Treatment modalities for patients with varus medial knee osteoarthritis

Abstract Osteoarthritis (OA) is one of the most common joint disorders in the Western population, which causes pain, stiffness, loss of function and disability. In patients with OA the cartilage, located at the ends of long bones, is damaged. OA is most prevalent in the knee joint. In case of varus malalignment the medial compartment of the knee is most commonly affected. The initial treatment of varus medial knee OA is non-operative, and consists of patient education, weight reduction, physical therapy, use of orthoses, intra-articular steroid injections and if needed pain medication. Orthoses are intended to unload the medial compartment of the knee. Not all patients experience benefit of orthoses and therapeutic effect vary between studies. Therefore the first aim of this thesis was to evaluate the therapeutic effect of orthoses in the treatment of varus medial knee OA. When non-operative treatment fails surgical treatment will mostly be considered. The surgical treatment consists of valgus high tibial osteotomy (HTO), unilateral knee arthroplasty (UKA) or a total knee arthroplasty (TKA). In case of isolated medial knee OA, a HTO or UKA is mostly the preferred intervention. OA is a chronic disease which could progress over years. One of the goals of a HTO is to slow down disease progression and to postpone the need for a TKA as long as possible, by unloading the diseased compartment. Multiple studies comparing different HTO techniques are published with a 1 or 2 year follow-up, however there is a lack of prospective long term results, especially for the relatively new opening-wedge technique. Therefore the second aim of this thesis was to study the long term results of both closing- and opening-wedge HTO. In general, results after TKA and HTO are good. However, a subset of patients has suboptimal improvement in pain, physical functioning, and quality of life and are not satisfied with their postoperative result. The explanation of these suboptimal results is not always completely physical. Psychological factors, such as anxiety and depressive symptoms or preoperative expectations, could be related to these suboptimal results. The ultimate goal of all orthopaedic procedures is patient satisfaction. Identification of modifiable risk factors for dissatisfaction could contribute to optimization of this important outcome. Therefore the final question addressed in this thesis is whether the different psychological factors are related to patient satisfaction after TKA. In Chapter 2 we summarized the literature about the therapeutic effect of orthoses in the treatment of knee OA. In this Cochrane review 13 studies including 1356 patients were included. Overall, quality of evidence found in these studies was moderate or low. The follow-up time varied from 1 – 24 months. No long term follow-up study determining the influence on progression of OA has been performed. We concluded that a valgus knee brace and a laterally wedged insole both have small beneficial effects in terms of improvement of pain, symptoms and functional outcome in patients with varus medial knee OA. No certain difference between both interventions was seen in this Cochrane review. The long term adherence was low for both intervention, especially the knee brace group. Moreover, there might be no difference in therapeutic effect between a laterally wedged insole and a neutral insole. In Chapter 3 we present the results of our biomechanical evaluation of the valgus knee brace and laterally wedged insole. In this study we performed gait analysis of patients with varus medial knee OA treated with one of these two interventions for six months. Gait analysis was performed at baseline and after six weeks of wearing the intervention. In this study we found that wedged insoles only unload the medial compartment at baseline. At baseline a reduction of the peak Knee Adduction Moment (surrogate measure of the medial load) of 3.6% was seen. No biomechanical alteration was seen after 6 weeks of wearing the insole. Valgus brace therapy did not result in any biomechanical alteration at baseline and after 6 weeks. So in this study we could not confirm that the beneficial effects of orthoses can be explained by a certain dynamical alteration, in other words a changed gait pattern. In Chapter 4 the six year results of our RCT comparing closing and opening-wedge HTO are presented. After six year opening-wedge HTO was associated with more complications (37% vs 9%), however closing-wedge HTO was associated with more early conversions to TKA (25% vs 8%). Of the patients who had no conversions to a TKA, no difference in clinical outcome and radiological alignment was seen. We present in Chapter 5 the results of a retrospective assessment of all patients who underwent a HTO in our clinic. We found in this study of 412 patients more adverse events in a closing-wedge group than in an opening-wedge group (28% versus 14%). Hardware was removed in 48% of the closing-wedge HTO’s and 71% of the openingwedge HTO’s. Another major adverse event was iliac crest pain, caused by harvesting the bone for spongiosaplasty (19,7% of the patients in the opening-wedge group). The survival of the opening-wedge group was significantly better than the closing-wedge group, when conversion to a prosthesis was taken as endpoint, however an equal number of patients were in need for a UKA or TKA in both groups. We summarized the literature about the influence of preoperative expectations on patient satisfaction after TKA in Chapter 6. In this systematic review 3 high and 5 low quality studies were included. Although it is a frequently assumed relation, we conclude in this review that there is only limited or conflicting evidence that high expectations lead to more dissatisfaction. However, moderate evidence was found that unfulfilled expectations lead to more dissatisfaction. In Chapter 7 we present the results of our multicenter study, in which we examined the prevalence of two important psychogical symptoms, namely depressive and anxiety symptoms in patients with end-stage OA of the knee. These psychological symptoms were measured with the Hospital Anxiety and Depression Scale, a widely used validated questionnaire. Besides, we determined the influence of these symptoms on the outcome of TKA. We found in this study a high prevalence of anxiety (20.3%) and depressive symptoms (22.7%) in a population with end stage knee OA. After surgery a significant decrease of the prevalence of these symptoms was seen. The prevalence of anxiety symptoms decreased to 14.8% and of depressive symptoms to 11.7%. Preoperative depressive symptoms predicted lower patient reported outcomes after surgery. Patients with preoperative anxiety or depressive symptoms were less satisfied postoperatively. The main topics of this thesis are placed in a broader perspective in Chapter 8. The limitations of this thesis and some recommendations for future research are discussed in this chapter

