| 1. |
- Wagner, Helene, 1966-
(författare)
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Genetic and Environmental Influences on Bone and Fractures
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sweden and Norway have the worldwide highest incidence of osteoporotic fractures. As these fractures constitute a tremendous and growing problem, primary prevention is of great importance. The principal causes of an osteoporotic fracture are a fall and a fragile skeleton. The aim of the studies reported in these papers was therefore to determine the genetic and environmental influences on fractures and the genetic influence on the two main reasons to the emergence of osteoporotic fractures; bone mineral density and propensity to fall. In the present thesis, we display that the heritability of fractures is dependent on fracture site and age. With increasing age, lifestyle becomes the dominant explanatory factor. These results indicate that focus should be on lifestyle interventions for the prevention of fractures in the elderly. Although the genetic liability to impaired balance is modest, twins with self-reported impaired balance have a substantially increased risk of osteoporotic fractures compared to their co-twin without impaired balance. Asking a patient about his or her balance might be a simple tool for future risk assessment. The genetic influence on bone phenotypes is under strong genetic influence in Swedish adult twins. These findings are in agreement with the results from previous studies in other countries, with a lower incidence of osteoporotic fractures compared to Sweden. The high heritability of bone phenotypes together with the low heritability of fractures at old age, indicates that bone mineral density has a modest influence on fracture risk at old age. In summary, based on the results in this thesis, more emphasis should be targeted to the prevention of falls, by strength and balance training in order to prevent the occurrence of low energy fractures in the elderly.
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| 2. |
- Pazarlis, Konstantinos, MD, 1983-
(författare)
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On the Diagnosis and Treatment of Lumbar Spinal Stenosis
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lumbar spinal stenosis (LSS) is the most common indication for spinal surgery. The aging global population is increasing the demand for strategies that promote physical activity among the elderly. As the prevalence of LSS rises, the condition gains constantly demographic and socioeconomic attention. Until recently, there has been no clear consensus regarding LSS treatment. Further, using electrodiagnostic examinations (EDX) as predictive tools to identify surgical candidates, could lead to a more tailored medical approach. Methodological issues in previous studies have left some questions unanswered. The necessity of extensive surgery for LSS remains a topic of debate among spinal surgeons, which this work addressed by analyzing data from 723 patients. Parts of the work aimed to compare surgery and structured non-surgical treatment for LSS (Paper I, II, III). Furthermore, it aimed to investigate, by means of EDX, whether the degree of neurological affection correlates to the surgical outcome of LSS (Paper I, II). Additionally, this work evaluated the radiological outcome for surgical vs non-surgical treatment for LSS in terms of sagittal balance parameters (Paper III, V). Finally, parts of this thesis aimed to confirm findings from previous studies regarding DA and DF for LSS with DS (Paper IV, V). The current thesis is based on two randomized controlled trials and a cohort study: the Uppsala Spinal Stenosis Trial, the Swedish Spinal Stenosis Study, and the Cohort Study on LSS with DS. Patient reported outcome measures from the Swedish National Quality Registry for Spine Surgery (Swespine) were used to collect follow-up data. We concluded that at six months, surgery with decompression leads to superior clinical outcome, compared to structured physical therapy. The improvement is not affected by delay of surgery (Paper II). EDX does not add predictive value when assessing the patients for eligibility before surgery (Paper II). DA improves the spinal sagittal balance, regardless of preoperative DS (Paper III) and provides good two-year clinical outcome in LSS with DS with low rate of complications, and low need for subsequent surgery (Paper IV). New radiological stenosis was less common two years after DA than after DF, in LSS with or without preoperative DS (Paper V).
