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  • 251. Heyde, Christoph-E.
    et al.
    Fakler, Johannes K.
    Hasenboehler, Erik
    Stahel, Philip F.
    John, Thilo
    Robinson, Yohan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Tschoeke, Sven K.
    Kayser, Ralph
    Pitfalls and complications in the treatment of cervical spine fractures in patients with ankylosing spondylitis2008In: Patient safety in surgery, ISSN 1754-9493, Vol. 2, p. 15-Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: Patients with ankylosing spondylitis are at significant risk for sustaining cervical spine injuries following trauma predisposed by kyphosis, stiffness and osteoporotic bone quality of the spine. The risk of sustaining neurological deficits in this patient population is higher than average. The present review article provides an outline on the specific injury patterns in the cervical spine, diagnostic algorithms and specific treatment modalities dictated by the underlying disease in patients with ankylosing spondylitis. An emphasis is placed on the risks and complication patterns in the treatment of these rare, but challenging injuries.

  • 252.
    Heyde, Christoph-E.
    et al.
    Universitätsklinikum Leipzig AöR, Klinik u. Poliklinik für Orthopädie, Unfallchirurgie u. Plastische Chirurgie, Bereich Wirbelsäulenchirurgie.
    Robinson, Yohan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Deszöe, Jeszenszky
    Wirbelsäulenchirurgie, Schulthess Klinik Zürich, Lengghalde 2, CH-8808 Zürich, Schweiz.
    Ätiologie und Pathogenese der Spondylodiszitis2017In: Die Wirbelsäule, ISSN 2509-8241, Vol. 01, no 04, p. 237-244Article in journal (Refereed)
    Abstract [en]

    The prevalence of both nonspecific „pyogenic“ and specific spondylodiscitides, for several reasons, increases. These diseases are still associated with relevant morbidity and mortality and are often diagnosed late because of the unspecific clinical manifestation. Knowledge of the epidemiology, etiology and pathogenesis of the different forms of spondylodiscitis can facilitate early diagnosis and subsequent therapy with special regard to early begin of that therapy. This article discusses the epidemiological data and key aspects of the etiology and pathogenesis of nonspecific pyogenic spondylodiscitis, as well as the various forms of specific spondylodiscitis in tuberculosis, brucellosis and fungal infections.

  • 253.
    Heyde, Christoph-E.
    et al.
    Klinik und Poliklinik für Orthopädische Chirurgie der Universität Leipzig.
    Tschöke, Sven-Kevin
    Klinik und Poliklinik für Orthopädische Chirurgie der Universität Leipzig.
    Robinson, Yohan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kayser, Ralph
    Klinik und Poliklinik für Orthopaedie und Orthopädische Chirurgie des Klinikums Greifswald.
    Kyphoplastie: Indikation und praktische Durchführung2012In: Internistische Praxis, ISSN 0020-9570, Vol. 52, no 3, p. 561-572Article in journal (Refereed)
  • 254. Heyde, Christoph-Eckhard
    et al.
    Tschöke, Sven-Kevin
    Robinson, Yohan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kayser, Ralph
    Kyphoplastie: Indikation und Durchführung2013In: Chirurgische Praxis, ISSN 0009-4846, Vol. 76, no 1, p. 63-74Article in journal (Refereed)
    Abstract [en]

    The minimally invasive procedure of kyphoplasty has become an established method of treatment in both osteoporotic compression fractures and malignant osteolytic lesions of the spine. In cautious consideration of the correct indication and technical implementation, kyphoplasty is a safe procedure with low risk of complications. In comparison to conservative treatment regimens, postoperative clinical outcome parameters have shown promising results in pain reduction and the improvement of function and quality of life in both short-term and mid-term evaluations. However, kyphoplasty as a surgical procedure shall always be considered a component within the overall therapeutic concept. Thus, a comprehensive medical attendance and the consistent treatment of the underlying disease are essential to a successful therapeutic outcome.

  • 255. Heyde, Christoph-Eckhard
    et al.
    Tschöke, Sven-Kevin
    Robinson, Yohan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kayser, Ralph
    Kyphoplastie: Indikation und praktische Durchführung. [Kyphoplasty. Indication and practical guidelines]2012In: Tägliche Praxis, ISSN 0494-464X, Vol. 53, no 4, p. 799-810Article in journal (Refereed)
    Abstract [en]

    The minimally invasive procedure of kyphoplasty has become an established method of treatment in both osteoporotic compression fractures and malignant osteolytic lesions of the spine. In cautious consideration of the correct indication and technical implementation, kyphoplasty is a safe procedure with low risk of complications. In comparison to conservative treatment regimens, postoperative clinical outcome parameters have shown promising results in pain reduction and the improvement of function and quality of life in both short-term and mid-term evaluations. However, kyphoplasty as a surgical procedure shall always be considered a component within the overall therapeutic concept. Thus, a comprehensive medical attendance and the consistent treatment of the underlying disease are essential to a successful therapeutic outcome.

  • 256. Hindy, George
    et al.
    Engström, Gunnar
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Traylor, Matthew
    Markus, Hugh S
    Melander, Olle
    Orho-Melander, Marju
    Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study2018In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 49, no 4, p. 820-827Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR).

    METHODS: Summary data on 185 genome-wide lipids-associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance-weighted MR was used to obtain the causal estimates. Inverse-variance-weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias.

    RESULTS: A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04-1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10-1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67-0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes.

    CONCLUSIONS: LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes.

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  • 257.
    Hirasawa, Atsuhiko
    et al.
    Aichi Med Univ, Dept Spine Ctr, Nagakute, Aichi, Japan; Aichi Med Univ, Dept Orthopaed Surg, Nagakute, Aichi, Japan.
    Robinson, Yohan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Olerud, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wakao, Norimitsu
    Aichi Med Univ, Dept Spine Ctr, Nagakute, Aichi, Japan.
    Kamiya, Mitsuhiro
    Aichi Med Univ, Dept Spine Ctr, Nagakute, Aichi, Japan; Aichi Med Univ, Dept Orthopaed Surg, Nagakute, Aichi, Japan.
    Murotani, Kenta
    Aichi Med Univ, Div Biostat, Clin Res Ctr, Nagakute, Aichi, Japan.
    Deie, Masataka
    Aichi Med Univ, Dept Orthopaed Surg, Nagakute, Aichi, Japan.
    Regional Differences in Diffuse Idiopathic Skeletal Hyperostosis: A Retrospective Cohort Study from Sweden and Japan2018In: Spine, ISSN 0362-2436, E-ISSN 1528-1159, Vol. 43, no 24, p. E1474-E1478Article in journal (Refereed)
    Abstract [en]

    Study Design: We retrospectively reviewed computed tomography (CT) records of patients in Japan and Sweden, which are both aging populations. Objective. To research the influence of ethnicity and region on diffuse idiopathic skeletal hyperostosis (DISH) prevalence.

    Summary of Background Data_ DISH can complicate nonsurgical treatment of spinal fractures and often requires surgical intervention. We previously reported a prevalence of DISH in Japan that was higher than that reported in other studies.

    Methods: We retrospectively reviewed CT records of patients in Japan and Sweden, which have both aging populations. Patients undergoing whole body CT during trauma examinations at an acute outpatient clinic in Uppsala University Hospital in a 1-year period were eligible for inclusion. Excluded were those less than 40 and more than or equal to 90 years old, and those with previous spinal surgery. The prevalence of DISH by sex and age was determined according to radiographic criteria by Resnick. Results from Sweden were compared with the Japan data, which we previously reported.

    Results: Age of the eligible subjects (265 men and 153 women) ranged from 40 to 89 years, with a mean age of 63.4 years. Among men, 86 (32.5%) were diagnosed with DISH, and the results by age (40s, 50s, 60s, 70s, and 80s) were: 6 (10.7%), 13 (22%), 35 (46.1%), 17 (34%), and 15 (62.5%) patients, respectively. Among women, 16 (10.5%) had DISH, and the results by age were as follows: 1 (2.6%), 1 (3.3%), 2 (6.7%), 6 (22.2%), and 6 (22.2%) patients, respectively. These results did not differ from those previously published for Japan (Fisher exact test, men: P = 1, 0.27, 0.12, 0.06, and 1, respectively; women: P = 0.49, 0.62, 0.5, 0.8, and 0.3, respectively).

    Conclusion: The presented cohort study revealed that ethnicity and region may not be notable factors of DISH prevalence, since patients from both Japan and Sweden had similar DISH prevalence.

    Level of Evidence: 3

  • 258. Hollberg, Karin
    et al.
    Marsell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Norgård, Maria
    Larsson, Tobias E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jonsson, Kenneth B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Andersson, Göran
    Osteoclast polarization is not required for degradation of bone matrix in rachitic FGF23 transgenic mice2008In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 42, no 6, p. 1111-1121Article in journal (Refereed)
    Abstract [en]

    Hypophosphatemic transgenic (tg) mice overexpressing FGF23 in osteoblasts display disorganized growth plates and reduced bone mineral density characteristic of rickets/osteomalacia. These FGF23 tg mice were used as an in vivo model to examine the relation between osteoclast polarization, secretion of proteolytic enzymes and resorptive activity. Tg mice had increased mRNA expression levels of the ostcoblast differentiation marker Runx2 and mineralization-promoting proteins alkaline phosphatase and bone sialoprotein in the long bones compared to wild type (wt) mice. In contrast, expression of alpha 1 (1) collagen, osteocalcin, dentin matrix protein 1 and osteopontin was unchanged, indicating selective activation of osteoblasts promoting mineralization. The number of osteoclasts was unchanged in tg compared to wt mice, as determined by histomorphometry, serum levels of TRAP 5b activity as well as mRNA expression levels of TRAP and cathepsin K. However, tg mice displayed elevated serum concentrations of C-terminal telopeptide of collagen I (CTX) indicative of increased bone matrix degradation. The majority of osteoclasts in FGF23 tg mice lacked ultrastructural morphological signs of proper polarization. However, they secreted both cathepsin K and MMP-9 at levels comparable to osteoclasts with ruffled borders. Mineralization of bone matrix thus appears essential for inducing osteoclast polarization but not for secretion of osteoclast proteases. Finally, release of CTX by freshly isolated osteoclasts was increased on demineralized compared to mineralized bovine bone slices, indicating that the mineral component limits collagen degradation. We conclude that ruffled borders are implicated in acidification and subsequent demineralization of the bone matrix, however not required for matrix degradation. The data collectively provide evidence that osteoclasts, despite absence of ruffled borders, effectively participate in the degradation of hypomineralized bone matrix in rachitic FGF23 tg mice.

  • 259. Holvik, K
    et al.
    Gjesdal, C G
    Tell, G S
    Grimnes, G
    Schei, B
    Apalset, E M
    Samuelsen, S O
    Blomhoff, R
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Meyer, H E
    Low serum concentrations of alpha-tocopherol are associated with increased risk of hip fracture: A NOREPOS study2014In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 25, no 11, p. 2545-2554Article in journal (Refereed)
    Abstract [en]

    We investigated the risk of hip fracture according to circulating alpha-tocopherol, a plant-derived substance with antioxidant properties, in community-dwelling older Norwegians. We found a linear increasing risk of hip fracture with lower serum alpha-tocopherol concentrations, with a 51 % higher risk in the lowest compared to the highest quartile.

    INTRODUCTION:

    Oxidative stress is a suggested contributing cause of osteoporosis and fractures. Vitamin E (α-tocopherol) has potent antioxidant properties in humans. The relationship between circulating α-tocopherol and fracture risk is not established. The aim of this study was to investigate the association between serum α-tocopherol concentrations and risk of hip fracture during up to 11 years of follow-up.

    METHODS:

    We performed a case-cohort analysis among 21,774 men and women aged 65-79 years who participated in four community-based health studies in Norway 1994-2001. Serum α-tocopherol concentrations at baseline were determined in 1,168 men and women who subsequently suffered hip fractures (median follow-up 8.2 years) and in a random sample (n = 1,434) from the same cohort. Cox proportional hazard regression adapted for gender-stratified case-cohort data was performed.

    RESULTS:

    Median (25, 75 percentile) serum α-tocopherol was 30.0 (22.6, 38.3) μmol/L, and it showed a linear inverse association with hip fracture: hazard ratio (HR) 1.11 (95 % confidence interval (CI) 1.04-1.20) per 10-μmol/L decrease in serum α-tocopherol, adjusted for gender and study center. The lowest compared to the highest quartile conferred an HR of 1.51 (95 % CI 1.17-1.95), adjusted for gender and study center. Adjustment for smoking, month of blood sample, BMI, education, physical inactivity, self-rated health, and serum 25-hydroxyvitamin D (25(OH)D) yielded similar results. Taking serum total cholesterol concentration into account attenuated the association somewhat: HR of hip fracture was 1.37 (95 % CI 1.05-1.77) in first versus fourth quartile of serum α-tocopherol/total cholesterol ratio.

