Functional clinical motor performance tests to assess potential fall risks in patients with haemophilia: A case-control study.

INTRODUCTION: Patients with haemophilia (PwH) are at increased risk of falls due to haemophilic arthropathy. Yet, studies on clinical tests associated with the risk of falling are scarce in PwH. AIMS: (1) To evaluate the feasibility of different clinical motor performance tests associated with the risk of falling in PwH; (2) to evaluate PwH's performance of these tests compared to a control group; (3) to identify possible influencing factors that affect performance. METHODS: Twenty-nine severe and moderate PwH (57.0 years, IQR: 48.0-61.5) and 29 healthy age- and BMI-matched control participants (CG) performed 13 different clinical tests (SPPB, timed up and go, push and release, functional reach, single-leg stance, knee and grip strength). Haemophilia joint health score (HJHS), kinesiophobia (TSK-11), subjective physical performance (HEP-Test-Q), falls efficiency (FES-I) and falls were assessed. RESULTS: No adverse events occurred. PwH showed impaired performance in all clinical tests, a lower falls efficiency and a higher HJHS than CG. PwH with higher HJHS, lower HEP-Test-Q and higher TSK-11 scores showed higher deficits. Largest discrepancies were observed in the single-leg stance with eyes open and knee extensor strength, where orthopaedically majorly affected PwH showed worse performance compared to minorly affected PwH and the CG, respectively. The prevalence of ≥1 fall in the last year was 27.6% (PwH) and 10.3% (CG). CONCLUSION: These clinical tests are feasible in PwH. Impaired joint status, a high kinesiophobia and low physical performance impair performance. These tests can be used by clinicians for gaining specific information on functional motor abilities of patients.

Physical activity and factor VIII levels in patients with haemophilia: A real-world prospective observational study.

INTRODUCTION: Regular physical activity (PA) is recommended for patients with haemophilia (PwH). For PwH it is crucial to ensure a sufficient factor level to prevent PA-induced bleedings. However, there is a gap in the literature dealing with specific factor levels, which are needed when performing specific types of PA. AIM: To provide data on factor VIII (FVIII) levels at the start of PA performed by PwH. METHODS: In this prospective 12-month real-world observational study, 23 PwH recorded every PA they performed and the FVIII levels at the start of the PA using a pharmacokinetic application. PA types were clustered according to the collision and injury risk into three categories (Cat I = low, Cat II = medium, Cat III = high risk). Haemophilia Joint Health Scores (HJHS) were performed at baseline, after 6 and 12 months. RESULTS: 795 PA sessions of Cat I, 193 of Cat II, and 23 of Cat III were documented. FVIII levels at the start of PA were different between categories (Cat I: 29.8 ± 32.1%, Cat II: 38.3 ± 33.4%, Cat III: 86.6 ± 29.2%). Out of all PA sessions, 145 (14%) were performed at a factor level of ≤3%. Three PA-induced bleeding occurred. Baseline HJHS was 14.5 ± 13.6 points and did not change throughout the study. CONCLUSION: This study provides real-life data on FVIII levels at the start of 1011 PA sessions. PwH are mainly active in low-risk sports with higher FVIII levels observed in Cat II and III, respectively. Only three PA-induced bleeding occurred, even though several PA were started with low FVIII levels.

TNFα-Induced Inflammation Model-Evaluation of Concentration and Passage-Dependent Effects on Bovine Chondrocytes.

