| 1. |
- Cabrita, Rita, et al.
(författare)
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Tertiary lymphoid structures improve immunotherapy and survival in melanoma
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 577:7791, s. 561-565
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Tidskriftsartikel (refereegranskat)abstract
- Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
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| 2. |
- Cabrita, Rita, et al.
(författare)
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Tertiary lymphoid structures improve immunotherapy and survival in melanoma.
- 2020
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Ingår i: Nature. - : Nature Publishing Group. - 1476-4687 .- 0028-0836. ; 577:7791, s. 561-565
-
Tidskriftsartikel (refereegranskat)abstract
- Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
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| 3. |
- Grassi, Lorenzo, et al.
(författare)
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3D Finite Element Models Reconstructed From 2D Dual-Energy X-Ray Absorptiometry (DXA) Images Improve Hip Fracture Prediction Compared to Areal BMD in Osteoporotic Fractures in Men (MrOS) Sweden Cohort
- 2023
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Ingår i: Journal of Bone and Mineral Research. - : John Wiley & Sons. - 0884-0431 .- 1523-4681. ; 38:9, s. 1258-1267
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Tidskriftsartikel (refereegranskat)abstract
- Bone strength is an important contributor to fracture risk. Areal bone mineral density (aBMD) derived from dual-energy X-ray absorptiometry (DXA) is used as a surrogate for bone strength in fracture risk prediction tools. 3D finite element (FE) models predict bone strength better than aBMD, but their clinical use is limited by the need for 3D computed tomography and lack of automation. We have earlier developed amethod to reconstruct the 3D hip anatomy froma 2D DXA image, followed by subject-specific FE-based prediction of proximal femoral strength. In the current study, we aim to evaluate the method's ability to predict incident hip fractures in a populationbased cohort (Osteoporotic Fractures in Men [MrOS] Sweden). We defined two subcohorts: (i) hip fracture cases and controls cohort: 120men with a hip fracture (<10 years frombaseline) and two controls to each hip fracture case, matched by age, height, and body mass index; and (ii) fallers cohort: 86men who had fallen the year before their hip DXA scan was acquired, 15 of which sustained a hip fracture during the following 10 years. For each participant, we reconstructed the 3D hip anatomy and predicted proximal femoral strength in 10 sideways fall configurations using FE analysis. The FE-predicted proximal femoral strength was a better predictor of incident hip fractures than aBMD for both hip fracture cases and controls (difference in area under the receiver operating characteristics curve, Delta AUROC = 0.06) and fallers (Delta AUROC = 0.22) cohorts. This is the first time that FE models outperformed aBMD in predicting incident hip fractures in a population-based prospectively followed cohort based on 3D FE models obtained from a 2D DXA scan. Our approach has potential to notably improve the accuracy of fracture risk predictions in a clinically feasible manner (only one single DXA image is needed) and without additional costs compared to the current clinical approach.
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| 4. |
- Grassi, Lorenzo, et al.
(författare)
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3d Finite Element Models Reconstructed From 2d Dxa Images Improve Hip Fracture Prediction Compared to Areal Bmd in Mros Sweden Cohort
- 2023
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Ingår i: Journal of Bone and Mineral Research. - 1523-4681. ; 38:9, s. 1258-1267
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Tidskriftsartikel (refereegranskat)abstract
- Bone strength is an important contributor to fracture risk. Areal bone mineral density (aBMD) derived from dual-energy X-ray absorptiometry (DXA) is used as a surrogate for bone strength in fracture risk prediction tools. 3D finite element (FE) models predict bone strength better than aBMD, but their clinical use is limited by the need for 3D computed tomography and lack of automation. We have earlier developed a method to reconstruct the 3D hip anatomy from a 2D DXA image, followed by subject-specific FE-based prediction of proximal femoral strength. In the current study, we aim to evaluate the method's ability to predict incident hip fractures in a population-based cohort (MrOS Sweden). We defined two sub-cohorts: (i) hip fracture cases and controls cohort: 120 men with a hip fracture (<10 years from baseline) and 2 controls to each hip fracture case, matched by age, height, and body mass index; (ii) fallers cohort: 86 men who had fallen the year before their hip DXA scan was acquired, 15 of which sustained a hip fracture during the following 10 years. For each participant, we reconstructed the 3D hip anatomy and predicted proximal femoral strength in 10 sideways fall configurations using FE analysis. The FE-predicted proximal femoral strength was a better predictor of incident hip fractures than aBMD for both hip fracture cases and controls (difference in area under the receiver operating characteristics curve, ΔAUROC = 0.06) and fallers (ΔAUROC = 0.22) cohorts. This is the first time that FE models outperform aBMD in predicting incident hip fractures in a population-based prospectively followed cohort based on 3D FE models obtained from a 2D DXA scan. Our approach has potential to notably improve the accuracy of fracture risk predictions in a clinically feasible manner (only one single DXA image is needed) and without additional costs compared to the current clinical approach.
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| 5. |
- Helgadottir, H., et al.