    CONCLUSIONS:

    Low serum concentrations of α-tocopherol were associated with increased risk of hip fracture in older Norwegians.

  • 260. Hostmann, Arwed
    et al.
    Jasse, Kerstin
    Schulze-Tanzil, Gundula
    Robinson, Yohan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Oberholzer, Andreas
    Ertel, Wolfgang
    Tschoeke, Sven K
    Biphasic onset of splenic apoptosis following hemorrhagic shock: critical implications for Bax, Bcl-2, and Mcl-1 proteins2008In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 12, no 1, p. R8-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The innate immune response to trauma hemorrhage involves inflammatory mediators, thus promoting cellular dysfunction as well as cell death in diverse tissues. These effects ultimately bear the risk of post-traumatic complications such as organ dysfunction, multiple organ failure, or adult respiratory distress syndrome. In this study, a murine model of resuscitated hemorrhagic shock (HS) was used to determine the apoptosis in spleen as a marker of cellular injury and reduced immune functions. METHODS: Male C57BL-6 mice were subjected to sham operation or resuscitated HS. At t = 0 hours, t = 24 hours, and t = 72 hours, mice were euthanized and the spleens were removed and evaluated for apoptotic changes via DNA fragmentation, caspase activities, and activation of both extrinsic and intrinsic apoptotic pathways. Spleens from untreated mice were used as control samples. RESULTS: HS was associated with distinct lymphocytopenia as early as t = 0 hours after hemorrhage without regaining baseline levels within the consecutive 72 hours when compared with sham and control groups. A rapid activation of splenic apoptosis in HS mice was observed at t = 0 hours and t = 72 hours after hemorrhage and predominantly confirmed by increased DNA fragmentation, elevated caspase-3/7, caspase-8, and caspase-9 activities, and enhanced expression of intrinsic mitochondrial proteins. Accordingly, mitochondrial pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins were inversely expressed within the 72-hour observation period, thereby supporting significant pro-apoptotic changes. Solely at t = 24 hours, expression of the anti-apoptotic Mcl-1 protein shows a significant increase when compared with sham-operated and control animals. Furthermore, expression of extrinsic death receptors were only slightly increased. CONCLUSION: Our data suggest that HS induces apoptotic changes in spleen through a biphasic caspase-dependent mechanism and imply a detrimental imbalance of pro- and anti-apoptotic mitochondrial proteins Bax, Bcl-2, and Mcl-1, thereby promoting post-traumatic immunosuppression.

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  • 261. Hovelius, Lennart
    et al.
    Rahme, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Primary anterior dislocation of the shoulder: long-term prognosis at the age of 40 years or younger.2016In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 24, no 2, p. 330-42Article in journal (Refereed)
    Abstract [en]

    PURPOSE: We describe the long-term prognosis in 257 first-time anterior shoulder dislocations (255 patients, aged 12-40 years) registered at 27 Swedish emergency units between 1978 and 1979.

    METHODS: Half the shoulders were immobilised for 3-4 weeks after repositioning. Follow-ups were performed after two (questionnaire), five (questionnaire), 10 (questionnaire and radiology) and 25 (questionnaire and radiology) years in 227 patients (229 shoulders). Twenty-eight patients died during the 25 years of observation.

    RESULTS: Early movement or immobilisation after the primary dislocation resulted in the same long-term prognosis. Recurrences increased up to 10 years of follow-up, but, after 25 years, 29 % of the shoulders with ≥2 recurrences appeared to have stabilised over time. Arthropathy increased from 9 % moderate to severe and 11 % mild at 10 years, to 34 % moderate to severe and 27 % mild after 25 years. Alcoholics had a poorer prognosis with respect to dislocation arthropathy (P < 0.001). Age <25 years and/or bilateral instability represent a poorer prognosis, where stabilising surgery is necessary in every second shoulder. Fracture of the greater tuberosity means a good prognosis, and we have found no evidence that athletic activity, gender, a Hill-Sachs lesion and minor rim fractures had any prognostic impact. During the 25 years in which these patients were followed, 28/255 died (11 %), representing a mortality rate (SMR) that was more than double that of the general Swedish population (P < 0.001).

    CONCLUSION: Almost half of all first-time dislocations at the age of <25 years will have stabilising surgery and two-thirds will develop different stages of arthropathy within 25 years.

  • 262. Hovelius, Lennart
    et al.
    Sandström, Björn
    Olofsson, Anders
    Svensson, Olle
    Rahme, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    The effect of capsular repair, bone block healing, and position on the results of the Bristow-Latarjet procedure (study III): long-term follow-up in 319 shoulders2012In: Journal of shoulder and elbow surgery, ISSN 1058-2746, E-ISSN 1532-6500, Vol. 21, no 5, p. 647-660Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    We evaluated the results of the May modification of the Bristow-Latarjet procedure ("coracoid in standing position") in 319 shoulders with respect to (1) coracoid healing and position and (2) surgical treatment of the joint capsule.

    METHODS:

    From 1980 until 2004, all shoulders with a Bristow-Latarjet repair were registered at our hospital. This study consists of 3 different cohorts with respect to follow-up. Series 1, 118 shoulders operated on during 1980 through 1985, had 15 years' radiographic and clinical follow-up. Series 2, 167 shoulders that had surgery during 1986 through 1999, underwent retrospective follow-up by a questionnaire and scores-Western Ontario Shoulder Instability Index; Disabilities of the Arm, Shoulder and Hand; and Subjective Shoulder Value-after 10 to 23 years. Series 3, 34 shoulders treated during 2000 through 2004, with an added modified Bankart repair ("capsulopexy") in 33 shoulders, were prospectively followed up for 5 to 8 years with the same questionnaire and scores as series 2.

    RESULTS:

    Of 319 shoulders, 16 (5%) had 1 or more redislocations and 3 of these (1%) had revision surgery because of remaining instability. One or more subluxations were reported in 41 shoulders (13%). The worst scores were found in 16 shoulders with 2 or more subluxations (P < .001). Radiographs showed bony healing in 246 of 297 shoulders (83%), fibrous union in 34 (13%), migration by 0.5 cm or more in 14 (5%), and no visualization in 3 (1%). Five of six shoulders that had the transplant positioned 1 cm or more medial to the glenoid rim had redislocations (83%, P = .001). Shoulders with migrated transplants did not differ from those with bony or fibrous healing with respect to redislocations and subluxations. When just a horizontal capsular shift was added to the transfer, the recurrence rate (redislocations or subluxations) decreased, with 2 of 53 (4%)compared with 37 of 208 (18%) with just anatomic closure of the capsule (P = .005), and the Western Ontario Shoulder Instability Index score improved (92 vs 85.6, P = .048). In total, for 307 of 319 shoulders (96%), patients were satisfied or very satisfied at final follow-up.

    CONCLUSION:

    The open Bristow-Latarjet procedure yields good and consistent results, with bony fusion of the coracoid in 83%. A position of the coracoid 1 cm or more medial to the rim meant significantly more recurrences. The rate of recurrences decreased and subjective results improved when a horizontal capsular shift was added to the coracoid transfer.

  • 263. Hovelius, Lennart
    et al.
    Vikerfors, Ola
    Olofsson, Anders
    Svensson, Olle
    Rahme, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bristow-Latarjet and Bankart: a comparative study of shoulder stabilization in 185 shoulders during a seventeen-year follow-up2011In: Journal of shoulder and elbow surgery, ISSN 1058-2746, E-ISSN 1532-6500, Vol. 20, no 7, p. 1095-1101Article in journal (Refereed)
    Abstract [en]

    Background: In 2 Swedish hospitals, 88 consecutive shoulders underwent Bankart repair (B), and 97 consecutive shoulders underwent Bristow-Latarjet repair (B-L) for traumatic anterior recurrent instability.

    Materials and methods: Mean age at surgery was 28 years (B-L group) and 27 years (B group). All shoulders had a follow-up by letter or telephone after a mean of 17 years (range, 13-22 years). The patients answered a questionnaire and completed the Western Ontario Shoulder Index (WOSI), Disability of Arm Shoulder and Hand (DASH), and SSV (Simple Shoulder Value) assessments.

    Results: Recurrance resulted revision surgery in 1 shoulder in the B-L group and in 5 shoulders in the B group (P=.08). Redislocation or subluxation after the index operation occurred in 13 of 97 B-L shoulders and in 25 of 87 of B shoulders (after excluding 1 patient with arthroplasty because of arthropathy, P=.017). Of the 96 Bristow shoulders, 94 patients were very satisfied/satisfied compared with 71 of 80 in the B series (P=.01). Mean WOSI score was 88 for B-L shoulders and 79 for B shoulders (P=.002). B-L shoulders also scored better on the DASH (P=.002) and SSV (P=.007). Patients had 11 degrees loss of subjectively measured outward rotation with the arm at the side after B-L repair compared with 19 degrees after Bankart (P=.012). The original Bankart, with tunnels through the glenoid rim, had less redislocation(s) or subluxation(s) than shoulders done with anchors (P=.048).

    Conclusions: Results were better after the Bristow-Latarjet repair than after Bankart repairs done with anchors with respect to postoperative stability and subjective evaluation. Shoulders with original Bankart repair also seemed to be more stable than shoulders repaired with anchors.

    Level of evidence: Level III, Retrospective Case Control Study, Treatment Study.

  • 264. Hsu, Yi-Hsiang
    et al.
    Zillikens, M. Carola
    Wilson, Scott G.
    Farber, Charles R.
    Demissie, Serkalem
    Soranzo, Nicole
    Bianchi, Estelle N.
    Grundberg, Elin
    Liang, Liming
    Richards, J. Brent
    Estrada, Karol
    Zhou, Yanhua
    van Nas, Atila
    Moffatt, Miriam F.
    Zhai, Guangju
    Hofman, Albert
    van Meurs, Joyce B.
    Pols, Huibert A. P.
    Price, Roger I.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Cupples, L. Adrienne
    Lusis, Aldons J.
    Schadt, Eric E.
    Ferrari, Serge
    Uitterlinden, Andre G.
    Rivadeneira, Fernando
    Spector, Timothy D.
    Karasik, David
    Kiel, Douglas P.
    An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits2010In: PLoS genetics, ISSN 1553-7390, Vol. 6, no 6, p. e1000977-Article in journal (Refereed)
    Abstract [en]

    Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6 x 10(-8)), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6 x 10(-13); SOX6, p = 6.4 x 10(-10)) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation.

  • 265.
    Hu, Lijuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Andersson, G.
    Jonsson, Kenneth B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Adamts1 is highly induced in rachitic bones of FGF23 transgenic mice and participates in degradation of non-mineralized bone matrix collagen2013In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 430, no 3, p. 901-906Article in journal (Refereed)
    Abstract [en]

    Transgenic mice overexpressing fibroblast growth factor 23 (FGF23) in osteoblasts have a rachitic bone phenotype. These mice display hypomineralized bones, increased expression of osteoblast markers, but osteoclast numbers are unaltered or slightly reduced. Paradoxically, they show increased serum levels of the bone resorption marker CTX, a type I collagen degradation fragment. Here we analyzed a matrix metalloproteinase- (MMP-) like secreted protease, Adamts1, that has previously been associated with osteoblastic type I collagen breakdown in vitro. Bones from FGF23 transgenic (tg) mice displayed increased Adamts1 protein upon both immunohistological staining and Western blotting. We further found Adamts1 protein together with excessively degraded type I collagen in the non-mineralized bone fraction of FGF23 tg mice. A similar degradation pattern of type I collagen was noticed upon forced expression of Adamts1 in osteoblastic cells in vitro. Importantly, these Adamts1-expressing osteoblastic cells exhibited increased release of CTX fragments when cultured on demineralized bone discs. Together, these results demonstrate for the first time that Adamts1 can be highly induced in bone tissue and that this MMP-like protease can increase osteoblastic release of CTX fragments from non-mineralized bone. Thus, Adamts1 potentially contributes to the increased serum levels of CTX in rickets/osteomalacia.

