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| 2. |
- Vicedo-Cabrera, A.M., et al.
(författare)
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The burden of heat-related mortality attributable to recent human-induced climate change
- 2021
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Ingår i: Nature Climate Change. - : Nature Publishing Group. - 1758-678X .- 1758-6798. ; 11:6, s. 492-500
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Tidskriftsartikel (refereegranskat)abstract
- Climate change affects human health; however, there have been no large-scale, systematic efforts to quantify the heat-related human health impacts that have already occurred due to climate change. Here, we use empirical data from 732 locations in 43 countries to estimate the mortality burdens associated with the additional heat exposure that has resulted from recent human-induced warming, during the period 1991–2018. Across all study countries, we find that 37.0% (range 20.5–76.3%) of warm-season heat-related deaths can be attributed to anthropogenic climate change and that increased mortality is evident on every continent. Burdens varied geographically but were of the order of dozens to hundreds of deaths per year in many locations. Our findings support the urgent need for more ambitious mitigation and adaptation strategies to minimize the public health impacts of climate change.
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| 4. |
- Sikkema, Lisa, et al.
(författare)
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An integrated cell atlas of the lung in health and disease
- 2023
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Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 29:6, s. 1563-1577
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Tidskriftsartikel (refereegranskat)abstract
- Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1 + profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.
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| 8. |
- Graham, R. Robert, et al.
(författare)
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Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus
- 2007
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:16, s. 6758-6763
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Tidskriftsartikel (refereegranskat)abstract
- Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 (IRF5), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5: the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine- and threonine-rich domain region, and a variant in a conserved polyA+ signal sequence that alters the length of the 3' UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease.
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| 10. |
- Purushotham, A, et al.
(författare)
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Age at diagnosis and distant metastasis in breast cancer--a surprising inverse relationship.
- 2014
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 50:10
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Predictors for site of distant metastasis and impact on survival in breast cancer are incompletely understood.METHODS: Clinico-pathological risk factors for site of distant metastasis and survival were analysed in patients with invasive breast cancer treated between 1986 and 2006.RESULTS: Of 3553 patients, with median follow-up 6.32years, 825 (23%) developed distant metastasis. The site of metastasis was bone in 196/825 (24%), viscera in 540/825 (65%) and unknown in 89 (11%). Larger primary invasive tumour size, higher tumour grade and axillary nodal positivity increased risk of metastasis to all sites. Lobular carcinoma was more likely to first metastasise to bone compared to invasive ductal carcinoma (NST). Oestrogen receptor (ER) negative, progesterone receptor (PgR) negative and/or Human epidermal growth factor (HER2) positive tumours were more likely to metastasise to viscera. A striking relationship between increasing age at diagnosis and a reduction in risk of distant metastasis to bone and viscera was observed. Median time to death from onset of metastatic disease was 1.52 (Interquartile range (IQR) 0.7-2.9)years for patients with bone metastasis and 0.7 (IQR 0.2-1.5)years for visceral metastasis. On multivariate analysis, despite the decrease in risk of distant metastasis with increasing age, there was an elevated hazard for death in patients >50years at diagnosis of metastasis if they developed bone metastasis, with a similar trend observed in the >70years age group if they developed visceral metastasis.CONCLUSION: These findings indicate that there are biological mechanisms underlying the impact of age on the development of distant metastasis and subsequent death. This may have important implications in the treatment of breast cancer.
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| 11. |
- Rohmer, Laurence, et al.
(författare)
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Comparison of Francisella tularensis genomes reveals evolutionary events associated with the emergence of human pathogenic strains
- 2007
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Ingår i: Genome Biology. - : BioMed Central. - 1465-6906 .- 1474-760X. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Francisella tularensis subspecies tularensis and holarctica are pathogenic to humans, whereas the two other subspecies, novicida and mediasiatica, rarely cause disease. To uncover the factors that allow subspecies tularensis and holarctica to be pathogenic to humans, we compared their genome sequences with the genome sequence of Francisella tularensis subspecies novicida U112, which is nonpathogenic to humans. RESULTS: Comparison of the genomes of human pathogenic Francisella strains with the genome of U112 identifies genes specific to the human pathogenic strains and reveals pseudogenes that previously were unidentified. In addition, this analysis provides a coarse chronology of the evolutionary events that took place during the emergence of the human pathogenic strains. Genomic rearrangements at the level of insertion sequences (IS elements), point mutations, and small indels took place in the human pathogenic strains during and after differentiation from the nonpathogenic strain, resulting in gene inactivation. CONCLUSION: The chronology of events suggests a substantial role for genetic drift in the formation of pseudogenes in Francisella genomes. Mutations that occurred early in the evolution, however, might have been fixed in the population either because of evolutionary bottlenecks or because they were pathoadaptive (beneficial in the context of infection). Because the structure of Francisella genomes is similar to that of the genomes of other emerging or highly pathogenic bacteria, this evolutionary scenario may be shared by pathogens from other species.
