ruminants (which have been neglected in past research); Economic impact studies, including cost effectiveness of control programmes; livestock vaccination, including national facilities for securing vaccines for the cattle population; management of infected animals (with the ban on bovine slaughter, alternatives such as sanctuaries must be explored); laboratory capacities and diagnostics (quality must be assured and better rapid tests developed); and increased awareness, making farmers, health workers, and the general public more aware of risks of brucellosis and zoonoses in general. Overall, the meeting participants agreed that brucellosis control will be challenging in India, but with collaboration to address the priority areas listed here, it could be possible.
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32.
  • Manchaiah, Vinaya, et al. (författare)
  • Features, Functionality, and Acceptability of Internet-Based Cognitive Behavioral Therapy for Tinnitus in the United States
  • 2020
  • Ingår i: American Journal of Audiology. - : American Speech-Language-Hearing Association. - 1059-0889 .- 1558-9137. ; 29:3, s. 476-490
  • Tidskriftsartikel (refereegranskat)abstract
    • ObjectiveAlthough tinnitus is one of the most commonly reported symptoms in the general population, patients with bothersome tinnitus are challenged by issues related to accessibility of care and intervention options that lack strong evidence to support their use. Therefore, creative ways of delivering evidence-based interventions are necessary. Internet-based cognitive behavioral therapy (ICBT) demonstrates potential as a means of delivering this support but is not currently available in the United States. This article discusses the adaptation of an ICBT intervention, originally used in Sweden, Germany, and the United Kingdom, for delivery in the United States. The aim of this study was to (a) modify the web platform's features to suit a U.S. population, (b) adapt its functionality to comply with regulatory aspects, and (c) evaluate the credibility and acceptability of the ICBT intervention from the perspective of health care professionals and patients with bothersome tinnitus.Materials/MethodInitially, the iTerapi ePlatform developed in Sweden was adopted for use in the United States. Functional adaptations followed to ensure that the platform's functional and security features complied with both institutional and governmental regulations and that it was suitable for a U.S. population. Following these adaptations, credibility and acceptance of the materials were evaluated by both health care professionals (n = 11) and patients with bothersome tinnitus (n = 8).ResultsSoftware safety and compliance regulatory assessments were met. Health care professionals and patients reported favorable acceptance and satisfaction ratings regarding the content, suitability, presentation, usability, and exercises provided in the ICBT platform. Modifications to the features and functionality of the platform were made according to user feedback.ConclusionsEnsuring that the ePlatform employed the appropriate features and functionalities for the intended population was essential to developing the Internet-based interventions. The favorable user evaluations indicated that the intervention materials were appropriate for the tinnitus population in the United States.
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33.
  • Maurer, Mathew S., et al. (författare)
  • Genotype and Phenotype of Transthyretin Cardiac Amyloidosis THAOS (Transthyretin Amyloid Outcome Survey)
  • 2016
  • Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 68:2, s. 161-172
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.Objectives: The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.Methods: Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189).Results: U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival.Conclusions: In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745)
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34.
  • Michno, Wojciech, 1992, et al. (författare)
  • Spatial Neurolipidomics at the Single Amyloid-β Plaque Level in Postmortem Human Alzheimer's Disease Brain
  • 2024
  • Ingår i: ACS CHEMICAL NEUROSCIENCE. - 1948-7193. ; 15:4, s. 877-888
  • Tidskriftsartikel (refereegranskat)abstract
    • Lipid dysregulations have been critically implicated in Alzheimer's disease (AD) pathology. Chemical analysis of amyloid-beta (A beta) plaque pathology in transgenic AD mouse models has demonstrated alterations in the microenvironment in the direct proximity of A beta plaque pathology. In mouse studies, differences in lipid patterns linked to structural polymorphism among A beta pathology, such as diffuse, immature, and mature fibrillary aggregates, have also been reported. To date, no comprehensive analysis of neuronal lipid microenvironment changes in human AD tissue has been performed. Here, for the first time, we leverage matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) through a high-speed and spatial resolution commercial time-of-light instrument, as well as a high-mass-resolution in-house-developed orbitrap system to characterize the lipid microenvironment in postmortem human brain tissue from AD patients carrying Presenilin 1 mutations (PSEN1) that lead to familial forms of AD (fAD). Interrogation of the spatially resolved MSI data on a single A beta plaque allowed us to verify nearly 40 sphingolipid and phospholipid species from diverse subclasses being enriched and depleted, in relation to the A beta deposits. This included monosialo-gangliosides (GM), ceramide monohexosides (HexCer), ceramide-1-phosphates (CerP), ceramide phosphoethanolamine conjugates (PE-Cer), sulfatides (ST), as well as phosphatidylinositols (PI), phosphatidylethanolamines (PE), and phosphatidic acid (PA) species (including Lyso-forms). Indeed, many of the sphingolipid species overlap with the species previously seen in transgenic AD mouse models. Interestingly, in comparison to the animal studies, we observed an increased level of localization of PE and PI species containing arachidonic acid (AA). These findings are highly relevant, demonstrating for the first time A beta plaque pathology-related alteration in the lipid microenvironment in humans. They provide a basis for the development of potential lipid biomarkers for AD characterization and insight into human-specific molecular pathway alterations.