(författare)
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Survival after introduction of adjuvant treatment in stage III melanoma: a nationwide registry-based study
- 2023
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Ingår i: Jnci-Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 41:16
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Tidskriftsartikel (refereegranskat)abstract
- Background Adjuvant treatments with PD-1 and BRAF+MEK inhibitors statistically significantly prolong recurrence-free survival in stage III cutaneous melanoma. Yet, the effect on overall survival is still unclear. Based on recurrence-free survival outcomes, these treatments have been approved and widely implemented. The treatments have considerable side effects and costs, and overall survival effect remains a highly anticipated outcome. Methods Clinical and histopathological parameters were obtained from the Swedish Melanoma Registry for patients diagnosed with stage III melanoma between 2016 and 2020. The patients were divided depending on if they were diagnosed before or from July 2018, based on the timepoint when adjuvant treatment was introduced in Sweden. Patients were followed up until the end of 2021. In this cohort study, melanoma-specific and overall survival were calculated using the Kaplan-Meier method and Cox-regression analyses. Results There were 1371 patients diagnosed with stage III primary melanoma in Sweden in 2016-2020. The 2-year overall survival rates, comparing the 634 patients in the precohort and the 737 in the postcohort, were 84.3% (95% confidence interval [CI] = 81.4% to 87.3%) and 86.1% (95% CI = 83.4% to 89.0%), respectively, with an adjusted hazard ratio of 0.91 (95% CI = 0.70 to 1.19, P = .51). Further, no statistically significant overall or melanoma-specific survival differences were seen when comparing the precohort and the postcohort in different subgroups for age, sex, or tumor characteristics. Conclusions In this nationwide population-based and registry-based study, no survival benefit was detected in patients diagnosed before or after the implementation of adjuvant treatment in stage III melanoma. These findings encourage a careful assessment of the current recommendations on adjuvant treatment.
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| 6. |
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| 7. |
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| 8. |
- Isaksson, Rebecka, et al.
(författare)
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Direct stimulation of angiotensin II type 2 receptor reduces nitric oxide production in lipopolysaccharide treated mouse macrophages
- 2020
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Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 868
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Tidskriftsartikel (refereegranskat)abstract
- The angiotensin II type 2 receptor (AT2) is upregulated after tissue damage and mediates protective functions in the renin-angiotensin-aldosterone system (RAAS). One of these is to inhibit inducible nitric oxide synthase (iNOS) in activated macrophages. In the present study, we assessed the effect of AT2 receptor ligands on nitric oxide production in murine macrophages as a potential assay to determine the functional activity of an AT2 receptor ligand. Mouse macrophage J744.2 and RAW264.7 were cultivated in lipopolysaccharide (LPS) to induce M1 differentiation and increase iNOS expression. Using Griess reagent and spectrophotometric analysis, the nitric oxide levels were determined, while employing Western blot and immunocytochemistry to determine basal protein expression.Using the first reported selective non-peptide AT2 receptor agonist, compound C21, we conclude that activation of AT2 receptor reduces nitric oxide production in M1 macrophages. Furthermore, the AT2 receptor selective ligand compound C38, a regioisomer of C21, reported as a selective AT2 receptor antagonist exhibits a similar effect on nitric oxide production. Thus, we propose C38 acts as a partial agonist in the macrophage system. Monitoring nitric oxide attenuation in M1 J744.1 and RAW264.7 macrophages provides a new method for characterizing functional activity of AT2 receptor ligands, foreseen to be valuable in future drug discovery programs.
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| 9. |
- Kok, Joeri, et al.
(författare)
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Augmenting a dynamic hip screw with a calcium sulfate/hydroxyapatite biomaterial
- 2021
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Ingår i: Medical Engineering and Physics. - : Elsevier BV. - 1350-4533. ; 92, s. 102-109
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Tidskriftsartikel (refereegranskat)abstract
- Internal fixation failure in hip fractures can lead to reoperation. Calcium sulfate/hydroxyapatite (CaS/HA) is a biomaterial that can be used for augmenting fracture fixation. We aimed to determine whether an injection of 2 ml CaS/HA increases the fixation of a dynamic hip screw inserted in synthetic and human trabecular bone. The study consists of two parts: 1) synthetic bone blocks (n = 74), with three subgroups: empty (cannulated screw, no injection), cannulated, and fenestrated; and 2) osteoporotic human femoral heads (n = 29), with the same subgroups. The heads were imaged using µCT. Bone volume fraction, insertion angle, and head diameter were measured. Pullout tests were performed and peak force, stiffness, and work were measured. The fenestrated group showed increases in pullout strength compared to no injection in the synthetic blocks. The cannulated group showed a higher pullout strength in low-density blocks. In the femoral heads, the variation was larger and there were no significant differences between groups. The bone volume fraction correlated with the peak force and work, and the insertion angle correlated with the stiffness. CaS/HA can improve the fixation of a dynamic hip screw. For clinical use, spreading of the material around the threads of the screw must be ensured.
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| 10. |
- Kok, Joeri, et al.