Inflammation models are widely used in the in vitro investigation of new therapeutic approaches for osteoarthritis. TNFα (tumor necrosis factor alpha) plays an important role in the inflammatory process. Current inflammation models lack uniformity and make comparisons difficult. Therefore, this study aimed to systematically investigate whether the effects of TNFα are concentration-dependent and whether chondrocyte expansion has an effect on the inflammatory model. Bovine chondrocytes were enzymatically isolated, expanded to passages 1-3, and transferred into a 3D pellet culture. Chondrocyte pellets were stimulated with recombinant bovine TNFα at different concentrations for 48 h to induce inflammation. Gene expression of anabolic (collagen 2, aggrecan, cartilage oligomeric protein (COMP)), catabolic (matrix metalloproteinases (MMP3, MMP13)), dedifferentiation (collagen 1) markers, inflammation markers (interleukin-6 (IL-6), nuclear factor kappa B (NFkB), cyclooxygenase-2 (COX), prostaglandin-E-synthase-2 (PTGES2)), and the apoptosis marker caspase 3 was determined. At the protein level, concentrations of IL-6, nitric oxide (NO), and sulfated glycosaminoglycans (GAG) were evaluated. Statistical analysis was performed using the independent t-test, and significance was defined as p < 0.05. In general, TNFα caused a decrease in anabolic markers and an increase in the expression of catabolic and inflammatory markers. There was a concentration-dependent threshold of 10 ng/mL to induce significant inflammatory effects. Most of the markers analyzed showed TNFα concentration-dependent effects (COMP, PRG4, AGN, Col1, MMP3, and NFkB). There was a statistical influence of selected gene expression markers from different passages on the TNFα chondrocyte inflammation model, including Col2, MMP13, IL-6, NFkB, COX2, and PTGES2. Considering the expression of collagen 2 and MMP3, passage 3 chondrocytes showed a higher sensitivity to TNFα stimulation compared to passages 1 and 2. On the other hand, MMP13, IL-6, NFkB, and caspase 3 gene expression were lower in P3 chondrocytes compared to the other passages. On the protein level, inflammatory effects showed a similar pattern, with cytokine effects starting at 10 ng/mL and differences between the passages. TNFα had a detrimental effect on cartilage, with a clear threshold observed at 10 ng/mL. Although TNFα effects showed concentration-dependent patterns, this was not consistent for all markers. The selected passage showed a clear influence, especially on inflammation markers. Further experiments were warranted to explore the effects of TNFα concentration and passage in long-term stimulation.

Effects of Different Hemoglobin Levels on Near-Infrared Spectroscopy-Derived Cerebral Oxygen Saturation in Elderly Patients Undergoing Noncardiac Surgery.

Background: Near-infrared spectroscopy (NIRS) is a commonly used technique to evaluate tissue oxygenation and prevent harmful cerebral desaturation in the perioperative setting. The aims of the present study were to assess whether surgery-related anemia can be detected via NIRS of cerebral oxygen saturation and to investigate the effects of different perioperative transfusion strategies on cerebral oxygenation, potentially affecting transfusion decision-making. Study Design and Methods: Data from the ongoing multicenter LIBERAL-Trial (liberal transfusion strategy to prevent mortality and anemia-associated ischemic events in elderly noncardiac surgical patients, LIBERAL) were used. In this single-center sub-study, regional cerebral oxygenation saturation (rSO2) was evaluated by NIRS at baseline, pre-, and post-RBC transfusion. The obtained values were correlated with blood gas analysis-measured Hb concentrations. Results: rSO2 correlated with Hb decline during surgery (r = 0.35, p < 0.0001). Different RBC transfusion strategies impacted rSO2 such that higher Hb values resulted in higher rSO2. Cerebral desaturation occurred at lower Hb values more often. Discussion: Cerebral oxygenation monitoring using NIRS provides noninvasive rapid and continuous information regarding perioperative alterations in Hb concentration without the utilization of patients' blood for blood sampling. Further investigations are required to demonstrate if cerebral rSO2 may be included in future individualized transfusion decision strategies.

Most subjectively affected joints in patients with haemophilia - what has changed after 20 years in Germany?

BACKGROUND: In patients with haemophilia (PwH), most frequently affected joints are the ankle, knee and elbow. Due to improved factor therapy in the last decades, these previous findings have to be verified in Germany. AIM: The aim of this study is to detect the most affected joint, evaluate the significance of the source of pain and determine the point prevalence of back pain in Germany today. PATIENTS AND METHODS: In a retrospective study, data of n = 300 patients with severe moderate and mild haemophilia were evaluated regarding the most affected joint, the most common source of pain, and the point prevalence of back pain. An anamnesis questionnaire and the German Pain Questionnaire were used for this assessment. RESULTS: The most affected joint in German PwH is still the ankle (41%), followed by the knee (27%) and the elbow (11%). The most common source of pain is also the ankle joint (32%). Back pain was also identified as one of the most common sources of pain, which is comparable to the elbow (elbow:15%; back:13%). The point prevalence in PwH for back pain was significantly higher compared to the general German population (P = .031). CONCLUSION: Our data showed that the ankle is still the most affected joint and the most common source of pain in Germany. These results also showed the relevance of back pain as a pain source. The evaluations also demonstrated the high point prevalence of back pain in PwH. Future therapies should also focus on the spine because joint changes affect posture.

