| 1. |
- Nordström, Peter, et al.
(författare)
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Geriatric Rehabilitation and Discharge Location After Hip Fracture in Relation to the Risks of Death and Readmission
- 2016
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Ingår i: Journal of the American Medical Directors Association. - : Elsevier. - 1525-8610 .- 1538-9375. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To investigate the effects of geriatric rehabilitation on short-term risk of death and readmission after a hip fracture were investigated in a nationwide cohort. In addition, the association of discharge location (nursing home or patient's home) with the short-term risk of death was assessed.DESIGN, SETTING, AND PARTICIPANTS: The cohort consisted of 89,301 individuals at least 50 years of age, with a first hip fracture registered in the Swedish quality register RIKSHÖFT, the years 2004-2012.MEASURES: Short-term risk of death and readmission to hospital after discharge was compared at 8 hospitals, where most patients received inpatient care in geriatric wards, and those treated at 71 regular hospitals.RESULTS: The risks of death within 30 days of admission were 7.1% in patients admitted to geriatric ward hospitals and 7.4% in those treated at regular hospitals (multivariable-adjusted hazard ratio [HR] 0.91, 95% CI 0.85-0.97), whereas the odds of readmission within 30 days of discharge were 8.7% and 9.8%, respectively (multivariable-adjusted odds ratio 0.86, 95% CI 0.81-0.91). The risk of death was influenced by discharge location and inpatient length of stay (LOS). Thus, for patients discharged to short-term nursing homes with a LOS of at most 10 days, each additional day of LOS reduction increased the risk of death within 30 days of discharge by 13% (HR 1.13, 95% CI 1.08-1.18). This association was reduced in patients discharged to permanent nursing homes (HR 1.04, 95% CI 1.02-1.07), and not significant in those discharged to their own home (OR 1.00, 95% CI 0.91-1.10).CONCLUSION: The risks of death and readmission were lower in patients with hip fracture who received care in hospitals with geriatric wards. The risk of death after discharge increased with shorter LOS, especially in patients discharged to short-term nursing homes.
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| 2. |
- Michaëlsson, Karl, et al.
(författare)
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Impact of hip fracture on mortality : a cohort study in hip fracture discordant identical twins
- 2014
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Ingår i: Journal of Bone and Mineral Research. - : Wiley-Blackwell. - 0884-0431 .- 1523-4681. ; 29:2, s. 424-431
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have shown a long-lasting higher mortality after hip fracture but the reasons of the excess risk is not well understood. We aimed to determine whether there exists a higher mortality after hip fracture when controlling for genetic constitution, shared environment, comorbidity and lifestyle by use of a nation-wide cohort study in hip fracture discordant monozygotic twins. All 286 identical Swedish twin pairs discordant for hip fracture (1972-2010) were identified. Comorbidity and lifestyle information was retrieved by registers and questionnaire information. We used intrapair Cox regression to compute multivariable-adjusted hazard ratios (HRs) for death. During follow-up, 143 twins with a hip fracture died (50%) compared to 101 twins (35%) without a hip fracture. Through the first year after hip fracture, the rate of death increased four-fold in women (HR 3.71; 95% confidence interval (CI) 1.32-10.40) and seven-fold in men (HR 6.67; 95% CI 1.47-30.13). The increased rate in women only persisted during the first year after hip fracture (HR after 1 year 0.99; 95% CI 0.66-1.50), whereas the corresponding HR in men was 2.58 (95% CI 1.02-6.62). The higher risk in men after the hip fracture event was successively attenuated during follow-up. After 5 years, the hazard ratio in men with a hip fracture was 1.19 (95% CI 0.29-4.90). On average, the hip fracture contributed to 0.9 years of life lost in women (95% CI 0.06-1.7) and 2.7 years in men (95% CI 1.7-3.7). The potential years of life lost associated with the hip fracture was especially pronounced in older men (>75 years), with an average loss of 47% (95% CI 31-61) of the expected remaining lifetime. We conclude that both women and men display a higher mortality after hip fracture independent of genes, comorbidity and lifestyle.
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| 3. |
- Nordström, Anna, 1973-, et al.
(författare)
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Interleukin-6 promoter polymorphism is associated with bone quality assessed by calcaneus ultrasound and previous fractures in a cohort of 75-year-old women.