(författare)
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Fracture behavior of a composite of bone and calcium sulfate/hydroxyapatite
- 2022
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Ingår i: Journal of the Mechanical Behavior of Biomedical Materials. - : Elsevier BV. - 1751-6161. ; 130
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Tidskriftsartikel (refereegranskat)abstract
- Calcium sulfate/hydroxyapatite (CaS/HA) biomaterials have been investigated for use in several orthopedic applications. However, the mechanical interactions between the composite of CaS/HA and bone at the microscale are still unknown. The aim of this study was to determine if and how augmentation with CaS/HA alters the fracture behavior of bone. Eleven cylinders of trabecular bone were drilled from human femoral heads and cleaned from bone marrow. Among them, five cylinders were injected with CaS/HA to generate composite specimens, while the others were kept intact. One extra specimen of pure CaS/HA was prepared. All specimens were compressed in situ using synchrotron X-ray tomography and imaged at ∼2% strain intervals. Structural properties were calculated from the images in unloaded state and mechanical properties were determined from the load-curves. CaS/HA alone displayed the highest peak force and stiffness and the lowest strain at fracture. All composite specimens had a higher peak force than the pure bone specimens and the composite specimens had higher toughness than the pure CaS/HA specimen. Furthermore, the fracture behavior was analyzed further to characterize the local deformations. The pure bone specimens presented damage in multiple trabeculae and the CaS/HA specimen displayed sharp transition in strains, with low strain in one load step and large cracks in the next. The composite specimens deformed uniformly, with the CaS/HA preventing tissue damage and the bone preventing cracks in the CaS/HA from propagating through the specimen. In conclusion, using tomography with in situ loading, it was possible to show how CaS/HA can help prevent bone tissue damage before global failure.
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| 11. |
- Liu, Yang, et al.
(författare)
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Bone mineral : A trojan horse for bone cancers. Efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin
- 2022
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Ingår i: Materials Today Bio. - : Elsevier BV. - 2590-0064. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Efficient systemic pharmacological treatment of solid tumors is hampered by inadequate tumor concentration of cytostatics necessitating development of smart local drug delivery systems. To overcome this, we demonstrate that doxorubicin (DOX), a cornerstone drug used for osteosarcoma treatment, shows reversible accretion to hydroxyapatite (HA) of both nano (nHA) and micro (mHA) size. nHA particles functionalized with DOX get engulfed in the lysosome of osteosarcoma cells where the acidic microenvironment causes a disruption of the binding between DOX and HA. The released DOX then accumulates in the mitochondria causing cell starvation, reduced migration and apoptosis. The HA+DOX delivery system was also tested in-vivo on osteosarcoma bearing mice. Locally delivered DOX via the HA particles had a stronger tumor eradication effect compared to the controls as seen by PET-CT and immunohistochemical staining of proliferation and apoptosis markers. These results indicate that in addition to systemic chemotherapy, an adjuvant nHA could be used as a carrier for intracellular delivery of DOX for prevention of tumor recurrence after surgical resection in an osteosarcoma. Furthermore, we demonstrate that nHA particles are pivotal in this approach but a combination of nHA with mHA could increase the safety associated with particulate nanomaterials while maintaining similar therapeutic potential.
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| 12. |
- Liu, Yang, et al.
(författare)
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Sustained and controlled delivery of doxorubicin from an in-situ setting biphasic hydroxyapatite carrier for local treatment of a highly proliferative human osteosarcoma
- 2021
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Ingår i: Acta Biomaterialia. - : Elsevier BV. - 1742-7061. ; 131, s. 555-571
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Tidskriftsartikel (refereegranskat)abstract
- Doxorubicin (DOX) is a cornerstone drug in the treatment of osteosarcoma. However, achieving sufficient concentration in the tumor tissue after systemic administration with few side effects has been a challenge. Even with the most advanced nanotechnology approaches, less than 5% of the total administered drug gets delivered to the target site. Alternatives to increase the local concentration of DOX within the tumor using improved drug delivery methods are needed. In this study, we evaluate a clinically approved calcium sulfate/hydroxyapatite (CaS/HA) carrier, both in-vitro and in-vivo, for local, sustained and controlled delivery of DOX to improve osteosarcoma treatment. In-vitro drug release studies indicated that nearly 28% and 36% of the loaded drug was released over a period of 4-weeks at physiological pH (7.4) and acidic pH (5), respectively. About 63% of the drug had been released after 4-weeks in-vivo. The efficacy of the released drug from the CaS/HA material was verified on two human osteosarcoma cell lines MG-63 and 143B. It was demonstrated that the released drug fractions functioned the same way as the free drug without impacting its efficacy. Finally, the carrier system with DOX was assessed using two clinically relevant human osteosarcoma xenograft models. Compared to no treatment or the clinical standard of care with systemic DOX administration, the delivery of DOX using a CaS/HA biomaterial could significantly hinder tumor progression by inhibiting angiogenesis and cell proliferation. Our results indicate that a clinically approved CaS/HA biomaterial containing cytostatics could potentially be used for the local treatment of osteosarcoma. Statement of significance: The triad of doxorubicin (DOX), methotrexate and cisplatin has routinely been used for the treatment of osteosarcoma. These drugs dramatically improved the prognosis, but 45-55% of the patients respond poorly to the treatment with low 5-year survival. In the present study, we repurpose the cornerstone drug DOX by embedding it in a calcium sulfate/hydroxyapatite (CaS/HA) biomaterial, ensuring a spatio-temporal drug release and a hypothetically higher and longer lasting intra-tumoral concentration of DOX. This delivery system could dramatically hinder the progression of a highly aggressive osteosarcoma compared to systemic administration, by inhibiting angiogenesis and cell proliferation. Our data show an efficient method for supplementary osteosarcoma treatment with possible rapid translational potential due to clinically approved constituents.