Changes of static and dynamic spine alignment in patients with severe haemophilia.

INTRODUCTION: Haemophilic arthropathy results in a restricted range of motion and pain that often affects gait. The effect of these gait changes on spinal posture has not been studied. AIM: To evaluate whether the altered joint situation in patients with haemophilia (PwH) leads to compensatory mechanisms evident in the trunk and spine, considering static and dynamic conditions. METHODS: PwH and healthy controls (20-65 years) were examined using rasterstereography in a controlled cohort study. Analysis was performed in static and dynamic conditions in regard to gait phases. Joint status was determined using the Haemophilia Joint Health Score (HJHS). RESULTS: Static measurements showed no group differences in PwH (n = 40) compared to healthy controls (n = 40) except pelvic torsion (median [25%-quartile;75%-quartile]: -1.9[-3.2;.9]° vs. .5[-1.1;1.9]°; P = .007). In contrast, under dynamic conditions PwH showed significantly higher trunk inclination and lower apex lumbar lordosis in all gait phases. Additionally, pelvic torsion was increased in mid stance and terminal swing. Considering joint status, PwH had a higher global HJHS (23.5[13.0;30.0] vs. 3.0[1.0;5.0]; P<.001). A significant moderate correlation was shown between the HJHS mobility score and spine parameters (r = .228-.588; P<.05). CONCLUSION: Degenerative joint changes in PwH lead to altered spine posture during gait. A reason could be the reduced mobility in the affected joint. Changes in spinal and pelvic posture lead to higher structural burdens; therefore, clinicians should focus on posture of spinal column during gait in daily treatment.

Outcome Predictors in Prosthetic Joint Infections--Validation of a risk stratification score for Prosthetic Joint Infections in 120 cases.

Prosthetic joint infections are a major challenge in total joint arthroplasty, especially in times of accumulating drug resistancies. Even though predictive risk classifications are a widely accepted tool to define a suitable treatment protocol a classification is still missing considering the difficulty in treating the -causative pathogen antibiotically. In this study, we present and evaluate a new predictive risk stratification for prosthetic joint infections in 120 cases, treated with a two-stage exchange. Treatment outcomes in 120 patients with proven prosthetic joint infections in hip and knee prostheses were regressed on time of infection, systemic risk factors, local risk factors and the difficulty in treating the causing pathogen. The main outcome variable was "definitely free of infection" after two years as published. Age, gender, and BMI were included as covariables and analyzed in a logistic regression model. 66 male and 54 female patients, with a mean age at surgery of 68.3 years±12.0 and a mean BMI of 26.05±6.21 were included in our survey and followed for 29.0±11.3 months. We found a significant association (p<0.001) between our score and the outcome parameters evaluated. Age, gender and BMI did not show a significant association with the outcome. These results show that our score is an independent and reliable predictor for the cure rate in prosthetic joint infections in hip and knee prostheses treated within a two-stage exchange protocol. Our score illustrates, that there is a statistically significant, sizable decrease in cure rate with an increase in score. In patients with prosthetic joint infections the validation of a risk score may help to identify patients with local and systemic risk factors or with infectious organisms identified as "difficult to treat" prior to the treatment or the decision about the treatment concept. Thus, appropriate extra care should be considered and provided.

Acetabular defect reconstruction in revision hip arthroplasty with a modular revision system and biological defect augmentation.

