| 1. |
- Wuttke, Matthias, et al.
(author)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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In: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Journal article (peer-reviewed)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 2. |
- Svensson, Akiko Kishi, et al.
(author)
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Incident diabetes mellitus may explain the association between sleep duration and incident coronary heart disease
- 2018
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 61:2, s. 331-341
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Journal article (peer-reviewed)abstract
- Aims/hypothesis: Sleep duration is a risk factor for incident diabetes mellitus and CHD. The primary aim of the present study was to investigate, in sex-specific analyses, the role of incident diabetes as the possible biological mechanism for the reported association between short/long sleep duration and incident CHD. Considering that diabetes is a major risk factor for CHD, we hypothesised that any association with sleep duration would not hold for cases of incident CHD occurring before incident diabetes (‘non-diabetes CHD’) but would hold true for cases of incident CHD following incident diabetes (‘diabetes-CHD’). Methods: A total of 6966 men and 9378 women aged 45–73 years from the Malmö Diet Cancer Study, a population-based, prospective cohort, who had answered questions on habitual sleep duration and did not have a history of prevalent diabetes or CHD were included in the analyses. Incident cases of diabetes and CHD were identified using national registers. Sex-specific Cox proportional hazards regression models were stratified by BMI and adjusted for known covariates of diabetes and CHD. Results: Mean follow-up times for incident diabetes (n = 1137/1016 [men/women]), incident CHD (n = 1170/578), non-diabetes CHD (n = 1016/501) and diabetes-CHD (n = 154/77) were 14.2–15.2 years for men, and 15.8–16.5 years for women. In men, short sleep duration (< 6 h) was associated with incident diabetes (HR 1.35, 95% CI 1.01, 1.80), CHD (HR 1.41, 95% CI 1.06, 1.89) and diabetes-CHD (HR 2.34, 95% CI 1.20, 4.55). Short sleep duration was not associated with incident non-diabetes CHD (HR 1.35, 95% CI 0.98, 1.87). Long sleep duration (≥ 9 h) was associated with incident diabetes (HR 1.37, 95% CI 1.03, 1.83), CHD (HR 1.33, 95% CI 1.01, 1.75) and diabetes-CHD (HR 2.10, 95% CI 1.11, 4.00). Long sleep duration was not associated with incident non-diabetes CHD (HR 1.33, 95% CI 0.98, 1.80). In women, short sleep duration was associated with incident diabetes (HR 1.53, 95% CI 1.16, 2.01), CHD (HR 1.46, 95% CI 1.03, 2.07) and diabetes-CHD (HR 2.88, 95% CI 1.37, 6.08). Short sleep duration was not associated with incident non-diabetes CHD (HR 1.29, 95% CI 0.86, 1.93). Conclusions/interpretation: The associations between sleep duration and incident CHD directly reflect the associations between sleep duration and incident diabetes. Incident diabetes may thus be the explanatory mechanism for the association between short and long sleep duration and incident CHD.
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| 3. |
- Svensson, Thomas, et al.
(author)
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Plasma concentration of Caspase-8 is associated with short sleep duration and the risk of incident diabetes mellitus
- 2018
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 103:4, s. 1592-1600
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Journal article (peer-reviewed)abstract
- Context: The biological mechanism for the association between sleep duration and incident diabetes mellitus (DM) is unclear. Sleep duration and Caspase-8, a marker of apoptotic activity, have both been implicated in beta cell function.Objective: To investigate the associations between sleep duration and plasma Caspase-8, and incident DM, respectively.Design: Prospective cohort study.Setting: The Malmö Diet and Cancer (MDC) Study is a population-based, prospective study run in the city of Malmö, Sweden.Participants: 4023 individuals from the MDC Study aged 45-68 years at baseline without a history of prevalent DM, and with information on habitual sleep duration.Main outcomes: Incident DM.Results: Mean follow-up time was 17.8 years. Sleep duration was the only behavioural variable significantly associated with plasma Caspase-8. Plasma Caspase-8 was significantly associated with incident DM per standard deviation of its transformed continuous form (hazard ratio [HR]= 1.24, 95% confidence interval [CI] 1.13-1.36), and when dichotomized into high (quartile 4) (HR=1.44, 95%CI: 1.19-1.74) compared to low (quartiles 1-3) concentrations. Caspase-8 interacted with sleep duration; compared to 7-8 hours of sleep and low plasma Caspase-8, individuals with high plasma Caspase-8 and sleep duration <6 hours (HR=3.54, 95%CI: 2.12-5.90), 6-7 hours (HR=1.81, 95%CI: 1.24-2.65), and 8-9 hours (HR=1.54, 95%CI: 1.09-2.18) were at significantly increased risks of incident DM.Conclusions: Sleep duration is associated with plasma Caspase-8. Caspase-8 independently predicts DM years before disease onset and modifies the effect of sleep duration on incident DM. Future studies should investigate if change of sleep duration modifies plasma concentrations of Caspase-8.