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| 3. |
- Schilcher, Jörg, 1978-
(författare)
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Epidemiology, Radiology and Histology of Atypical Femoral Fractures : Development of understanding
- 2013
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Ingår i: Acta Orthopaedica. - Linköping : Linköping University Electronic Press. - 1745-3674 .- 1745-3682. ; 84:S352, s. 1-26
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bisphosphonates have been used successfully in the prevention of osteoporosis-related fractures for over two decades. Only recently an association between bisphosphonate use and femoral insufficiency fractures – atypical femoral fractures – has been found.Bone remodeling is necessary to maintain a healthy skeleton. With age this process can get out of balance and bone resorption can outweigh formation of new bone. This can lead to osteoporosis and fractures that occur after minor trauma. Almost half of all women 50 years of age or older will suffer an osteoporosis related fracture during their remaining life. Bisphosphonates inhibit bone resorption, and after some years of treatment an increase in bone mass can be noted. This increase in bone mass can reduce fracture risk by as much as half. However, bisphosphonate use seems associated with the development of femoral insufficiency fractures, so called atypical femoral fractures. This thesis aimed to estimate the risk of atypical femoral fractures in the population and its association with bisphosphonate use. It also describes the radiographic and histologic features of these fractures in order to improve our understanding of the pathophysiological background.Study 1) All women 55 years of age and older, who had sustained a femoral shaft fracture during 2008, were identified through the Swedish National Patient Register. Radiographs of 1234 women were reviewed, and 59 patients with atypical fractures and 263 control patients with common femoral shaft fractures were identified. Atypical femoral fractures were defined by their stress fracture-like appearance. In a cohort analysis, we estimated an age-adjusted relative risk of 47 for bisphosphonate users to suffer an atypical femoral fracture compared to non-users. A total of 78% of the patients with an atypical fracture and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33. The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. These results indicate that bisphosphonate use is strongly associated with atypical femoral fractures. The absolute risk is low and benefits of treatment will outweigh the risks.Study 2) A transverse fracture line and a small but visible callus reaction are well established radiographic features of stress fractures. Radiographs from 59 atypical fracture patients and 218 control patients from Study 1 were re-reviewed to measure fracture angles and to detect callus reactions. The majority of the patients with a transverse fracture angle used bisphosphonates. Fracture angle and callus reaction had a high specificity to detect bisphosphonate treatment. When an oblique fracture line was chosen to define atypical femoral fractures in the cohort from Study 1, the association of atypical femoral fractures to bisphosphonate use became attenuated. Therefore, a correct case definition of atypical femoral fractures is necessary for adequate risk calculations.Study 3) Bone biopsies from 8 patients with atypical femoral fractures were obtained during surgical fixation. The histological analysis of the fracture site itself showed a thin fracture line running perpendicular to the long axis of the femur. Despite ongoing remodeling in the bone adjacent to the fracture gap, no healing occurred within the gap itself. Necrotic material in the gap suggests that strains within the gap might prohibit ingrowth of cells necessary for healing. This mechanism of inhibited healing might share similarities with that of stress fractures in athletes. Although it is highly likely that bisphosphonates play a causative role, the pathogenesis of these fractures is still unclear. It may involve a reduced capacity for targeted remodeling.
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| 4. |
- Ahlström, Björn
(författare)
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The epidemiology of risk factors and short and long-term outcome in the Swedish intensive care cohort
- 2021
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dissertation presented at Uppsala University to be publicly examined on Zoom: https://uu-se.zoom.us/j/7214327760, Tuesday, 11 May 2021 at 13:00 for the degree of Licentiate of Philosophy (Faculty of Medicine). The examination will be conducted in English and Swedish. Chairman of the Examining committee: Professor Karl Michaëlsson (Medical epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala) Abstract Ahlström, B. 2021. The epidemiology of risk factors and short- and long-term out-come in the Swedish intensive care cohort. 76 pp. Severe sepsis and septic shock, linked to persistent organ dysfunctions, have poor short- and long-term mortality outcomes. These conditions also adversely affect health-related quality of life. After intensive care with severe sepsis and septic shock, memory and other cognitive functions have shown deterioration. In addition, there are indications of an increased risk of dementia. Yet, whether severe sepsis and septic shock are independently linked to dementia or dementia development is linked to more general severe illness remains unclear. In the Swedish intensive care cohort we compared 16 115 one-year sepsis survivors without previous dementia to 194 219 patients (controls) admitted to intensive care for other reasons using a Cox proportional hazards model. The crude risk of dementia was increased in the severe sepsis and septic shock group. However, after adjustment for demographics, comorbidities and factors reflecting the severity of acute illness, severe sepsis and septic shock was found not to be a significant risk factor of incident dementia with a haz-ard ratio of 1.01 (95% confidence interval 0.91-1.11). Thus, we concluded that although the incidence of dementia is high after intensive care, severe sepsis or septic shock is not causative. Coronavirus disease 2019 (COVID-19) has put a tremendous strain on the healthcare system in general and intensive care, in particular, since its emergence in Wuhan, China, in late 2019. Risk factors of ICU admission and mortality from COVID-19 were reported early during the pandemic, but only as univariate variables. Under the hypothesis that there are several independent risk factors of critical COVID-19, we used statistical models to explore demographic characteristics and comorbidi-ties in the first 1 981 ICU-admitted patients with COVID-19 in Sweden. On the risk of ICU admission, we also included matched population controls in a 1:4 ratio. Hypertension, type 2 diabetes mellitus, chronic renal failure, asthma, obesity, solid organ transplant recipient and immunosuppressant medications were independent risk factors of ICU admission. Oral anticoagulants were associated with a protective effect. Stroke, asthma, chronic obstructive pulmonary disease and treatment with renin-angiotensin-aldosterone inhibitors were independent risk factors of ICU mortality. Treatment with statins was protective. Our findings suggest that there are several independent risk factors of ICU admission and ICU mortality in COVID-19.Björn Ahlström, Department of Surgical Sciences, Anaesthesiology and Intensive Care, Uppsala University, SE-75185 Uppsala, Sweden and Centre of clinical research, Region Dalarna, SE-79182 Falun, Sweden.