PURPOSE: Revision of failed total hip arthroplasty with severe acetabular bone loss represents a rare but challenging problem. Anatomic reconstruction with biological defect augmentation as solid bone transplants or cancellous bone restores bone stock while providing good component stability. The objective of this study was to present short- to mid-term results of revision total hip arthroplasty with a modular ring system in a consecutive series of patients with severe acetabular bone loss. METHODS: We retrospectively reviewed 39 consecutive patients (39 hips) with severe acetabular bone loss (Paprosky type 3 A and 3 B) reconstructed with revision total hip arthroplasty using the cementless modular ring system MRS-Titan®. The MRS-Titan® consists of independent ring systems that are adapted modularly to the defect situation. Combined with acetabular defect reconstruction by using cancellous bone in impaction grafting technique, the MRS-Titan® system offers a cement-free revision system that enables defect-adapted customization to individual anatomic matters, bridging of the acetabular bone defect and reconstruction of the centre of rotation. Initial stability of the implant was obtained by screw fixation. Harris hip score and sequential radiographs were used to evaluate clinical and radiographic results. RESULTS: At an average follow up of 31 months (range 12-69 months) 33 of 39 (84.6 %) of the implants were considered radiographically stable without signs of acetabular migration of more than 2 mm in the horizontal or vertical direction, implant rotation or screw breakage. Complications included six implant failures (15 %). We recorded one aseptic loosening of the MRS prosthesis after 20 months. Five patients (12.8 %) had to undergo revision surgery because of periprosthetic joint infection. Two patients had a dislocation postoperatively. The mean Harris hip score improved from 27 ± 14 points preoperatively to 76 ± 15 points at the time of last follow up. CONCLUSION: By achieving stable implant fixation and providing potential for biological fixation, treatment of severe acetabular bone loss in revision total hip arthroplasty with the modular ring system MRS-Titan provides a durable solution with good clinical and radiographic results and allows us to accomplish major goals of reconstruction.

Validation of the Charlson comorbidity index in patients undergoing revision total hip arthroplasty.

PURPOSE: The Charlson comorbidity index (CCI) was developed to quantify the influence of comorbidities on survival. The age-related CCI respects patients' age as an additional risk factor. There are several studies available based on administrative data regarding functional outcome, implant survival, resource use and length of hospital stay in patients undergoing primary total hip arthroplasty (THA). To date, there is a lack of knowledge regarding the correlation of the CCI and the age-related CCI in case of revision total hip arthroplasty (RTHA). OBJECTIVE: Our objective was to validate the influence of the CCI and age-related CCI in patients undergoing RTHA regarding complication rate, resource use implant survival and mortality rate. METHODS: Between October 2007 and November 2012, 142 consecutive patients undergoing RTHA were included in this retrospective study. Routine clinical data were collected and analysed as anonymized aggregated data. In accordance to CCI and age-related CCI the rate of complications (internal medical and surgical complications), the length of hospital stay and the need for ICU treatment and the mortality rate was evaluated. Kaplan-Meier survivorship was used to determine implant survival. RESULTS: Twenty-one patients (15%) had a low risk CCI, 59 patients (41%) a moderate risk CCI and 62 patients (44%) a high risk CCI. The mean follow-up was 27 months (range 24-70 months). In total, we recorded 57 complications (40%), of which 45 were surgical (79%) and 12 were internal medical complications (21%). Twenty-four patients (17%) had to undergo revision surgery. CCI and age-related CCI had no influence regarding implant survival. We recorded a significant influence of the age-related CCI in regard to the necessity of postoperative intensive care unit stay and the length of total hospital stay. Further we recorded a significant influence of the CCI and the age-related CCI regarding postoperative complications and internal complications, postoperative dislocation and the need for surgical revision. CONCLUSION: In summary, we conclude that the CCI and the age-related CCI are strong predictors regarding complication rate in patients undergoing RTHA. In a short- to mid-term follow-up, no influence on implant survival is detectable.

Comparison of Minced Cartilage Implantation with Autologous Chondrocyte Transplantation in an In Vitro Inflammation Model.

