| 1. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 2. |
- Botvinik-Nezer, Rotem, et al.
(författare)
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Variability in the analysis of a single neuroimaging dataset by many teams
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 582, s. 84-88
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Tidskriftsartikel (refereegranskat)abstract
- Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses(1). The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset(2-5). Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed. The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.
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| 3. |
- Ades, M., et al.
(författare)
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Global Climate : in State of the climate in 2019
- 2020
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 101:8, s. S17-S127
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Tidskriftsartikel (refereegranskat)
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| 4. |
- Ades, M., et al.
(författare)
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GLOBAL CLIMATE
- 2020
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Ingår i: BULLETIN OF THE AMERICAN METEOROLOGICAL SOCIETY. - 0003-0007 .- 1520-0477. ; 101:8
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Arndt, D. S., et al.
(författare)
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State of the Climate in 2016
- 2017
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 98:8, s. S1-S280
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Tidskriftsartikel (refereegranskat)abstract
- In 2016, the dominant greenhouse gases released into Earth's atmosphere-carbon dioxide, methane, and nitrous oxide-continued to increase and reach new record highs. The 3.5 +/- 0.1 ppm rise in global annual mean carbon dioxide from 2015 to 2016 was the largest annual increase observed in the 58-year measurement record. The annual global average carbon dioxide concentration at Earth's surface surpassed 400 ppm (402.9 +/- 0.1 ppm) for the first time in the modern atmospheric measurement record and in ice core records dating back as far as 800000 years. One of the strongest El Nino events since at least 1950 dissipated in spring, and a weak La Nina evolved later in the year. Owing at least in part to the combination of El Nino conditions early in the year and a long-term upward trend, Earth's surface observed record warmth for a third consecutive year, albeit by a much slimmer margin than by which that record was set in 2015. Above Earth's surface, the annual lower troposphere temperature was record high according to all datasets analyzed, while the lower stratospheric temperature was record low according to most of the in situ and satellite datasets. Several countries, including Mexico and India, reported record high annual temperatures while many others observed near-record highs. A week-long heat wave at the end of April over the northern and eastern Indian peninsula, with temperatures surpassing 44 degrees C, contributed to a water crisis for 330 million people and to 300 fatalities. In the Arctic the 2016 land surface temperature was 2.0 degrees C above the 1981-2010 average, breaking the previous record of 2007, 2011, and 2015 by 0.8 degrees C, representing a 3.5 degrees C increase since the record began in 1900. The increasing temperatures have led to decreasing Arctic sea ice extent and thickness. On 24 March, the sea ice extent at the end of the growth season saw its lowest maximum in the 37-year satellite record, tying with 2015 at 7.2% below the 1981-2010 average. The September 2016 Arctic sea ice minimum extent tied with 2007 for the second lowest value on record, 33% lower than the 1981-2010 average. Arctic sea ice cover remains relatively young and thin, making it vulnerable to continued extensive melt. The mass of the Greenland Ice Sheet, which has the capacity to contribute similar to 7 m to sea level rise, reached a record low value. The onset of its surface melt was the second earliest, after 2012, in the 37-year satellite record. Sea surface temperature was record high at the global scale, surpassing the previous record of 2015 by about 0.01 degrees C. The global sea surface temperature trend for the 21st century-to-date of +0.162 degrees C decade(-1) is much higher than the longer term 1950-2016 trend of +0.100 degrees C decade(-1). Global annual mean sea level also reached a new record high, marking the sixth consecutive year of increase. Global annual ocean heat content saw a slight drop compared to the record high in 2015. Alpine glacier retreat continued around the globe, and preliminary data indicate that 2016 is the 37th consecutive year of