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35.
  • Palm, Angelica A., et al. (författare)
  • Interferon Alpha-Inducible Protein 27 Expression Is Linked to Disease Severity in Chronic Infection of Both HIV-1 and HIV-2
  • 2022
  • Ingår i: Frontiers in Virology. - : Frontiers Media SA. - 2673-818X. ; 2
  • Tidskriftsartikel (refereegranskat)abstract
    • Disease progression is slower in HIV-2, as compared with HIV-1 infection, in accordance with low or undetectable plasma viremia at viral setpoint. However, it is unclear why most HIV-2 infected individuals are still at risk of developing AIDS. To explore if specific host responses are linked to HIV disease severity, we have compared blood gene expression profiles between HIV seronegative and HIV-1, HIV-2 or dually HIV-1/HIV-2 infected individuals. In this study the gene encoding Interferon alpha-inducible protein 27 (IFI27) was found to be the most differentially expressed. Detailed expression analysis revealed significantly higher IFI27 expression in HIV infected individuals compared with seronegative individuals, irrespectively of HIV type. Moreover, IFI27 expression was higher in HIV-1 than in HIV-2 infected individuals. Multiple linear regression analysis, adjusting for age and sex, showed also that plasma viral load was the strongest predictor of IFI27 expression, followed by CD4% and HIV type. In line with this, IFI27 expression was found to be higher in HIV-2 viremic, compared with HIV-2 aviremic individuals. Still, HIV-2 aviremic individuals displayed elevated IFI27 expression compared with seronegative individuals. Furthermore, in HIV-2 infected individuals, IFI27 expression was also correlated with plasma markers previously linked to inflammation and disease progression in HIV infection. Taken together, our findings suggest that sustained elevation of type I interferon signaling, here reflected by elevated IFI27 expression in the chronic infection phase, is a key pathogenic feature of both HIV-1 and HIV-2
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36.
  • Papareddy, Praveen, et al. (författare)
  • A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection
  • 2019
  • Ingår i: Nature Microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 4:12, s. 2442-2455
  • Tidskriftsartikel (refereegranskat)abstract
    • Severe infectious diseases are often characterized by an overwhelming and unbalanced systemic immune response to microbial infections. Human antithrombin (hAT) is a crucial coagulation inhibitor with anti-inflammatory activities. Here we identify three hAT-binding proteins (CD13, CD300f and LRP-1) on human monocytes that are involved in blocking the activity of nuclear factor-kappa B. We found that the modulating effect is primarily restricted to the less abundant beta-isoform (h beta AT) of hAT that lacks N-glycosylation at position 135. Individuals with a mutation at this position have increased production of h beta AT and analysis of their blood, which was stimulated ex vivo with lipopolysaccharide, showed a decreased inflammatory response. Similar findings were recorded when heterozygotic mice expressing hAT or h beta AT were challenged with lipopolysaccharide or infected with Escherichia coli bacteria. Our results finally demonstrate that in a lethal E. coli infection model, survival rates increased when mice were treated with h beta AT one hour and five hours after infection. The treatment also resulted in a reduction of the inflammatory response and less severe organ damage.
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37.