The current gold standard to treat large cartilage defects is autologous chondrocyte transplantation (ACT). As a new surgical method of cartilage regeneration, minced cartilage implantation (MCI) is increasingly coming into focus. The aim of this study is to investigate the influence of chondrogenesis between isolated and cultured chondrocytes compared to cartilage chips in a standardized inflammation model with the proinflammatory cytokine TNFα. Articular chondrocytes from bovine cartilage were cultured according to the ACT method to passage 3 and transferred to spheroid culture. At the same time, cartilage was fragmented (<1 mm3) to produce cartilage chips. TNFα (20 ng/mL) was supplemented to simulate an inflammatory process. TNFα had a stronger influence on the passaged chondrocytes compared to the non-passaged ones, affecting gene expression profiles differently between isolated chondrocytes and cartilage chips. MCI showed less susceptibility to TNFα, with reduced IL-6 release and less impact on inflammation markers. Biochemical and histological analyses supported these findings, showing a greater negative influence of TNFα on the passaged pellet cultures compared to the unpassaged cells and MCI constructs. This study demonstrated the negative influence of TNFα on chondrogenesis in a chondrocyte spheroid culture and cartilage fragment model. Passaged chondrocytes are more sensitive to cytokine influences compared to non-passaged cells and chondrons. This suggests that MCI may have superior regeneration potential in osteoarthritic conditions compared to ACT. Further investigations are necessary for the translation of these findings into clinical practice.

Seroprevalence and Association of Toxoplasma gondii with Bone Health in a Cohort of Osteopenia and Osteoporosis Patients.

Considering the fact that Toxoplasma is a common parasite of humans and Toxoplasma bradyzoites can reside in skeletal muscle, T. gondii-mediated immune responses may modulate the progression and pathophysiology of another musculoskeletal disorder, osteoporosis. In the current study, we investigated the association of bone health and Toxoplasma gondii infection status. A total of 138 patients living in Germany with either osteopenia or osteoporosis were included in the study, and they were categorized into two groups, T. gondii uninfected (n = 74) and infected (n = 64), based on the presence of T. gondii-specific IgG antibodies. The demographic and clinical details of the study subjects were collected from the medical records. Logistic regression analysis was performed to delineate the association of bone health parameters with the infection status. The prevalence of toxoplasmosis was 46.4% in the study participants. The infected individuals with osteopenia and osteoporosis showed higher levels of mean spine and femoral T score, Z score, and bone mineral density (BMD), indicating improved bone health compared to the uninfected group. Logistic regression analysis showed that subjects with T. gondii infection displayed increased odds of having a higher mean femur T score, femur BMD, and femur Z score even after adjusting for age, creatinine, and urea levels. However, when the duration of drug intake for osteoporosis was taken into account, the association lost statistical significance. In summary, in this study, an improvement in osteopenia and osteoporosis was observed in Toxoplasma-infected patients, which may be partly due to the longer duration of drug intake for osteoporosis in the infected patient group.

Osteomyelitis is associated with increased anti-inflammatory response and immune exhaustion.

Introduction: Osteomyelitis (OMS) is a bone infection causing bone pain and severe complications. A balanced immune response is critical to eradicate infection without harming the host, yet pathogens manipulate immunity to establish a chronic infection. Understanding OMS-driven inflammation is essential for disease management, but comprehensive data on immune profiles and immune cell activation during OMS are lacking. Methods: Using high-dimensional flow cytometry, we investigated the detailed innate and adaptive systemic immune cell populations in OMS and age- and sex-matched controls. Results: Our study revealed that OMS is associated with increased levels of immune regulatory cells, namely T regulatory cells, B regulatory cells, and T follicular regulatory cells. In addition, the expression of immune activation markers HLA-DR and CD86 was decreased in OMS, while the expression of immune exhaustion markers TIM-3, PD-1, PD-L1, and VISTA was increased. Members of the T follicular helper (Tfh) cell family as well as classical and typical memory B cells were significantly increased in OMS individuals. We also found a strong correlation between memory B cells and Tfh cells. Discussion: We conclude that OMS skews the host immune system towards the immunomodulatory arm and that the Tfh memory B cell axis is evident in OMS. Therefore, immune-directed therapies may be a promising alternative for eradication and recurrence of infection in OMS, particularly in individuals and areas where antibiotic resistance is a major concern.

Relationship between foot pressure and spinal parameters in healthy adults - A systematic review.

