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Contents 1

Final push

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Facts and Figures 2013

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Research Projects P ercutaneous Bone Cement Refixation of Loosened Hip Prostheses. D.F. Malan P atellofemoral Pressure Changes after MPFL Reconstruction. A. Rood  Stromal Cell-Derived Factor-1 Stimulates Cell Recruitment, Vascularization and Osteogenic Differentiation. R.M. Eman

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PhD Theses

2013 Review Final Push Prof. Riekie de Vet looks back on her time as a member of the Anna Foundation’s Scientific Advisory Board from 2005 till 2013. The most surprising project that prof. Riekie de Vet remembers is the orthopaedic application of a water drill developed at the Delft University of Technology. “The researchers wanted to experiment with this instrument that uses a jet of water to drill. They hoped that it would

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Travel Grants for Young Researchers

be possible to drill into bone and to simultaneously drain away any residues.“

Science Bug. D. Ring  Speedy Research with Feeling. A. Bot G  reater Range of Methods. T. Hoogeboom Bitten by the Trauma Virus. W. van der Wal

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Travel Grant A  broad, but Back in Leiden within Two Hours. S. Peters

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Obituaries prof. F. Duijfjes dr. G. Onvlee

What is the strength of the Anna Foundation? “The Anna Foundation is suited for projects that are not yet ready for big grant proposals. It gives aspiring researchers a chance to perform a try out. Sometimes, interesting results lead to further exploration of the data. The Anna Foundation can support such unforeseen extra analyses.  Financing the expertise of a methodologist is also a possibility. The Anna Foundation’s support is usually intended for material rather than for personal expenses. This support for material can often be the final push needed to convince research groups to start a pilot study. Subsequently, the pilot can be a useful leg up to a bigger project.” How does the Scientific Advisory Board function? “We all assessed the proposals at home, which meant a weekend of reading. In our meetings we compared notes and discussed which proposals were the best. We always held very enjoyable and constructive meetings, and the board members represented all the disciplines in which the Anna Foundation is active.”


Facts and Figures 2013 Research projects finished in 2013 Annual round of about 50 proposals, approval of Scientific Advisory Board, maximum budget of € 15,000 per proposal. Six projects were finished in 2013. Budgets varied from a few thousand to 12,000 euros. Three projects are highlighted in this review.

PhD Theses The Anna Fonds gives grants as contribution in the printing and distribution of PhD theses relevant for the field of orthopaedics (€ 200 - 400 per thesis). 40 were awarded in 2013 and about 10 proposals were rejected.

Travel Grants for Young Doctors and Researchers The Anna Fonds awarded 19 grants in 2013. Four impressions of students or junior doctors who received a grant in 2012 demonstrate the benefits of the training abroad.

Financials The 2013 financial overview was still being compiled at the time of printing this review. Available at www.annafonds.nl from May 2014.

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Donations Do you want more and better orthopaedic treatment options for arthrosis, osteoporosis, bone and joint trauma and congenital malformation, also aiming at long term effectiveness? Donate to Anna Fonds | NOREF, to • Attract talented researchers to the field • Facilitate and stimulate research. The Anna Fonds is ANBI-recognized. Donations are tax deductible. IBAN NL43ABNA0566938014 2


Research projects awarded in 2013 The Scientific Advisory Board prioritizes requests for research projects. Nine research projects were awarded in 2013. Job van Susante (1968), Ziekenhuis Rijnstate, Arnhem: Asymptomatic pseudotumours after metal-on-metal hip arthroplasty. Jasper van Tiel (1984), Erasmus MC, Rotterdam: Quantitative MRI techniques to measure knee cartilage quality: Clinical validation and evaluation. Emiel van IJsseldijk (1981), LUMC, Leiden: In vivo validation of model-based wear measurements for knee protheses. Marrigje Meijer (1987), UMCG, Groningen: Clinical biomechanical study of the stability of tibial trabecular metal cones with and without stem. W.F.H. Peter (1965), VUmc, Amsterdam: Validation of a patient-reported computer animation questionnaire (AAQ) for measuring functional limitations of patients with hip and knee osteoarthritis. Loek Loozen (1986), UMC Utrecht, Utrecht: Non-viral gene therapy of several growth factors to stimulate in vivo bone formation. W. Boot (1986), UMC Utrecht, Utrecht: Detection and identification of bacteria in orthopaedic low-grade infections. Roderick Holewijn (1990), VUmc, Amsterdam, and Tom Schlösser (1987), UMC Utrecht, Utrecht: Changes in movement freedom and posterior extension possibilities of the thoracal spine by posterior releases.

