| 1. |
- Albrecht, F., et al.
(författare)
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Unraveling Parkinson's disease heterogeneity using subtypes based on multimodal data
- 2022
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Ingår i: Parkinsonism and Related Disorders. - : Elsevier BV. - 1353-8020 .- 1873-5126. ; 102, s. 19-29
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Tidskriftsartikel (refereegranskat)abstract
- Background: Parkinson's disease (PD) is a clinically and neuroanatomically heterogeneous neurodegenerative disease characterized by different subtypes. To this date, no studies have used multimodal data that combines clinical, motor, cognitive and neuroimaging assessments to identify these subtypes, which may provide complementary, clinically relevant information. To address this limitation, we subtyped participants with mild-moderate PD based on a rich, multimodal dataset of clinical, cognitive, motor, and neuroimaging variables. Methods: Cross-sectional data from 95 PD participants from our randomized EXPANd (EXercise in PArkinson's disease and Neuroplasticity) controlled trial were included. Participants were subtyped using clinical, motor, and cognitive assessments as well as structural and resting-state MRI data. Subtyping was done by random forest clustering. We extracted information about the subtypes by inspecting their neuroimaging profiles and descriptive statistics. Results: Our multimodal subtyping analysis yielded three PD subtypes: a motor-cognitive subtype characterized by widespread alterations in brain structure and function as well as impairment in motor and cognitive abilities; a cognitive dominant subtype mainly impaired in cognitive function that showed frontoparietal structural and functional changes; and a motor dominant subtype impaired in motor variables without any brain alterations. Motor variables were most important for the subtyping, followed by gray matter volume in the right medial postcentral gyrus. Conclusions: Three distinct PD subtypes were identified in our multimodal dataset. The most important features to subtype PD participants were motor variables in addition to structural MRI in the sensorimotor region. These findings have the potential to improve our understanding of PD heterogeneity, which in turn can lead to personalized interventions and rehabilitation.
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| 2. |
- de Boniface, J., et al.
(författare)
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Survival and axillary recurrence following sentinel node-positive breast cancer without completion axillary lymph node dissection: the randomized controlled SENOMAC trial
- 2017
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Background: The role of axillary lymph node dissection (ALND) has increasingly been called into question among patients with positive sentinel lymph nodes. Two recent trials have failed to show a survival difference in sentinel node-positive breast cancer patients who were randomized either to undergo completion ALND or not. Neither of the trials, however, included breast cancer patients undergoing mastectomy or those with tumors larger than 5 cm, and power was debatable to show a small survival difference. Methods: The prospective randomized SENOMAC trial includes clinically node-negative breast cancer patients with up to two macrometastases in their sentinel lymph node biopsy. Patients with T1-T3 tumors are eligible as well as patients prior to systemic neoadjuvant therapy. Both breast-conserving surgery and mastectomy, with or without breast reconstruction, are eligible interventions. Patients are randomized 1: 1 to either undergo completion ALND or not by a web-based randomization tool. This trial is designed as a non-inferiority study with breast cancer-specific survival at 5 years as the primary endpoint. Target accrual is 3500 patients to achieve 80% power in being able to detect a potential 2.5% deterioration of the breast cancer-specific 5-year survival rate. Follow-up is by annual clinical examination and mammography during 5 years, and additional controls after 10 and 15 years. Secondary endpoints such as arm morbidity and health-related quality of life are measured by questionnaires at 1, 3 and 5 years. Discussion: Several large subgroups of breast cancer patients, such as patients undergoing mastectomy or those with larger tumors, have not been included in key trials; however, the use of ALND is being questioned even in these groups without the support of high-quality evidence. Therefore, the SENOMAC Trial will investigate the need of completion ALND in case of limited spread to the sentinel lymph nodes not only in patients undergoing any breast surgery, but also in neoadjuvantly treated patients and patients with larger tumors.
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| 3. |
- Forgetta, V., et al.