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| 13. |
- Magnusson, Beatrice M., et al.
(författare)
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A prospective observational cohort study of traumatic brain injury in the northern region of Sweden
- 2022
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Ingår i: Brain Injury. - : Taylor & Francis. - 0269-9052 .- 1362-301X. ; 36:2, s. 191-198
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Generally, to map epidemiological and demographic features of patients with traumatic brain injury (TBI) in Umeå county, Sweden. Specifically, to evaluate the subjects needing a computed tomography (CT) of the head after suffering from TBI and frequencies of 1) intracranial lesions detected with CT, 2) need for neurosurgical intervention and 3) admission to hospital.METHODS: Patients with a suspected TBI, undergoing CT within 24 hours of arrival to hospital, were included in a database for evaluation.RESULTS: Out of 302 patients (63% male), 83% were GCS 13-15, 7% were GCS 9-12 and 10% were GCS <9. The frequency of abnormal CT findings was 23% in GCS 13-15, 67% in GCS 9-12 and 97% in GCS <9. Neurosurgical intervention was needed by 4% of those with GCS 13-15, 52% of those with GCS 9-12 and by 76% of those with GCS <9.CONCLUSIONS: Subjects with GCS 13-15 had higher frequencies of abnormal CT findings, need for neurosurgical intervention and hospital admission than previously reported. A similar trend was observed for patients with GCS 9-12, which can be of serious nature, with a higher frequency of need for neurosurgical intervention than previously described.
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| 14. |
- Mallalieu, Adam, 1995, et al.
(författare)
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Sustainability criteria for introducing new technologies in low-income contexts
- 2024
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Ingår i: Proceedings of the Design Society. - : Cambridge University Press. ; 4, s. 1359-1368
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Konferensbidrag (refereegranskat)abstract
- Introducing new technologies in low-income contexts have potential for positive social impact, and such efforts are made by humanitarian engineering non-govermental organisations (NGOs). The impact can increase if a systemic sustainability perspective is considered in the design process. Sustainability criteria are identified using a literature study combined with an empirical study together with a Swedish NGO. These criteria are synthesized into a simplified Sustainability Fingerprint tool which is evaluated and deemed to be useful when introducing new technologies in low-income contexts. © 2024 Proceedings of the Design Society. All rights reserved.
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| 15. |
- Martinsson Bonde, Julian, 1992, et al.
(författare)
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Morpheus: The Development and Evaluation of a Software Tool for Morphological Matrices
- 2022
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Ingår i: Proceedings of NordDesign 2022: How Product and Manufacturing Design Enable Sustainable Companies and Societies.
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Konferensbidrag (refereegranskat)abstract
- The Morphological Matrix is a well-known and established method for synthesising concepts in engineering design. With the aim to improve its applicability, the method has been implemented into a software tool, which then has been introduced in engineering courses at Chalmers University of Technology. In this paper, the tool and its most important functions are presented and discussed, along with experiences from its use in design projects. It was demonstrated that the tool can ease the process of creating and modifying morphological matrices. Furthermore, the tool demonstrated the ability to generate and keep track of large quantities of solutions, which has previously been difficult as morphological matrices are typically hand drawn or created using an Excel sheet. However, less desired effects were encountered as the tool was perceived by some students as more of a screening and down-selection method, rather than as a tool for synthesising concepts. The learnings and the way forward in education and the industrial context are discussed.
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| 16. |
- Molin, Jenny, 1974-, et al.
(författare)
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From traditional counselling to health‐promoting conversations? Registered nurses' experiences of providing health counselling to people living with severe mental ill‐health in supported housing
- 2023
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Ingår i: International Journal of Mental Health Nursing. - : John Wiley & Sons. - 1445-8330 .- 1447-0349. ; 32:3, s. 875-883
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Tidskriftsartikel (refereegranskat)abstract
- People with severe mental ill-health have lower life expectancies than the rest ofthe population, partly due to unhealthy lifestyles. Counselling to help these people improve their health can also be complex, and registered nurses are key to its success.The aim of this study was to elucidate registered nurses' experiences of providing health counselling to people living with severe mental ill-health in supported housing. We conducted eight individual semi-structured interviews with registered nurses working in this context and subjected the responses to qualitative content analysis. The results show that registered nurses who counsel people with severe mental ill-health feel dispirited, but they defend their often fruitless endeavours and strive, through health counselling, to help these people meet healthier lifestyle goals. Shifting the focus from traditional health counselling to person-centred care using health-promoting conversations could strengthen registered nurses in their efforts towards improving lifestyles among people living with severe mental ill-healthin supported housing. Therefore, to facilitate healthier lifestyles among this population, we recommend that community healthcare support registered nurses working in supported housing by educating them in the use of health-promoting conversations, including teach-back techniques.
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| 17. |
- Raina, Deepak Bushan, et al.