Orthopaedic surgeon Denise Eygendaal, Amphia Hospital in Breda, has been elected as 2014 ‘Top Doctor’. The election of the Top Doctor is organized by Mednet and the ‘Orde van Medisch Specialisten’. Medical specialists were able to vote for ten nominated doctors. Denise Eygendaal, the 2013 Anna Award winner, received 24% of the 1100 votes. She is the elbow specialist in the field of orthopaedics.

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Anna Award winner elected as 2014 ‘Top Doctor’

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Research Projects Percutaneous Bone Cement Refixation of Loosened Hip Prostheses: the Effect of Interface Tissue Removal on Injected Cement Volumes D.F. Malan, E.R. Valstar, R.G.H.H. Nelissen, Department of Orthopaedics, LUMC, Leiden Revision surgery has higher perioperative mortality and morbidity rates in elderly and high-risk groups. Hip prosthesis refixation by minimally invasive percutaneous cement injection is an experimental treatment for patients with aseptic prosthesis loosening. The incompressible periprosthetic fibrous tissue is not removed during this injection and may impede sufficient cement flow.

purpose To quantify whether injected cement volumes differed between a group undergoing only percutaneous cement injections to refix loose hip prostheses, and a group undergoing pre-operative gene-directed enzyme pro-drug therapy to remove fibrous interface tissue prior to percutaneous cement injection.

patients We analyzed seventeen cases (14 female, 3 male, ages 72-91, ASA categories 2-4) that were treated at our institution. Osteolytic lesions and injected cement were manually delineated using 3D CT image segmentation, and the deposition of injected cement was quantified.

results Patients who underwent pre-operative gene-directed enzyme therapy to remove fibrous tissue exhibited larger injected cement volumes than those who did not.

conclusion

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We conclude that prior removal of periprosthetic fibrous interface tissue may enable improved cement penetration which may lead to better refixation of aseptically loosened prostheses.

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publication submitted The first author received I 4000 from the Anna Foundation.


Patellofemoral Pressure Changes after Static and Dynamic MPFL Reconstruction A. Rood, G. Hannink, A. Lentink, S. Koeter, N. Verdonschot, A. van Kampen. Department of Orthopaedic Surgery, Radboudumc, Nijmegen Instability between the upper leg and patella (patellofemoral instability) can often be cured by surgery. One surgical method is reconstructing the Medial PatelloFemoral Ligament (MPFL). This can be done by attaching the new ligament to the bony structures using tunnels and/or screws, or by attaching the graft to soft tissue on both sides, only. After reconstructions, the patellofemoral pressure can change, which may lead to a higher rate of patellofemoral arthrosis.

purpose Which method of MPFL reconstruction best approaches the original situation in terms of patellofemoral pressure?

groups Seven fresh frozen knee specimens were tested using a pressure sensor and a knee joint motion and loading apparatus. Pressures and contact areas were measured in the following five conditions: A. normal, B. cut (the MPFL was cut by opening the medial arthrotomy), C. dynamic reconstruction of the MPFL (graft attached only to soft tissues), D. partial dynamic MPFL reconstruction (graft attached by fixing through two bony tunnels and attaching them together on top), and E. static reconstruction of MPFL (graft stapled onto the femur).

results Mean patellofemoral pressures increased slightly with deeper flexion. The static reconstruction (E) showed a higher mean pressure than the baseline (A) and dynamic reconstructions (C). The peak pressures of the dynamic reconstruction looked most like the baseline condition.

conclusion The patellofemoral pressures in the dynamic reconstructions most resembled the normal situation, more than the ones in the static reconstruction.

submitted to American Journal of Sports Medicine, 2014 The first author received I 12,000 from the Anna Foundation.