negative annual mass balance. Across the Northern Hemisphere, snow cover for each month from February to June was among its four least extensive in the 47-year satellite record. Continuing a pattern below the surface, record high temperatures at 20-m depth were measured at all permafrost observatories on the North Slope of Alaska and at the Canadian observatory on northernmost Ellesmere Island. In the Antarctic, record low monthly surface pressures were broken at many stations, with the southern annular mode setting record high index values in March and June. Monthly high surface pressure records for August and November were set at several stations. During this period, record low daily and monthly sea ice extents were observed, with the November mean sea ice extent more than 5 standard deviations below the 1981-2010 average. These record low sea ice values contrast sharply with the record high values observed during 2012-14. Over the region, springtime Antarctic stratospheric ozone depletion was less severe relative to the 1991-2006 average, but ozone levels were still low compared to pre-1990 levels. Closer to the equator, 93 named tropical storms were observed during 2016, above the 1981-2010 average of 82, but fewer than the 101 storms recorded in 2015. Three basins-the North Atlantic, and eastern and western North Pacific-experienced above-normal activity in 2016. The Australian basin recorded its least active season since the beginning of the satellite era in 1970. Overall, four tropical cyclones reached the Saffir-Simpson category 5 intensity level. The strong El Nino at the beginning of the year that transitioned to a weak La Nina contributed to enhanced precipitation variability around the world. Wet conditions were observed throughout the year across southern South America, causing repeated heavy flooding in Argentina, Paraguay, and Uruguay. Wetter-than-usual conditions were also observed for eastern Europe and central Asia, alleviating the drought conditions of 2014 and 2015 in southern Russia. In the United States, California had its first wetter-than-average year since 2012, after being plagued by drought for several years. Even so, the area covered by drought in 2016 at the global scale was among the largest in the post-1950 record. For each month, at least 12% of land surfaces experienced severe drought conditions or worse, the longest such stretch in the record. In northeastern Brazil, drought conditions were observed for the fifth consecutive year, making this the longest drought on record in the region. Dry conditions were also observed in western Bolivia and Peru; it was Bolivia's worst drought in the past 25 years. In May, with abnormally warm and dry conditions already prevailing over western Canada for about a year, the human-induced Fort McMurray wildfire burned nearly 590000 hectares and became the costliest disaster in Canadian history, with $3 billion (U.S. dollars) in insured losses.
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| 6. |
- Arndt, D. S., et al.
(författare)
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STATE OF THE CLIMATE IN 2017
- 2018
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 99:8, s. S1-S310
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Forskningsöversikt (refereegranskat)
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| 7. |
- Axfors, Cathrine, et al.
(författare)
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Association between convalescent plasma treatment and mortality in COVID-19 : a collaborative systematic review and meta-analysis of randomized clinical trials
- 2021
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Ingår i: BMC Infectious Diseases. - : BioMed Central (BMC). - 1471-2334. ; 21:1
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Forskningsöversikt (refereegranskat)abstract
- Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, ). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I-2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.
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| 8. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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| 9. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 10. |
- Bruschettini, Matteo, et al.
(författare)
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Sustained versus standard inflations during neonatal resuscitation to prevent mortality and improve respiratory outcomes
- 2017
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Ingår i: Cochrane Database of Systematic Reviews. - 1361-6137. ; 2017:7
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Forskningsöversikt (refereegranskat)abstract