  • 266.
    Hu, Lijuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Jonsson, Kenneth B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Andersén, Harriet
    Edenro, Anne
    Bohlooly-Y, Mohammad
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Over-expression of Adamts1 in mice alters bone mineral density2012In: Journal of Bone and Mineral Metabolism, ISSN 0914-8779, E-ISSN 1435-5604, Vol. 30, no 3, p. 304-311Article in journal (Refereed)
    Abstract [en]

    ADAMTS1, a secreted multifunctional metalloproteinase with disintegrin and thrombospondin motifs, is an early response gene of parathyroid hormone (PTH) in osteoblasts. Mice engineered to lack Adamts1 are smaller compared to wild-type (WT) mice and ADAMTS1 metalloproteinase activity has been shown to increase osteoblastic growth in collagen gels. However, there are no reports investigating the consequence of Adamts1 over-expression on bone tissue in vivo. Here, we analyze bones of female and male transgenic (TG) mice over-expressing mouse Adamts1 using peripheral quantitative computed tomography to evaluate its effect on bone shape and mineral density. Western blotting of protein extracts and immunohistochemistry of bone sections reveal increased presence of Adamts1 protein in TG bones compared to WT bones. Phenotypic analyses of femur show that female TG mice have reduced metaphyseal total density, trabecular bone mineral density and trabecular mineral content. In contrast, male TG mice which were without changes in the metaphysis showed increased total density and cortical density at the mid-diaphysis cortical site. Female TG mice showed no significant changes at the cortical site compared to WT mice. Furthermore, diaphyseal endosteal compartment was only affected in male TG mice. Along these lines, Adamts1 increased blood levels of PTH only in females whereas it reduced osteocalcin levels only in males. These results reveal that Adamts1 has an impact on bone mineral density and thus further confirm Adamts1 as a potent regulator of bone remodeling.

  • 267.
    Huang, Tianyi
    et al.
    Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA.
    Townsend, Mary K.
    H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Tampa, FL USA.
    Wentzensen, Nicolas
    NCI, Div Canc Epidemiol & Genet, NIH, Washington, DC USA.
    Trabert, Britton
    NCI, Div Canc Epidemiol & Genet, NIH, Washington, DC USA.
    White, Emily
    Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA.
    Arslan, Alan A.
    NYU, Sch Med, Dept Populat Hlth, New York, NY USA;NYU, Dept Environm Med, Sch Med, 550 1St Ave, New York, NY 10016 USA;NYU, Dept Obstet & Gynecol, Sch Med, New York, NY 10016 USA.
    Weiderpass, Elisabete
    WHO, Int Agcy Res Canc, Lyon, France.
    Buring, Julie E.
    Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, 181 Longwood Ave, Boston, MA 02115 USA.
    Clendenen, Tess V.
    NYU, Sch Med, Dept Populat Hlth, New York, NY USA.
    Giles, Graham G.
    Canc Council Victoria, Canc Epidemiol Div, Melbourne, Vic, Australia;Univ Melbourne, Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia;Monash Univ, Monash Hlth, Sch Clin Sci, Precis Med, Clayton, Vic, Australia.
    Lee, I-Min
    Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, 181 Longwood Ave, Boston, MA 02115 USA.
    Milne, Roger L.
    Canc Council Victoria, Canc Epidemiol Div, Melbourne, Vic, Australia;Univ Melbourne, Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia;Monash Univ, Monash Hlth, Sch Clin Sci, Precis Med, Clayton, Vic, Australia.
    Onland-Moret, N. Charlotte
    Univ Utrecht, Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    Peters, Ulrike
    Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA.
    Sandler, Dale P.
    NIEHS, Bethesda, MD USA.
    Schouten, Leo J.
    Maastricht Univ, GROW Sch Oncol & Dev Biol, Maastricht, Netherlands.
    van den Brandt, Piet A.
    Maastricht Univ, GROW Sch Oncol & Dev Biol, Maastricht, Netherlands.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Zeleniuch-Jacquotte, Anne
    NYU, Sch Med, Dept Populat Hlth, New York, NY USA;NYU, Dept Environm Med, Sch Med, 550 1St Ave, New York, NY 10016 USA.
    Tworoger, Shelley S.
    Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA;H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Tampa, FL USA;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
    Reproductive and Hormonal Factors and Risk of Ovarian Cancer by Tumor Dominance: Results from the Ovarian Cancer Cohort Consortium (OC3)2020In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 29, no 1, p. 200-207Article in journal (Refereed)
    Abstract [en]

    Background: Laterality of epithelial ovarian tumors may reflect the underlying carcinogenic pathways and origins of tumor cells.

    Methods: We pooled data from 9 prospective studies participating in the Ovarian Cancer Cohort Consortium. Information on measures of tumor size or tumor dominance was extracted from surgical pathology reports or obtained through cancer registries. We defined dominant tumors as those restricted to one ovary or where the dimension of one ovary was at least twice as large as the other, and nondominant tumors as those with similar dimensions across the two ovaries or peritoneal tumors. Competing risks Cox models were used to examine whether associations with reproductive and hormonal risk factors differed by ovarian tumor dominance.

    Results: Of 1,058 ovarian cancer cases with tumor dominance information, 401 were left-dominant, 363 were right-dominant, and 294 were nondominant. Parity was more strongly inversely associated with risk of dominant than nondominant ovarian cancer (P-heterogeneity = 0.004). Ever use of oral contraceptives (OC) was associated with lower risk of dominant tumors, but was not associated with nondominant tumors (Pheterogeneity = 0.01). Higher body mass index was associated with higher risk of left-dominant tumors, but not significantly associated with risk of right-dominant or nondominant tumors (P-heterogeneity = 0.08).

    Conclusions: These data suggest that reproductive and hormonal risk factors appear to have a stronger impact on dominant tumors, which may have an ovarian or endometriosis origin.

    Impact: Examining the associations of ovarian cancer risk factors by tumor dominance may help elucidate the mechanisms through which these factors influence ovarian cancer risk.

  • 268. Huisstede, Bionka M A
    et al.
    Hoogvliet, Peter
    Coert, J Henk
    Fridén, Jan
    Wilbrand, Stephen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Dupuytren disease: european hand surgeons, hand therapists, and physical medicine and rehabilitation physicians agree on a multidisciplinary treatment guideline: results from the HANDGUIDE Study2013In: Plastic and reconstructive surgery (1963), ISSN 0032-1052, E-ISSN 1529-4242, Vol. 132, no 6, p. 964e-976eArticle in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Multidisciplinary treatment guidelines for Dupuytren disease can aid in optimizing the quality of care for patients with this disorder. Therefore, this study aimed to achieve consensus on a multidisciplinary treatment guideline for Dupuytren disease.

    METHODS:

    A European Delphi consensus strategy was initiated. A systematic review reporting on the effectiveness of interventions was conducted and used as an evidence-based starting point for this study. In total, 39 experts (hand surgeons, hand therapists, and physical medicine and rehabilitation physicians) participated in the Delphi consensus strategy. Each Delphi round consisted of a questionnaire, an analysis, and a feedback report.

    RESULTS:

    After four Delphi rounds, consensus was achieved on the description, symptoms, and diagnosis of Dupuytren disease. No nonsurgical interventions were included in the guideline. Needle and open fasciotomy, and a limited fasciectomy and dermofasciectomy, were seen as suitable surgical techniques for Dupuytren disease. Factors relevant for choosing one of these surgical techniques were identified and divided into patient-related (age, comorbidity), disease-related (palpable cord, previous surgery in the same area, skin involvement, time of recovery, recurrences), and surgeon-related (years of experience) factors. Associations of these factors with the choice of a specific surgical technique were reported in the guideline. Postsurgical rehabilitation should always include instructions and exercise therapy; postsurgical splinting should be performed on indication. Relevant details for the use of surgical and postsurgical interventions were described.

    CONCLUSION:

    This treatment guideline is likely to promote further discussion on related clinical and scientific issues and may therefore contribute to better treatment of patients with Dupuytren disease.

  • 269.
    Hulsart Billström, Gry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bone Regeneration with Cell-free Injectable Scaffolds2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Bone is a remarkable multifunctional tissue with the ability to regenerate and remodel without generating any scar tissue. However, bone loss due to injury or diseases can be a great challenge and affect the patient significantly. Autologous bone grafting is commonly used throughout the world. Autograft both fills the void and is bone inductive, housing the particular cells that are needed for bone regeneration. However, a regenerative complement to autograft is of great interest as the use of biomaterials loaded with bioactive molecules can avoid donor site morbidity and the problem of a limited volume of material. Two such regenerative products that utilise bone morphogenetic protein (BMP)-7 and -2 have been used for more than a decade clinically. Unfortunately, several side effects have been reported, such as severe swelling due to inflammation and ectopic bone formation. Additionally, the products require open surgery and use of supra physiological doses of the BMPs due to poor localisation and retention of the growth factor. The purpose of this thesis was to harness the strong inductive capacity of the BMP-2 by optimising the carrier of this bioactive protein, thereby minimising the side effects that are associated with the clinical products and facilitating safe and localised bone regeneration. We focused on an injectable hyaluronan-based carrier developed through polymer chemistry at the University of Uppsala. The strategy was to use the body’s own regenerative pathway to stimulate and enhance bone healing in a manner similar to the natural bone-healing process. The hyaluronan-based carrier has a similar composition to the natural extracellular matrix and is degraded by resident enzymes. Earlier studies have shown improved properties when adding hydroxyapatite, a calcium phosphate that constitutes the inorganic part of the bone matrix. In Paper I, the aim was to improve the carrier by adding other forms of calcium phosphate. The results indicated that bone formation was enhanced when using nano-sized hydroxyapatite. In Paper II, we discovered the importance of crushing the material, thus enhancing permeability and enlarging the surface area. We wished to further develop the carrier system, but were lacking an animal model with relatively high throughput, facilitated access, paired data, and we were also committed to the 3Rs of refinement, reduction, and replacement. To meet these challenges, we developed and refined an animal model, and this is described in Paper III. In Paper IV, we sought to further optimise the biomaterial properties of the hydrogel through covalent bonding of bisphosphonates to the hyaluronan hydrogel. This resulted in exceptional retention of the growth factor BMP-2. In Paper V, SPECT/PET/µCT was combined as a tri-modal imaging method to allow visualisation of the biomaterial’s in situ action, in terms of drug retention, osteoblast activity and mineralisation. Finally, in Paper VI the correlation between existing in vitro results with in vivo outcomes was observed for an array of biomaterials. The study identified a surprisingly poor correlation between in vitro and in vivo assessment of biomaterials for osteogenesis.

    List of papers
    1. Calcium phosphates compounds in conjunction with hydrogel as carrier for BMP-2: A study on ectopic bone formation in rats
    Open this publication in new window or tab >>Calcium phosphates compounds in conjunction with hydrogel as carrier for BMP-2: A study on ectopic bone formation in rats
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    2011 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 7, no 8, p. 3042-3049Article in journal (Refereed) Published
    Abstract [en]

    Current treatment of fractures often involves the use of bone graft or bone morphogenetic proteins (BMP) to induce fracture healing, especially in patients with a compromised healing capacity. BMP has to be delivered in conjunction with a carrier. Unfortunately, there are drawbacks and limitations with current carriers, including their bovine origin which carries the risk of an immunological response. The physical properties also limit the use to open surgical procedures, as it cannot be injected. New carriers with improved properties are therefore needed. The aim of this study was to assess the ectopic bone forming capability of various calcium phosphate compounds when used in conjunction with a hydrogel as the carrier for BMP-2. Five different ceramic additives were tested, including beta-tricalcium phosphate and four types of hydroxyapatite (HAP) (nanoHAP, HAP, clods of HAP >100 mu m, and the biomimetic HAP Ostim35 (R)). The compounds were injected into the thigh muscle of rats, where it formed a gel in situ. After 4 weeks bone formation was evaluated by peripheral quantitative computed tomography and histology. The major finding was that the 20 nm nanoHAP yielded a higher bone density than the other additives (P = 0.0008, ANOVA with Tukey's multiple comparison test). We hypothesize that the higher bone density induced by nanoHAP might be due to nanocrystals of calcium phosphate acting as direct building blocks for biomineralization.