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- Arathimos, R, et al.
(författare)
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Latent subtypes of manic and/or irritable episode symptoms in two population-based cohorts
- 2022
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Ingår i: The British journal of psychiatry : the journal of mental science. - : Royal College of Psychiatrists. - 1472-1465. ; 221:6, s. 722-731
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Tidskriftsartikel (refereegranskat)abstract
- Mood disorders are characterised by pronounced symptom heterogeneity, which presents a substantial challenge both to clinical practice and research. Identification of subgroups of individuals with homogeneous symptom profiles that cut across current diagnostic categories could provide insights in to the transdiagnostic relevance of individual symptoms, which current categorical diagnostic systems cannot impart.AimsTo identify groups of people with homogeneous clinical characteristics, using symptoms of manic and/or irritable mood, and explore differences between groups in diagnoses, functional outcomes and genetic liability.MethodWe used latent class analysis on eight binary self-reported symptoms of manic and irritable mood in the UK Biobank and PROTECT studies, to investigate how individuals formed latent subgroups. We tested associations between the latent classes and diagnoses of psychiatric disorders, sociodemographic characteristics and polygenic risk scores.ResultsFive latent classes were derived in UK Biobank (N = 42 183) and were replicated in the independent PROTECT cohort (N = 4445), including ‘minimally affected’, ‘inactive restless’, active restless’, ‘focused creative’ and ‘extensively affected’ individuals. These classes differed in disorder risk, polygenic risk score and functional outcomes. One class that experienced disruptive episodes of mostly irritable mood largely comprised cases of depression/anxiety, and a class of individuals with increased confidence/creativity reported comparatively lower disruptiveness and functional impairment.ConclusionsFindings suggest that data-driven investigations of psychopathological symptoms that include sub-diagnostic threshold conditions can complement research of clinical diagnoses. Improved classification systems of psychopathology could investigate a weighted approach to symptoms, toward a more dimensional classification of mood disorders.
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| 19. |
- Chua, S. J., et al.
(författare)
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Age-related natural fertility outcomes in women over 35 years: a systematic review and individual participant data meta-analysis
- 2020
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Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 35:8, s. 1808-1820
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Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION: What is the rate of natural conception leading to ongoing pregnancy or livebirth over 6-12 months for infertile women of age >= 35 years? SUMMARY ANSWER: Natural conception rates were still clinically relevant in women aged 35 years and above and were significantly higher in women with unexplained infertility compared to those with other diagnoses. WHAT IS KNOWN ALREADY: In recent years, increasing numbers of women have attempted to conceive at a later age, resulting in a commensurate increase in the need for ART. However, there is a lack of data on natural fertility outcomes (i.e. no interventions) in women with increasing age. STUDY DESIGN, SIZE, DURATION: A systematic review with individual participant data (IPD) meta-analysis was carried out. PubMed, MEDLINE, EMBASE, the Cochrane Library, clinicaltrials.gov were searched until 1 July 2018 including search terms 'fertility service', 'waiting list', 'treatment-independent' and 'spontaneous conception'. Language restrictions were not imposed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were studies (at least partly) reporting on infertile couples with female partner of age >= 35 years who attended fertility services, underwent fertility workup (e.g. history, semen analysis, tubal status and ovulation status) and were exposed to natural conception (e.g. independent of treatment such as IVF, ovulation induction and tubal surgery). Studies that exclusively studied only one infertility diagnosis, without including other women presenting to infertility services for other causes of infertility, were excluded. For studies that met the inclusion criteria, study authors were contacted to provide IPD, after which fertility outcomes for women of age >= 35 years were retrieved. Time to pregnancy or livebirth and the effect of increasing age on fertility outcomes after adjustment for other prognostic factors were analysed. Quality of studies was graded with the Newcastle-Ottawa Scale (non-randomised controlled trials (RCTs)) or the Cochrane Risk of Bias tool (for RCTs). MAIN RESULTS AND THE ROLE OF CHANCE: We included nine studies (seven cohort studies and two RCTs) (n = 4379 women of at least age 35 years), with the observed composite primary outcome of ongoing pregnancy or livebirth occurring in 429 women (9.8%) over a median follow-up of 5 months (25th to 75th percentile: 