- Background: At birth, infants' lungs are fluid-filled. For newborns to have a successful transition, this fluid must be replaced by air to enable effective breathing. Some infants are judged to have inadequate breathing at birth and are resuscitated with positive pressure ventilation (PPV). Giving prolonged (sustained) inflations at the start of PPV may help clear lung fluid and establish gas volume within the lungs. Objectives: To assess the efficacy of an initial sustained (> 1 second duration) lung inflation versus standard inflations (≤ 1 second) in newly born infants receiving resuscitation with intermittent PPV. Search methods: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1), MEDLINE via PubMed (1966 to 17 February 2017), Embase (1980 to 17 February 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 17 February 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles to identify randomised controlled trials and quasi-randomised trials. Selection criteria: Randomised controlled trials (RCTs) and quasi-RCTs comparing initial sustained lung inflation (SLI) versus standard inflations given to infants receiving resuscitation with PPV at birth. Data collection and analysis: We assessed the methodological quality of included trials using Cochrane Effective Practice and Organisation of Care Group (EPOC) criteria (assessing randomisation, blinding, loss to follow-up, and handling of outcome data). We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data and mean, standard deviation (SD), and weighted mean difference (WMD) for continuous data. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Main results: Eight trials enrolling 941 infants met our inclusion criteria. Investigators in seven trials (932 infants) administered sustained inflation with no chest compressions. Use of sustained inflation had no impact on the primary outcomes of this review - mortality in the delivery room (typical RR 2.66, 95% confidence interval (CI) 0.11 to 63.40; participants = 479; studies = 5; I2 not applicable) and mortality during hospitalisation (typical RR 1.01, 95% CI 0.67 to 1.51; participants = 932; studies = 7; I2 = 19%); the quality of the evidence was low for death in the delivery room (limitations in study design and imprecision of estimates) and was moderate for death before discharge (limitations in study design of most included trials). Amongst secondary outcomes, duration of mechanical ventilation was shorter in the SLI group (mean difference (MD) -5.37 days, 95% CI -6.31 to -4.43; participants = 524; studies = 5; I2 = 95%; low-quality evidence). Heterogeneity, statistical significance, and magnitude of effects of this outcome are largely influenced by a single study: When this study was removed from the analysis, the effect was largely reduced (MD -1.71 days, 95% CI -3.04 to -0.39, I2 = 0%). Results revealed no differences in any of the other secondary outcomes (e.g. rate of endotracheal intubation outside the delivery room by 72 hours of age (typical RR 0.93, 95% CI 0.79 to 1.09; participants = 811; studies = 5; I2 = 0%); need for surfactant administration during hospital admission (typical RR 0.97, 95% CI 0.86 to 1.10; participants = 932; studies = 7; I2 = 0%); rate of chronic lung disease (typical RR 0.95, 95% CI 0.74 to 1.22; participants = 683; studies = 5; I2 = 47%); pneumothorax (typical RR 1.44, 95% CI 0.76 to 2.72; studies = 6, 851 infants; I2 = 26%); or rate of patent ductus arteriosus requiring pharmacological treatment (typical RR 1.08, 95% CI 0.90 to 1.30; studies = 6, 745 infants; I2 = 36%). The quality of evidence for these secondary outcomes was moderate (limitations in study design of most included trials - GRADE) except for pneumothorax (low quality: limitations in study design and imprecision of estimates - GRADE). Authors' conclusions: Sustained inflation was not better than intermittent ventilation for reducing mortality in the delivery room and during hospitalisation. The number of events across trials was limited, so differences cannot be excluded. When considering secondary outcomes, such as need for intubation, need for or duration of respiratory support, or bronchopulmonary dysplasia, we found no evidence of relevant benefit for sustained inflation over intermittent ventilation. The duration of mechanical ventilation was shortened in the SLI group. This result should be interpreted cautiously, as it can be influenced by study characteristics other than the intervention. Future RCTs should aim to enrol infants who are at higher risk of morbidity and mortality, should stratify participants by gestational age, and should provide more detailed monitoring of the procedure, including measurements of lung volume and presence of apnoea before or during the SLI.
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| 11. |
- Bruschettini, Matteo, et al.