    Keywords
    Calcium phosphates, Hydrogel, Injectable, Nanosized, In vivo
    National Category
    Medical and Health Sciences Polymer Chemistry Engineering and Technology
    Research subject
    Chemistry with specialization in Polymer Chemistry; Engineering Science with specialization in Materials Science
    Identifiers
    urn:nbn:se:uu:diva-157018 (URN)10.1016/j.actbio.2011.04.021 (DOI)000293259500004 ()
    Available from: 2011-08-16 Created: 2011-08-15 Last updated: 2018-06-26Bibliographically approved
    2. Morphological differences in BMP-2-induced ectopic bone between solid and crushed hyaluronan hydrogel templates
    Open this publication in new window or tab >>Morphological differences in BMP-2-induced ectopic bone between solid and crushed hyaluronan hydrogel templates
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    2013 (English)In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 24, no 5, p. 1201-1209Article in journal (Refereed) Published
    Abstract [en]

    The possibility to affect bone formation by using crushed versus solid hydrogels as carriers for bone morphogenetic protein 2 (BMP-2) was studied. Hydrogels, based on chemical crosslinking between hyaluronic acid and poly(vinyl alcohol) derivatives, were loaded with BMP-2 and hydroxyapatite. Crushed and solid forms of the gels were analyzed both in vitro via a release study using I-125 radioactive labeling of BMP-2, and in vivo in a subcutaneous ectopic bone model in rats. Dramatically different morphologies were observed for the ectopic bone formed in vivo in the two types of gels, even though virtually identical release profiles were observed in vitro. Solid hydrogels induced formation of a dense bone shell around non-degraded hydrogel, while crushed hydrogels demonstrated a uniform bone formation throughout the entire sample. These results suggest that by crushing the hydrogel, the construct's three-dimensional network becomes disrupted. This could expose unreacted functional groups, making the fragment's surfaces reactive and enable limited chemical fusion between the crushed hydrogel fragments, leading to similar in vitro release profiles. However, in vivo these interactions could be broken by enzymatic activity, creating a macroporous structure that allows easier cell infiltration, thus, facilitating bone formation.

    National Category
    Engineering and Technology Natural Sciences Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-201244 (URN)10.1007/s10856-013-4877-6 (DOI)000318510200008 ()
    Available from: 2013-06-10 Created: 2013-06-10 Last updated: 2018-12-04
    3. A uni-cortical femoral defect model in the rat: evaluation using injectable hyaluronan hydrogel as a carrier for bone morphogenetic protein-2
    Open this publication in new window or tab >>A uni-cortical femoral defect model in the rat: evaluation using injectable hyaluronan hydrogel as a carrier for bone morphogenetic protein-2
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    2015 (English)In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 9, no 7, p. 799-807Article in journal (Refereed) Published
    Abstract [en]

    The development of biomaterial for bone regeneration requires animal models that are reliable and designed to mimic clinically relevant situations. We have previously investigated hydrogels comprised of modified hyaluronic acid and polyvinyl alcohol in models of ectopic bone formation. This hydrogel induces bone regeneration when loaded with bone morphogenetic proteins (BMPs). To allow further optimization of hydrogels, we developed a new, femoral, non-critical-sized cortical defect model. In the rat femur, we drilled standardized, elongated unilateral cortical defects that did not require stabilization and that could be created bilaterally to allow paired comparisons of biomaterials. After optimizing the defect size, subsequent stress fractures occurred in only 8% and the defect healed partially over the 40 day study period. In a time-course experiment, we treated bone defects with the previously studied hyaluronan hydrogel loaded with 10 µg hydroxyapatite and 6 µg BMP-2. The shape of the defect allowed controlled containment of the material within the defect. The defect in the right leg was left untreated, while the left defect was filled with 40 µl of the BMP hydrogel. As determined by pQCT analysis, the treated defects had a higher bone mineral content, bone area and bone density than control defects. The relative difference was greatest between the groups at 10 and 20 days and diminished as the defect healed in the untreated legs. We conclude that this animal model allows facile and rapid screening of biomaterials for bone regeneration in cortical femoral defects without requiring external fixation.

    National Category
    Other Natural Sciences Other Medical Sciences not elsewhere specified
    Identifiers
    urn:nbn:se:uu:diva-189868 (URN)10.1002/term.1655 (DOI)000357881900006 ()23225778 (PubMedID)
    Available from: 2013-01-04 Created: 2013-01-04 Last updated: 2017-12-06Bibliographically approved
    4. Bisphosphonate-Linked Hyaluronic Acid Hydrogel Sequesters and Enzymatically Releases Active Bone Morphogenetic Protein-2 for Induction of Osteogenic Differentiation
    Open this publication in new window or tab >>Bisphosphonate-Linked Hyaluronic Acid Hydrogel Sequesters and Enzymatically Releases Active Bone Morphogenetic Protein-2 for Induction of Osteogenic Differentiation
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    2013 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 14, no 9, p. 3055-3063Article in journal (Refereed) Published
    Abstract [en]

    Regeneration of bone by delivery of bone morphogenetic proteins (BMPs) from implantable scaffolds is a promising alternative to the existing autologous bone grafting procedures. Hydrogels are used extensively in biomaterials as delivery systems for different growth factors. However, a controlled release of the growth factors is necessary to induce bone formation, which can be accomplished by various chemical functionalities. Herein we demonstrate that functionalization of a hyaluronan (HA) hydrogel with covalently linked bisphosphonate (BP) ligands provides efficient sequestering of BMP-2 in the resulting HA-BP hydrogel. The HA-BP hydrogel was investigated in comparison with its analogue lacking BP groups (HA hydrogel). While HA hydrogel released 100% of BMP-2 over two weeks, less than 10% of BMP-2 was released from the HA-BP hydrogel for the same time. We demonstrate that the sequestered growth factor can still be released by enzymatic degradation of the HA-BP hydrogel. Most importantly, entrapment of BMP-2 in HA-BP hydrogel preserves the growth factor bioactivity, which was confirmed by induction of osteogenic differentiation of mesenchymal stem cells (MSCs) after the cells incubation with the enzymatic digest of the hydrogel. At the same time, the hydrogels degradation products were not toxic to MSCs and osteoblasts. Furthermore, BP-functionalization of HA hydrogels promotes adhesion of the cells to the surface of HA hydrogel. Altogether, the present findings indicate that covalent grafting of HA hydrogel with BP groups can alter the clinical effects of BMPs in bone tissue regeneration.

    National Category
    Medical Biotechnology
    Identifiers
    urn:nbn:se:uu:diva-219176 (URN)10.1021/bm400639e (DOI)000330095500012 ()
    Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2017-12-05Bibliographically approved
    5. Non-invasive tri-modal visualisation of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept.
    Open this publication in new window or tab >>Non-invasive tri-modal visualisation of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept.
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    bone tissue engineering; hydrogel; computed tomography; positron emission tomography; single-photon emission computed tomography; bone morphogenetic protein 2
    National Category
    Biological Sciences Other Medical Sciences
    Research subject
    Biology
    Identifiers
    urn:nbn:se:uu:diva-234698 (URN)
    Funder
    EU, FP7, Seventh Framework Programme
    Available from: 2014-10-24 Created: 2014-10-23 Last updated: 2017-01-10
    6. A surprisingly poor correlation between in vitro and in vivo testing of biomaterials for bone regeneration: Results of a multicentre analysis
    Open this publication in new window or tab >>A surprisingly poor correlation between in vitro and in vivo testing of biomaterials for bone regeneration: Results of a multicentre analysis
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    2016 (English)In: European Cells and Materials, ISSN 1473-2262, E-ISSN 1473-2262, Vol. 31, p. 312-322Article in journal (Refereed) Published
    Abstract [en]

    New regenerative materials and approaches need to be assessed through reliable and comparable methods for rapid translation to the clinic. There is a considerable need for proven in vitro assays that are able to reduce the burden on animal testing, by allowing assessment of biomaterial utility predictive of the results currently obtained through in vivo studies. The purpose of this multicentre review was to investigate the correlation between existing in vitro results with in vivo outcomes observed for a range of biomaterials. Members from the European consortium BioDesign, comprising 8 universities in a European multicentre study, provided data from 36 in vivo studies and 47 in vitro assays testing 93 different biomaterials. The outcomes of the in vitro and in vivo experiments were scored according to commonly recognised measures of success relevant to each experiment. The correlation of in vitro with in vivo scores for each assay alone and in combination was assessed. A surprisingly poor correlation between in vitro and in vivo assessments of biomaterials was revealed indicating a clear need for further development of relevant in vitro assays. There was no significant overall correlation between in vitro and in vivo outcome. The mean in vitro scores revealed a trend of covariance to in vivo score with 58 %. The inadequacies of the current in vitro assessments highlighted here further stress the need for the development of novel approaches to in vitro biomaterial testing and validated pre-clinical pipelines.

    Keywords
    in vivo, in vitro, correlation, biomaterials, multicentre study
    National Category
    Biomaterials Science
    Identifiers
    urn:nbn:se:uu:diva-306778 (URN)10.22203/eCM.v031a20 (DOI)000384895100020 ()27215739 (PubMedID)
    Funder
    EU, FP7, Seventh Framework Programme, 262948
    Available from: 2016-11-16 Created: 2016-11-03 Last updated: 2017-11-29Bibliographically approved
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  • 270.
    Hulsart Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Blom, Ashley W.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Beswick, Andrew D.
    Application of scaffolds for bone regeneration strategies: Current trends and future directions2013In: Injury, ISSN 0020-1383, E-ISSN 1879-0267, Vol. 44, p. S28-S33Article in journal (Refereed)
    Abstract [en]

    Scaffolds are extensively used in surgery to replace missing bone and to achieve bony union and fusion. An ideal scaffold should not only maintain, induce, and restore biological functions where cells, extracellular matrix, and growth factors are needed, but also have the right properties with respect to degradation, cell binding, cellular uptake, non-immunogenicity, mechanical strength, and flexibility. Here we examine both the basic science behind the development of scaffolds and comprehensively and systematically review the clinical applications. 

  • 271.
    Hulsart Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Janson, Oscar
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Welch, Ken
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Thromboinflammation as bioactivity assessment of H2O2-alkali modified titanium surfaces2019In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 30, no 6, article id 66Article in journal (Refereed)
    Abstract [en]

    The release of growth factors from platelets, mediated by the coagulation and the complement system, plays an important role in the bone formation around implants. This study aimed at exploring the thromboinflammatory response of H2O2-alkali soaked commercially pure titanium grade 2 discs exposed to whole human blood, as a way to assess the bioactivity of the discs. Commercially pure titanium grade 2 discs were modified by soaking in H2O2, NaOH and Ca(OH)2. The platelet aggregation, coagulation activation and complement activation was assessed by exposing the discs to fresh whole blood from human donors. The platelet aggregation was examined by a cell counter and the coagulation and complement activation were assessed by ELISA-measurements of the concentration of thrombin-antithrombin complex, C3a and terminal complement complex. The modified surface showed a statistically significant increased platelet aggregation, coagulation activation and complement activation compared to unexposed blood. The surface also showed a statistically significant increase of coagulation activation compared to PVC. The results of this study showed that the H2O2-alkali soaked surfaces induced a thromboinflammatory response that indicates that the surfaces are bioactive.

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  • 272.
    Hulsart Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Asplund, Veronika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Bergman, Kristoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry.
    Marsell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Antoni, Gunnar
    Enheten för nuklearmedicin och PET, Section of Nuclear Medicine and PET.
    Non-invasive tri-modal visualisation of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept.Manuscript (preprint) (Other academic)
  • 273.
    Hulsart Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Asplund, Veronika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Bergman, Kristoffer
    TERMIRA, Stockholm, Sweden.
    Marsell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept2018In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 285, p. 178-186Article in journal (Refereed)
    Abstract [en]

    Bone morphogenetic proteins (BMP's) are vital for bone and cartilage formation, where bone morphogenetic protein-2 (BMP-2) is acknowledged as a growth factor in osteoblast differentiation. However, uncontrolled delivery may result in adverse clinical effects. In this study we investigated the possibility for longitudinal and non-invasive monitoring of implanted [125I]BMP-2 retention and its relation to ossification at the site of implantation. A unilateral critically sized femoral defect was produced in the left limb of rats while the right femur was retained intact as a paired reference control. The defect was filled with a hyaluronan hydrogel with 25% hydroxyapatite alone (carrier control; n = 2) or combined with a mixture of [125I]BMP-2 (150 μg/ml; n = 4). Bone formation was monitored using micro computed tomography (μCT) scans at 1, 3, 5, 7, 9 and 12 weeks. The retention of [125I]BMP-2 was assessed with single photon emission computed tomography (SPECT), and the bone healing process was followed with sodium fluoride (Na18F) using positron emission tomography (PET) at day 3 and at week 2, 4, and 6. A rapid burst release of [125I]BMP-2 was detected via SPECT. This was followed by a progressive increase in uptake levels of [18F]fluoride depicted by PET imaging that was confirmed as bone formation via μCT. We propose that this functional, non-invasive imaging method allows tri-modal visualisation of the release of BMP-2 and the following in vivo response. We suggest that the potential of this novel technique could be considered for preclinical evaluation of novel smart materials on bone regeneration.