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publication

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Stromal Cell-Derived Factor-1 Stimulates Cell Recruitment, Vascularization and Osteogenic Differentiation. R.M. Eman, E.T. Hoorntje, M.C. Kruyt, F.C. Öner, J. Alblas, W.J.A. Dhert. Department of Orthopaedics, UMC Utrecht The use of growth factors in osteogenic constructs to promote recruitment of bone-forming endogenous cells is not apparent, whilst the advantage of circumventing cell-seeding techniques before implantation is highly recognized. The chemokine stromal cell-derived factor 1-∝ (SDF-1∝) protein is known to have various effects on bone regeneration.

purpose Is the chemokine stromal cell-derived factor-1∝ (SDF-1∝) able to recruit (enough) mesenchymal stem cells to stimulate bone formation?

groups SDF-1∝ was used in very low concentrations to investigate bone formation. The additive effect of SDF-1∝ on endogenous cell recruitment and vascularization was investigated in a hybrid construct, consisting of a ceramic biomaterial, hydrogel, and SDF-1∝, in an ectopic mouse model.

results We demonstrated in vivo that local presence of low concentrations of SDF-1∝ resulted in a significant increase in recruited endogenous cells, which remained present for several weeks. SDF-1∝ stimulated vascularization in these hybrid constructs, as shown by the enhanced formation of erythrocyte-filled vessels. The presence of CD31-positive capillaries/small vessels after six weeks in vivo substantiated this finding. The SDF-1∝ treatment showed increased numbers of cells that could differentiate to the osteogenic lineage after six weeks of implantation, demonstrated by expression of collagen I and osteocalcin.

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conclusion

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We were able to demonstrate the beneficial effects of the local application of a single growth factor in a hybrid construct on the formation of vessels, which is advantageous for bone formation. In addition, the recruited cells formed a collagen matrix and were able to differentiate towards the osteogenic lineage. These results are important for the improvement of implants for bone regeneration.

publication Tissue Eng Part A. 2013 Oct 22. The first author received I 11,755 from the Anna Foundation for this study and a second one.


PhD Theses The Anna Fonds granted contribution in the printing and distribution of 40 PhD theses. Four outstanding PhD theses are presented here. Roelof Waaijman (1974) Improving footwear to prevent ulcer recurrence in diabetes: analysis of adherence and pressure reduction. University of Amsterdam Plantar foot ulcer recurrence, often occurring in patients with advanced diabetes and leading to dangerous infections and amputations (with considerable emotional loss), cannot be avoided by merely using orthopaedic footwear, unless complemented with regular measurements of peak foot pressure. To avoid problems improved off-loading custom-made footwear should be worn regularly. Promotor: F. Nollet Co-promotors: S.A. Bus, M. de Haart J.M. Brinkman (1975) Fixation stability and new surgical concepts of osteotomies around the knee. Utrecht University, 2013 Current concepts of surgical osteotomy in the lateral compartment of the knee in particular have led to better results i.e. to fewer postoperative fixation stability problems. Moreover, results from new implants for femoral varus osteotomies were encouraging, especially when postoperativere habilitation was appropriate. Promotor:  R.M. Castelein Co-promotor: R.J. van Heerwaarden Marjolein Caron (1985) Novel perspectives in regulation of chondrogenic differentiation. Maastricht University, 2013 Molecular pathways involved in regulating the chondrogenic phase of endochondral ossification were clarified. These findings not only show a logical way to stimulate cartilage and endochondral bone (re)generation, but may also provide valuable information on how to keep differentiating progenitor cells or mature chondrocytes in the desired differentiation phase. Promotor:  L.W. van Rhijn Co-promotors: T.J.M. Welting, P.J. Emans

Promotor:  prof. P. Buma Co-promotors: R.M. Bloem, B.W. Schreurs, P. Pilot

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Nina Mathijssen ( 1980) Novel perspectives to improve the outcome of bone impaction grafting in revision surgery of total hip arthroplasties. Radboud University, Nijmegen Based on an experimental study in goats, bone impact grafting used during hip revision surgery could be improved substantially by treatment of the allograft bone chips during grafting without unduly increasing the risk of infections.