(författare)
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Sustained versus standard inflations during neonatal resuscitation to prevent mortality and improve respiratory outcomes
- 2020
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Ingår i: The Cochrane database of systematic reviews. - 1361-6137. ; 3
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: At birth, infants' lungs are fluid-filled. For newborns to have a successful transition, this fluid must be replaced by air to enable gas exchange. Some infants are judged to have inadequate breathing at birth and are resuscitated with positive pressure ventilation (PPV). Giving prolonged (sustained) inflations at the start of PPV may help clear lung fluid and establish gas volume within the lungs. OBJECTIVES: To assess the benefits and harms of an initial sustained lung inflation (SLI) (> 1 second duration) versus standard inflations (≤ 1 second) in newborn infants receiving resuscitation with intermittent PPV. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 3), MEDLINE via PubMed (1966 to 1 April 2019), Embase (1980 to 1 April 2019), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 1 April 2019). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles to identify randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing initial sustained lung inflation (SLI) versus standard inflations given to infants receiving resuscitation with PPV at birth. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of included trials using Cochrane Effective Practice and Organisation of Care Group (EPOC) criteria (assessing randomisation, blinding, loss to follow-up, and handling of outcome data). We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data; and mean standard deviation (SD), and weighted mean difference (WMD) for continuous data. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: Ten trials enrolling 1467 infants met our inclusion criteria. Investigators in nine trials (1458 infants) administered sustained inflation with no chest compressions. Use of sustained inflation had no impact on the primary outcomes of this review: mortality in the delivery room (typical RR 2.66, 95% confidence interval (CI) 0.11 to 63.40 (I² not applicable); typical RD 0.00, 95% CI -0.02 to 0.02; I² = 0%; 5 studies, 479 participants); and mortality during hospitalisation (typical RR 1.09, 95% CI 0.83 to 1.43; I² = 42%; typical RD 0.01, 95% CI -0.02 to 0.04; I² = 24%; 9 studies, 1458 participants). The quality of the evidence was low for death in the delivery room because of limitations in study design and imprecision of estimates (only one death was recorded across studies). For death before discharge the quality was moderate: with longer follow-up there were more deaths (n = 143) but limitations in study design remained. Among secondary outcomes, duration of mechanical ventilation was shorter in the SLI group (mean difference (MD) -5.37 days, 95% CI -6.31 to -4.43; I² = 95%; 5 studies, 524 participants; low-quality evidence). Heterogeneity, statistical significance, and magnitude of effects of this outcome are largely influenced by a single study at high risk of bias: when this study was removed from the analysis, the size of the effect was reduced (MD -1.71 days, 95% CI -3.04 to -0.39; I² = 0%). Results revealed no differences in any of the other secondary outcomes (e.g. risk of endotracheal intubation outside the delivery room by 72 hours of age (typical RR 0.91, 95% CI 0.79 to 1.04; I² = 65%; 5 studies, 811 participants); risk of surfactant administration during hospital admission (typical RR 0.99, 95% CI 0.91 to 1.08; I² = 0%; 9 studies, 1458 participants); risk of chronic lung disease (typical RR 0.99, 95% CI 0.83 to 1.18; I² = 0%; 4 studies, 735 participants); pneumothorax (typical RR 0.89, 95% CI 0.57 to 1.40; I² = 34%; 8 studies, 1377 infants); or risk of patent ductus arteriosus requiring pharmacological treatment (typical RR 0.99, 95% CI 0.87 to 1.12; I² = 48%; 7 studies, 1127 infants). The quality of evidence for these secondary outcomes was moderate (limitations in study design ‒ GRADE) except for pneumothorax (low quality: limitations in study design and imprecision of estimates ‒ GRADE). We could not perform any meta-analysis in the comparison of the use of initial sustained inflation versus standard inflations in newborns receiving resuscitation with chest compressions because we identified only one trial for inclusion (a pilot study of nine preterm infants). AUTHORS' CONCLUSIONS: Our meta-analysis of nine studies shows that sustained lung inflation without chest compression was not better than intermittent ventilation for reducing mortality in the delivery room (low-quality evidence ‒ GRADE) or during hospitalisation (moderate-quality evidence ‒ GRADE), which were the primary outcomes of this review. However, the single largest study, which was well conducted and had the greatest number of enrolled infants, was stopped early for higher mortality rate in the sustained inflation group. When considering secondary outcomes, such as rate of intubation, rate or duration of respiratory support, or bronchopulmonary dysplasia, we found no benefit of sustained inflation over intermittent ventilation (moderate-quality evidence ‒ GRADE). Duration of mechanical ventilation was shortened in the SLI group (low-quality evidence ‒ GRADE); this result should be interpreted cautiously, however, as it might have been influenced by study characteristics other than the intervention. There is no evidence to support the use of sustained inflation based on evidence from our review.