- 2004
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Ingår i: Osteoporosis international. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 15:10, s. 820-6
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin 6 (IL-6) is a multifunctional cytokine and a potent stimulator of bone resorption and has been implicated in the pathogenesis of osteoporosis in postmenopausal women. The aim of this study was to investigate if a functional IL-6 promoter polymorphism (-174) was related to bone mass and fractures in a cohort consisting of 964 postmenopausal Caucasian women aged 75 years. Bone mineral density (BMD; g/cm2) of the femoral neck, lumbar spine and total body was measured using dual energy X-ray absorptiometry (DXA). Quantitative ultrasound (QUS) was also measured in the calcaneus and quantified as speed of sound (SOS; m/s), broadband ultrasound attenuation (BUA; dB/MHz), and stiffness index (SI). IL-6 genotypes was determined by restriction fragment length polymorphism (RFLP) using the restriction enzyme NlaIII. The frequencies of the different IL-6 genotypes were 27.5% (GG), 47.9% (GC), 24.6% (CC). The IL-6 polymorphism (presence of G) was independently related to a lower stiffness (beta=-0.07; P=0.03) and BUA (beta=-0.08; P=0.02), but not to BMD at any site measured by DXA. In the cohort, 420 subjects (44%) reported at least one fracture during their lifetime, and 349 (36%) reported at least one fracture after the age of 50. Using binary logistic regression, the IL-6 polymorphism (presence of G) was significantly related to an increased risk of a previous fracture during life (odds ratio 1.46, 95% CI 1.08-1.97) and to an increased risk of a fracture occurring after 50 years of age (odds ratio 1.37, 95% CI 1.004-1.88). The risk was further increased for fractures grouped as osteoporotic fractures (odds ratio 1.67, 95% CI 1.14-2.45), including forearm fractures (odds ratio 1.59, 95% CI 1.05-2.40). In conclusion, presence of G allele in the IL-6 promoter polymorphism at position -174 is independently related to previous fractures in postmenopausal women. This association may be related primarily to an altered bone quality identified by QUS and not a lower bone mass. This is also the first demonstration of association of IL-6 gene polymorphism to calcaneal QUS.
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| 4. |
- Nordström, Peter, et al.
(författare)
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Bisphosphonate Use After Hip Fracture in Older Adults : A Nationwide Retrospective Cohort Study
- 2017
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Ingår i: Journal of the American Medical Directors Association. - : Elsevier BV. - 1525-8610 .- 1538-9375. ; 18:6, s. 515-521
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The aim of this study was to investigate the association between bisphosphonate use and the risk of new fracture in a nationwide cohort of individuals with previous hip fractures, with emphasis on individuals above 80 years of age. Design, setting, and participants: From a nationwide cohort with hip fracture (2006-2012) (n = 93, 601), each individual prescribed bisphosphonates after hip fracture (n = 5845) was matched with up to three individuals not prescribed bisphosphonates, resulting in a cohort of 21,363 individuals. Main outcome measure: A new hip fracture. Results: During a mean follow-up period of 2.98 (range, 0.02-8) years, 4581 fractures occurred in the cohort. Before the initiation of bisphosphonate therapy, individuals later prescribed bisphosphonates had an increased risk of hip fracture (multivariable adjusted odds ratio [OR], 2.63; 95% confidence interval [CI], 2.23-3.24) compared with controls. In the period after bisphosphonate therapy initiation, individuals prescribed bisphosphonates had a lower risk of hip fracture (multivariable adjusted hazard ratio [HR], 0.76; 95% CI, 0.65-0.90) compared with controls. Similar effects were seen after the initiation of bisphosphonates in individuals aged more than 80 years (HR, 0.79; 95% CI, 0.62-0.99). In contrast, the initiation of bisphosphonate therapy did not influence the risk of injurious falls not resulting in fracture (HR, 0.95; 95% CI, 0.86-1.05). Conclusion: Bisphosphonate use was associated with a decreased risk of hip fracture in this nationwide cohort of older men and women, with similar risk reductions in individuals older than 80 years.
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| 5. |
- Nordström, Peter, et al.