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  • 274.
    Hulsart Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Stelzl, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Procter, Philip
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Applied Material Science.
    Pujari-Palmer, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Applied Material Science.
    Insley, Gerard
    GPBio Ltd, Unit 4D, Western Business Pk, Shannnon, Clare, Ireland.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Applied Material Science.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    In vivo safety assessment of a bio-inspired bone adhesive2020In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 31, no 2, article id 24Article in journal (Refereed)
    Abstract [en]

    A new class of materials, bone adhesives, could revolutionise the treatment of highly fragmented fractures. We present the first biological safety investigation of a bio-inspired bone adhesive. The formulation was based upon a modified calcium phosphate cement that included the amino acid phosphoserine. This material has recently been described as substantially stronger than other bioresorbable calcium phosphate cements. Four adhesive groups with the active substance (phosphoserine) and two control groups without phosphoserine were selected for in vitro and in vivo biocompatibility testing. The test groups were subject for cell viability assay and subcutaneous implantation in rats that was followed by gene expression analysis and histology assessment after 6 and 12 weeks. All adhesive groups supported the same rate of cell proliferation compared to the alpha-TCP control and had viability between 45-64% when compared to cell control. There was no evidence of an increased immune response or ectopic bone formation in vivo. To conclude, this bio-inspired bone adhesive has been proven to be safe, in the present study, without any harmful effects on the surrounding soft tissue. 

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  • 275.
    Hulsart-Billstrom, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    BMP-2 Induced bone regeneration visualized by PET and SPECT2014In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 8, p. 513-513Article in journal (Other academic)
  • 276.
    Hulsart-Billstrom, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nouhi, Shirin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Physics.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Öhman, Caroline
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Iodine-enhanced contrast applicable for microcomputed tomography2014In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 8, p. 245-246Article in journal (Refereed)
  • 277.
    Hulsart-Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bergman, Kristoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Andersson, Brittmarie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Jonsson, Kenneth B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    A uni-cortical femoral defect model in the rat: evaluation using injectable hyaluronan hydrogel as a carrier for bone morphogenetic protein-22015In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 9, no 7, p. 799-807Article in journal (Refereed)
    Abstract [en]

    The development of biomaterial for bone regeneration requires animal models that are reliable and designed to mimic clinically relevant situations. We have previously investigated hydrogels comprised of modified hyaluronic acid and polyvinyl alcohol in models of ectopic bone formation. This hydrogel induces bone regeneration when loaded with bone morphogenetic proteins (BMPs). To allow further optimization of hydrogels, we developed a new, femoral, non-critical-sized cortical defect model. In the rat femur, we drilled standardized, elongated unilateral cortical defects that did not require stabilization and that could be created bilaterally to allow paired comparisons of biomaterials. After optimizing the defect size, subsequent stress fractures occurred in only 8% and the defect healed partially over the 40 day study period. In a time-course experiment, we treated bone defects with the previously studied hyaluronan hydrogel loaded with 10 µg hydroxyapatite and 6 µg BMP-2. The shape of the defect allowed controlled containment of the material within the defect. The defect in the right leg was left untreated, while the left defect was filled with 40 µl of the BMP hydrogel. As determined by pQCT analysis, the treated defects had a higher bone mineral content, bone area and bone density than control defects. The relative difference was greatest between the groups at 10 and 20 days and diminished as the defect healed in the untreated legs. We conclude that this animal model allows facile and rapid screening of biomaterials for bone regeneration in cortical femoral defects without requiring external fixation.

  • 278.
    Hulsart-Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bergman, Kristoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Bowden, Tim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Engstrand, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    The Effect of Incubation Time of Preformed Injectable Hydrogels on Bone Formation when used as Carrier for rhBMP-22011In: TERMIS-EU 2011 Abstracts, 2011Conference paper (Refereed)
  • 279.
    Hulsart-Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Carlsson, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    In vivo and in vitro performance of Sr-doped hydroxyapatite composite in the form of hollow nano-spheres2012Conference paper (Refereed)
  • 280.
    Hulsart-Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Univ Southampton, Inst Dev Sci, Ctr Human Dev Stem Cells & Regenerat, Bone & Joint Res Grp, Southampton SO9 5NH, Hants, England.
    Dawson, J. I.
    Univ Southampton, Inst Dev Sci, Ctr Human Dev Stem Cells & Regenerat, Bone & Joint Res Grp, Southampton SO9 5NH, Hants, England..
    Hofmann, S.
    Swiss Fed Inst Technol Zurich ETHZ, Inst Biomech, Vladimir Prelog Weg 3, CH-8093 Zurich, Switzerland.;Eindhoven Univ Technol, Dept Biomed Engn, POB 513, NL-5600 MB Eindhoven, Netherlands.;Eindhoven Univ Technol, Inst Complex Mol Syst, POB 513, NL-5600 MB Eindhoven, Netherlands..
    Müller, R.
    Swiss Fed Inst Technol Zurich ETHZ, Inst Biomech, Vladimir Prelog Weg 3, CH-8093 Zurich, Switzerland..
    Stoddart, M. J.
    AO Res Inst Davos, Davos, Switzerland..
    Alini, M.
    AO Res Inst Davos, Davos, Switzerland..
    Redl, H.
    Ludwig Boltzmann Inst Expt & Clin Traumatol, European Inst Excellence Tissue Engn & Regenerat, AUVA Res Ctr, Austrian Cluster Tissue Regenerat,Vienna Branch, Vienna, Austria..
    El Haj, A.
    Keele Univ, Inst Sci & Technol Med, Stoke On Trent, Staffs, England..
    Brown, R.
    UCL, Tissue Repair & Engn Ctr, Inst Orthopaed, Stanmore Campus, London, England..
    Salih, V.
    Univ Plymouth, Peninsula Sch Med & Dent, Plymouth, Devon, England.;UCL, Eastman Dent Inst, London, England..
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Oreffo, R. O. C.
    Univ Southampton, Inst Dev Sci, Ctr Human Dev Stem Cells & Regenerat, Bone & Joint Res Grp, Southampton SO9 5NH, Hants, England..
    A surprisingly poor correlation between in vitro and in vivo testing of biomaterials for bone regeneration: Results of a multicentre analysis2016In: European Cells and Materials, ISSN 1473-2262, E-ISSN 1473-2262, Vol. 31, p. 312-322Article in journal (Refereed)
    Abstract [en]

    New regenerative materials and approaches need to be assessed through reliable and comparable methods for rapid translation to the clinic. There is a considerable need for proven in vitro assays that are able to reduce the burden on animal testing, by allowing assessment of biomaterial utility predictive of the results currently obtained through in vivo studies. The purpose of this multicentre review was to investigate the correlation between existing in vitro results with in vivo outcomes observed for a range of biomaterials. Members from the European consortium BioDesign, comprising 8 universities in a European multicentre study, provided data from 36 in vivo studies and 47 in vitro assays testing 93 different biomaterials. The outcomes of the in vitro and in vivo experiments were scored according to commonly recognised measures of success relevant to each experiment. The correlation of in vitro with in vivo scores for each assay alone and in combination was assessed. A surprisingly poor correlation between in vitro and in vivo assessments of biomaterials was revealed indicating a clear need for further development of relevant in vitro assays. There was no significant overall correlation between in vitro and in vivo outcome. The mean in vitro scores revealed a trend of covariance to in vivo score with 58 %. The inadequacies of the current in vitro assessments highlighted here further stress the need for the development of novel approaches to in vitro biomaterial testing and validated pre-clinical pipelines.

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  • 281.
    Hulsart-Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Hu, Qinghong
    Centre of Biopathways and Biomaterials, Dept of Chemistry, Zhejiang University, Hangzhou, Zhejiang, China .
    Bergman, Kristoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Jonsson, Kenneth B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Åberg, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Tang, Ruikang
    Centre of Biopathways and Biomaterials, Dept of Chemistry, Zhejiang University, Hangzhou, Zhejiang, China .
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Calcium phosphates compounds in conjunction with hydrogel as carrier for BMP-2: A study on ectopic bone formation in rats2011In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 7, no 8, p. 3042-3049Article in journal (Refereed)
    Abstract [en]

    Current treatment of fractures often involves the use of bone graft or bone morphogenetic proteins (BMP) to induce fracture healing, especially in patients with a compromised healing capacity. BMP has to be delivered in conjunction with a carrier. Unfortunately, there are drawbacks and limitations with current carriers, including their bovine origin which carries the risk of an immunological response. The physical properties also limit the use to open surgical procedures, as it cannot be injected. New carriers with improved properties are therefore needed. The aim of this study was to assess the ectopic bone forming capability of various calcium phosphate compounds when used in conjunction with a hydrogel as the carrier for BMP-2. Five different ceramic additives were tested, including beta-tricalcium phosphate and four types of hydroxyapatite (HAP) (nanoHAP, HAP, clods of HAP >100 mu m, and the biomimetic HAP Ostim35 (R)). The compounds were injected into the thigh muscle of rats, where it formed a gel in situ. After 4 weeks bone formation was evaluated by peripheral quantitative computed tomography and histology. The major finding was that the 20 nm nanoHAP yielded a higher bone density than the other additives (P = 0.0008, ANOVA with Tukey's multiple comparison test). We hypothesize that the higher bone density induced by nanoHAP might be due to nanocrystals of calcium phosphate acting as direct building blocks for biomineralization.

  • 282.
    Hulsart-Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Jonsson, Kenneth B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bergman, Kristoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    The use of a Large but not Critically Sized Fermoral Bone Defect in a Rat Model for Assesment of the Bone Forming Capacity of Various Bioactive Scaffolds2011In: TERMIS-EU 2011 Abstracts, 2011Conference paper (Refereed)
  • 283.
    Hulsart-Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Piskounova, Sonya
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Andersson, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bergman, Kristoffer
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bowden, Tim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Morphological differences in BMP-2-induced ectopic bone between solid and crushed hyaluronan hydrogel templates2013In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 24, no 5, p. 1201-1209Article in journal (Refereed)
    Abstract [en]

    The possibility to affect bone formation by using crushed versus solid hydrogels as carriers for bone morphogenetic protein 2 (BMP-2) was studied. Hydrogels, based on chemical crosslinking between hyaluronic acid and poly(vinyl alcohol) derivatives, were loaded with BMP-2 and hydroxyapatite. Crushed and solid forms of the gels were analyzed both in vitro via a release study using I-125 radioactive labeling of BMP-2, and in vivo in a subcutaneous ectopic bone model in rats. Dramatically different morphologies were observed for the ectopic bone formed in vivo in the two types of gels, even though virtually identical release profiles were observed in vitro. Solid hydrogels induced formation of a dense bone shell around non-degraded hydrogel, while crushed hydrogels demonstrated a uniform bone formation throughout the entire sample. These results suggest that by crushing the hydrogel, the construct's three-dimensional network becomes disrupted. This could expose unreacted functional groups, making the fragment's surfaces reactive and enable limited chemical fusion between the crushed hydrogel fragments, leading to similar in vitro release profiles. However, in vivo these interactions could be broken by enzymatic activity, creating a macroporous structure that allows easier cell infiltration, thus, facilitating bone formation.

  • 284.
    Hulsart-Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Piskounova, Sonya
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Andersson, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bergman, Kristoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bowden, Tim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Improved bone formation through increased surface area of hyaluronan-based hydrogels when used as carriers for BMP-2Manuscript (preprint) (Other academic)
    Abstract
  • 285.
    Hulsart-Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Pankotai, Eszter
    Department of Orthopedics, Semmelweis University, Budapest, Ungern.
    Weszl, Miklos
    Department of Orthopedics, Semmelweis University, Budapest, Ungern.
    Carlsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Lacza, Zsombor
    Department of Orthopedics, Semmelweis University, Budapest, Ungern.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bone forming potential of Sr doped hydroxyapatite hollow spheres in a rat vertebral bone defect model2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no supplement 1, p. S114-Article in journal (Refereed)
  • 286.
    Hulsart-Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Pankotai, Eszter
    Department of Orthopedics, Semmelweis University.
    Weszl, Miklós
    Department of Orthopedics, Semmelweis University.
    Forster-Horváth, Csaba
    Department of Orthopedics, Semmelweis University.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Lacza, Zsombor
    Department of Orthopedics, Semmelweis University.
    Osteogenic potential of Sr-doped calcium phosphate hollow spheres in vitro and in vivo2013In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 101, no 8, p. 2322-2331Article in journal (Refereed)
    Abstract [en]

    Treatment of osteoporotic fractures with conventional surgical methods is associated with a high rate of complications. Intense search for new treatment options includes development of specific biomaterials aimed to be part of the surgical armamentarium. Strontium doped calcium phosphate spheres (SrCPS) is a new material that might be of interest due to the influence on osteoclast and osteoblast activity. In the present study, we successfully constructed hollow spherical SrCPS particles with a diameter of ∼700 nm and shell thickness of ∼150 nm. The Sr content was about 20 wt %. Cell viability and cytotoxicity were investigated in vitro with concentrations from 0 to 1000 μg/mL of SrCPS in medium extract in a day chase study. The in vivo biocompatibility was tested in a delayed bone-healing model in a rat vertebral defect by histology, μCT, and nanoSPECT. The SrCPS showed no toxicity in vitro with comparable cell number in all concentrations. Increased metabolism was seen in the cell viability study in cells exposed to 400 and 600 μg/mL. SPECT showed good biocompatibility with no local adverse effects and an increased osteoblast activity as compared to adjacent vertebra. SrCPS implantation induced bone formation and resulted in complete resorption and defect consolidation.