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Travel Grants for Young Doctors and Researchers The Anna Fonds gives grants to students, doctors and postdocs who wish to go abroad for practical and/or research training. By stimulating MSc or PhD students who are considering or have decided to pursue orthopedic research, the Anna Fonds hopes to bind them to this challenging field which is often in competition with other fields of medicine. The Anna Fonds awarded 19 travel grants in 2013. Four impressions of students or trainees who received a grant in 2012 demonstrate the benefits of the training abroad. One of the favorite destinations is the Hand and Upper Extremity Service of the Department of Orthopaedic Surgery at Massachusetts General Hospital (MGH) in Boston, where researchers are supervised in doing clinical research by David Ring, MD PhD (1967). In December 2013, David Ring was in Amsterdam to attend the PhD defense of one of these visitors; Arjen Bot. This was an ideal opportunity to ask him what his secret to successfully guiding those Dutch visitors in research is. The science bug: Hypotheses and study questions are crucial The exchange started in 2002, when David Ring and Job Doornberg (AMC Amsterdam) met. In 2005 they both defended their PhDs in Amsterdam and since then a lot of Dutch students have attended Boston. Ring: ‘It is great to have smart, passionate, dedicated young people. You could not wish for a better group of students. The hardest thing about my job is coming up with enough ideas for research.’ Dutch students praise your efficiency in their reports to Anna Fonds. How can you be so responsive? “I want to be connected. Email is a very comfortable way of communicating on the protocol and data analysis. We may end up doing ten, twenty or even thirty drafts for a paper. We start with just tables, then methods and results, then introduction and discussion, and finally the abstract. Thus we waste less time, I make sure that we follow our protocol and that the student understands the analysis, and I get a chance to better understand how to interpret the data. I hope that they will end up loving science. To avoid unnecessary work and tedium we do things stepwise. And I have seen it happen, young people who get bitten by the science bug.” David Ring

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Speedy Research with Feeling dr Arjan Bot (1985) Resident in orthopaedic surgery since March 2013 (Amsterdam, Alkmaar) Hand and Upper Extremity Service of the Department of Orthopaedic Surgery at Massachusetts General Hospital in Boston, February 2011 - March 2013 Friday December 13th, 2013, nothing unusual seemed to be happening in the Agnietenkapel in the center of Amsterdam: a young researcher, Arjan Bot, was defending his PhD. But this graduation was unusual in three respects: Bot finished his PhD research quickly; in just two and a half years, his research was done in Boston, and orthopaedic problems turned out to be influenced by psychological problems. Bot explains how this came to be: “Becoming a miniexpert and contributing to research and thus to patient care, was what I wanted to do after graduating as a physician. Through my experiences, I had learned that psychological factors are important. I read about the way that dr. David Ring handled a mistake in the New England Journal of Medicine. He impressed me with his integrity. Other researchers told me that he had been conducting a lot of research.” The Anna Foundation supported Arjan Bot with a travel grant and he spent two years in Boston doing research with David Ring. “He also inspired me in the consultation room. He has a very disarming way of speaking with patients, by naming the feeling he sees in the patient for example. He is very efficient in his research. Although he was working on research with at least twenty people, he did not have any problems remembering the details of my studies and answered all my e-mails promptly.”

Arjan Bot (in the back, second left)

‘Pain and psychological factors are better predictors of disability than physical impairment after distal radius fractures.’ Statement in Arjan Bot’s PhD thesis: Illness behavior in patients with musculoskeletal disease.