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| 12. |
- Cheng, Xiaoxiao, et al.
(författare)
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Structure and Interactions of the Human Programmed Cell Death 1 Receptor
- 2013
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 288:17, s. 11771-11785
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Tidskriftsartikel (refereegranskat)abstract
- PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC' sheet, which is flexible and completely lacks a C '' strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC' sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1.ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3-4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.
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| 13. |
- Davis, Tyler W., et al.
(författare)
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Simple process-led algorithms for simulating habitats (SPLASH v.1.0) : Robust indices of radiation, evapotranspiration and plant-available moisture
- 2017
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 10:2, s. 689-708
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Tidskriftsartikel (refereegranskat)abstract
- Bioclimatic indices for use in studies of ecosystem function, species distribution, and vegetation dynamics under changing climate scenarios depend on estimates of surface fluxes and other quantities, such as radiation, evapotranspiration and soil moisture, for which direct observations are sparse. These quantities can be derived indirectly from meteorological variables, such as near-surface air temperature, precipitation and cloudiness. Here we present a consolidated set of simple process-led algorithms for simulating habitats (SPLASH) allowing robust approximations of key quantities at ecologically relevant timescales. We specify equations, derivations, simplifications, and assumptions for the estimation of daily and monthly quantities of top-of-the-atmosphere solar radiation, net surface radiation, photosynthetic photon flux density, evapotranspiration (potential, equilibrium, and actual), condensation, soil moisture, and runoff, based on analysis of their relationship to fundamental climatic drivers. The climatic drivers include a minimum of three meteorological inputs: precipitation, air temperature, and fraction of bright sunshine hours. Indices, such as the moisture index, the climatic water deficit, and the Priestley-Taylor coefficient, are also defined. The SPLASH code is transcribed in C++, FORTRAN, Python, and R. A total of 1 year of results are presented at the local and global scales to exemplify the spatiotemporal patterns of daily and monthly model outputs along with comparisons to other model results.
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| 14. |
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| 15. |
- Flannick, Jason, et al.
(författare)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 16. |
- Fuchsberger, Christian, et al.
(författare)
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The genetic architecture of type 2 diabetes
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 17. |
- Henderson, Pamela, et al.
(författare)
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In-situ fireside corrosion testing of superheater materials with coal, wood and straw fuels for conventional and asvanced steam temperatures
- 2005
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Ingår i: VGB PowerTech. - Essen, Germany : VGB PowerTech eV. - 1435-3199. ; 84:6, s. 53-59
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Tidskriftsartikel (refereegranskat)abstract
- An increase in the steam temperature of a power station increases the electrical efficiency of the turbine. This in turn leads to a reduction in the cost of electricity and in environmental emissions produced per unit of electricity generated. However, higher steam temperatures give rise to more aggressive corrosive environments and the choice of material becomes more important. In addition, the aggressiveness of the fuels also depends on their chemical compositions. As part of a European research programme (COST 522) fireside corrosion tests of superheater and waterwall materials have been performed in-situ in industrial boilers or combustion test facilities, simulating conventional and higher steam temperatures. The fuels used were, straw, wood (logging residues) and coal. Goals were set at different maximum steam temperatures and lifetimes according to the fuel. The targets were: coal 650°C/100,000 h, wood 580°C/40,000 h and straw 580°C/20,000 h .A wide range of materials was tested. An overriding constraint was that the materials must be economically viable and not impose exceptional fabrication requirements. Some materials were tested in a number of combustion environments, allowing useful comparisons to be made. The results showed that for a given superheater alloy, temperature and fuel, the corrosion rate depended on the alloy’s position in a superheater bank. Tubes on the outside, exposed to the flue gas, corroded faster than those positioned deeper in a bank. Tubes experiencing a greater heat flux will corrode more rapidly. Poorly controlled combustion will also increase corrosion. Straw was much more corrosive than wood (logging