Performance and structure of single-mode bosonic codes

The early Gottesman, Kitaev, and Preskill (GKP) proposal for encoding a qubit in an oscillator has recently been followed by cat- and binomial-code proposals. Numerically optimized codes have also been proposed, and we introduce new codes of this type here. These codes have yet to be compared using the same error model; we provide such a comparison by determining the entanglement fidelity of all codes with respect to the bosonic pure-loss channel (i.e., photon loss) after the optimal recovery operation. We then compare achievable communication rates of the combined encoding-error-recovery channel by calculating the channel's hashing bound for each code. Cat and binomial codes perform similarly, with binomial codes outperforming cat codes at small loss rates. Despite not being designed to protect against the pure-loss channel, GKP codes significantly outperform all other codes for most values of the loss rate. We show that the performance of GKP and some binomial codes increases monotonically with increasing average photon number of the codes. In order to corroborate our numerical evidence of the cat/binomial/GKP order of performance occurring at small loss rates, we analytically evaluate the quantum error-correction conditions of those codes. For GKP codes, we find an essential singularity in the entanglement fidelity in the limit of vanishing loss rate. In addition to comparing the codes, we draw parallels between binomial codes and discrete-variable systems. First, we characterize one- and two-mode binomial as well as multi-qubit permutation-invariant codes in terms of spin-coherent states. Such a characterization allows us to introduce check operators and error-correction procedures for binomial codes. Second, we introduce a generalization of spin-coherent states, extending our characterization to qudit binomial codes and yielding a new multi-qudit code.Comment: 34 pages, 11 figures, 4 tables. v3: published version. See related talk at https://absuploads.aps.org/presentation.cfm?pid=1351

The effectiveness of a training for patients with unexplained physical symptoms: protocol of a cognitive behavioral group training and randomized controlled trial

Abstract: BACKGROUND: In primary care, up to 74% of physical symptoms is classified as unexplained. These symptoms can cause high levels of distress and healthcare utilization. Cognitive behavioral therapy has shown to be effective, but does not seem to be attractive to patients. An exception herein is a therapy based on the consequences model, which distinguishes itself by its labeling of psychosocial distress in terms of consequences rather than as causes of physical symptoms. In secondary care, 81% of the patients accepts this therapy, but in primary care the outcome is poor. We assume that positive outcome can also be reached in primary care, when the consequences model is modified and used bottom-up in an easily accessible group training, in which patients are relieved of being blamed for their symptoms. Our aim is to investigate the (cost-)effectiveness of this training. METHODS AND DESIGN: A randomized controlled trial is designed. One hundred patients are randomized to either the group training or the waiting list. Physicians in general practices and outpatients clinics of general hospitals refer patients. Referral leads to inclusion if patients are between 18 and 65 years old, understand Dutch, have no handicaps impeding participation and the principal DSM-IV-TR classification is undifferentiated somatoform disorder or chronic pain disorder. In contrast to other treatment effect studies, the co-morbidity of a personality disorder does not lead to exclusion. By this, we optimize the comparability between the study population and patients in daily practice enlarging the generalization possibilities. Also in contrast to other effect studies, we chose quality of life (SF-36) instead of physical symptoms as the primary outcome measure. The SF-6D is used to estimate Quality Adjusted Life Years (QALYs). Costs are measured with the Trimbos/iMTA Questionnaire for Costs associated with Psychiatric Illness. Measurements are scheduled at baseline, after the training or waiting list, three and twelve months after the training. The differences between measurements are analyzed according to the intention-to-treat principle. The cost-effectiveness is expressed as costs per QALY, using multiple sensitivity analyses on the basis of a probabilistic model of the trial. DISCUSSION: If we show that our group training is (cost-)effective, more patients could be served, their quality of life could be improved while costs might be reduced. As the training is investigated in a heterogeneous patient group i

Factorization of Seiberg-Witten Curves and Compactification to Three Dimensions

We continue our study of nonperturbative superpotentials of four-dimensional N=2 supersymmetric gauge theories with gauge group U(N) on R^3 x S^1, broken to N=1 due to a classical superpotential. In a previous paper, hep-th/0304061, we discussed how the low-energy quantum superpotential can be obtained by substituting the Lax matrix of the underlying integrable system directly into the classical superpotential. In this paper we prove algebraically that this recipe yields the correct factorization of the Seiberg-Witten curves, which is an important check of the conjecture. We will also give an independent proof using the algebraic-geometrical interpretation of the underlying integrable system.Comment: laTeX, 14 pages, uses AMSmat