(författare)
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Length of hospital stay after hip fracture and short term risk of death after discharge : a total cohort study in Sweden
- 2015
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Ingår i: The BMJ. - : BMJ. - 1756-1833. ; 350
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate relation between inpatient length of stay after hip fracture and risk of death after hospital discharge.SETTING: Population ≥50 years old living in Sweden as of 31 December 2005 with a first hip fracture the years 2006-12.PARTICIPANTS: 116 111 patients with an incident hip fracture from a closed nationwide cohort.MAIN OUTCOME MEASURE: Death within 30 days of hospital discharge in relation to hospital length of stay after adjustment for multiple covariates.RESULTS: Mean inpatient length of stay after a hip fracture decreased from 14.2 days in 2006 to 11.6 days in 2012 (P<0.001). The association between length of stay and risk of death after discharge was non-linear (P<0.001), with a threshold for this non-linear effect of about 10 days. Thus, for patients with length of stay of ≤10 days (n=59 154), each 1-day reduction in length of stay increased the odds of death within 30 days of discharge by 8% in 2006 (odds ratio 1.08 (95% confidence interval 1.04 to 1.12)), which increased to16% in 2012 (odds ratio 1.16 (1.12 to 1.20)). In contrast, for patients with a length of stay of ≥11 days (n=56 957), a 1-day reduction in length of stay was not associated with an increased risk of death after discharge during any of the years of follow up.LIMITATIONS: No accurate evaluation of the underlying cause of death could be performed.CONCLUSION: Shorter length of stay in hospital after hip fracture is associated with increased risk of death after hospital discharge, but only among patients with length of stay of 10 days or less. This association remained robust over consecutive years.
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| 6. |
- Nordström, Peter, et al.
(författare)
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Risks of Myocardial Infarction, Death, and Diabetes in Identical Twin Pairs With Different Body Mass Indexes
- 2016
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Ingår i: JAMA Internal Medicine. - : American Medical Association (AMA). - 2168-6106 .- 2168-6114. ; 176:10, s. 1522-1529
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Observational studies have shown that obesity is a major risk factor for cardiovascular disease and death. The extent of genetic confounding in these associations is unclear. OBJECTIVE To compare the risk of myocardial infarction (MI), type 2 diabetes, and death in monozygotic (MZ) twin pairs discordant for body mass index (BMI). DESIGN, SETTING, AND PARTICIPANTS A cohort of 4046 MZ twin pairs with discordant BMIs (difference >0.01) was identified using the nationwide Swedish twin registry. The study was conducted from March 17, 1998, to January 16, 2003, with follow-up regarding incident outcomes until December 31, 2013. MAIN OUTCOMES AND MEASURES The combined primary end point of death or MI and the secondary end point of incident diabetes were evaluated in heavier compared with leaner twins in a co-twin control analysis using multivariable conditional logistic regression. RESULTS Mean (SD) baseline age for both cohorts was 57.6 (9.5) years (range, 41.9-91.8 years). During a mean follow-up period of 12.4 (2.5) years, 203 MIs (5.0%) and 550 deaths (13.6%) occurred among heavier twins (mean [SD] BMI, 25.9 [3.6] [calculated as weight in kilograms divided by height in meters squared]) compared with 209 MIs (5.2%) and 633 deaths (15.6%) among leaner twins (mean [SD] BMI, 23.9 [3.1]; combined multivariable adjusted odds ratio [OR], 0.75; 95% CI, 0.63-0.91). Even in twin pairs with BMI discordance of 7.0 or more (mean [SE], 9.3 [0.7]), where the heavier twin had a BMI of 30.0 or more (n = 65 pairs), the risk of MI or death was not greater in heavier twins (OR, 0.42; 95% CI, 0.15-1.18). In contrast, in the total cohort of twins, the risk of incident diabetes was greater in heavier twins (OR, 2.14; 95% CI, 1.61-2.84). Finally, increases in BMI since 30 years before baseline were not associated with the later risk of MI or death (OR, 0.97; 95% CI, 0.89-1.05) but were associated with the risk of incident diabetes (OR, 1.13; 95% CI, 1.01-1.26). CONCLUSIONS AND RELEVANCE In MZ twin pairs, higher BMI was not associated with an increased risk of MI or death but was associated with the onset of diabetes. These results may suggest that lifestyle interventions to reduce obesity are more effective in decreasing the risk of diabetes than the risk of cardiovascular disease or death.
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| 7. |
- Nordström, Peter, et al.