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| 4. |
- Zamora, Juan Carlos, et al.
(author)
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Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
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In: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
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Journal article (peer-reviewed)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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| 5. |
- Fresia, Maria, et al.
(author)
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Use case characterization, KPIs and preferred suitable frequency ranges for future 5G systems between 6 GHz and 100 GHz
- 2015
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Reports (other academic/artistic)abstract
- In this deliverable use cases and KPIs of interest for mmMAGIC are characterized. Eight usecases suitable for 5G systems operating in the range 6-100GHz are identified in terms ofrequirements. In particular, the following use cases are analyzed: Media on demand; Cloudservices; Dense urban society with distributed crowds; Smart offices; Immersive 5G earlyexperience in targeting hot spots; 50+Mbps everywhere; Moving hot spots; Tactileinternet/video augmented robotic control and remote-robot manipulation surgery. For each ofthe use cases, the more critical KPIs are identified and the gap from the current technologyis also described.An analysis of frequency ranges for future 5G systems between 6 GHz and 100 GHz is reported. A frequency assessment study is conducted in order to compare the frequency ranges for the suitability of delivering key KPIs.
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| 6. |
- Hagmarker, Linn, et al.
(author)
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Characterisation of a planar dosimetry method estimating the absorbed dose to the bone marrow during 177Lu-DOTATATE treatment
- 2016
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer. - 1619-7070 .- 1619-7089.
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Conference paper (other academic/artistic)abstract
- Aim: An image based method for bone marrow dosimetry, earlier presented by our research group, has shown a significant correlation between the absorbed dose to the bone marrow and haematological toxicity in 177Lu-DOTATATE treatment. The aim of this study was to further evaluate and optimise the method. Materials and Methods: 46 patients with advanced neuroendocrine tumours were treated with 177Lu -DOTATATE on 2-6 occasions. The patients were evaluated using the 4 planar gamma camera images collected at 2, 24, 48 and 168 hours after injection. The whole body was divided into a high- and a low uptake compartment, using a threshold based segmentation tool in the image platform PhONSAi, developed in-house. The segmentation tool starts by including the highest uptake focus and then gradually includes foci with lower and lower uptakes until a threshold is reached where the number of foci escalates. The threshold determines the proportion of the foci that is included in the two compartments. Visual inspection was used to determine the threshold valuewhere all high uptake tissues (i.e. kidney, spleen, liver and tumours) were included in the high uptake compartment. For thresholds around this value the activity in the two compartments was determined by the conjugate view method and the bonemarrow dose was calculated as a sum of the self and cross dose in the low uptake compartment and the cross dose from the high uptake compartment. Results: The visual analysis implies a threshold value of 10%of the maximum number of foci. A correlation was found between the absorbed bone marrow dose and haematological toxicity with p-values ranging from 0.001 to 0.02 for thresholds between 2 % and 25 %, the strongest correlation was found at 15 %. The mean absorbed bone marrow dose were 0.20-0.22 Gy per 7.4 GBq for threshold values between 10-25 %, and increased to 0.28 Gy for the lower values. No significant difference was observed in coefficient of variation (8.2-8.7 %) for the individual mean absorbed doses when varying the threshold value. Conclusion: The individual variation in absorbed dose is maintained at a low level when varying the threshold value for the determination of the compartment sizes. This implies that the method is stable for estimation of bone marrow doses and its correlation to haematological toxicity.
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| 7. |
- Hagmarker, Linn, et al.
(author)
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Evaluation of planar versus hybrid SPECT image methodology for bone marrow dosimetry during 177Lu-DOTATATE treatments reveals the obstacles with bone marrow metastases and cross-irradiation for the SPECT activity concentration quantification
- 2018
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In: 31st Annual Congress of the European Association of Nuclear Medicine (EANM’18). 13-17 October, Dusseldorf, Germany.