Greater Range of Methods Thomas Hoogeboom (1982), PhD Physiotherapist and Movement Scientist Physical Therapy Program, Department of Physical Medicine and Rehabilitation, University of Colorado, Denver, Colorado, USA, May - October 2012 Linear and curvilinear relationship between knee range of motion and physical functioning in people with knee osteoarthritis: a cross-sectional study. Published in PLoS ONE: http://dx.plos.org/ambra-doi-resolver/10.1371/journal.pone.0076173. Plus three other projects. Hoogeboom extended his research experience in Denver. One of his projects was an evaluation of the use of the knee range of motion (ROM) in the management of patients with osteoarthritis.

Thomas Hoogeboom (right)

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“Many health care providers still consider knee range of motion a crucial outcome parameter in the management of people with osteoarthritis, and therefore go to great lengths to achieve an ‘optimal’ knee ROM. This was also the case in Denver.” In the literature, it has been shown that ROM is unrelated to the functioning of the patient. However, this had only been evaluated with models that assume linearity. Hoogeboom argues: “In my opinion, it was unlikely that every additional degree in knee ROM will reflect better physical functioning of the patient. One may reason that a patient needs a minimal knee ROM to perform the most important activities; cut-offs in ROM may thus be much more relevant.” Therefore, a study was performed in collaboration with physical therapists and orthopedic surgeons in a local hospital in Denver. No relevant cut-off for knee ROM in relation to functioning was found. “The people at the physical therapy program of the University of Colorado want me back as a consultant researcher. So, hopefully, I will go back to Denver; a beautiful city with 300 sunny days a year, ski resorts at an hour’s drive away, and friendly people, soon.”

Bitten by the Trauma Virus Wybren van der Wal (1977) Presentation ‘Fight Bite’ hand injuries Fellowship in Adult Trauma, Orthopaedic Trauma Unit, Royal Infirmary of Edinburgh, Scotland, August 1, 2012 - February 5, 2013

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Van der Wal spent six months of his orthopaedic fellowship at the Edinburgh Orthopaedic Trauma Unit: “Once a week I was on call, usually with Mr. Oliver, the consultant to whom I was assigned. Up to forty admissions in one on call period were no exception. The following day a ward round would be done to see all the admitted patients. After this, two or three trauma theatres would be running all day, one of which would be running in the evening.” Van der Wal wanted to broaden and deepen his experience of trauma surgery, and he was given the opportunity to do so. The Edinburgh Orthopaedic Trauma Unit serves a population of about 650,000 people, making it one of the biggest trauma units worldwide. Van der Wal held a presentation about the sequelae of a fight bite. Besides the enormous amount of work and the great learning experience, he was also able to enjoy life in Scotland: “Edinburgh is a very attractive city. Many cultural festivals take place in Edinburgh and there are numerous cheerful pubs.”

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Wybren van der Wal


Stichting Anna Fonds | NOREF Postbus 1021 2340 BA Oegstgeest 071 523 22 24 info@annafonds.nl ABN AMRO IBAN NL43ABNA0566938014

The Anna Fonds is an ANBI acknowledged foundation. Board members Prof. J.W.W. Coebergh C.L. Onvlee, MSc H.H. Friederich, MBA, MD Prof. R.G.H.H. Nelissen (representing Orthopaedic Professors) (until 2014) Prof. B.J. van Royen (scientific secretary of NOV) Scientific Advisory Board Prof. J.W.W. Coebergh, chairman, since 2014 Prof. S. Bierma-Zeinstra, Department of General Practice, Erasmus MC, Rotterdam, new in 2013 Prof. A. van Kampen, Orthopaedic traumatology, RadboudUMC, Nijmegen Prof. W.J.A. Dhert, Orthopaedics/Biomedical Imaging, UMC Utrecht Prof. R.L. Diercks, Orthopaedics/Sports Medicine, UMC Groningen Dr R.M. Bloem, Orthopaedic surgeon, Reinier de Graaf Gasthuis, Delft Dr W.J.C.M. Marijnissen, Orthopaedic surgeon, Albert Schweizer Ziekenhuis, Dordrecht Prof. F. Nollet, Rehabilitation, AMC Amsterdam, new in 2013 Secretariat Mrs. C.C. van Leeuwen-Hoogeveen Colofon Copy and text editing: Anja Edwards van Muijen, J.W.W. Coebergh Design: Opus Design Print: Drukkerij Nivo Anna Fonds | NOREF Policy 2014 Board member (incoming chairman) Hubert Friederich presented the outlines of the policy at the autumn NOV meeting, October 11, 2013, http://www.annafonds.nl/pagina/Beleid/2067/ ANNA Fonds | NOREF 2 013 Rev ie w