BACKGROUND: Foot pressure has an essential impact on the entire musculoskeletal chain. So far, the direct influence of foot pressure onto the spinal posture and vice versa is still unclear. RESEARCH QUESTION: The aim of this study was to determine the relationship between foot pressure and spinal posture in healthy adults under static and dynamic conditions. METHODS: Systematic research was conducted using PubMed to demonstrate the relationship between foot pressure and spinal posture. The search strategy was based on the PICOS selection criteria. The risk of bias within the studies was assessed using SIGN rankings. RESULTS: Based on the search strategy, 719 articles were identified by screening title and abstract. 11 studies with moderate methodological quality partially showed a relationship between foot pressure and spinal posture (SIGN:2-1- and B-D). Apart from the foot pressure, the included studies analyzed parameters of muscle thickness (sonography), trunk displacement, head position, posterior tilt angle, trunk tilt, pelvic rotation, spinal range of motion, or spinal motion. Strength training and increased muscle thickness in the lumbar spine ensure decreased foot pressure. The head position partly induces a change of foot pressure under static conditions. No correlation was identified between spinal posture and foot pressure during forward and backward walking without manipulation. The static and dynamic measurements only show statistical correlations between foot and back muscles. SIGNIFICANCE: Foot pressure and spinal posture seem to be interrelated under static and dynamic conditions. Static and dynamic measurements are necessary for body posture analysis, as the conditions do not always show consistent results. Due to the small number of studies and low sample sizes, further investigations are necessary to gain more precise perception of the interplay of the spine and foot pressure. For better comparison, more homogeneous studies investigating similar spine parameters are needed.

Smartphone Use-Influence on Posture and Gait during Standing and Walking.

Prolonged gaze at a smartphone is characterized by pronounced flexion of the cervical spine and is associated with health risks. In addition, it is suspected that smartphone distraction could lead to gait changes. Therefore, the aim of this study was to detect smartphone-associated postural changes at thoracic and lumbar levels as well as gait changes. Spinal analysis was performed prospectively in 21 healthy men using the DIERS 4Dmotion®Lab in a controlled crossover design to evaluate posture-associated parameters while standing and walking. The examination sequence provided three randomized gaze directions: GN = Gaze Neutral; S1H = Smartphone one-handed; S2H = Smartphone two-handed. Results reveal a higher vertebra prominens (VP)-flexion in S1H (23.8° ± 6.9°; p ≤ 0.001) and S2H (22.4° ± 4.7°; p ≤ 0.001) compared to GN (17.6° ± 3.8°). Kyphosis angles were also different with higher values observed in S1H (58.8° ± 5.8°; p ≤ 0.001) and S2H (61.6° ± 4.9°; p ≤ 0.001) compared to GN (49.1° ± 4.6°). During walking, similar results were observed in kyphosis angles. No differences were observed in gait during smartphone use (p = 0.180-0.883). The study revealed a significantly increased inclination of the lower cervical and thoracic spine during smartphone use. However, the inclination was larger during S2H. Standing or walking conditions did not affect the measurement outcomes. Long-term smartphone use associated with a larger inclination of the cervical and thoracic spine might result in increased pressure and shear forces acting on vertebral bodies, intervertebral discs, and muscles, which potentially increases the risk of spinal pain and disease.

Preoperative embolization of renal cell carcinoma metastases to the bone prior to stabilization procedures does not result in reduction in intraoperative blood loss.

PURPOSE: The effect of preoperative embolization of bone metastases prior to stabilization procedures in reducing intraoperative blood loss remains controversial. This study aimed to analyze the effect of preoperative embolization on orthopedic stabilization procedures of the extremities and spine in cases with bone metastases from renal cell carcinomas. In particular, do these patients suffer less blood loss during the operation and do they need lesser fluid replacements or packed red cell bags intra- and perioperatively? Does preoperative embolization reduce the duration of surgery? METHODS: We retrospectively reviewed stabilization procedures of the spine and extremities at our institution between 2011 and 2021 for group differences (embolization vs. no embolization) in terms of blood loss, fluid substitution, need for packed red cell transfusions, tumor size, and duration of surgery. RESULTS: We reviewed 79 stabilization procedures of the spine (n = 36) and extremities (n = 43), of which 30 included preoperative embolization procedures. Surprisingly, the embolization group showed a statistically significant increase in blood loss, the need for fluid substitution, and red cell transfusions. Subgroup analysis revealed a significant negative effect of preoperative embolization on stabilization procedures of the extremities. CONCLUSION: Based on our data, preoperative embolization of renal cell carcinoma metastases of the extremities had a negative effect on intraoperative blood loss and the need for fluid substitution and should therefore be avoided. Our data did not show an effect on stabilization procedures of the spine.