  • Srivastava, R., et al. (författare)
  • In silico analysis of thioredoxins and glutaredoxins
  • 2005
  • Ingår i: Journal of Plant Biochemistry and Biotechnology. - 0971-7811 .- 0974-1275. ; 14:2, s. 121-126
  • Tidskriftsartikel (refereegranskat)abstract
    • Thioredoxins (TRXs) and glutaredoxins (GRXs) are ubiquitous small redox proteins belonging to the thioredoxin (TRX) superfamily. They regulate several cellular functions via mediating a dithiol/disulphide exchange in target proteins. Thioredoxins have been classified into several subgroups based on their structural homologs. In an attempt to identify thioredoxin proteins which have not been characterized, an EST database survey of Lycopersicon esculentum, Glycine max, Helianthus annus, Secale cereale, Solanum tuberosum, Apis mellifera ligustica, Oncorhynchus mykiss, Salmo salar, and whole genome survey for Drosophila melanogaster, Rattus norvegicus and Caenorhabditis briggsae was performed. Several glutaredoxin and glutaredoxin-like proteins from Ricinus communis, Vercinia fordii, Lycopersicon esculentum, Tilia platyphyllos, Populus tremuloides, Triticum aestivum and Oryza sativa were also characterized. The deduced amino acid sequences were aligned and phylogenetic trees were constructed to determine the consensus sequences and for establishing interrelationships amongst the new and established thioredoxin and glutaredoxins. Based on the alignments, proteins were designated to their respective classes and subcellular localization predictions were used to predict their possible site of actions. In silico analysis has identified several new thioredoxins, glutaredoxins and related proteins and provided insight into their evolutionary relationships.
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38.
  • Stadnik, Z. M., et al. (författare)
  • Mossbauer and transport studies of amorphous and icosahedral Zr-Ni-Cu-Ag-Al alloys
  • 2002
  • Ingår i: Journal of Physics. - : IOP Publishing. - 0953-8984 .- 1361-648X. ; 14:27, s. 6883-6896
  • Tidskriftsartikel (refereegranskat)abstract
    • The alloy Zr65Al7.5Ni10Cu7.3Fe0.2Ag10 in the amorphous and icosahedral states, and the bulk amorphous alloy Zr65Al7.5Ni10Cu7.5Ag10, have been studied with Fe-57 Mossbauer spectroscopy, electrical resistance and magnetoresistance techniques. The average quadrupole splitting in both alloys decreases with temperature as T-3/2. The average quadrupole splitting in the icosahedral alloy is the largest ever reported for a metallic system. The lattice vibrations of the Fe atoms in the amorphous and:icosahedral alloys are well described by a simple Debye model, with the characteristic Mossbauer temperatures of 379(29) and 439(28) K, respectively. Amorphous alloys Zr65Al7.5Ni10Cu7.5Ag10 and Zr65Al7.5Ni10Cu7.3Fe0.2Ag10 have been found to be superconducting with the transition temperature, T, of about 1.7 K. The magnitude of T, and the critical field slope at T, are in agreement with previous work on Zr-based amorphous superconductors, while the low-temperature normal state resistivity is-larger than typical results for binary and ternary Zr-based alloys. The resistivity of icosahedral Zr65Al7.5Ni10Cu7.3Fe0.2Ag10 is larger-than that for the amorphous ribbon of the same composition, as inferred both from direct measurements on the ribbons and from the observed magnetoresistance. However the icosahedral sample is non-superconducting in the measurement range down to 1.5 K. The results for the resistivity and the superconducting T-c both suggest a stronger electronic disorder in the icosahedral phase than in the amorphous phase.
  •  
39.
  • Vaidya, A. S., et al. (författare)
  • Estimation of arterial stiffness through pulse transit time measurement
  • 2014
  • Ingår i: BIODEVICES 2014 - 7th Int. Conference on Biomedical Electronics and Devices, Proceedings; Part of 7th International Joint Conference on Biomedical Engineering Systems and Technologies, BIOSTEC 2014. - : SCITEPRESS - Science and and Technology Publications. - 9789897580130 ; , s. 238-242
  • Konferensbidrag (refereegranskat)abstract
    • Early detection of cardiovascular disease (CVD) and its treatment is significantly expected to reduce the mortality rate across the world. While several diagnostic techniques have been developed for early detection of the CVD, recent focus has been on measuring the 'arterial stiffness', which appears to be a major indicator of onset of cardio vascular disease. In this work, authors consider three mathematical models that relate pulse wave velocity (PWV) with arterial stiffness. While one model considers blood to be a nonviscous and incompressible fluid, the other considers it to be a viscous and compressible. Pulse transit time has been measured experimentally for five different individuals of different ages and heights from where PWV has been estimated. Using values of PWV, Young's modulus of elasticity has been derived. Data related to arteries such as radius, wall thickness, density and viscosity of blood have been taken from published literature where these parameters have been measured using techniques such as MRI. Initial results indicate that different models predict different estimates for arterial stiffness that depend on assumptions made.