  • 287.
    Hulsart-Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Yuen, Pik Kwan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Marsell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ossipov, Dmitri
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Bisphosphonate-Linked Hyaluronic Acid Hydrogel Sequesters and Enzymatically Releases Active Bone Morphogenetic Protein-2 for Induction of Osteogenic Differentiation2013In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 14, no 9, p. 3055-3063Article in journal (Refereed)
    Abstract [en]

    Regeneration of bone by delivery of bone morphogenetic proteins (BMPs) from implantable scaffolds is a promising alternative to the existing autologous bone grafting procedures. Hydrogels are used extensively in biomaterials as delivery systems for different growth factors. However, a controlled release of the growth factors is necessary to induce bone formation, which can be accomplished by various chemical functionalities. Herein we demonstrate that functionalization of a hyaluronan (HA) hydrogel with covalently linked bisphosphonate (BP) ligands provides efficient sequestering of BMP-2 in the resulting HA-BP hydrogel. The HA-BP hydrogel was investigated in comparison with its analogue lacking BP groups (HA hydrogel). While HA hydrogel released 100% of BMP-2 over two weeks, less than 10% of BMP-2 was released from the HA-BP hydrogel for the same time. We demonstrate that the sequestered growth factor can still be released by enzymatic degradation of the HA-BP hydrogel. Most importantly, entrapment of BMP-2 in HA-BP hydrogel preserves the growth factor bioactivity, which was confirmed by induction of osteogenic differentiation of mesenchymal stem cells (MSCs) after the cells incubation with the enzymatic digest of the hydrogel. At the same time, the hydrogels degradation products were not toxic to MSCs and osteoblasts. Furthermore, BP-functionalization of HA hydrogels promotes adhesion of the cells to the surface of HA hydrogel. Altogether, the present findings indicate that covalent grafting of HA hydrogel with BP groups can alter the clinical effects of BMPs in bone tissue regeneration.

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    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
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    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.
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    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.
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    H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA.
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    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
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    Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA.
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    Catalan Inst Oncol IDIBELL, Canc Prevent & Control Program, Barcelona, Spain;CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain;Univ Barcelona, Dept Clin Sci, Fac Med, Barcelona, Spain.
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    Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA.
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    Univ Barcelona, Dept Gastroenterol, Hosp Clin, Inst Invest Biomed August Pi & Sunyer IDIBAPS,Ctr, Barcelona, Spain.
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    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
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    Hellen Hlth Fdn, Athens, Greece;Univ Athens, WHO Collaborating Ctr Nutr & Hlth, Unit Nutr Epidemiol & Nutr Publ Hlth, Dept Hyg Epidemiol & Med Stat,Sch Med, Athens, Greece.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
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    Univ N Carolina, Dept Med, Sch Med, Chapel Hill, NC 27515 USA.
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    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.
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    Ctr Hosp Univ CHU Nantes, Serv Genet Med, Nantes, France.
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    St Jamess Univ Leeds, Leeds Inst Med Res, Leeds, W Yorkshire, England.
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    Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA;Univ Utah, Dept Populat Hlth Sci, Salt Lake City, UT USA.
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    German Inst Human Nutr Potsdam Rehbrucke, Dept Epidemiol, Potsdam, Germany.
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    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany;German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany;Natl Ctr Tumor Dis NCT, Heidelberg, Germany;German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany.
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    Med Univ Vienna, Inst Canc Res, Dept Med 1, Vienna, Austria.
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    Tech Univ Dresden, Dept Med 1, Univ Hosp Dresden, Dresden, Germany.
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    Univ Melbourne, Colorectal Oncogen Grp, Dept Clin Pathol, Parkville, Vic, Australia;Univ Melbourne, Ctr Canc Res, Victorian Comprehens Canc Ctr, Parkville, Vic, Australia;Royal Melbourne Hosp, Genom Med & Family Canc Clin, Parkville, Vic, Australia.
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    Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA.
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    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
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    Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA.
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    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany;UCCH, Canc Epidemiol Grp, Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany.
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    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.
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    Chonnam Natl Univ Hosp, Dept Hematol Oncol, Hwasun, South Korea.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
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    Imperial Coll London, Dept Epidemiol & Biostat, London, England;Imperial Coll London, Dept Surg & Canc, London, England.
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    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
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    Ohio State Univ, Dept Canc Biol & Genet, Columbus, OH 43210 USA;Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA.
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    Johns Hopkins Univ, Inst Med Genet, CIDR, Baltimore, MD USA.
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    Univ Utrecht, Julius Ctr Hlth Sci & Primary Care, Univ Med Ctr Utrecht, Utrecht, Netherlands.
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    St Jamess Univ Leeds, Leeds Inst Med Res, Leeds, W Yorkshire, England.
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    Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia;Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
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    Wageningen Univ & Res, Div Human Nutr & Hlth, Wageningen, Netherlands.
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    Cedars Sinai Med Ctr, Dept Med, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA;Univ Southern Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA USA.
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    Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA.
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    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia;Univ Tasmania, Menzies Inst Med Res, Hobart, Tas, Australia.
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    Univ Toronto, Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada.
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    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA.
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    NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
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    Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, 1124 Columbia St, Seattle, WA 98104 USA.
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    Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA.
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    Univ Hawaii, Canc Res Ctr, Honolulu, HI 96813 USA.
    Gsur, Andrea
    Med Univ Vienna, Inst Canc Res, Dept Med 1, Vienna, Austria.
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    WHO, Nutr & Metab Sect, Int Agcy Res Canc, Lyon, France.
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    Stanford Univ, Dept Med, Div Oncol, Stanford, CA 94305 USA.
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    Tech Univ Dresden, Dept Med 1, Univ Hosp Dresden, Dresden, Germany.
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    Ohio State Univ, Ctr Comprehens Canc, Div Human Genet, Dept Internal Med, Columbus, OH 43210 USA.
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    Umea Univ, Dept Radiat Sci, Oncol Unit, Umea, Sweden.
    Hayes, Richard B.
    NYU, Sch Med, Div Epidemiol, Dept Populat Hlth, New York, NY USA.
    Hofer, Philipp
    Med Univ Vienna, Inst Canc Res, Dept Med 1, Vienna, Austria.
    Hoffmeister, Michael
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Hopper, John L.
    Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia;Seoul Natl Univ, Dept Epidemiol, Sch Publ Hlth, Seoul, South Korea;Seoul Natl Univ, Inst Hlth & Environm, Seoul, South Korea.
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    Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
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    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.
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    Ontario Inst Canc Res, Toronto, ON, Canada.
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    Harvard Univ, Dept Epidemiol, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA;Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England.
    Ibanez-Sanz, Gemma
    Catalan Inst Oncol IDIBELL, Canc Prevent & Control Program, Barcelona, Spain;Bellvitge Univ Hosp, Gastroenterol Dept, Barcelona, Spain;Bellvitge Biomed Res Inst IDIBELL, Colorectal Canc Grp, ONCOBELL Program, Barcelona, Spain.
    Idos, Gregory E.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA.
    Ingersoll, Roxann
    Johns Hopkins Univ, Inst Med Genet, CIDR, Baltimore, MD USA.
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    Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA.
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    Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30329 USA.
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    Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia.
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    Harvard Med Sch, Boston, MA 02114 USA;Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA;Harvard Univ, Dept Epidemiol, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA.
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    Johns Hopkins Univ, Dept Epidemiol, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA.
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    Univ N Carolina, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC 27515 USA.
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    Univ Oxford, Canc Epidemiol Unit, Nuffield Dept Populat Hlth, Oxford, England.
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    Chonnam Natl Univ, Dept Surg, Hwasun Hosp & Med Sch, Hwasun, South Korea.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
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    Univ Hawaii Manoa, Off Publ Hlth Studies, Honolulu, HI 96822 USA.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
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    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany.
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    Ctr Hosp Univ CHU Nantes, Serv Genet Med, Nantes, France.
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    Chonnam Natl Univ, Sch Med, Dept Prevent Med, Gwangju, South Korea;Chonnam Natl Univ, Jeonnam Reg Canc Ctr, Hwasun Hosp, Hwasun, South Korea.
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    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
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    Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
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    Univ Hawaii, Canc Res Ctr, Honolulu, HI 96813 USA.
    Leal, Suzanne M.
    Baylor Coll Med, Ctr Stat Genet, Dept Mol & Human Genet, Houston, TX 77030 USA.
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    Natl Univ, Inst Canc, Dept Haematol Oncol, Singapore, Singapore;Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore.
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    Carmel, Clalit Hlth Serv, Personalized Genom Serv, Haifa, Israel;Lady Davis Carmel Med Ctr, Dept Community Med & Epidemiol, Haifa, Israel;Clalit Natl Canc Control Ctr, Haifa, Israel.
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    Ontario Inst Canc Res, Toronto, ON, Canada.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
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    Case Western Reserve Univ, Ctr Community Hlth Integrat, Cleveland, OH 44106 USA;Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA.
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    Christian Albrechts Univ Kiel, Inst Epidemiol, PopGen Biobank, Kiel, Germany.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
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    Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Lindor, Noralane M.
    Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ USA.
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    Johns Hopkins Univ, Inst Med Genet, CIDR, Baltimore, MD USA.
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    Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
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    Natl Inst Hlth & Welf, Dept Publ Hlth Solut, Helsinki, Finland.
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    Case Western Reserve Univ, Dept Med, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA;Case Western Reserve Univ, Dept Genet, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA;Univ Hosp Cleveland, Cleveland, OH 44106 USA.
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    CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain;Univ Leon, Biomed Inst IBIOMED, Leon, Spain.
    Masala, Giovanna
    Inst Canc Res Prevent & Clin Network ISPRO, Canc Risk Factors & Life Style Epidemiol Unit, Florence, Italy.
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    Univ Southern Calif, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA.
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    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA.
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    Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia;Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
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    Univ Barcelona, Dept Gastroenterol, Hosp Clin, Inst Invest Biomed August Pi & Sunyer IDIBAPS,Ctr, Barcelona, Spain.
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    WHO, Nutr & Metab Sect, Int Agcy Res Canc, Lyon, France.
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    Umea Univ, Dept Radiat Sci, Oncol Unit, Umea, Sweden.
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    Czech Acad Sci, Dept Mol Biol Canc, Inst Expt Med, Prague, Czech Republic;IIGM, Turin, Italy.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.
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    Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, 1275 York Ave, New York, NY 10021 USA;Weill Cornell Med Coll, Dept Med, New York, NY USA.
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    Broad Inst Harvard & MIT, Cambridge, MA USA;Harvard Univ, Dept Epidemiol, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA;Harvard Med Sch, Program MPE Mol Pathol Epidemiol, Dept Pathol, Brigham & Womens Hosp, Boston, MA USA;Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02115 USA.
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    Univ Utrecht, Julius Ctr Hlth Sci & Primary Care, Univ Med Ctr Utrecht, Utrecht, Netherlands.
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    IIGM, Turin, Italy;Univ Turin, Dept Med Sci, Turin, Italy.
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    Mem Univ, Clin Epidemiol Unit, Sch Med, St John, NF, Canada.
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    Ohio State Univ, Ctr Comprehens Canc, Div Human Genet, Dept Internal Med, Columbus, OH 43210 USA.
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    Univ Paris 05, Lab Math Appl MAP5, CNRS, UMR 8145, Paris, France;Univ Paris Saclay, CESP, INSERM, U1018,Fac Med,Univ Paris Sud,UVSQ,Gustave Roussy, Villejuif, France.
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    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.
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    Lady Davis Carmel Med Ctr, Dept Community Med & Epidemiol, Haifa, Israel.
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    Johns Hopkins Univ, Dept Epidemiol, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA.
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    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
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    Johns Hopkins Univ, Inst Med Genet, CIDR, Baltimore, MD USA.
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    Vanderbilt Univ, Sch Med, Div Epidemiol, Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA.
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    Lady Davis Carmel Med Ctr, Dept Community Med & Epidemiol, Haifa, Israel;Clalit Natl Canc Control Ctr, Haifa, Israel;Technion Israel Inst Technol, Ruth & Bruce Rappaport Fac Med, Haifa, Israel.
    Rennert, Hedy S.
    Lady Davis Carmel Med Ctr, Dept Community Med & Epidemiol, Haifa, Israel;Clalit Natl Canc Control Ctr, Haifa, Israel;Technion Israel Inst Technol, Ruth & Bruce Rappaport Fac Med, Haifa, Israel.
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    Imperial Coll London, Sch Publ Hlth, London, England.
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    CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain;Univ Granada, Escuela Andaluza Salud Publ, Inst Invest Biosanitaria Ibs GRANADA, Hosp Univ Granada, Granada, Spain.
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    Johns Hopkins Univ, Inst Med Genet, CIDR, Baltimore, MD USA.
    Sakoda, Lori C.
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA;Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA.
    Schafmayer, Clemens
    Univ Hosp Schleswig Holstein, Dept Gen & Thorac Surg, Campus Kiel, Kiel, Germany.
    Schoen, Robert E.
    Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA.
    Seminara, Daniela
    NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA.
    Shah, Mitul
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England.
    Shelford, Tameka
    Johns Hopkins Univ, Inst Med Genet, CIDR, Baltimore, MD USA.
    Shin, Min-Ho
    Chonnam Natl Univ, Sch Med, Dept Prevent Med, Gwangju, South Korea.
    Shulman, Katerina
    Hillel Yaffe Med Ctr, Oncol Unit, Hadera, Israel.
    Sieri, Sabina
    Fdn IRCCS Ist Nazl Tumori, Epidemiol & Prevent Unit, Milan, Italy.
    Slattery, Martha L.
    Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA.
    Southey, Melissa C.
    Univ Melbourne, Genet Epidemiol Lab, Dept Pathol, Melbourne, Vic, Australia.
    Stadler, Zsofia K.
    Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA.
    Stegmaier, Christa
    Saarland Canc Registry, Saarbrucken, Germany.
    Su, Yu-Ru
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
    Tangen, Catherine M.
    Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, 1124 Columbia St, Seattle, WA 98104 USA.
    Thibodeau, Stephen N.
    Mayo Clin, Div Lab Genet, Dept Lab Med & Pathol, Rochester, MN USA.
    Thomas, Duncan C.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA.
    Thomas, Sushma S.
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
    Toland, Amanda E.
    Ohio State Univ, Ctr Comprehens Canc, Dept Canc Biol & Genet, Columbus, OH 43210 USA;Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Columbus, OH 43210 USA.
    Trichopoulou, Antonia
    Hellen Hlth Fdn, Athens, Greece;Univ Athens, WHO Collaborating Ctr Nutr & Hlth, Unit Nutr Epidemiol & Nutr Publ Hlth, Dept Hyg Epidemiol & Med Stat,Sch Med, Athens, Greece.
    Ulrich, Cornelia M.
    Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA;Univ Utah, Dept Populat Hlth Sci, Salt Lake City, UT USA.
    Van den Berg, David J.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA.
    van Duijnhoven, Franzel J. B.
    Wageningen Univ & Res, Div Human Nutr & Hlth, Wageningen, Netherlands.
    Van Guelpen, Bethany
    Umea Univ, Dept Radiat Sci, Oncol Unit, Umea, Sweden.
    van Kranen, Henk
    Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands.
    Vijai, Joseph
    Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA.
    Visvanathan, Kala
    Johns Hopkins Univ, Dept Epidemiol, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA.
    Vodicka, Pavel
    Czech Acad Sci, Dept Mol Biol Canc, Inst Expt Med, Prague, Czech Republic;Charles Univ Prague, Inst Biol & Med Genet, Fac Med 1, Prague, Czech Republic;Charles Univ Prague, Fac Med, Plzen, Czech Republic;Charles Univ Prague, Biomed Ctr Pilsen, Plzen, Czech Republic.
    Vodickova, Ludmila
    Czech Acad Sci, Dept Mol Biol Canc, Inst Expt Med, Prague, Czech Republic;Charles Univ Prague, Inst Biol & Med Genet, Fac Med 1, Prague, Czech Republic;Charles Univ Prague, Fac Med, Plzen, Czech Republic;Charles Univ Prague, Biomed Ctr Pilsen, Plzen, Czech Republic.
    Vymetalkova, Veronika
    Czech Acad Sci, Dept Mol Biol Canc, Inst Expt Med, Prague, Czech Republic;Charles Univ Prague, Inst Biol & Med Genet, Fac Med 1, Prague, Czech Republic;Charles Univ Prague, Fac Med, Plzen, Czech Republic;Charles Univ Prague, Biomed Ctr Pilsen, Plzen, Czech Republic.
    Weigl, Korbinian
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany;German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany;Heidelberg Univ, Med Fac, Heidelberg, Germany.
    Weinstein, Stephanie J.
    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.
    White, Emily
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
    Win, Aung Ko
    Royal Melbourne Hosp, Genom Med & Family Canc Clin, Parkville, Vic, Australia;Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia.
    Wolf, C. Roland
    Univ Dundee, Sch Med, Dundee, Scotland.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Woods, Michael O.
    Mem Univ Newfoundland, Discipline Genet, St John, NF, Canada.
    Wu, Anna H.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA.
    Zaidi, Syed H.
    Ontario Inst Canc Res, Toronto, ON, Canada.
    Zanke, Brent W.
    Univ Toronto, Div Hematol, Toronto, ON, Canada.
    Zhang, Qing
    Fred Hutchinson Canc Res Ctr, Genom Shared Resource, 1124 Columbia St, Seattle, WA 98104 USA.
    Zheng, Wei
    Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Ingram Canc Ctr,Vanderbilt Ep, Nashville, TN 37212 USA.
    Scacheri, Peter C.
    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Case Comprehens Canc Ctr, Cleveland, OH USA.
    Potter, John D.
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
    Bassik, Michael C.
    Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
    Kundaje, Anshul
    Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA;Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
    Casey, Graham
    Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA.
    Moreno, Victor
    Catalan Inst Oncol IDIBELL, Canc Prevent & Control Program, Barcelona, Spain;CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain;Univ Barcelona, Dept Clin Sci, Fac Med, Barcelona, Spain;Bellvitge Biomed Res Inst IDIBELL, Colorectal Canc Grp, ONCOBELL Program, Barcelona, Spain.
    Abecasis, Goncalo R.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.
    Nickerson, Deborah A.
    Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
    Gruber, Stephen B.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA.
    Hsu, Li
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA;Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
    Peters, Ulrike
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.
    Discovery of common and rare genetic risk variants for colorectal cancer2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 1, p. 76-87Article in journal (Refereed)
    Abstract [en]