residues). The difference in corrosiveness increased with increasing temperature above a metal temperature of about 520°C. The corrosion rates of the alloys tested during wood-firing were only a little higher than those from firing coal with a medium to high chlorine content. Straw and wood are often collectively known as “biomass”, but the corrosion they cause can vary by a factor of 5 or more. No difference could be found in the fireside corrosion rates of the steels TP 347H and TP 347HFG, when tested under similar conditions. Esshete 1250 also showed similar fireside corrosion rates to347 instraw and wood boilers and at temperatures below 650°Cin coal boilers. Several alloys were identified to resist corrosion in coal-fired plant at metal temperatures of680°C(steam temperatures650°C) and high heat fluxes. Adequate high temperature creep strength remains more problematic. At lower heat fluxes (resulting in lower corrosion rates) more candidate alloys exist. It is expected that the goals set can be achieved with the use of suitable alloys in the case of wood, waste and coal. For wood (logging residues) TP347, Esshete 1250 and 50Ni50Cr coatings showed sufficient corrosion resistance at the target temperatures. In the coal case HR3C fulfills the requirements of strength and corrosion resistance with a high heat flux and Super 304H and SAVE 25 if the heat flux is low. HR11N and IN671 are suitable for use as claddings on a substrate with the appropriate creep strength. The goal set for straw firing was ambitious, a steam temperature of580°C, and in this case a combination of material, combustion technology and boiler design are needed.
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| 18. |
- Jáuregui Renaud, Kathrine, et al.
(författare)
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Acute Stress in Health Workers during Two Consecutive EpidemicWaves of COVID-19
- 2022
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1660-4601. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- The COVID-19 pandemic has provoked generalized uncertainty around the world, with health workers experiencing anxiety, depression, burnout, insomnia, and stress. Although the effects of the pandemic on mental health may change as it evolves, the majority of reports have been web-based, cross-sectional studies. We performed a study assessing acute stress in frontline healthworkers during two consecutive epidemic waves. After screening for trait anxiety/depression and dissociative experiences, we evaluated changes in acute stress, considering resilience, state anxiety, burnout, depersonalization/derealization symptoms, and quality of sleep as cofactors. During the first epidemic wave (April 2020), health workers reported acute stress related to COVID-19, which was related to state anxiety. After the first epidemic wave, acute stress decreased, with no increase during the second epidemic wave (December 2020), and further decreased when vaccination started.During the follow-up (April 2020 to February 2021), the acute stress score was related to bad quality of sleep. However, acute stress, state anxiety, and burnout were all related to trait anxiety/depression, while the resilience score was invariant through time. Overall, the results emphasize the relevance of mental health screening before, during,
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| 19. |
- Kassebaum, Nicholas J., et al.
(författare)
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Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015 : a systematic analysis for the Global Burden of Disease Study 2015
- 2016
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1603-1658
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Tidskriftsartikel (refereegranskat)abstract
- Background Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. Findings Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs off set by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2.9 years (95% uncertainty interval 2.9-3.0) for men and 3.5 years (3.4-3.7) for women, while HALE at age 65 years improved by 0.85 years (0.78-0.92) and 1.2 years (1.1-1.3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. Interpretation Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum.
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| 20. |
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| 21. |
- Kowalec, Kaarina, et al.
(författare)
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Common variation near IRF6 is associated with IFN-beta-induced liver injury in multiple sclerosis
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:8, s. 1081-
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2.3 × 10–8, odds ratio = 8.3, 95% confidence interval = 3.6–19.2). Analysis of an independent cohort of IFN-β-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 × 10–5) and alkaline phosphatase (P = 4.9 × 10-4). We show that these findings may be applicable to predicting IFN-β-induced liver injury, offering insight into its safer use.
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| 22. |
- O'Donnell, Colm Pf, et al.
(författare)
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Sustained versus standard inflations during neonatal resuscitation to prevent mortality and improve respiratory outcomes.