(författare)
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A facile one-stage treatment of critical bone defects using a calcium sulfate/hydroxyapatite biomaterial providing spatiotemporal delivery of bone morphogenic protein-2 and zoledronic acid
- 2020
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 6:48
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Tidskriftsartikel (refereegranskat)abstract
- Bone morphogenic proteins (BMPs) are the only true osteoinductive molecules. Despite being tremendously potent, their clinical use has been limited for reasons including supraphysiological doses, suboptimal delivery systems, and the pro-osteoclast effect of BMPs. Efforts to achieve spatially controlled bone formation using BMPs are being made. We demonstrate that a carrier consisting of a powder of calcium sulfate/hydroxyapatite (CaS/HA) mixed with bone active molecules provides an efficient drug delivery platform for critical femoral defect healing in rats. The bone-active molecules were composed of osteoinductive rhBMP-2 and the bisphosphonate, and zoledronic acid (ZA) was chosen to overcome BMP-2-induced bone resorption. It was demonstrated that delivery of rhBMP-2 was necessary for critical defect healing and restoration of mechanical properties, but codelivery of BMP-2 and ZA led to denser and stronger fracture calluses. Together, the CaS/HA biomaterial with rhBMP-2 and/or ZA can potentially be used as an off-the-shelf alternative to autograft bone.
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| 18. |
- Raina, Deepak Bushan, et al.
(författare)
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A New Augmentation Method for Improved Screw Fixation in Fragile Bone
- 2022
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Ingår i: Frontiers in Bioengineering and Biotechnology. - : Frontiers Media SA. - 2296-4185. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Pertrochanteric fractures (TF) due to osteoporosis constitute nearly half of all proximal femur fractures. TFs are treated with a surgical approach and fracture fixation is achieved using metallic fixation devices. Poor quality cancellous bone in osteoporotic patients makes anchorage of a fixation device challenging, which can lead to failure of the fracture fixation. Methods to reinforce the bone-implant interface using bone cement (PMMA) and other calcium phosphate cements in TFs have been described earlier but a clear evidence on the advantage of using such biomaterials for augmentation is weak. Furthermore, there is no standardized technique for delivering these biomaterials at the bone-implant interface. In this study, we firstly describe a method to deliver a calcium sulphate/hydroxyapatite (CaS/HA) based biomaterial for the augmentation of a lag-screw commonly used for TF fixation. We then used an osteoporotic Sawbones model to study the consequence of CaS/HA augmentation on the immediate mechanical anchorage of the lag-screw to osteoporotic bone. Finally, as a proof-of-concept, the method of delivering the CaS/HA biomaterial at the bone-implant interface as well as spreading of the CaS/HA material at this interface was tested in patients undergoing treatment for TF as well as in donated femoral heads. The mechanical testing results indicated that the CaS/HA based biomaterial increased the peak extraction force of the lag-screw by 4 times compared with un-augmented lag-screws and the results were at par with PMMA. The X-ray images from the patient series showed that it was possible to inject the CaS/HA material at the bone-implant interface without applying additional pressure and the CaS/HA material spreading was observed at the interface of the lag-screw threads and the bone. Finally, the spreading of the CaS/HA material was also verified on donated femoral heads and micro-CT imaging indicated that the entire length of the lag-screw threads was covered with the CaS/HA biomaterial. In conclusion, we present a novel method for augmenting a lag-screw in TFs, which could potentially reduce the risk of fracture fixation failure and reoperation in fragile osteoporotic patients.
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| 19. |
- Raina, Deepak Bushan, et al.
(författare)
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Synthesis and Characterization of a Biocomposite Bone Bandage for Controlled Delivery of Bone-Active Drugs in Fracture Nonunions
- 2020
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Ingår i: ACS Biomaterials Science and Engineering. - : American Chemical Society (ACS). - 2373-9878. ; 6:5, s. 2867-2878
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Tidskriftsartikel (refereegranskat)abstract
- Fracture nonunions are common in orthopedics and their treatment often involves multiple surgical interventions. The aim of this study was to fabricate and characterize a gelatin-nano-hydroxyapatite membrane (GM)-based bone bandage for controlled delivery of bio-active molecules; recombinant human bone morphogenic protein-2 (rhBMP-2) and zoledronic acid (ZA) to promote osteoinduction and prevent callus resorption, respectively. In vitro cell-material interaction experiments using MC3T3 cells seeded on the GM indicated good biocompatibility. rhBMP-2-functionalized GM promoted osteogenic differentiation of MC3T3 cells and the rhBMP-2 bio-activity thus remained, as indicated by increased levels of alkaline phosphatase compared to only GM. The GM released a small amount (1.1%) of rhBMP-2 in vitro over a period of 5 weeks, demonstrating a strong interaction of rhBMP-2 with the GM. In the first animal study, the GM specimens loaded with rhBMP-2 or with the combination of rhBMP-2 + ZA were placed in the abdominal muscle pouch of rats. In the GM + rhBMP-2 + ZA group, significantly higher bone volume (21.5 ± 5.9 vs 2.7 ± 1.0 mm3) and area (3.3 ± 2.3 vs 1.0 ± 0.4 mm2) of bone were observed compared to GM + rhBMP-2 after 4 weeks, as indicated by micro-computed tomography and histomorphometry, respectively. Finally, a nonunion model in rats was used to evaluate the efficacy of the GM bandage and bio-active molecules in healing of fracture nonunions. The GM functionalized with rhBMP-2 + ZA led to higher bone formation around the fracture (63.9 ± 19.0 vs 31.8 ± 3.7 mm3) and stronger fracture callus (110.8 ± 46.8 vs 45.6 ± 17.8 N) compared to the empty controls. However, the overall union rate was only marginally improved. The GM alone or combined with ZA did not aid in bone healing in this model. Thus, this study shows that controlled delivery of rhBMP-2 + ZA via the developed GM is a promising approach that could aid in earlier full load bearing in patients with nonunion.