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40.
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41.
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42.
  • Whiss, Per A., et al. (författare)
  • Kinetics of platelet P-selectin mobilization : Concurrent surface expression and release induced by thrombin or PMA, and inhibition by the NO Donor SNAP
  • 1998
  • Ingår i: Cell Communication & Adhesion. - : Informa UK Limited. - 1541-9061 .- 1543-5180. ; 6:4, s. 289-300
  • Tidskriftsartikel (refereegranskat)abstract
    • Activated platelets and endothelium surface express the cell adhesion molecule P-selectin (CD62P), which plays an important role in mediating interactions with leukocytes. Increased levels of a functional soluble form of P-selectin (sP-selectin) have been reported in several pathological states but it is not clear whether this circulating sP-selectin originates from platelets and/or endothelial cells. Here we describe the concurrent kinetics of intracellular storage, surface expression and release of platelet P-selectin induced by thrombin or the protein kinase C activator PMA. Platelet activation with submaximal concentrations of thrombin (0.1 U/ml) resulted in a rapid decrease of intracellular P-selectin. This decrease of intracellular P-selectin concurred with a gradual increase of surface expression and an initial increase of sP-selectin. Our results indicate that intracellular stores of P-selectin were only partly mobilized upon activation with submaximal concentrations of thrombin. A high concentration of thrombin (1.0 U/ml) induced a rapid and nearly total decrease of intracellular stores and a more pronounced, but transient, increase of surface expression. The release of P-selectin was fast and occurred during the initial activation phase. The NO donor SNAP inhibited both surface expression and release of platelet P-selectin in a similar manner. PMA (0.1–1.01 µM) mediated a more slow, gradual and sustained surface expression and release of P-selectin than thrombin. Thus, surface expression and release of platelet P-selectin show different kinetics depending on the mode of activation.
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43.
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44.
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45.
  • Whiss, Per A., et al. (författare)
  • Modulation of P-selectin expression on isolated human platelets y an NO donor assessed by a novel ELISA application
  • 1997
  • Ingår i: JIM - Journal of Immunological Methods. - 0022-1759 .- 1872-7905. ; 200:1-2, s. 135-143
  • Tidskriftsartikel (refereegranskat)abstract
    • Adhesion molecules such as P-selectin are potential markers for evaluating platelet activation and studying the role of cell-cell interactions in numerous biological processes related to hemostasis and inflammation. The expression of P-selectin and related molecules has previously been quantified with different techniques. As an alternative to the most common method, flow cytometry, we have developed a useful ELISA method to simultaneously analyse 96 samples for platelet expression of P-selectin. Samples may be stored for at least 7 days at 4°C prior to analysis. The method is simple, reproducible, flexible and requires only standard equipment. Washed platelets (WP) from healthy male volunteers, at a concentration of 1 × 107/microtiter plate well, were stimulated with various known platelet activators and fixed with 0.1% formaldehyde for 10 min. The fixed WP were centrifuged to form a confluent layer in the wells and then incubated with optimal dilutions of primary antibodies (1/2000) directed against P-selectin, CD41, CD9 and secondary antibodies conjugated with alkaline phosphatase. Our results show that P-selectin expression on WP increases significantly upon stimulation with thrombin (0.1–1.0 U/ml), ADP (10 μM) and epinephrine (100 μM). The induction of P-selectin expression by thrombin is fast and has different kinetics depending on the concentration of the agonist. Prior incubation with the nitric oxide donor SNAP (10 μM) inhibits the up-regulation of P-selectin induced by sub-maximal concentrations of thrombin (p < 0.05). This ELISA is suitable for studying the expression and regulation of P-selectin and other surface molecules on human platelets in various pathological states.
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46.
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