(författare)
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Development of a polygenic risk score to improve screening for fracture risk: A genetic risk prediction study
- 2020
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Ingår i: PLoS medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 17:7
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Tidskriftsartikel (refereegranskat)abstract
- Background Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-can identify low-risk individuals who can safely be excluded from a fracture risk screening program. Methods and findings A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed "gSOS", and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N= 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)-based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r(2)= 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk. Conclusions Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention. Author summaryWhy was this study done? Osteoporosis screening identifies only a small proportion of the screened population to be eligible for intervention. The prediction of heritable risk factors using polygenic risk scores could decrease the number of screened individuals by reassuring those with low genetic risk. We investigated whether the genetic prediction of heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-could be incorporated into an established screening guideline to identify individuals at low risk for osteoporosis. What did the researchers do and find? Using UK Biobank, we developed a polygenic risk score (gSOS) consisting of 21,717 genetic variants that was strongly correlated with SOS ( = 23.2%). Using the National Osteoporosis Guideline Group clinical assessment guidelines in 5 validation cohorts, we estimate that reassuring individuals with a high gSOS, rather than doing further assessments, could reduce the number of clinical-risk-factor-based Fracture Risk Assessment Tool (FRAX) tests and bone-density-measurement-based FRAX tests by 37% and 41%, respectively, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention. What do these findings mean? We show that genetic pre-screening could reduce the number of screening tests needed to identify individuals at risk of osteoporotic fractures. Therefore, the potential exists to improve the efficiency of osteoporosis screening programs without large losses in sensitivity or specificity to identify individuals who should receive an intervention. Further translational studies are needed to test the clinical applications of this polygenic risk score; however, our work shows how such scores could be tested in the clinic.
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| 4. |
- Kanis, J A, et al.
(författare)
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Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.
- 2023
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Ingår i: Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. - : Springer Nature. - 1433-2965 .- 0937-941X. ; 34:12, s. 2027-2045
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Tidskriftsartikel (refereegranskat)abstract
- A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX.The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD).We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted β-coefficients.A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination.A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.
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| 5. |
- Pedersen, Lars, et al.
(författare)
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Surgery to relieve nasal obstruction: outcome for 366 patients operated on by one senior surgeon
- 2021
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Ingår i: European Archives of Oto-Rhino-Laryngology. - : Springer Science and Business Media LLC. - 0937-4477 .- 1434-4726. ; 278, s. 3867-3875
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Tidskriftsartikel (refereegranskat)abstract
- Background Studies of patient-rated outcome in septoplasty and turbinoplasty most frequently involve several surgeons with varying surgical skills, techniques and experience. The aim of the present study was to evaluate outcome based on one experienced surgeon. Methods Three hundred and sixty-six consecutive patients referred for nasal obstruction were included. All the patients were examined with nasal endoscopy before and after decongestion, they filled out a nose VAS and rated their overall general health before and three to six months after surgery. The patients underwent septoplasty, septoplasty plus turbinoplasty or turbinoplasty. Results The mean nose VAS for nasal obstruction (0-100) preoperatively was 64.7 for all patients. Patients undergoing septoplasty (n = 159) were younger than patients undergoing septoplasty + turbinoplasty (n = 79) or patients undergoing turbinoplasty alone (n = 128). The nose VAS for nasal obstruction improved significantly in all three groups and 25% had a normal nose VAS after surgery in the septoplasty and septoplasty + turbinoplasty groups compared to only 8% in the turbinoplasty alone group. There was no significant difference in the improvement in nasal obstruction between septoplasty and septoplasty + turbinoplasty, but the septoplasty + turbinoplasty group experienced a significantly greater improvement in general health. Conclusions In 366 patients operated on by one experienced surgeon, septoplasty and septoplasty + turbinoplasty were more effective at relieving nasal obstruction than turbinoplasty alone. Septoplasty + turbinoplasty resulted in a greater improvement in general health than septoplasty alone, despite the same improvement in nasal obstruction, indicating a beneficial effect of additional turbinoplasty in septoplasty.