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| 5. |
- Knutsson, Björn
(författare)
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Lumbar spinal stenosis : Body mass index and the patient's perspective
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During recent decades, lumbar spinal stenosis (LSS) has become the most common indication for spine surgery, a change that coincides with a higher worldwide prevalence of overweight and obesity. Thus, surgical treatment of LSS in the overweight and obese population is common and increasing in scope.The overall aim of this thesis was to investigate whether body mass index (BMI) is related to the development of LSS, and whether BMI is linked to outcome after surgery for LSS. We further evaluated whether there are specific experiences of LSS from a patient perspective.Data were obtained for all patients registered in the Swedish Spine Register who had undergone surgery for LSS between January 1, 2006 and June 30, 2008. After adjusting for differences in baseline characteristics, patients with obesity showed both poorer results after surgery and a higher rate of dissatisfaction than patients with normal weight (odds ratio 1.73; 95% confidence interval, CI, 1.36-2.19).Furthermore, patients with obesity in the cohort reported modest weight loss at follow-up (2.0 kg; 95% CI, 1.5-2.4), and only 8% reported a clinical important weight loss 2 years after surgery.Our analysis of 389,132 construction workers, showed that overweight (incidence rate ratio, IRR 1.68; 95% CI, 1.54-1.83) and obesity (IRR 2.18; 95% CI, 1.87-2.53) were associated with an increased future risk in developing LSS when compared with patients with normal weight.To gain insight into the patients' perspective of LSS, we performed interviews with 18 patients who were on a waiting list for LSS surgery. The transcripts, analyzed with content analysis, revealed that living with LSS is a physical, mental and social challenge in which resources to cope with the condition are of major importance.In summary, obesity is associated with poorer results after surgery, and patients with obesity report modest weight loss during follow-up. In addition, obesity is associated with an increased risk to develop LSS. Our findings revealed that being a patient with LSS, naturally involves considerable suffering and pain, but it also implies being a person with his or her own resources who is able to cope with these adverse conditions.
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| 6. |
- Leavy, Breiffni, 1977-
(författare)
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Fall-Related Hip Fracture : Predisposing and Precipitating Factors
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A physically inactive lifestyle is a predisposing risk factor for fall-related hip fracture. The circumstances, or precipitating factors, surrounding hip fractures are, however, not well understood, a factor of relevance for Swedish adults who have one of the highest hip fracture risks in the world. The aims of this thesis, therefore, were: to explore perceptions of physical activity (PA) among older adults, to describe the circumstances surrounding hip fracture events and the health characteristics of those who experience them.Four observational studies were conducted involving qualitative, epidemiological and mixed method designs. Participants in study I were recruited from community settings in Stockholm and Dublin (n=30). Studies II-IV (sample sizes, n=484, n=125, n=477) were based on a population-based sample of people admitted to Uppsala University hospital due to hip fracture. Study IV also incorporated the background population of Uppsala county in 2010 (n=117 494).Analysis of PA perceptions in study I revealed that PA which is functional nature is perceived as most meaningful among certain participants. The uptake of PA in later years was a means of creating a new self-identify and being active in outdoor environments was an important culture-specific motivator to PA among Swedish participants. Analysis of hip fractures patterns in studies II-III showed that: hip fractures among psychotropic drug users were twice as likely to occur during night-time hours compared to those occurring among people not receiving these drugs. Additionally, the fall-related hip fractures of community dwellers with poorest health and function tended to occur indoors during positional changes. In study IV, all categories of disease (according to the International Classification of Diseases, 10th Revision) were seen to be positively associated with hip fracture. Cardiovascular disease and previous injury (including previous fracture) posed the highest relative and absolute fracture risks.Detailed investigation of hip fracture circumstances reveal patterns in health and functional characteristics, which provide information regarding predisposing and precipitating factors for these events. This knowledge, in combination with findings regarding PA perceptions, can be used when identifying individuals at high risk for hip fracture and when tailoring fracture prevention at an individual level to those at risk.
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| 7. |
- Lundmark, Per Erik, 1976-
(författare)
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Genetic and Genomic Analysis of DNA Sequence Variation
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The studies in this thesis describe the application of genotyping and allele specific expression analysis to genetic studies. The role of the gene NPC1 in Triglyceride metabolism was explored in mouse models and in humans on the population level in study I. NPC1 was found to affect hepatic triglyceride metabolism, and to be relevant for controlling serum triglyceride levels in mice and potentially in humans. In study II the utility of the HapMap CEU samples was investigated for tagSNP selection in six European populations. The HapMap CEU was found to be representative for tagSNP selection in all populations while allele frequencies differed significantly in the sample from Kuusamo, Finland. In study III the power of Allele specific expression as a tool for the mapping of cis-regulatory variation was compared to standard eQTL analysis, ASE was found to be the more powerful type of analysis for a similar sample size. Finally ASE mapping was applied to regions reported to harbour long non-coding RNAs and associated SNPs were compared to published trait-associations. This revealed strong cis-regulatory SNPs of long non-coding RNAs with reported trait or disease associations.