    To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

  • 291.
    Hållmarker, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Sandin, Fredrik
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Cancer incidence in participants in a long-distance ski race (Vasaloppet, Sweden) compared to the background population.2015In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 51, no 4, p. 558-568Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We studied the association between taking part in a long distance ski race and cancer incidence to address the hypothesis that a lifestyle involving a high degree of physical activity (PA) lowers cancer incidence with a pattern that is different by cancer site.

    METHODS: Cancer incidence was estimated in a large cohort of skiers (n=185,412) participating in the Vasaloppet long distance ski race in Sweden 1989-2010 and non-participants in the ski race, randomly selected from the Swedish general population (n=184,617). Data include race finishing times as a measurement of physical fitness. Hazard ratios (HRs) and net probability of cancer over twenty years of follow-up were estimated for all invasive cancer, and separately for prostate, breast, colo-rectal and lung cancer, and groups of cancers with presumed relation to lifestyle.

    FINDINGS: Participating in Vasaloppet was associated with a relative risk reduction for all invasive cancer of 6% (95% confidence interval 2-9%) and a relative risk reduction of 32% (95% confidence interval 28-37%) of cancer sites where there is epidemiological evidence that smoking, bodyweight, regular PA and consumption of fruit and vegetables are aetiological factors. For skin cancer the risk was increased, as for prostate cancer. Skiers with shorter finishing times had lower incidence of cancer.

    INTERPRETATION: This study indicates that it is unrealistic to reduce overall population cancer incidence drastically with life style. However, cancers that are epidemiologically associated with life style factors were significantly reduced by what presumably is a blend of non-smoking, normal body weight, sound dietary habits and PA. Our data thus provide additional support for present days' recommendations about life style prevention. Higher health awareness is associated with attendance to screening, which may explain our results for prostate cancer.

    FUNDING: University fund, independent funds from an insurance company and a private foundation.

  • 292.
    Hållmarker, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Mora Hosp, Dept Internal Med, S-79285 Mora, Sweden.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ärnlöv, Johan
    Dalarna Univ, Sch Hlth & Social Studies, S-79188 Falun, Sweden;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, S-17177 Stockholm, Sweden.
    Åsberg, Signild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Wester, Per
    Umea Univ, Dept Publ Hlth & Clin Sci, S-90185 Umea, Sweden;Danderyd Hosp, Karolinska Inst, Dept Clin Sci, S-18288 Stockholm, Sweden.
    Hellberg, Dan
    Ctr Clin Res, S-79182 Falun, Sweden.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    James, Stefan K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Survival and incidence of cardiovascular diseases in participants in a long-distance ski race (Vasaloppet, Sweden) compared to the background population2018In: European Heart Journal - Quality of Care and Clinical Outcomes, ISSN 2058-5225, E-ISSN 2058-1742, Vol. 4, no 2, p. 91-97Article in journal (Refereed)
    Abstract [en]

    We studied the relationship between taking part in a long-distance ski race and incidence of cardiovascular diseases (CVDs) to address the hypothesis that lifestyle lowers the incidence. A cohort of 399 630 subjects in Sweden, half were skiers in the world's largest ski race, and half were non-skiers. Non-skiers were frequency matched for sex, age, and year of race. Individuals with severe diseases were excluded. The endpoints were death, myocardial infarction, or stroke. The subjects were followed up for a maximum of 21.8 years and median of 9.8 years. We identified 9399 death, myocardial infarction, or stroke events among non-skiers and 4784 among the Vasaloppet skiers. The adjusted hazard ratios (HRs) comparing skiers and non-skiers were 0.52 [95% confidence interval (CI) 0.49-0.54] for all-cause mortality, 0.56 (95% CI 0.52-0.60) for myocardial infarction and 0.63 (95% CI 0.58-0.67) for stroke and for all three outcomes 0.56 (95% CI 0.54-0.58). The results were consistent across subgroups: age, sex, family status, education, and race year. For skiers, a doubling of race time was associated with a higher age-adjusted risk of 19%, and male skiers had a doubled risk than female skiers, with a HR 2.06 (95% CI 1.89-2.41). The outcome analyses revealed no differences in risk of atrial fibrillation between skiers and non-skiers. This large cohort study provides additional support for the hypothesis that individuals with high level of physical activity representing a healthy lifestyle, as evident by their participation in a long-distance ski race, have a lower risk of CVD or death.

  • 293.
    Hållmarker, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Michaelsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Arnlov, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Cardiac Arrest in a Long-Distance Ski Race (Vasaloppet) in Sweden2012In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 60, no 15, p. 1431-1432Article in journal (Refereed)
  • 294.
    Hållmarker, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Medicinkliniken Mora Landstinget Dalarna.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Högskolan Dalarna, Falun.
    Hellberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Centrum för klinisk forskning, Dalarna, Falun.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Risk of recurrent ischaemic events after myocardial infarction in long-distance ski race participants2016In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 23, no 3, p. 282-290Article in journal (Refereed)
    Abstract [en]

    AIMS: To study whether a high level of physical activity prior to myocardial infarction (MI) also protects against recurrent MI (re-MI) or death.