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Conference paper (other academic/artistic)abstract
- Introduction. The aim of this study is to compare the recently developed planar image-based method for bone marrow dosimetry with a hybrid method using SPECT/CT imaging at 24 h.p.i. of 177Lu-DOTATATE. Predictive ability of the methods is compared by investigating correlations of determined absorbed bone marrow dose, with haematological toxicity during the course of four treatment cycles. The aim is also to investigate the activity distribution in the vertebral column, and how the hybrid methodology can be optimized. Methods and Materials. 45 patients with advanced neuroendocrine tumours treated with 177Lu-DOTATATE at Sahlgrenska University Hospital in 2011-2016 (ILUMINET-study, EUDRACT nr 2011-etc) were included in this study. Absorbed bone marrow doses were calculated as the sum of the cross-doses from high-uptake organs and the remainder of the body, and the self-dose. Cross-doses were determined by time-activity curves created using planar images and a two-compartment method in the image platform PhONSAi. The self-dose was calculated using the time-activity concentration curve for the remainder of the body adjusted with the activity concentration determined in spheres placed in the vertebral bodies in SPECT-images. To improve recovery and reduce cross-irradiation of false counts in the SPECT-image, we utilized the Monte Carlo based reconstruction code SARec. Three activity concentrations were calculated to represent the activity concentration in the bone marrow; one mean (mean SPECT) and one median (median SPECT) activity concentration based on all visible vertebras and one where vertebras enclosing metastases were manually excluded (w/o Mets SPECT). Results. The planar method, the hybrid methods mean SPECT, median SPECT, and w/o Mets SPECT, yielded absorbed bone marrow doses after treatment cycle one at 0.19 (0.12-0.32), 0.35 (0.12-1.25), 0.29 (0.11-0.92) and 0.29 (0.15-0.81) Gy/7.4 GBq, respectively. A significant dose-response relationship was established after treatment cycle one between decreased platelet counts and absorbed bone marrow dose using the planar method (p=0.025, r=-0.16). With hybrid methods, a significant correlation was firstly found after treatment cycle two between absorbed dose and decreased platelet counts using median SPECT (p=0.018, r=-0.35). Conclusion. Early significant dose-response relationships were established. Despite using SARec-reconstructed SPECT-imaging for specific measurement of activity concentration in bone marrow cavities, the hybrid methods were not able to perform better than the planar method. The hybrid methods yielded higher absorbed bone marrow doses compared to the planar method as both bone metastases and cross-irradiation will influence the activity quantification. Further studies on minimizing influence of bone metastases and cross-irradiation are on-going.
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| 8. |
- Hemmingsson, Jens, 1986, et al.
(author)
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Autoradiography and biopsy measurements of a resected hepatocellular carcinoma treated with 90 yttrium radioembolization demonstrate large absorbed dose heterogeneities
- 2018
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In: Advances in Radiation Oncology. - : Elsevier BV. - 2452-1094. ; 3:3, s. 439-446
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Journal article (peer-reviewed)abstract
- © 2018 The Authors Purpose: Radioembolization is an alternative palliative treatment for hepatocellular carcinoma. Here, we examine the uptake differences between tumor tissue phenotypes and present a cross-section of the absorbed dose throughout a liver tissue specimen. Methods and materials: A patient with hepatocellular carcinoma was treated with90Y radioembolization followed by liver tissue resection. Gamma camera images and autoradiographs were collected and biopsy tissue samples were analyzed using a gamma well counter and light microscopy. Results: An analysis of 25 punched biopsy tissue samples identified 4 tissue regions: Normal tissue, viable tumor tissue with and without infarcted areas, and tumor areas with postnecrotic scar tissue. Autoradiography and biopsy tissue sample measurements showed large dose differences between viable and postnecrotic tumor tissue (159 Gy vs 23 Gy). Conclusions: Radioembolization of 90 yttrium with resin microspheres produces heterogeneous-absorbed dose distributions in the treatment of unifocal hepatic malignancies that could not be accurately determined with current gamma camera imaging techniques.
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| 9. |
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| 10. |
- Högberg, Jonas, 1976, et al.
(author)
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Increased absorbed liver dose in Selective Internal Radiation Therapy (SIRT) correlates with increased sphere-cluster frequency and absorbed dose inhomogeneity
- 2015
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In: EJNMMI Physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 2:1
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Journal article (peer-reviewed)abstract
- Background The higher tolerated mean absorbed dose for selective internal radiation therapy (SIRT) with intra-arterially infused 90Y microspheres compared to external beam therapy is speculated to be caused by absorbed dose inhomogeneity, which allows for liver regeneration. However, the complex liver microanatomy and rheology makes modelling less valuable if the tolerance doses are not based on the actual microsphere distribution. The present study demonstrates the sphere distribution and small-scale absorbed dose inhomogeneity and its correlation with the mean absorbed dose in liver tissue resected after SIRT. Methods A patient with marginally resectable cholangiocarcinoma underwent SIRT 9 days prior to resection including adjacent normal liver tissue. The resected specimen was formalin-fixed and sliced into 1 to 2-mm sections. Forty-one normal liver biopsies 6-8 mm in diameter were punched from these sections and the radioactivity measured. Sixteen biopsies were further processed for detailed analyses by consecutive serial sectioning of 15 30-μm sections per biopsy, mounted and stained with haematoxylin-eosin. All sections were scrutinised for isolated or conglomerate spheres. Small-scale dose distributions were obtained by applying a 90Y-dose point kernel to the microsphere distributions. Results A total of 3888 spheres were found in the 240 sections. Clusters were frequently found as strings in the arterioles and as conglomerates in small arteries, with the largest cluster comprising 453 spheres. An increased mean absorbed dose in the punch biopsies correlated with large clusters and a greater coefficient of variation. In simulations the absorbed dose was 5–1240 Gy; 90% were 10-97 Gy and 45% were <30 Gy, the assumed tolerance in external beam therapy. Conclusions Sphere clusters were located in both arterioles and small arteries and increased in size with increasing sphere concentration, resulting in increased absorbed dose inhomogeneity, which contradicts earlier modelling studies.
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