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| 8. |
- Snellman, Greta, 1978-
(författare)
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Boning up on Vitamin D : Observational Studies on Bone and Health
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The primary function of vitamin D in humans is to maintain sufficient circulating calcium concentrations. Low vitamin D levels could result in excessive calcium resorption from bone. Vitamin deficiency may therefore decrease bone mineral density (BMD), resulting in an increased risk of fracture. This thesis sought to determine the association between vitamin D intake and bone health and to estimate circulating levels of vitamin D optimal for bone health without increasing the risk for non-bone disease. Furthermore, the thesis assessed the difference in performance between common serum vitamin D assays and the genetic influence of vitamin D status. In prospective population-based cohorts, blood concentrations <40 nmol/L (lowest 5%) increased the risk of fracture in elderly men. Low levels were further associated with a slight decrease in lumbar spine BMD. Both high (>98 nmol/L) and low (<46 nmol/L) vitamin D levels were associated with higher cancer and overall mortality. In another cohort, also of older men and women, no association was found between vitamin D levels and fracture. Low vitamin D levels were weakly associated with decreased total body BMD in men but not in women. Dietary intake of vitamin D over a 20-year period in more than 60,000 Swedish women was not associated with osteoporosis or fracture, regardless of calcium intake. During summer, dietary vitamin D intake and other life style habits are of minor importance for the variation in vitamin D levels relative to sun exposure and genes. In summer time, genes explain about half of the variation in vitamin D levels, but none of the variance in winter time. The variability between vitamin D assays was substantial. Three assays classified 8, 22 and 43% of the same study population as vitamin D insufficient if <50 nmol/L was set as the insufficiency level. Based on the results in this thesis, low 25(OH)D levels and low dietary vitamin D intake are not a major cause of fractures in community-dwelling elderly Swedish women and men. Differences in assay performance and potential negative health outcomes of high 25(OH)D levels need to be considered.
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| 9. |
- Sundström, Johan, Professor, 1971-, et al.
(författare)
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Risk factors for subarachnoid haemorrhage : a nationwide cohort of 950 000 adults
- 2019
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 48:6, s. 2018-2025
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Subarachnoid haemorrhage (SAH) is a devastating disease, with high mortality rate and substantial disability among survivors. Its causes are poorly understood. We aimed to investigate risk factors for SAH using a novel nationwide cohort consortium.METHODS: We obtained individual participant data of 949 683 persons (330 334 women) between 25 and 90 years old, with no history of SAH at baseline, from 21 population-based cohorts. Outcomes were obtained from the Swedish Patient and Causes of Death Registries.RESULTS: During 13 704 959 person-years of follow-up, 2659 cases of first-ever fatal or non-fatal SAH occurred, with an age-standardized incidence rate of 9.0 [95% confidence interval (CI) (7.4-10.6)/100 000 person-years] in men and 13.8 [(11.4-16.2)/100 000 person-years] in women. The incidence rate increased exponentially with higher age. In multivariable-adjusted Poisson models, marked sex interactions for current smoking and body mass index (BMI) were observed. Current smoking conferred a rate ratio (RR) of 2.24 (95% CI 1.95-2.57) in women and 1.62 (1.47-1.79) in men. One standard deviation higher BMI was associated with an RR of 0.86 (0.81-0.92) in women and 1.02 (0.96-1.08) in men. Higher blood pressure and lower education level were also associated with higher risk of SAH.CONCLUSIONS: The risk of SAH is 45% higher in women than in men, with substantial sex differences in risk factor strengths. In particular, a markedly stronger adverse effect of smoking in women may motivate targeted public health initiatives.
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| 10. |
- Titova, Olga E., et al.
(författare)
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Comprehensive analyses of circulating cardiometabolic proteins and objective measures of fat mass
- 2023
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Ingår i: International Journal of Obesity. - : Springer Nature. - 1476-5497 .- 0307-0565. ; 47:11, s. 1043-1049
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Tidskriftsartikel (refereegranskat)abstract
- Background: The underlying molecular pathways for the effect of excess fat mass on cardiometabolic diseases is not well understood. Since body mass index is a suboptimal measure of body fat content, we investigated the relationship of fat mass measured by dual-energy X-ray absorptiometry with circulating cardiometabolic proteins. Methods: We used data from a population-based cohort of 4950 Swedish women (55–85 years), divided into discovery and replication samples; 276 proteins were assessed with three Olink Proseek Multiplex panels. We used random forest to identify the most relevant biomarker candidates related to fat mass index (FMI), multivariable linear regression to further investigate the associations between FMI characteristics and circulating proteins adjusted for potential confounders, and principal component analysis (PCA) for the detection of common covariance patterns among the proteins. Results: Total FMI was associated with 66 proteins following adjustment for multiple testing in discovery and replication multivariable analyses. Five proteins not previously associated with body size were associated with either lower FMI (calsyntenin-2 (CLSTN2), kallikrein-10 (KLK10)), or higher FMI (scavenger receptor cysteine-rich domain-containing group B protein (SSC4D), trem-like transcript 2 protein (TLT-2), and interleukin-6 receptor subunit alpha (IL-6RA)). PCA provided an efficient summary of the main variation in FMI-related circulating proteins involved in glucose and lipid metabolism, appetite regulation, adipocyte differentiation, immune response and inflammation. Similar patterns were observed for regional fat mass measures. Conclusions: This is the first large study showing associations between fat mass and circulating cardiometabolic proteins. Proteins not previously linked to body size are implicated in modulation of postsynaptic signals, inflammation, and carcinogenesis.