(författare)
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Traumatic brain injury and young onset dementia : a nationwide cohort study
- 2014
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 75:3, s. 374-381
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Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate the association between traumatic brain injuries (TBIs) and the risk of young onset dementia (YOD), that is, dementia before 65 years of age. Methods The study cohort comprised 811,622 Swedish men (mean age = 18 years) conscripted for military service between 1969 and 1986. TBIs, dementia, and covariates were extracted from national registers. Time-dependent exposures using Cox proportional hazard regression models were evaluated. Results During a median follow-up period of 33 years, there were 45,249 men with at least 1 TBI in the cohort. After adjustment for covariates, 1 mild TBI (hazard ratio [HR] = 1.0, 95% confidence interval [CI] = 0.5-2.0), at least 2 mild TBIs (HR = 2.5, 95% CI = 0.8-8.1), or 1 severe TBI (HR = 0.7, 95% CI = 0.1-5.2) were not associated with Alzheimer dementia (AD). Other types of dementia were strongly associated with the risk of 1 mild TBI (HR = 3.8, 95% CI = 2.8-5.2), at least 2 mild TBIs (HR = 10.4, 95% CI = 6.3-17.2), and 1 severe TBI (HR = 11.4, 95% CI = 7.4-17.5) in age-adjusted analysis. However, these associations were largely attenuated after adjustment for covariates (1 mild TBI: HR = 1.7; at least 2 mild TBIs: HR = 1.7; 1 severe TBI: HR = 2.6; p < 0.05 for all). Interpretation In the present study, we found strong associations between YOD of non-AD forms and TBIs of different severity. These associations were, however, markedly attenuated after multivariate adjustment.
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| 8. |
- Albinsson, Sebastian, et al.
(författare)
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Differential dependence of stretch and shear stress signaling on caveolin-1 in the vascular wall
- 2008
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Ingår i: American Journal of Physiology: Cell Physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 294, s. 271-279
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Tidskriftsartikel (refereegranskat)abstract
- The role of caveolae in stretch- vs. flow-induced vascular responses was investigated using caveolin-1 deficient (KO) mice. Portal veins were stretched longitudinally for 5 min (acute) or 72 h (organ culture). Basal ERK1/2 and Akt phosphorylation were increased in organ-cultured KO veins, as were protein synthesis and vessel wall cross-section. Stretch stimulated acute phosphorylation of ERK1/2 and long-term phosphorylation of focal adhesion kinase (FAK) and cofilin, but did not affect Akt phosphorylation. Protein synthesis, and particularly synthesis of smooth muscle differentiation markers, was increased by stretch. These effects did not differ in portal veins from KO and control mice, which also showed the same contractile response to membrane depolarization and inhibition by the Rho kinase inhibitor Y-27632. KO carotid arteries had increased wall cross-section and responded to pressurization (120 mmHg) for 1 h with increased ERK1/2 but not Akt phosphorylation, similar to control arteries. Shear stress by flow for 15 min, on the other hand, increased phosphorylation of Akt in carotids from control but not KO mice. In conclusion, caveolin-1 contributes to a low basal ERK1/2 and Akt activity and is required for Akt-dependent signals in response to shear stress (flow), but is not essential for trophic effects of stretch (pressure) in the vascular wall. Key words: Hypertrophy, vasoconstriction, vascular smooth muscle, endothelium, nitric oxide.
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| 9. |
- Almén, Markus Sällman, et al.
(författare)
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Mapping the human membrane proteome : a majority of the human membrane proteins can be classified according to function and evolutionary origin
- 2009
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Ingår i: BMC Biology. - : Springer Science and Business Media LLC. - 1741-7007. ; 7, s. 50-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Membrane proteins form key nodes in mediating the cell's interaction with the surroundings, which is one of the main reasons why the majority of drug targets are membrane proteins. RESULTS: Here we mined the human proteome and identified the membrane proteome subset using three prediction tools for alpha-helices: Phobius, TMHMM, and SOSUI. This dataset was reduced to a non-redundant set by aligning it to the human genome and then clustered with our own interactive implementation of the ISODATA algorithm. The genes were classified and each protein group was manually curated, virtually evaluating each sequence of the clusters, applying systematic comparisons with a range of databases and other resources. We identified 6,718 human membrane proteins and classified the majority of them into 234 families of which 151 belong to the three major functional groups: receptors (63 groups, 1,352 members), transporters (89 groups, 817 members) or enzymes (7 groups, 533 members). Also, 74 miscellaneous groups with 697 members were determined. Interestingly, we find that 41% of the membrane proteins are singlets with no apparent affiliation or identity to any human protein family. Our results identify major differences between the human membrane proteome and the ones in unicellular organisms and we also show a strong bias towards certain membrane topologies for different functional classes: 77% of all transporters have more than six helices while 60% of proteins with an enzymatic function and 88% receptors, that are not GPCRs, have only one single membrane spanning alpha-helix. Further, we have identified and characterized new gene families and novel members of existing families. CONCLUSION: Here we present the most detailed roadmap of gene numbers and families to our knowledge, which is an important step towards an overall classification of the entire human proteome. We estimate that 27% of the total human proteome are alpha-helical transmembrane proteins and provide an extended classification together with in-depth investigations of the membrane proteome's functional, structural, and evolutionary features.
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| 10. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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