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| 20. |
- Scott, Aaron M., et al.
(författare)
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Population scale proteomics enables adaptive digital twin modelling in sepsis
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Sepsis is one of the leading causes of mortality in the world. Currently, the heterogeneity of sepsis makes it challenging to determine the molecular mechanisms that define the syndrome. Here, we leverage population scale proteomics to analyze a well-defined cohort of 1364 blood samples taken at time-of-admission to the emergency department from patients suspected of sepsis. We identified panels of proteins using explainable artificial intelligence that predict clinical outcomes and applied these panels to reduce high-dimensional proteomics data to a low-dimensional interpretable latent space (ILS). Using the ILS, we constructed an adaptive digital twin model that accurately predicted organ dysfunction, mortality, and early-mortality-risk patients using only data available at time-of-admission. In addition to being highly effective for investigating sepsis, this approach supports the flexible incorporation of new data and can generalize to other diseases to aid in translational research and the development of precision medicine.Competing Interest StatementThe authors have declared no competing interest.Funding StatementL.M. is funded by the Swedish Research Council (grant number VR-2020-02419), the Wallenberg foundation (grant number 2016.0023) and Alfred Österlunds Foundation. J.M. is a Wallenberg academy fellow (KAW 2017.0271) and is also funded by the Swedish Research Council (Vetenskapsrådet, VR) (2019-01646 and 2018-05795), the Wallenberg foundation (KAW2016.0023, KAW2019.0353 and KAW2020.0299), and Alfred Österlunds Foundation. E.M. is funded by Wenner-Gren Foundation (FT2020-0003), the Crafoord Foundation, and the Swedish Society of Medicine (SLS-985287). F.K. is funded by Region Skåne ALF project and the Crafoord Foundation. A.L. is funded by the Swedish Research Council VR 2023-02707 and Region Skåne ALF project 2022-0146.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval for the study was obtained from the Swedish National Ethics Committee (file numbers 2022-01454-01, 2014/741 and 2016/271).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesData produced in the present study are available upon reasonable request to the authors
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| 21. |
- Sezgin, Erdem Aras, et al.
(författare)
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A combined fracture and mortality risk index useful for treatment stratification in hip fragility fractures
- 2021
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Ingår i: Joint Diseases and Related Surgery. - 2687-4784. ; 32:3, s. 583-589
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: In this study, we aimed to assess the stratification ability of the Fracture and Mortality Risk Evaluation (FAME) index for reoperation, new fragility fracture, and mortality during one-year follow-up. Patients and methods: Between November 2018 and July 2019, a total of 94 consecutive hip fragility fracture patients from two centers (20 males, 74 females; mean age: 79.3±8.9 years; range, 57 to 100 years) were retrospectively analyzed. The patients were classified into high, intermediate, and low fracture and mortality risk groups according to the Fracture Risk Assessment Tool (FRAX) score and Sernbo score, respectively, as well as nine combined categories according to the FAME index. Hospital records were reviewed to identify re-fractures (reoperations, implant failure, new fragility fractures on any site) and mortality at one year following the FAME index classification. Results: Overall re-fracture and mortality rates were 20.2% and 33%, respectively. High fracture risk category (FRAX-H) was significantly associated with higher re-fracture (odds ratio [OR]: 2.9, 95% confidence interval [CI]: 1-8.2, p=0.037) and mortality rates compared to others (OR: 3.7, 95% CI: 1.5-9.3, p=0.003). The patients classified within the FRAX-H category (n=35) had different mortality rates according to their Sernbo classification; i.e., patients classified as low mortality risk (Sernbo-L) (n=17) had lower mortality rates compared to others in this group (n=18) (35.3% and 66.7%, respectively), indicating a low statistical significance (OR: 0.3, 95% CI: 0.1-1.1, p=0.063). Similarly, within patients classified in Sernbo-L category (n=64), those classified as high fracture risk (FRAX-H) (n=17) had significantly higher re-fracture rates compared to others in this group (n=47) (35.3% and 8.5%, respectively), (OR: 5.9; 95% CI: 1.4-24.5), (p=0.017). Multivariate logistic regression analyses adjusting for covariates (age, sex, length of hospital stay and BMI) yielded similar results. Conclusion: The FAME index appears to be a useful stratification tool for allocating patients in a randomized-controlled trial for augmentation of hip fragility fractures.
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| 22. |
- Sezgin, Erdem Aras, et al.