Agonistic and antagonistic targeting of immune checkpoint molecules differentially regulate osteoclastogenesis.

Introduction: Immune checkpoint inhibitors are used in the treatment of various cancers and have been extensively researched with regard to inflammatory and autoimmune diseases. However, this revolutionary therapeutic strategy often provokes critical auto-inflammatory adverse events, such as inflammatory reactions affecting the cardiovascular, gastrointestinal, nervous, and skeletal systems. Because the function of these immunomodulatory co-receptors is highly cell-type specific and the role of macrophages as osteoclast precursors is widely published, we aimed to analyze the effect of immune checkpoint inhibitors on these bone-resorbing cells. Methods: We established an in vitro model of osteoclastogenesis using human peripheral blood mononuclear cells, to which various immune checkpoints and corresponding antagonistic antibodies were administered. Formation of osteoclasts was quantified and cell morphology was analyzed via immunofluorescence staining, cell size measurements, and calculation of cell numbers in a multitude of samples. Results: These methodical approaches for osteoclast research achieved objective, comparable, and reproducible results despite the great heterogeneity in the form, size, and number of osteoclasts. In addition to the standardization of experimental analyses involving osteoclasts, our study has revealed the substantial effects of agonistic and antagonistic checkpoint modulation on osteoclastogenesis, confirming the importance of immune checkpoints in bone homeostasis. Discussion: Our work will enable more robust and reproducible investigations into the use of immune checkpoint inhibitors in conditions with diminished bone density such as osteoporosis, aseptic loosening of endoprostheses, cancer, as well as the side effects of cancer therapy, and might even pave the way for novel individualized diagnostic and therapeutic strategies.

Osteoporosis Remains Constant in Patients with Hemophilia-Long-Term Course in Consideration of Comorbidities.

INTRODUCTION: Patients with hemophilia (PWHs) suffer from an increased risk of osteoporosis. Multiple hemophilia and hemophilic arthropathy associated factors correlate with a low bone mineral density (BMD) in PWHs. The aim of this study was to assess the long-term development of BMD in PWH as well as to analyze potentially influencing factors. METHODS: A total of 33 adult PWHs were evaluated in a retrospective study. General medical history, specific-hemophilia-associated comorbidities, joint status using the Gilbert score, calcium level, and vitamin D level as well as at least two results of bone density measurements with a minimum range of 10 years per patient were taken into account. RESULTS: The BMD did not change significantly from one point of measurement to the other. A total of 7 (21.2%) cases of osteoporosis and 16 (48.5%) cases of osteopenia were identified. The two following significant correlations could be revealed: the higher the patients' body mass index, the higher their BMD (r = 0.41; p = 0.022). Moreover, a high Gilbert score came along with a low BMD (r = -0.546; p = 0.003). CONCLUSION: Even if PWHs frequently suffer from a reduced BMD, our data suggest that their BMD remains constant on a low level in the course of time. A risk factor of osteoporosis often found in PWHs is a vitamin D deficiency and joint destruction. Therefore, a standardized screening of PWHs on BMD reduction by collecting vitamin D blood level and assessing joint status seems appropriate.

In Vitro Biocompatibility of the Novel Ceramic Composite Baghdadite for Defect Augmentation in Revision Total Hip Arthroplasty.

