| 1. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 3. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 4. |
- Elf, Anna-Karin, et al.
(författare)
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Evaluation of sstr2 expression in si-nets and relation to overall survival after prrt
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:9
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Tidskriftsartikel (refereegranskat)abstract
- (1) Purpose: Small intestinal neuroendocrine tumors (SI-NETs) often present with distant metastases at diagnosis. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a systemic treatment that increases overall survival (OS) in SI-NET patients with stage IV disease. However, the treatment response after PRRT, which targets somatostatin receptor 2 (SSTR2), is variable and predictive factors have not been established. This exploratory study aims to evaluate if SSTR2 expression in SI-NETs could be used to predict OS after PRRT treatment. (2) Methods: Using a previously constructed Tissue Micro Array (TMA) we identified tissue samples from 42 patients that had received PRRT treatment during 2006–2017 at Sahlgrenska University hospital. Immunohistochemical expression of SSTR2, Ki-67 and neuroendocrine markers synaptophysin and Chromogranin A (CgA) were assessed. A retrospective estimation of177Lu-DOTATATE uptake in 33 patients was performed. Data regarding OS and non-surgical treatment after PRRT were collected. Another subgroup of 34 patients with paired samples from 3 tumor sites (primary tumor, lymph node and liver metastases) was identified in the TMA. The SSTR2 expression was assessed in corresponding tissue samples (n = 102). (3) Results: The patients were grouped into Low SSTR2 or High SSTR2 groups based upon on levels of SSTR2 expression. There was no significant difference in177Lu-DOTATATE uptake between the groups. The patients in the Low SSTR2 group had significantly longer OS after PRRT than the patients in the High SSTR2 group (p = 0.049). PRRT treated patients with low SSTR2 expression received less additional treatment compared with patients with high SSTR2 expression. SSTR2 expression did not vary between tumor sites but correlated within patients. (4) Conclusion: The results from the present study suggest that retrospective evaluation of SSTR2 expression in resected tumors cannot be used to predict OS after PRRT. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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| 5. |
- Hallqvist, Andreas, 1973, et al.
(författare)
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Optimizing the Schedule of PARP Inhibitors in Combination with 177Lu-DOTATATE: A Dosimetry Rationale.
- 2021
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- 177Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair 177Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (TNED). The aim of this study was to investigate how to enhance 177Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with 177Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during 177Lu-DOTATATE treatment, the concept of relative biological effectiveness (RBE) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of 177Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an RBE value of 2 for both the tumour and normal tissues, the TNED was increased compared to 177Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of 177Lu-DOTATATE treatment and be continued for up to four weeks to optimize the TNED. Based on these results, a phase I trial assessing the combination of olaparib and 177Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267).
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| 6. |
- Hassellöv, Ida-Maja, 1974, et al.
(författare)
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ICES Viewpoint background document: Impact from exhaust gas cleaning systems (scrubbers) on the marine environment (Ad hoc).
- 2020
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Shipping is a diverse industry that connects the world. The distribution and intensity of commercial shipping is increasing and there is a growing need to assess and mitigate the impacts of vessel activities on the marine environment. New global standards on sulphur content in marine fuels have led to an increasing number of ships installing exhaust gas cleaning systems (EGCS), also known as scrubbers, to reduce their emissions of sulphur oxides to the atmosphere. Ships equipped with a scrubber can continue to use heavy fuel oil, and the process results in discharges of large volumes of acidified water that contain a mix of contaminants, such as heavy metals, polycyclic aromatic hydrocarbons (PAHs), oil residues, and nitrates. For the most common type of scrubber, open loop, this polluted water is directly discharged back to the sea, trading reductions in air pollution for increased water pollution. The scrubber discharge mixture has demonstrated toxic effects in laboratory studies, causing immediate mortality in plankton and exhibiting negative synergistic effects. The substances found in scrubber discharge water are likely to have further impacts in the marine environment through bioaccumulation, acidification and eutrophication. The impacts of scrubber discharge water can be completely avoided through the use of alternative fuels, such as distilled low sulphur fuels. Distilled fuels have the added benefit that they remove the threat of heavy fuel oil spills from shipping activities. If the use of alternative fuels is not adopted, and scrubbers continue to be considered an equivalent method to meet the sulphur emissions limits, then there is urgent need for: 1) significant investment in technological advances and port reception facilities to allow zero discharge closed loop scrubber systems; 2) improved protocols and standards for measuring, monitoring and reporting on scrubber discharge water acidity and pollutants; 3) evidence-based regulations on scrubber water discharge limits that consider the full suite of contaminants.
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| 7. |
- Marin, Ida, et al.