(författare)
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Combined fracture and mortality risk evaluation for stratifying treatment in hip fracture patients : A feasibility study
- 2020
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Ingår i: Joint Diseases and Related Surgery. - 2687-4784. ; 31:2, s. 163-168
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: This study aims to test the feasibility of the Fracture and Mortality Risk Evaluation (FAME) Index. Patients and methods: Two academic centers in Lithuania and Turkey participated in this retrospective study conducted between November 2018 and July 2019. A total of 100 consecutive patients (22 males, 78 females; mean age 78.9 years; range, 45 to 100 years) with low energy proximal femur fractures admitted for surgery were included in the study. Fracture Risk Assessment tool (FRAX) and the Sernbo scores were calculated and patients were classified into one of the nine subcategories of the FAME Index. Results: Demographics and FAME Index classifications were similar between centers. Patients with high risk of fracture and low risk of mortality accounted for 18% of all patients, which is the FAME Index subcategory to theoretically benefit from cancellous bone augmentation during internal fixation of a fragility hip fracture the most. Conclusion: The FAME Index was successfully applied in clinical emergency setting utilizing a simple form, and demonstrated promising potential in stratification of hip fractures most suitable for screw and device augmentation. Larger studies with at least one-year of follow-up are warranted to verify the validity of FAME Index.
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| 23. |
- Syrén, Eva-Lena, et al.
(författare)
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Cardiovascular complications after common bile duct stone extractions
- 2021
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Ingår i: Surgical Endoscopy. - : Springer. - 0930-2794 .- 1432-2218. ; 35:7, s. 3296-3302
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Tidskriftsartikel (refereegranskat)abstract
- Background: Common bile duct stone (CBDS) is a common condition the rate of which increases with age. Decision to treat in particular elderly and frail patients with CBDS is often complex and requires careful assessment of the risk for treatment-related cardiovascular complications. The aim of this study was to compare the rate of postoperative cardiovascular events in CBDS patients treated with the following: ERCP only; cholecystectomy only; cholecystectomy followed by delayed ERCP; cholecystectomy together with ERCP; or ERCP followed by delayed cholecystectomy.Methods: The study was based on data from procedures for gallstone disease registered in the Swedish National Quality Register for Cholecystectomy and Endoscopic Retrograde Cholangiopancreatography (GallRiks) 2006–2014. ERCP and cholecystectomy procedures performed for confirmed or suspected CBDS were included. Postoperative events were registered by cross-matching GallRiks with the National Patient Register (NPR). A postoperative cardiovascular event was defined as an ICD-code in the discharge notes indicating myocardial infarct, pulmonary embolism or cerebrovascular disease within 30 days after surgery. In cases where a patient had undergone ERCP and cholecystectomy on separate occasions, the 30-day interval was timed from the first intervention.Results: A total of 23,591 underwent ERCP or cholecystectomy for CBDS during the study period. A postoperative cardiovascular event was registered in 164 patients and death within 30 days in 225 patients. In univariable analysis, adverse cardiovascular event and death within 30 days were more frequent in patients who underwent primary ERCP (p < 0.05). In multivariable analysis, adjusting for history of cardiovascular disease or events, neither risk for cardiovascular complication nor death within 30 days remained statistically significant in the ERCP group.Conclusions: Primary ERCP as well as cholecystectomy may be performed for CBDS with acceptable safety. More studies are required to provide reliable guidelines for the management of CBDS.
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| 24. |
- Syrén, Eva-Lena, et al.
(författare)
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Outcome of ERCP related to case-volume
- 2022
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Ingår i: Surgical Endoscopy. - : Springer. - 0930-2794 .- 1432-2218. ; 36, s. 5339-5347
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: In some studies, high endoscopic retrograde cholangiopancreatography (ERCP) case-volume has been shown to correlate to high success rate in terms of successful cannulation and fewer adverse events. The aim of this study was to analyze the association between ERCP success and complications, and endoscopist and centre case-volumes.METHODS: Data were obtained from the Swedish National Register for Gallstone Surgery and ERCP (GallRiks) on all ERCPs performed for Common Bile Duct Stone (CBDS) (n = 17,873) and suspected or confirmed malignancy (n = 6152) between 2009 and 2018. Successful cannulation rate, procedure time, intra- and postoperative complication rates and post-ERCP pancreatitis (PEP) rate, were compared with endoscopist and centre ERCP case-volumes during the year preceding the procedure as predictor.RESULTS: In multivariable analyses of the CBDS group adjusting for age, gender and year, a high endoscopist case-volume was associated with higher successful cannulation rate, lower complication and PEP rates, and shorter procedure time (p < 0.05). Centres with a high annual case-volume were associated with high successful cannulation rate and shorter procedure time (p < 0.05), but not lower complication and PEP rates. When indication for ERCP was malignancy, a high endoscopist case-volume was associated with high successful cannulation rate and low PEP rates (p < 0.05), but not shorter procedure time or low complication rate. Centres with high case-volume were associated with high successful cannulation rate and low complication and PEP rates (p < 0.05), but not shorter procedure time.CONCLUSIONS: The results suggest that higher endoscopist and centre case-volumes are associated with safer ERCP and successful outcome.
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| 25. |
- Syrén, Eva-Lena, et al.