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| 11. |
- Zheng, Rui, 1990-
(författare)
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Metabolomics, body composition and fracture
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, I evaluated the impact of pre-centrifugation sample management on the plasma metabolome, providing verification for the protocol used in a study where I applied metabolomics to better understand the role of body composition in fracture occurrence using a large population-based cohort. In paper 1, I applied untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis to plasma samples (n = 471) from healthy donors to predict and evaluate the effect of pre-centrifugation temperature and delay time on metabolomics data using a combination of random forest and generalized linear models. I found that delayed treatment (up to 210 min) of blood samples can induce variation to the plasma metabolome at all three temperatures (4, 25 and 37 °C) and thus blood samples should be managed as expediently as possible, preferably at room temperature. Metabolite panels were constructed and validated to predict the pre-centrifugation management conditions of plasma samples.In paper 2, I used a full cohort of men and women (n = 44,366), and a subcohort of women (n = 5022) to investigate the associations between anthropometrics or body composition and fracture risk. I found that lower body mass index (BMI), prior loss of BMI and higher central obesity were associated with increased risks of fracture. The joint analysis revealed that prior gain of BMI was protective against fracture only in individuals with normal weight. The associations between lean mass index (LMI) or fat mass index (FMI) and fracture risk were heavily dependent on bone mineral density (BMD) in the study population. Based on findings of paper 2, a metabolome-wide association of LMI, FMI and BMD was conducted in the subcohort. Metabolites associated with at least one body composition outcome were then associated with hip fracture risk, resulting in the discovery of twenty-three metabolites of interest. Network analysis of these hip fracture-related metabolites highlighted the important role of lysoglycerophospholipids in the skeletomuscular-adipose crosstalk. Mendelian randomization analyses suggested several causal associations between these hip fracture-related metabolites and body composition measures or bone-related clinical biomarkers.In summary, metabolites can reflect perturbations induced by pre-centrifugation management of samples and thus provide valuable information of sample quality. To optimally prevent fractures at older age, low BMI, prior BMI loss and central obesity should be avoided. Metabolites reflecting differences in, and crosstalk of skeletomuscular-adipose tissues may contribute to a further understanding of fracture occurrence and discoveries of actionable targets for prevention.
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| 12. |
- Blomberg, Hans, 1963-
(författare)
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Influence of The Education and Training of Prehospital Medical Crews on Measures of Performance and Patient Outcomes
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prehospital care has developed dramatically the last decades with the implementation of new devices and educational concepts. Clinical decisions and treatments have moved out from the hospitals to the prehospital setting. In Sweden this has been accompanied by an increase in the level of competence, i.e. by introducing nurses in the ambulances. With some exceptions the scientific support for these changes is poor.This thesis deals with such changes in three different subsets of prehospital care: Cardiopulmonary resuscitation (CPR), the stroke chain of survival and trauma care.We assessed the performance of ambulance crews during CPR, using a mechanical compression device, as compared to CPR using manual compressions. There was a strikingly poor quality of compressions using the mechanical device compared to CPR with manual compressions. The result calls for caution when implementing a chest compression device in clinical practice and reinforce the importance of randomised controlled trials to evaluate new interventions. Careful attention should be given to the assurance of correct application of the device. Further implementation without evaluation of the quality of mechanical compressions in a clinical setting is discouraged.Among patients with a prehospital suspicion of stroke we analysed the ambulance nurses’ ability to select the correct patient subset eligible for a CT scan as a preparation for potential thrombolysis. The results do not support an implementation of a bypass of the emergency department, using ambulance nurse competence to select patients eligible and suitable for a CT scan without a preceding assessment by a physician.The association between the Prehospital Trauma Life Support (PHTLS) course and the outcome in victims of trauma was analysed in two observational studies. A study covering one county gave some support for a protective effect from PHTLS, but the estimate had a low precision. A nationwide study, covering all of Sweden, could not confirm those results. Although there was a reduction in mortality over time coinciding with the implementation of PHTLS, it did not appear to be associated with the implementation of PHTLS. Thus, we could not detect any clear beneficial impact of the PHTLS course on the outcome of trauma patients.
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| 13. |
- Brüggemann, Anders
(författare)
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Hip Revision Surgery : Identification of Genetic Markers and Evaluation of Novel Treatment Strategies
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Total hip arthroplasty (THA) is, despite its overall good outcome, for some patients followed by hip revision surgery. This seems in parts to be because of genetic susceptibility to revision surgery. The most common reason for revision surgery is aseptic loosening followed by periprosthetic joint infection and dislocation. Cups made of porous tantalum (TM cups) were thought to be favorable in revision surgery to address aseptic loosening, but they seem to confer an increased risk of dislocation. The effectiveness and biocompatibility in vivo of TM cups have not been researched. Dual mobility cups (DMCs) with two articulating surfaces are proposed to prevent dislocation to a higher degree than standard polyethylene liners.Our hypotheses were that TM cups are superior to their historical treatment alternative in terms of re-revision rates; that the combination of DMC cemented into TM cups would decrease the risk for dislocation after revision surgery; that tantalum ion liberation is marginal after the use of TM cups; and that certain risk genes are associated with an increased risk for revision surgery after total joint arthroplasty.Studies I&II were register-based cohort studies comparing the implant survival of TM cups and conventional acetabular reinforcement rings (study I), and the combination of TM cups/DMC with TM cups/standard polyethylene liners (study II). We found that TM cups perform equally well as reinforcement rings, but that the two implants differ in their failure mechanisms. Cementing a DMC into TM cups adequately addressed the issue of recurrent dislocation. In study III we investigated whether tantalum ion liberation does occur after implantation of a TM cups and how this affects patients’ immunological response by comparison of three groups: primary non-tantalum THA, primary tantalum THA and revision tantalum THA. We found the highest concentration of tantalum ions in the revision cases, yet tantalum ions were not associated with an immunological response, and we found no signs of alteration in the investigated lymphocyte subsets. Study IV aimed to identify possible risk genes for revision surgery after total hip or knee replacement by a genome wide association study. We found six significant risk genes for the endpoint revision surgery for any reason, and three for the endpoint revision due to aseptic loosening. We found a variety of suggestive risk genes within the region coding for the ABO-system.In conclusion, the novel treatment options TM cups and DMC show good results in hip revision surgery, but longer follow-up is warranted. The use of porous tantalum seems not to be associated with the immunological activation that can be observed in metallosis. The risk for revision surgery is associated with certain risk genes.