2.5-8.5 months). Studies were of moderate to high quality. The probability of natural conception significantly decreased with any diagnosis of infertility, when compared with unexplained infertility. We found non-linear effects of female age and duration of infertility on ongoing pregnancy and tabulated the predicted probabilities for unexplained infertile women aged 35-42 years with either primary or secondary infertility and with a duration of infertility from 1 to 6 years. For a 35-year-old woman with 2 years of primary unexplained infertility, the predicted probability of natural conception leading to ongoing pregnancy or livebirth was 0.15 (95% CI 0.11-0.19) after 6 months and 0.24 (95% CI 0.17-0.30) after 12 months. For a 42-year-old woman, this decreased to 0.08 (95% CI 0.04-0.11) after 6 months and 0.13 (95% CI 0.07-0.18) after 12 months. LIMITATIONS, REASONS FOR CAUTION: In the studies selected, there were different study designs, recruitment strategies in different centres, protocols and countries and different methods of assessment of infertility. Data were limited for women above the age of 40 years. WIDER IMPLICATIONS OF THE FINDINGS: Women attending fertility services should be encouraged to pursue natural conception while waiting for treatment to commence and after treatment if it is unsuccessful. Our results may aid in counselling women, and, in particular, for those with unexplained infertility.
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| 21. |
- Gillett, A, et al.
(författare)
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Interleukin 18 receptor 1 expression distinguishes patients with multiple sclerosis
- 2010
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 16:9, s. 1056-1065
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Tidskriftsartikel (refereegranskat)abstract
- Definition of dysregulated immune components in multiple sclerosis may help in the identification of new therapeutic targets. Deviation of the interleukin 18 receptor 1 (IL18R1) is of particular interest since the receptor is critical for experimental neuroinflammation. The objective of this study was to determine whether expression of IL18R1 varies between multiple sclerosis patients and controls, and to test genetic association of IL18R1 with multiple sclerosis. We used quantitative real-time PCR to assess mRNA levels of IL18R1 in cerebrospinal fluid and peripheral blood mononuclear cells of 191 patients with multiple sclerosis, 61 patients with clinically isolated syndrome and 168 controls having other neurological disorders. Association was tested in 2153 patients with multiple sclerosis and 1733 controls using 13 tagging single nucleotide polymorphisms within the IL18R1 gene. We found that patients with multiple sclerosis had increased IL18R1 mRNA expression in both cerebrospinal fluid cells ( p < 0.05) and peripheral blood mononuclear cells ( p < 0.05) compared with controls. Patients with clinically isolated syndrome had elevated levels compared with controls in cerebrospinal fluid cells ( p < 0.001) but not in peripheral blood mononuclear cells. The gene was not associated to multiple sclerosis. We conclude that the increased expression of IL18R1 may contribute pathogenically to disease and is therefore a potential therapeutic target. The absence of a genetic association in the IL18R1 gene itself suggests regulation from other parts of the genome, or as part of the inflammatory cascade in multiple sclerosis without a prime genetic cause.
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| 22. |
- Canadel, Josep G., et al.
(författare)
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Contributions to accelerating atmospheric CO2 growth from economic activity, carbon intensity, and efficiency of natural sinks
- 2007
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 104:47, s. 18866-18870
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Tidskriftsartikel (refereegranskat)abstract
- The growth rate of atmospheric carbon dioxide (CO2), the largest human contributor to human-induced climate change, is increasing rapidly. Three processes contribute to this rapid increase. Two of these processes concern emissions. Recent growth of the world economy combined with an increase in its carbon intensity have led to rapid growth in fossil fuel CO2 emissions since 2000: comparing the 1990s with 2000–2006, the emissions growth rate increased from 1.3% to 3.3% y −1. The third process is indicated by increasing evidence (P = 0.89) for a long-term (50-year) increase in the airborne fraction (AF) of CO2 emissions, implying a decline in the efficiency of CO2 sinks on land and oceans in absorbing anthropogenic emissions. Since 2000, the contributions of these three factors to the increase in the atmospheric CO2 growth rate have been ≈65 ± 16% from increasing global economic activity, 17 ± 6% from the increasing carbon intensity of the global economy, and 18 ± 15% from the increase in AF. An increasing AF is consistent with results of climate–carbon cycle models, but the magnitude of the observed signal appears larger than that estimated by models. All of these changes characterize a carbon cycle that is generating stronger-than-expected and sooner-than-expected climate forcing.
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