Adverse events and survival after closing- and opening-wedge high tibial osteotomy: a comparative study of 412 patients

Purpose: Varus medial knee osteoarthritis (OA) can be treated with a closing-wedge (CW) or opening-wedge (OW) high tibial osteotomy (HTO). Little is known about the adverse event (AE) rate of these techniques. The purpose of this study was to examine the AE rate and survival rate of a consecutive series of 412 patients undergoing CW- or OW-HTO. Methods: Medical records were retrospectively screened, and all patients who underwent HTO from 1993 to 2012 at the Erasmus University Medical Centre were assessed with a self-administered questionnaire. Patients filled in the intermittent and constant osteoarthritis pain score, knee injury and osteoarthritis outcome score, and a general questionnaire focusing on AE. Results: Medical records of 412 patients (354 CW- and 112 OW-HTOs) were screened. Of the 358 eligible patients, 291 (81 %) returned their questionnaire. A total of 80 AE (17 %) were found in 466 osteotomies. In the CW-group, 47 (13 %) serious adverse events (SAE) and 2 (0.6 %) AE were found. In the OW-group, 17 (15 %) SAE and 14 (13 %) AE were found. The most common AE was in 14 (4 %) patients of the CW-group sensory palsy of the common peroneal nerve. The most common AE in the OW-group was persistent pain at the iliac crest [11 (9.8 %) patients]. Hardware was removed in 48 % of the CW-osteotomies and 71 % of the OW-osteotomies (p < 0.05). The probability of survival was 75 % after 10 years in the CW-group versus 90 % in the OW-group (p < 0.05). In both groups, an equal number of patients were “in need for prosthesis” according to OARSI criteria. Conclusion: OW-HTO was associated with more AE than CW-HTO. OW-HTO resulted in better survival than CW-HTO. However, in both groups an equal number of patients were in need for prosthesis. Level of evidence: Retrospective comparative study, Level III

Pitfalls when comparing COVID-19-related outcomes across studies-lessons learnt from the ERACODA collaboration

Reported outcomes, such as incidence rates of mortality and intensive care unit admission, vary widely across epidemiological coronavirus disease 2019 (COVID-19) studies, including in the nephrology field. This variation can in part be explained by differences in patient characteristics, but also methodological aspects must be considered. In this review, we reflect on the methodological factors that contribute to the observed variation in COVID-19-related outcomes and their risk factors that are identified in the various studies. We focus on issues that arose during the design and analysis phase of the European Renal Association COVID-19 Database (ERACODA), and use examples from recently published reports on COVID-19 to illustrate these issues

Effect of zoledronic acid on the doxycycline-induced decrease in tumour burden in a bone metastasis model of human breast cancer

Bone is one of the most frequent sites for metastasis in breast cancer patients often resulting in significant clinical morbidity and mortality. Bisphosphonates are currently the standard of care for breast cancer patients with bone metastasis. We have shown previously that doxycycline, a member of the tetracycline family of antibiotics, reduces total tumour burden in an experimental bone metastasis mouse model of human breast cancer. In this study, we combined doxycycline treatment together with zoledronic acid, the most potent bisphosphonate. Drug administration started 3 days before the injection of the MDA-MB-231 cells. When mice were administered zoledronic acid alone, the total tumour burden decreased by 43% compared to placebo treatment. Administration of a combination of zoledronic acid and doxycycline resulted in a 74% decrease in total tumour burden compared to untreated mice. In doxycycline- and zoledronate-treated mice bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface and volume, whereas a decrease in bone resorption was also observed. Doxycycline greatly reduced tumour burden and could also compensate for the increased bone resorption. The addition of zoledronate to the regimen further decreased tumour burden, caused an extensive decrease in bone-associated soft tissue tumour burden (93%), and sustained the bone volume, which could result in a smaller fracture risk. Treatment with zoledronic acid in combination with doxycycline may be very beneficial for breast cancer patients at risk for osteolytic bone metastasis

Sex differences in COVID-19 mortality risk in patients on kidney function replacement therapy

Peer reviewe

Nonperturbative Superpotentials and Compactification to Three Dimensions

We consider four-dimensional N=2 supersymmetric gauge theories with gauge group U(N) on R^3 x S^1, in the presence of a classical superpotential. The low-energy quantum superpotential is obtained by simply replacing the adjoint scalar superfield in the classical superpotential by the Lax matrix of the integrable system that underlies the 4d field theory. We verify in a number of examples that the vacuum structure obtained in this way matches precisely that in 4d, although the degrees of freedom that appear are quite distinct. Several features of 4d field theories, such as the possibility of lifting vacua from U(N) to U(tN), become particularly simple in this framework. It turns out that supersymmetric vacua give rise to a reduction of the integrable system which contains information about the field theory but also about the Dijkgraaf-Vafa matrix model. The relation between the matrix model and the quantum superpotential on R^3 x S^1 appears to involve a novel kind of mirror symmetry.Comment: LaTeX, 45 pages, uses AmsMath, minor correction, reference adde