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| 6. |
- Persson, Jonas, et al.
(författare)
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Molecular evolution of specific human antibody against MUC1 mucin results in improved recognition of the antigen on tumor cells.
- 2009
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Ingår i: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. - : Springer Science and Business Media LLC. - 1423-0380 .- 1010-4283. ; 30:4, s. 221-31
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Tidskriftsartikel (refereegranskat)abstract
- The MUC1 mucin is differentially expressed and glycosylated in cancer tissue as opposed to healthy tissue. Due to these differences, MUC1 is considered a potential biomarker suitable for cancer diagnosis and therapy. In a previous study, the human MUC1-specific antibody 12ESC-6 was able to bind a sequence variant of the tandem repeat of MUC1 that is not recognized by many other MUC1-specific antibodies. It was also found to bind efficiently to MUC1-carrying cells. We have now used 12ESC-6 as starting point for random mutagenesis to isolate variants with improved ability to bind MUC1 in human tumor tissue. The resulting 12ESC-6 variants were shown to recognize not only the naked MUC1 tandem repeat but even more so glycosylated variants thereof, in particular those carrying the GalNAc (Tn) glycoform. Selected variants of 12ESC-6 demonstrated improved staining of MUC1 on cell lines using flow cytometry and improved staining of the antigen in breast tumor tissue by immunohistochemistry. Molecular evolution and specific fine-tuning thus have the potential to improve the performance of antibody specificities targeting tumor-associated epitopes on MUC1 mucin.
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| 7. |
- Vala, CecilieHongslo, 1983, et al.
(författare)
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Risk for hip fracture before and after total knee replacement in Sweden
- 2020
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 31:5, s. 887-895
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Tidskriftsartikel (refereegranskat)abstract
- We studied the risk for hip fracture before and after total knee replacement (TKR) in the entire population in Sweden. Women and men had a low risk for hip fracture before TKR but an increased risk the first year after TKR. Purpose It is known that osteoarthritis is associated with high bone mass. We therefore studied the risk of hip fracture before and after total knee replacement (TKR), risk of different hip fracture types, and risk subdivided in genders and age groups. Methods We followed the total Swedish population born between 1902 and 1952 (n = 4,258,934) during the period 1987-2002 and identified all patients with TKR due to primary OA (n = 39,291), and all patients with hip fracture (n = 195,860) in the Swedish National Inpatient Register. The risk time analyses were based on Poisson regression models. Results The hazard ratio (HR) for hip fracture the last year before TKR was 0.86 (95% CI 0.74 to 1.00) and the first year after 1.26 (95% CI 1.11 to 1.42) compared to individuals without TKR. The HR for femoral neck fracture 0-10 years after TKR was 0.95 (95% CI 0.89 to 1.01) and for trochanteric fracture was 1.13 (95% CI 1.06 to 1.21). The HR for hip fracture in the age group 50-74 was 1.28 (95% CI 1.14 to 1.43) and in the age group 75-90 years was 0.99 (95% CI 0.94 to 1.04) 0-10 years after TKR, compared to individuals without TKR. Conclusion Individuals had a low risk for hip fracture before TKR but an increased risk the first year after TKR. The risk in individuals below age 75 years and for trochanteric fractures was increased after TKR. Possible explanations include changed knee kinematics after a TKR, physical activity level, fall risk, and other unknown factors.
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| 8. |
- Vandenput, Liesbeth, 1974, et al.
(författare)
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Update of the fracture risk prediction tool FRAX : a systematic review of potential cohorts and analysis plan
- 2022
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Ingår i: Osteoporosis International. - : Springer. - 0937-941X .- 1433-2965. ; 33:10, s. 2103-2136
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Forskningsöversikt (refereegranskat)abstract
- Summary: We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures.Introduction: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors.Methods: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible.Results: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed.Conclusions: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).
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