- 2015
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Ingår i: Cochrane Database of Systematic Reviews. - 1469-493X. ; 7:7, s. 004953-004953
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Forskningsöversikt (refereegranskat)abstract
- At birth, infants' lungs are fluid-filled; this fluid must be replaced by air to allow for effective breathing. Some infants are judged to have inadequate breathing at birth and are resuscitated with positive pressure ventilation (PPV). Giving prolonged (sustained) inflations at the start of PPV may help clear lung fluid and establish gas volume in the lungs.
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| 23. |
- Raghavan, Maanasa, et al.
(författare)
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Genomic evidence for the Pleistocene and recent population history of Native Americans
- 2015
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 349:6250
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Tidskriftsartikel (refereegranskat)abstract
- Howand when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we found that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (ka) and after no more than an 8000-year isolation period in Beringia. After their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 ka, one that is now dispersed across North and South America and the other restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative "Paleoamerican" relict populations, including the historical Mexican Pericues and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.
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| 24. |
- Scherhaufer, S., et al.
(författare)
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Environmental assessment of the valorisation and recycling of selected food production side flows
- 2020
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Ingår i: Resources, Conservation and Recycling. - : Elsevier B.V.. - 0921-3449 .- 1879-0658. ; 161
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Tidskriftsartikel (refereegranskat)abstract
- Residues from the food manufacturing industry require management options with the best overall environmental outcome. The identification of sustainable solutions depends however, on many influencing factors such as energy input, transport distance, and substituted product. This study shows the influence of the choice of substituted products on the overall greenhouse gas (GHG) emissions for three specific food side-flows and their treatment in the European Union: animal blood, apple pomace and brewers’ spent grain (BSG). In a direct comparison of possible treatment options, it is notable that the conversion to food ingredients (valorisation) does not always result in reduced environmental net impacts (GHG savings), which means that other options at lower levels of the waste hierarchy might be more beneficial to the environment. The further use of apple pomace or BSG for the production of food ingredients is only advantageous if the processing emissions are smaller than the emissions from the substituted products. The use of food side-flows as animal feed shows environmental advantages in all scenarios, as the use of conventional feed, such as soybean meal or hay, is reduced and so are the GHG emissions. The anaerobic digestion of food side-flows is associated with significant GHG emissions, but alternative energy also display a high GHG factor when based on fossil resources. The measuring of circularity in the food sector is a challenge in itself due to the complexity of renewable materials. This study shall help to understand the interwoven influences of certain parameters to the results. © 2020 The Author(s)
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| 25. |
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| 26. |
- Tarrason Risa, Gabriel, et al.
(författare)
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The proteasome controls ESCRT-III-mediated cell division in an archaeon
- 2020
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 369:6504
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Tidskriftsartikel (refereegranskat)abstract
- Sulfolobus acidocaldarius is the closest experimentally tractable archaeal relative of eukaryotes and, despite lacking obvious cyclin-dependent kinase and cyclin homologs, has an ordered eukaryote-like cell cycle with distinct phases of DNA replication and division. Here, in exploring the mechanism of cell division in S. acidocaldarius, we identify a role for the archaeal proteasome in regulating the transition from the end of one cell cycle to the beginning of the next. Further, we identify the archaeal ESCRT-III homolog, CdvB, as a key target of the proteasome and show that its degradation triggers division by allowing constriction of the CdvB1:CdvB2 ESCRT-III division ring. These findings offer a minimal mechanism for ESCRT-III-mediated membrane remodeling and point to a conserved role for the proteasome in eukaryotic and archaeal cell cycle control.
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| 27. |
- Venkatesan, Meera, et al.
(författare)
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Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes : parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.
- 2014
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Ingår i: The American journal of tropical medicine and hygiene. - : American Society of Tropical Medicine and Hygiene. - 1476-1645 .- 0002-9637. ; 91:4, s. 833-43
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Tidskriftsartikel (refereegranskat)abstract
- Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.
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| 28. |
- Wang, Haidong, et al.
(författare)
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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
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1459-1544
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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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| 29. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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