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| 14. |
- Byberg, Liisa, et al.
(författare)
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Total mortality after changes in leisure time physical activity in 50 year old men : 35 year follow-up of population based cohort
- 2009
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 338, s. b688-
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To examine how change in level of physical activity after middle age influences mortality and to compare it with the effect of smoking cessation.Design: Population based cohort study with follow-up over 35 years.Setting: Municipality of Uppsala, Sweden.Participants: 2205 men aged 50 in 1970-3 who were reexamined at ages 60, 70, 77, and 82 years.Main Outcome Measure: Total (all cause) mortality.Results: The absolute mortality rate was 27.1, 23.6, and 18.4 per 1000 person years in the groups with low, medium, and high physical activity, respectively. The relative rate reduction attributable to high physical activity was 32% for low and 22% for medium physical activity. Men who increased their physical activity level between the ages of 50 and 60 continued to have a higher mortality rate during the first five years of follow-up (adjusted hazard ratio 2.64, 95% confidence interval 1.32 to 5.27, compared with unchanged high physical activity). After 10 years of follow-up their increased physical activity was associated with reduced mortality to the level of men with unchanged high physical activity (1.10, 0.87 to 1.38). The reduction in mortality associated with increased physical activity (0.51, 0.26 to 0.97, compared with unchanged low physical activity) was similar to that associated with smoking cessation (0.64, 0.53 to 0.78, compared with continued smoking).Conclusions: Increased physical activity in middle age is eventually followed by a reduction in mortality to the same level as seen among men with constantly high physical activity. This reduction is comparable with that associated with smoking cessation
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| 15. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 16. |
- Hellström, Hans-Olov, 1962-
(författare)
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Bone and Aluminium
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Osteoporosis is a major health care problem, by reason of its devastating consequences, in particular hip fractures. Worldwide it has been estimated that the incidence of hip fracture will increase to more than 6 million per year by 2050 compared to 1.7 million per year in 1990. Osteoporosis can be caused by various factors namely, genetic, lifestyle and environmental factors, and since the rising incidence of its consequences is not fully explained by the growing age of the population, there is an urgent need to identify individual causal factors of this condition. The present research has focused on aluminium, one potential environmental factor of importance for bone disease, and its possible relation to osteoporosis, since it is known to cause osteoporosis-like bone disease and has been associated with induction of progressive central nervous system diseases.Aluminium is the third most common element in the earth’s crust and the most abundant metal (8%). It is widely utilized industrially and it is also naturally present in many foods. Although aluminium is ubiquitous in the human environment, evolution has not given it an essential biological function.The aluminium content of bone was measured by inductively coupled mass spectrometry in a large group of patients suffering from hip fractures, high energy fractures and osteoarthrosis. An exponential increase in aluminium content of bone with age was found (p=0.0004). However, no significant association of aluminium in bone with occurrence of hip fracture or dementia could be found, and no indirect evidence was obtained, e.g. through bone mineral density or biomechanical properties, that aluminium is involved in the pathogenesis of osteoporosis. Although we accumulate aluminium in bone throughout our lives, and there are experimental suggestions that aluminium induces premature cell death, the body content of this metal does not seem to influence the overall mortality risk.
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| 17. |
- Laszkowska, M., et al.