Private Donations to Anna Fonds | NOREF 2013-2014 Biomet Nederland BV DePuy, a Johnson & Johnson company Zimmer Netherlands BV Heraeus Kulzer Benelux BV Pro-Motion Medical BV Rotterdam Academic OrthopaedicResearch (van Linge) Foundation Stryker Netherlands BV

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Travel grant Abroad, but Back in Leiden within Two Hours Sebastian Peters Fellowship at the university hospitals in Leuven, Belgium, August 2012 – August 2013 Two scientific articles published, one submitted, three in preparation. At present: hand and wrist surgeon in Leuven. At the university Hospital for two days a week, and at Heilig Hart Hospital for three days a week. Sebastian Peters, orthopaedic surgeon, is passionate about the hand and wrist. Two years ago, this presented him with three problems: in the Netherlands, orthopaedic surgeons have to operate on other joints as well, there is competition from plastic surgeons and few jobs are available. He wished to specialize in hand surgery as well as to undertake research. After considering Canada, New Zealand und the UK, he ended up in Leuven. “Belgium really is another country than the Netherlands. You have to immigrate and take care of all the administrative business that comes with immigrating, and you have to adjust to a different culture. For example, we have young children, and here in Belgium they are allowed to just be children. They are not pushed to behave beyond their age or to take part in every craze. Life and work are directed at enjoying life. We decided to stay in Belgium, but can still be back in Leiden within two hours. Furthermore, in my current work I am able to combine the most beautiful of two worlds: hand surgery in an academic and hand surgery in a peripheral setting.”

Obituaries Two famous and dedicated orthopaedic Annakliniek surgeons passed away in the last two months of 2013: Freek Duijfjes & Gerard Onvlee In speeches at his 80th birthday party in 1998, and in a Liber Amicorum, edited by Ruud Poll, prof. Freek Duijfjes (1918-2013) was described by most of his pupil orthopaedic surgeons as a very dedicated professional who taught both the surgical trade, as well as guided numerous innovations into orthopaedic practice, especially for children and young adults with congenital conditions, for patients with rheumatoid arthritis, arthritic problems and bone tumors. Duifjes initiated the establishment of the still-functioning national Bone Tumour Committee in Leiden, in collaboration with a radiologist and a pathologist. Prof. Frederik Duijfjes, worked as an orthopaedic surgeon at the Annakliniek since 1952. Academic Hospital Leiden, since 1977, PhD in 1965, professor of Orthopaedics at University of Leiden (1970 – 1983). Gerard Onvlee (1926-2013), orthopaedic surgeon AZ Leiden (1970 – 1991), became experienced in traumatology and surgical treatment of lepra affected extremities, after having worked in Indonesia as a general doctor. This laid the foundation for his thesis on diabetic patients with the same type of problems, which was written in 1998. He started a bone bank at his home in the mid 70s. He also worked in Congo between 1991 and 1995.

Source: Scaphoid malunion with 180° rotation of the proximal pole after treatment for trans-scaphoid perilunate fracture dislocation. S. J. Peters, M. P. W. van Nuffel and I. Degreef. J Hand Surg Eur, 8 January 2013


Anna Fonds|NOREF 2013 Review