(författare)
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Establishment of a clinical SPECT/CT protocol for imaging of(161)Tb
- 2020
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Ingår i: Ejnmmi Physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background It has been proposed, and preclinically demonstrated, that(161)Tb is a better alternative to(177)Lu for the treatment of small prostate cancer lesions due to its high emission of low-energy electrons.Tb-161 also emits photons suitable for single-photon emission computed tomography (SPECT) imaging. This study aims to establish a SPECT protocol for(161)Tb imaging in the clinic. Materials and methods Optimal settings using various gamma-camera collimators and energy windows were explored by imaging a Jaszczak phantom, including hollow-sphere inserts, filled with(161)Tb. The collimators examined were extended low-energy general purpose (ELEGP), medium-energy general purpose (MEGP), and low-energy high resolution (LEHR), respectively. In addition, three ordered subset expectation maximization (OSEM) algorithms were investigated: attenuation-corrected OSEM (A-OSEM); attenuation and dual- or triple-energy window scatter-corrected OSEM (AS-OSEM); and attenuation, scatter, and collimator-detector response-corrected OSEM (ASC-OSEM), where the latter utilized Monte Carlo-based reconstruction. Uniformity corrections, using intrinsic and extrinsic correction maps, were also investigated. Image quality was assessed by estimated recovery coefficients (RC), noise, and signal-to-noise ratio (SNR). Sensitivity was determined using a circular flat phantom. Results The best RC and SNR were obtained at an energy window between 67.1 and 82.1 keV. Ring artifacts, caused by non-uniformity, were removed with extrinsic uniformity correction for the energy window between 67.1 and 82.1 keV, but not with intrinsic correction. Analyzing the lower energy window between 48.9 and 62.9 keV, the ring artifacts remained after uniformity corrections. The recovery was similar for the different collimators when using a specific OSEM reconstruction. Recovery and SNR were highest for ASC-OSEM, followed by AS-OSEM and A-OSEM. When using the optimized parameter setting, the resolution of(161)Tb was higher than for(177)Lu (8.4 +/- 0.7 vs. 10.4 +/- 0.6 mm, respectively). The sensitivities for(161)Tb and(177)Lu were 7.41 and 8.46 cps/MBq, respectively. Conclusion SPECT with high resolution is feasible with(161)Tb; however, extrinsic uniformity correction is recommended to avoid ring artifacts. The LEHR collimator was the best choice of the three tested to obtain a high-resolution image. Due to the complex emission spectrum of low-energy photons, window-based scatter correction had a minor impact on the image quality compared to using attenuation correction only. On the other hand, performing attenuation, scatter, and collimator-detector correction clearly improved image quality. Based on these data, SPECT-based dosimetry for(161)Tb-labeled radiopharmaceuticals is feasible.
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| 10. |
- Rydén, Tobias, et al.
(författare)
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Deep learning generation of synthetic intermediate projections improves 177 Lu SPECT images reconstructed with sparsely acquired projections
- 2021
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 62:4, s. 528-534
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Tidskriftsartikel (refereegranskat)abstract
- The aims were to decrease 177Lu-SPECT (single-photon emission computed tomography) acquisition time by reducing the number of projections and to circumvent image degradation by adding deep learning-generated synthesized projections. Methods: We constructed a deep convolutional U-structured network for generating synthetic intermediate projections (CUSIP). The number of SPECT investigations was 352 for training, 37 for validation, and 15 for testing. The input was every fourth projection of 120 acquired SPECT projections, i.e., 30 projections. The output was 30 synthetic intermediate projections (SIPs) per CUSIP. SPECT images were reconstructed with 120 or 30 projections, or 120 projections where 90 SIPs were generated from the 30 projections (30-120SIP); using 3 CUSIPs. The reconstructions were performed with two ordered subset expectation maximization (OSEM) algorithms: attenuation-corrected (AC)-OSEM, and attenuation, scatter, and collimator response-corrected (ASCC)-OSEM. Image quality of SIPs and SPECT images were quantitatively evaluated with root mean square error, peak signal-to-noise-ratio (PSNR), and structural similarity (SSIM) index metrics. From a Jaszczak SPECT Phantom, the recovery and signal-to-noise ratio (SNR) were determined. In addition, an experienced observer qualitatively assessed the SPECT image quality of the test set. Kidney activity concentrations, as determined from the different SPECT images, were compared. Results: The generated SIPs had a mean SSIM value of 0.926 (0.061). For AC-OSEM, the reconstruction with 30-120SIP had higher SSIM (0.993 vs. 0.989; p<0.001) and PSNR (49.5 vs. 47.2; p<0.001) values than the reconstruction with 30 projections. ASCC-OSEM had higher SSIM and PSNR values than AC-OSEM (p<0.001). There was a minor loss in recovery for the 30-120SIP set, but SNR was clearly improved compared to the 30-projection set. The observer assessed 27/30 of the images reconstructed with 30 projections as having unacceptable noise levels, whereas corresponding values were 2/60 for the 30-120SIP and 120 projection sets. Image quality did not differ significantly between the 30-120SIP and 120 projection reconstructions. The kidney activity concentration was similar between the different projection sets, excepting a minor reduction of 2.5% for the ASCC-OSEM 30-120SIP. Conclusion: Adopting synthetic intermediate projections for sparsely acquired projections considerably recovers image quality and could allow reduced SPECT acquisition time in clinical dosimetry protocols.
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