(författare)
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Systematic review with meta-analysis : the prevalence of coeliac disease in patients with osteoporosis
- 2018
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Ingår i: Alimentary Pharmacology and Therapeutics. - : Blackwell Publishing. - 0269-2813 .- 1365-2036. ; 48:6, s. 590-597
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Forskningsöversikt (refereegranskat)abstract
- Background: Earlier studies have produced highly varying risk estimates for the prevalence of coeliac disease (CD) in osteoporosis.Aims: To investigate the prevalence of CD among individuals with osteoporosis.Methods: We conducted a systematic review of articles published in PubMed, Medline or EMBASE through May 2017 to identify studies looking at prevalence of CD in patients with osteoporosis. Search terms included "coeliac disease" combined with fractures, bone disease, bone density, densitometry, "osteoporos", "osteomal", "osteodys" or "dexa" or "dxa" or "skelet". Non-English papers with English-language abstracts were included. We used fixed-effects inverse variance-weighted models, and tested heterogeneity through subgroup analysis as well as through meta-regression.Results: We identified eight relevant studies, comprising data from 3188 individuals with osteoporosis. Of these, 59 individuals (1.9%) had CD. A weighted pooled analysis demonstrated biopsy-confirmed CD in 1.6% (95% CI=1.1%-2.0%) of individuals with osteoporosis. The heterogeneity was moderate (I-2=40.1%), and influenced by the underlying CD prevalence in the general population. After adding four studies (n=814) with CD defined as positive tissue transglutaminase or endomysial antibodies, the pooled prevalence was comparable (1.6%; 95% CI=1.2%-2.0%).Conclusions: About 1 in 62 individuals with osteoporosis, or 1.6%, have biopsy-verified CD. This prevalence is comparable to that in the general population. These findings argue against routinely screening patients with osteoporosis for CD, which is contrary to current guideline recommendations. Additional studies are needed to determine the true utility of such screening programs.
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| 18. |
- Lind, Lars, et al.
(författare)
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On the association between body fat and left ventricular mass
- 2019
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Ingår i: Journal of Hypertension. - 0263-6352 .- 1473-5598. ; 37:8, s. 1699-1704
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: As intervention studies have shown a reduction in body weight to be paralleled with a reduction in left ventricular mass (LVM), we quantified a hypothesized causal relationship between fat mass and LVM, and how much of these effects that was mediated by blood pressure (BP), diabetes and adipokines. Also visceral and subcutaneous adipose tissue (VAT and SAT) were explored in the same fashion.Methods: In the Prospective Study of the Vasculature in Uppsala Seniors study (n = 1016, 50% women, all aged 70 years), LVM was measured by echocardiography (indexed for lean mass, LVMI), fat and lean mass by dual-energy X-ray. VAT and SAT were measured by abdominal MRI (in n = 275).Results: In a structural equation model adjusting for sex, the total effect of fat mass on LVMI was large (standardized coefficient 0.280, P = 3.2 × 10−15, 95% confidence interval 0.210–0.349). Out of the total effect of fat mass on LVMI, 29.0% was mediated by BP and glucose (P = 2.4 × 10−12). The BP pathway was most important, mediating 24.4% of the total effect of fat mass on LVMI (P = 4.6 × 10−7), while the glucose pathway accounted for 4.6% (P = 0.033). The association of VAT with LVMI (0.202, P = 2.4 × 10−4) was slightly weaker than that of SAT with LVMI (0.283, P = 1.0 × 10−6). Of several measured adipokines, leptin was a significant mediator of the effect of fat mass on LVMI (P = 3.0 × 10−3).Conclusion: One-third of the hypothesized association between body fat and LVMI was mediated by BP and glucose in this population-based cohort. Leptin was also an important mediator. Visceral adipose tissue was not more closely related to LVMI than subcutaneous abdominal fat.
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| 19. |
- Lind, Lars, et al.
(författare)
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Plasma Protein Profiling of Incident Cardiovascular Diseases : A Multisample Evaluation
- 2023
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Ingår i: CIRCULATION-GENOMIC AND PRECISION MEDICINE. - : Wolters Kluwer. - 2574-8300. ; 16:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Proteomic profiling could potentially disclose new pathophysiological pathways for cardiovascular diseases (CVD) and improve prediction at the individual level. We therefore aimed to study the plasma protein profile associated with the incidence of different CVDs.METHODS: Plasma levels of 245 proteins suspected to be linked to CVD or metabolism were measured in 4 Swedish prospective population-based cohorts (SIMPLER [Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research], ULSAM (Uppsala Longitudinal Study of Adult Men), EpiHealth, and POEM [Prospective Investigation of Obesity, Energy Production, and Metabolism]) comprising 11 869 individuals, free of CVD diagnoses at baseline. Our primary CVD outcome was defined by a combined end point that included either incident myocardial infarction, stroke, or heart failure.RESULTS: Using a discovery/validation approach, 42 proteins were associated with our primary composite end point occurring in 1163 subjects. In separate meta-analyses for each of the 3 CVD outcomes, 49 proteins were related to myocardial infarction, 34 to ischemic stroke, and 109 to heart failure. Thirteen proteins were related to all 3 outcomes. Of those, urokinase plasminogen activator surface receptor, adrenomedullin, and KIM-1 (kidney injury molecule 1) were also related to several markers of subclinical CVD in Prospective Investigation of Obesity, Energy production and Metabolism, reflecting myocardial or arterial pathologies. In prediction analysis, a lasso selection of 11 proteins in ULSAM improved the discrimination of CVD by 3.3% (P<0.0001) in SIMPLER when added to traditional risk factors.CONCLUSIONS: Protein profiling in multiple samples disclosed several new proteins to be associated with subsequent myocardial infarction, stroke, and heart failure, suggesting common pathophysiological pathways for these diseases. KIM-1, urokinase plasminogen activator surface receptor, and adrenomedullin were novel early markers of CVD. A selection of 11 proteins improved the discrimination of CVD.