(författare)
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Postoperative rendezvous endoscopic retrograde cholangiopancreaticography as an option in the management of choledocholithiasis
- 2020
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Ingår i: Surgical Endoscopy. - : Springer. - 0930-2794 .- 1432-2218. ; 34:11, s. 4883-4889
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Rendezvous endoscopic retrograde cholangiopancreaticography (ERCP) is a well-established method for treatment of choledocholithiasis. The primary aim of this study was to determine how different techniques for management of common bile duct stone (CBDS) clearance in patients undergoing cholecystectomy have changed over time at tertiary referral hospitals (TRH) and county/community hospitals (CH). The secondary aim was to see if postoperative rendezvous ERCP is a safe, effective and feasible alternative to intraoperative rendezvous ERCP in the management of CBDS.METHODS: Data were retrieved from the Swedish registry for cholecystectomy and ERCP (GallRiks) 2006-2016. All cholecystectomies, where CBDS were found at intraoperative cholangiography, and with complete 30-day follow-up (n = 10,386) were identified. Data concerning intraoperative and postoperative complications, readmission and reoperation within 30 days were retrieved for patients where intraoperative ERCP (n = 2290) and preparation for postoperative ERCP were performed (n = 2283).RESULTS: Intraoperative ERCP increased (7.5% 2006; 43.1% 2016) whereas preparation for postoperative ERCP decreased (21.2% 2006; 17.2% 2016) during 2006-2016. CBDS management differed between TRHs and CHs. Complications were higher in the postoperative rendezvous ERCP group: Odds Ratio [OR] 1.69 (95% confidence interval [CI] 1.16-2.45) for intraoperative complications and OR 1.50 (CI 1.29-1.75) for postoperative complications. Intraoperative bleeding OR 2.46 (CI 1.17-5.16), postoperative bile leakage OR 1.89 (CI 1.23-2.90) and postoperative infection with abscess OR 1.55 (CI 1.05-2.29) were higher in the postoperative group. Neither post-ERCP pancreatitis, postoperative bleeding, cholangitis, percutaneous drainage, antibiotic treatment, ICU stay, readmission/reoperation within 30 days nor 30-day mortality differed between groups.CONCLUSIONS: Techniques for management of CBDS found at cholecystectomy have changed over time and differ between TRH and CH. Rendezvous ERCP is a safe and effective method. Even though intraoperative rendezvous ERCP is the preferred method, postoperative rendezvous ERCP constitutes an acceptable alternative where ERCP resources are lacking or limited.
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| 26. |
- Syrén, Eva-Lena
(författare)
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Risk factors for and Strategies to Prevent Complications of Endoscopic Retrograde Cholangiopancreatography
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aim: The overall aim of this thesis was to study risk factors for and strategies to prevent complications of Endoscopic Retrograde Cholangiopancreatography (ERCP). Methods: Prospectively registered data from the Swedish National Quality Register for Gallstone Surgery and ERCP (GallRiks) 2006-2018 were retrospectively retrieved and reviewed. In Study I, ERCP procedures performed for common bile duct stones (CBDS), were analysed and cross-checked with the National Patient Register (NPR) in order to assess risk factors for post-ERCP pancreatitis (PEP). In Study II, different techniques for CBDS clearance over time at different hospital levels and the effectiveness and safety of postoperative rendezvous ERCP compared to intraoperative rendezvous ERCP were studied. In Study III, the rate of postoperative cardiovascular events in CBDS-patients treated with ERCP only, cholecystectomy only, cholecystectomy followed by delayed ERCP, cholecystectomy together with ERCP, or ERCP followed by delayed cholecystectomy were analysed. In Study IV, associations between ERCP success and complications, and endoscopist- and centre case-volumes regarding procedures for CBDS, and suspected or confirmed malignancy were analysed. Results: Women, patients<65 years, patients with hyperlipidaemia, and those with a previous history of recent acute pancreatitis had a higher risk for PEP, while patients with diabetes had a lower risk (all p<0.05). Intraoperative ERCP increased during the period of the study, whereas preparation for postoperative ERCP decreased. CBDS management differed between different hospital levels. Total rate of intra- and postoperative complications as well as intraoperative bleeding, postoperative bile leakage, and postoperative infection with abscess were higher in the postoperative rendezvous ERCP group (all p<0.05). However, PEP, postoperative bleeding, cholangitis, percutaneous drainage, antibiotic treatment, ICU stay, readmission/reoperation within 30 days, and 30-day mortality did not differ between the groups. Nor did risk for cardiovascular complication or death within 30 days differ between patients treated for CBDS by cholecystectomy and/or ERCP. A high endoscopist case-volume was associated with higher successful cannulation rate and lower PEP rate (p<0.05). Centres with a high annual case-volume were associated with higher successful cannulation rates (p<0.05). Conclusions: Age, sex, hyperlipidaemia, and previous history of recent acute pancreatitis all increased the risk for PEP while diabetes reduced the risk. Techniques for management of CBDS discovered at cholecystectomy have changed over time and differ between hospitals levels. Though intraoperative rendezvous ERCP is the method of choice, postoperative rendezvous ERCP is an acceptable alternative when adequate ERCP resources are lacking or limited. Primary ERCP as well as cholecystectomy for CBDS may be performed with acceptable safety. Higher endoscopist- and centre case-volumes lead to safer and more successful ERCP.
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