    METHODS AND RESULTS: A longitudinal study of a primary cohort consisting of 204,038 skiers with a proved substantially high level of physical activity in the world's largest long-distance ski race, Vasaloppet, and 499,543 non-skiers selected from the Swedish population. Individuals with severe diseases at baseline were excluded. In the nationwide clinical register, Swedeheart, we identified 7092 individuals with a first MI incident between 1989 and 2010. Of these, 1039 (0.5%) were skiers and 6053 (1.2%) were non-skiers. One hundred and sixty-three (15.7%) skiers and 1352 (22.3%) non-skiers suffered a re-MI or died during follow-up (median 4.44 years), corresponding to an incidence rate of 38.9 (95% confidence interval (CI) 33.2-45.4)/1000 person-years and 55.6 (95% CI 52.7-58.7)/1000 person-years, respectively. Severity of MI in both groups was the same. For skiers compared to non-skiers the unadjusted hazard ratio (HR) for re-MI was 0.66 (95% CI 0.52-0.82). For death or re-MI, HR was 0.70 (95% CI 0.59-0.82) with consistent results in subgroups based on race year, age, gender, education level, marital status. After adjustment for also smoking, diabetes, hypertension and cardiovascular medication, HR was 0.80 (95% CI 0.67-0.97).

    CONCLUSIONS: This large cohort study supports the hypothesis that patients with MI and with prior physical activity and healthy lifestyle, as evidenced by their participation in a long-distance ski race, have a lower risk of subsequent re-MI or death.

  • 295.
    Hållmarker, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Reply to" Airway Remodeling and Cardiac Arrest in Long-Distance Ski Races" Journal of the American College of Cardiology, Volume 61, Issue 3, 22 January 2013, Pages 388-3892013In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 61, no 3, p. 389-Article in journal (Other academic)
  • 296.
    Hållmarker, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Åsberg, Signild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Högskolan Dalarna Falun.
    Hellberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Centrum klinisk forskning Dalarna Falun.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wester, Per
    Medicin och folhälsa Umeå Universitet.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Risk of Recurrent Stroke and Death After First Stroke in Long‐Distance Ski Race Participants2015In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 4, no 10, article id e002469Article in journal (Refereed)
    Abstract [en]

    Background Physical activity is of benefit for primary prevention of cardiovascular diseases, but it appears to increase the risk for atrial fibrillation. We aimed to study a cohort of patients following a first stroke in individuals with previous high physical activity, compare them to the general population with respect to recurrent stroke and death, and relate these to atrial fibrillation.

    Methods and Results From the participants of the Vasaloppet, the world's largest ski‐race, and matched individuals from the general population (n=708 604), we identified 5964 patients hospitalized with a first‐time stroke between 1994 and 2010. Individuals with severe diseases were excluded. One half percent of skiers and 1% of nonskiers were hospitalized due to stroke. The incidence rate was 8.3 per 100 person‐years among skiers and 11.1 among nonskiers. The hazard ratio (HR) for recurrent stroke or death between the 2 groups was 0.76 (95% CI 0.67 to 0.86). The result was consistent in subgroups. The HR for death was 0.66 (95% CI 0.56 to 0.78) and for recurrent stroke 0.82 (95% CI 0.70 to 0.96). After adjustment for smoking and socioeconomic factors, the HR for death was consistent at 0.70 (95% CI 0.56 to 0.87) while the HR for recurrent stroke was not statistically significant. Outcomes for skiers with atrial fibrillation tended to show a lower risk than for nonskiers.

    Conclusions This large cohort study supports the hypothesis that patients with a stroke and with prior regular physical activity have a lower risk of death, while their risk for recurrent stroke is similar to that of nonskiers. The skiers had a higher incidence of atrial fibrillation, but still no increased risk of recurring stroke.

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  • 297.
    Iderberg, Hanna
    et al.
    Ivbar Inst, Hantverkargatan 8, S-11221 Stockholm, Sweden;Karolinska Inst, Dept Learning Informat Management & Eth, Med Management Ctr, Stockholm, Sweden.
    Willers, Carl
    Ivbar Inst, Hantverkargatan 8, S-11221 Stockholm, Sweden;Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden.
    Borgstrom, Fredrik
    Ivbar Inst, Hantverkargatan 8, S-11221 Stockholm, Sweden;Karolinska Inst, Dept Learning Informat Management & Eth, Med Management Ctr, Stockholm, Sweden.
    Hedlund, Rune
    Sahlgrens Univ Hosp, Dept Orthopaed, Gothenburg, Sweden.
    Hagg, Olle
    Spine Ctr Goteborg, Gothenburg, Sweden.
    Moller, Hans
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.
    Ornstein, Ewald
    Orebro Univ Hosiptal, Dept Orthopaed, Orebro, Sweden.
    Sandén, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Stalberg, Holger
    Stockholm Cty Council, Halso O Sjukvardsforvaltningen, Stockholm, Sweden.
    Torevall-Larsson, Hans
    Falu Lasarett, Falun, Sweden.
    Tullberg, Tycho
    Stockholm Spine Ctr AB, Lowenstromska Sjukhuset, Upplands Vasby, Sweden.
    Fritzell, Peter
    Futurum Acad, Jonkoping, Sweden;St Goran Hosp, Stockholm, Sweden.
    Predicting clinical outcome and length of sick leave after surgery for lumbar spinal stenosis in Sweden: a multi-register evaluation2019In: European spine journal, ISSN 0940-6719, E-ISSN 1432-0932, Vol. 28, no 6, p. 1423-1432Article in journal (Refereed)
    Abstract [en]

    Purpose: Lumbar spinal stenosis (LSS) can be surgically treated, with variable outcome. Studies have linked socioeconomic factors to outcome, but no nation-wide studies have been performed. This register-based study, including all patients surgically treated for LSS during 2008-2012 in Sweden, aimed to determine predictive factors for the outcome of surgery.

    Methods: Clinical and socioeconomic factors with impact on outcome in LSS surgery were identified in several high-coverage registers, e.g., the national quality registry for spine surgery (Swespine, FU-rate 70-90%). Multivariate regression analyses were conducted to assess their effect on outcome. Two patient-reported outcome measures, Global Assessment of leg pain (GA) and the Oswestry Disability Index (ODI), as well as length of sick leave after surgery were analyzed.

    Results: Clinical and socioeconomic factors significantly affected health outcome (both GA and ODI). Some predictors of a good outcome (ODI) were: being born in the EU, reporting no back pain at baseline, a high disposable income and a high educational level. Some factors predicting a worse outcome were previous surgery, having had back pain more than 2years, having comorbidities, being a smoker, being on social welfare and being unemployed.

    Conclusions: The study highlights the relevance of adding socioeconomic factors to clinical factors for analysis of patient-reported outcomes, although the causal pathway of most predictors' impact is unknown. These findings should be further investigated in the perspective of treatment selection for individual LSS patients. The study also presents a foundation of case mix algorithms for predicting outcome of surgery for LSS.

  • 298.
    Ingelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vasan, Ramachandran S.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Blomhoff, Rune
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Circulating retinol-binding protein 4, cardiovascular risk factors and prevalent cardiovascular disease in elderly2009In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 206, no 1, p. 239-244Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Our aim was to examine relations of serum retinol-binding protein 4 (RBP4) to cardiovascular risk factors, and prevalent metabolic syndrome (MetS) and cardiovascular disease (CVD) in a large community-based sample of elderly. METHODS: We evaluated cross-sectional relations of serum RBP4 to cardiovascular risk factors including anthropometrical measures, blood pressure, lipid measures, fasting glucose and insulin, body fat distribution including truncal fat by dual-energy x-ray absorptiometry (DXA), homeostasis model assessment insulin resistance (HOMA-IR) and prevalent MetS in one thousand eight 70-year old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), and in five hundred seven 82-year old men from Uppsala Longitudinal Study of Adult Men (ULSAM). In ULSAM, we also examined associations with prevalent CVD. RESULTS: RBP4 concentrations were positively correlated with serum triglycerides (r=0.30; P<0.0001 in both samples), whereas correlations with body mass index (BMI), waist circumference, sagittal abdominal diameter, total and truncal fat mass, total cholesterol, fasting glucose and HOMA-IR were weak. In multivariable-adjusted models, RBP-4 was associated with MetS (odds ratio (OR), 1.16 and 1.33; 95% confidence interval (CI), 0.99-1.37 and 1.05-1.67 per 1-standard deviation (SD) increase in PIVUS and ULSAM, respectively), and prior cerebrovascular disease (OR, 1.37; 95% CI, 1.00-1.88 per 1-SD increase in ULSAM), but not with prior myocardial infarction. CONCLUSION: In elderly, RBP4 concentrations were associated with MetS and its components in both sexes, and prior cerebrovascular disease in men. These findings are consistent with the hypothesis that circulating RBP4 could be a marker of metabolic complications and possibly also atherosclerosis and overt CVD.

  • 299.
    Ingelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Relative importance and conjoint effects of obesity and physical inactivity for the development of insulin resistance2009In: European Journal of Cardiovascular Prevention & Rehabilitation, ISSN 1741-8267, E-ISSN 1741-8275, Vol. 16, no 1, p. 28-33Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Obesity and physical inactivity are related to the development of insulin resistance, but their relative importance and conjoint effects are unclear. METHODS: We related body mass index (BMI) and self-reported leisure-time physical activity (PA) at the age of 50 years to insulin sensitivity measured with euglycemic insulin clamp technique and the presence of metabolic syndrome (MetS) at a subsequent examination, 20 years later, in 862 men free from diabetes and MetS at baseline. RESULTS: In a multivariable model including BMI, PA, homeostasis model assessment insulin resistance index, erythrocyte sedimentation rate, and all components of MetS at baseline, both BMI (beta, -0.19 mg/kg bodyweight/min per 1 kg/m; P<0.0001) and PA (adjusted least square means, 5.1, 5.2, 5.4, and 6.2 mg/kg bodyweight/min in individuals with sedentary, moderate, regular, and athletic PA, respectively; P=0.0035) were significant predictors of insulin sensitivity at age 70. When categorizing individuals into four groups by BMI and PA at baseline, insulin sensitivity at the age of 70 years decreased significantly over the following categories: multivariable-adjusted least square means, 5.8 (low BMI/high PA); 5.6 (low BMI/low PA); 5.1 (high BMI/high PA); and 4.6 (high BMI/low PA) mg/kg bodyweight/min, respectively; P value of less than 0.0001. CONCLUSION: In our community-based sample of middle-aged men, BMI and PA were independent predictors of insulin resistance after 20 years of follow-up. Our results imply that obesity and physical inactivity may increase insulin resistance and metabolic risk by partly independent pathways, and emphasize the importance of strategies that address both obesity and physical inactivity to achieve increased public health.

  • 300. Jaafar, G.
    et al.
    Persson, G.
    Svennblad, Bodil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sandblom, G.
    Outcomes of antibiotic prophylaxis in acute cholecystectomy in a population-based gallstone surgery registry2014In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 101, no 2, p. 69-73Article in journal (Refereed)
    Abstract [en]

    Background

    The aim of this study was to assess the effect of antibiotic prophylaxis (AP) on postoperative infections in acute cholecystectomy.

    Methods

    The study was based on acute cholecystectomies registered in the nationwide Swedish Register for Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (GallRiks) between 2006 and 2010. The association between AP and the risk of postoperative infectious complications was tested in a multivariable regression analysis, with stepwise addition of age, sex, duration of operation, indication for surgery, surgical approach (laparoscopic versus open) and American Society of Anesthesiologists (ASA) fitness grade as co-variables. Postoperative infections requiring antibiotic treatment and postoperative abscesses were defined as outcome measures.

    Results

    AP was given to 9549 (68<bold>6</bold> per cent) of 13 911 patients. Postoperative infections requiring antibiotic treatment occurred following 1070 procedures (7<bold>7</bold> per cent), including 805 patients (8<bold>4</bold> per cent) who received AP (P < 0<bold>001</bold> versus patients without AP). Postoperative abscesses developed after 273 procedures (2<bold>0</bold> per cent), including 208 patients (2<bold>2</bold> per cent) who received AP (P = 0<bold>007</bold>). In univariable analysis, the odds ratio for development of infectious complications necessitating treatment with antibiotics was 1<bold>42</bold> (95 per cent confidence interval 1<bold>23</bold> to 1<bold>64</bold>) for those who received APversus those who did not, and for postoperative abscesses it was 1<bold>47</bold> (1<bold>11</bold> to 1<bold>95</bold>). In multivariable analysis, adjusting for confounders, the odds ratios were 0<bold>93</bold> (0<bold>79</bold> to 1<bold>10</bold>) and 0<bold>88</bold> (0<bold>64</bold> to 1<bold>21</bold>) respectively.

    Conclusion

    The present study suggests that AP provides no benefit in acute cholecystectomy. No benefit from antibiotics

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