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| 20. |
- Ludvigsson, Jonas F., 1969-, et al.
(författare)
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Adaptation of the Charlson Comorbidity Index for Register-Based Research in Sweden
- 2021
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Ingår i: Clinical Epidemiology. - : Dove Medical Press Ltd.. - 1179-1349. ; 13, s. 21-41
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Comorbidity indices are often used to measure comorbidities in register-based research. We aimed to adapt the Charlson comorbidity index (CCI) to a Swedish setting.Methods: Four versions of the CCI were compared and evaluated by disease-specific experts.Results: We created a cohesive coding system for CCI to 1) harmonize the content between different international classification of disease codes (ICD-7,8,9,10), 2) delete incorrect codes, 3) enhance the distinction between mild, moderate or severe disease (and between diabetes with and without end-organ damage), 4) minimize duplication of codes, and 5) briefly explain the meaning of individual codes in writing.Conclusion: This work may provide an integrated and efficient coding algorithm for CCI to be used in medical register-based research in Sweden.
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| 21. |
- Mitchell, Adam
(författare)
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Insights into the Effects of Type 2 Diabetes on Bone Health
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of hip fracture, despite a stable or even greater bone mineral density (BMD). Bone area is linked to hip fracture risk independent of BMD and smaller bone area has been reported in T2DM subjects at the radius and tibia, but information at the hip is lacking. The Mediterranean diet is associated with a lower risk of hip fracture yet the mechanisms are unclear. The diet’s effect on T2DM status may be a possible mechanism. This thesis aims to discern the effects fasting glucose levels and T2DM have on bone.In paper I, clinical cut offs of fasting glucose used to define T2DM, were used to explore the association with BMD, bone area and bone turnover markers in the Swedish mammography cohort clinical (SMCC) and the Uppsala longitudinal study of adult men (ULSAM). T2DM was associated with greater BMD yet lower bone area at the total hip when compared to those without T2DM. T2DM was also associated with lower levels of bone turnover markers.In paper II, a Mendelian randomisation (MR) study was used to assess the potential causal effects of genetically predicted fasting glucose concentrations on bone area and BMD in partici-pants from SMCC, the prospective investigation in the vasculature of Uppsala seniors (PIVUS) and ULSAM. Results suggest an increase in genetically predicted fasting glucose concentrations may be a causal risk factor for lower bone area and possibly greater BMD.In paper III, the association between T2DM status and change in bone area and BMD over 8 years, was analysed in the SMCC, PIVUS and ULSAM. Those with incident T2DM had a lesser expansion in bone area at the total hip compared to those without T2DM.In paper IV, causal inference mediation analyses were used to estimate the direct effect of Mediterranean diet on the risk of hip fracture and the possible mediating effects of T2DM and BMI in the Swedish mammography cohort (SMC) and the cohort of Swedish men (COSM). Results showed a direct effect of the Mediterranean diet on the risk of hip fracture but ruled out the effects of T2DM and BMI as major mediators.In summary, T2DM and fasting glucose were associated with lower bone area at the hip. This may provide important mechanistic evidence as to why those with T2DM have a greater risk of hip fracture. We cannot rule out mediation or counteracting effects but there is an effect of Medi-terranean diet on hip fracture that does not go through T2DM and BMI.
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| 22. |
- Östman, Bengt, 1953-
(författare)
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Influence of Oxidative Stress on Muscle and Bone
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Reactive oxygen species (ROS) induce oxidative stress and although are primarily recognized for playing a deleterious biological role, they can be beneficial to cell systems. ROS are extremely short-lived and normally tightly regulated by antioxidant defence systems. Cells react to oxidative stress in different ways, which primarily depends on cell type, stress severity, or both. There is a general limitation in extrapolating to humans conclusions drawn from in vitro and animal studies because of important species-specific differences. Therefore, the general aim of this thesis was to study the influence of oxidative stress on human muscle and bone in vivo. In paper I we presented a one-step HPLC method optimized for the simultaneous determination of purine degradation products in small microdialysis samples. The clinical utility of the method was successfully tested in a patient with traumatic brain injury. In paper II we evaluated microdialysis as an in vivo method to characterize the relative kinetics of ROS-related metabolites in human skeletal muscle exposed to ischaemia-reperfusion. Results indicated that microdialysis was feasible and safe to use in monitoring metabolic events during tourniquet-assisted surgery. In paper III we investigated the association between an oxidative stress marker (urinary 8-iso-PGF2α) and bone mineral density (BMD) and whether α-tocopherol modified the association. The main finding was the negative association between 8-iso-PGF2α and BMD and that the association was further dependent on serum α-tocopherol level. In paper IV we performed a randomized controlled trial to evaluate the influence of Q10 supplementation on exercise performance and metabolites of muscular damage. We did not observe any effects on exercise capacity after 8 weeks of Q10 administration. Nor did we find a significant effect on serum markers related to oxidative stress. In conclusion we have studied the influence of oxidative stress on muscle and bone in vivo in humans. The oxidative stress was triggered by four different causes (trauma, ischemia-reperfusion, ageing, and exercise exhaustion).
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