Biological augmentation of bony defects in weight-bearing areas of both the acetabulum and the femur remains challenging. The calcium-silicate-based ceramic Baghdadite is a very interesting material to be used in the field of revision total hip arthroplasty for the treatment of bony defects in weight-bearing and non-weight-bearing areas alike. The aim of this study was to investigate the biocompatibility of Baghdadite utilizing an osteoblast-like, human osteosarcoma cell line (MG-63) and the human monocytic leukemia-derived cell line (THP-1). THP-1-derived macrophages and MG-63 were indirectly exposed to Baghdadite for 7 days using a transwell system. Viability was assessed with MTT assay and pH analysis. To investigate proliferation rate, both cell lines were labelled using CFSE and flow cytometrically analyzed. ELISA was used to measure the secretion of IL-1ß, IL-6 and TNFα. The investigation of viability, while showing a slight difference in optical density for the MTT assays in MG-63 cells, did not present a meaningful difference between groups for both cell lines. The comparison of pH and the proportion of living cells between groups did not present with a significant difference for both THP-1 and MG-63. Baghdadite did not have a relevant impact on the proliferation rate of the investigated cell lines. Mean fluorescence intensity was calculated between groups with no significant difference. Baghdadite exerted a proinflammatory effect, which could be seen in an upregulated production of TNFα in macrophages. Production of IL-1ß and IL-6 was not statistically significant, but the IL-6 ELISA showed a trend to an upregulated production as well. A similar effect on MG-63 was not observed. No relevant cytotoxicity of Baghdadite ceramics was encountered. Baghdadite ceramics exhibit a proinflammatory potential by significantly increasing the secretion of TNFα in THP-1-derived macrophages. Whether this proinflammatory potential results in a clinically relevant effect on osteointegration is unclear and requires further investigation. Baghdadite ceramics provide an interesting alternative to conventional bone substitutes and should be further investigated in a biomechanical and in vivo setting.

Peak pressure during gait in patients with severe haemophilia: A controlled cross-sectional study.

BACKGROUND: Patients with severe haemophilia suffer from bleeding-related joint changes in which the ankle joint is most frequently affected. In the resulting gait changes, the forefoot is involved by reducing the foot pressure. However, it is unclear which changes in foot pressure are present in the individual's foot zones. RESEARCH QUESTION: The aim of the study was to determine whether compensation mechanisms are present in the foot zones regarding the peak pressure under dynamic conditions and to identify possible underlying mechanisms for gait changes. METHODS: In a controlled cross-sectional study, a pedobarography was performed during gait with a standardized speed (3 km/h) in patients with haemophilia (PwH;n = 40) and healthy controls (Con;n = 40). Pressure pain thresholds (PPT) were detected, and Haemophilia Joint Health Score (HJHS) was performed to determine the current joint status. RESULTS: PwH showed a decreased peak pressure in metatarsals II-IV and heel compared to Con. Patients with major-affected ankle joints (determined with the HJHS) showed a decreased single-step length, stride-length and stride-time. Accordingly, the cadence was increased by 10 ± 11 steps/min in PwH compared to Con. Furthermore, PwH showed decreased ankle range of motion (ROM) in HJHS and an altered pain perception due to reduced PPT. SIGNIFICANCE: PwH showed a changed gait pattern in peak pressure compared to Con. A restricted rolling behavior, which might be caused by movement restrictions and pain sensation, leads to reduced pressure in the center forefoot, resulting in a shorter stride-length. Future therapies should focus on maintaining joint mobility for better rolling behavior and improving ankle joints' stability to achieve a balanced load between the midfoot, heel, and forefoot. The use of insoles adapted to our data, based on group differences between PwH and Con, could be supportive in this case.

Falling and fall risk in adult patients with severe haemophilia.

The objective of this study was to define fall rates and to identify possible fall risk factors in adult patients with severe haemophilia. PATIENTS, MATERIAL, METHODS: 147 patients with severe haemophilia A and B were evaluated using a standardized test battery consisting of demographic, medical and clinical variables and fall evaluation. RESULTS: 41 (27.9 %) patients reported a fall in the past 12 months, 22 (53.7 %) of them more than once. Young age, subjective gait insecurity and a higher number of artificial joints seem to be risk factors for falling. CONCLUSION: Falls seem to be a common phenomenon in patients with severe haemophilia. Fall risk screening and fall prevention should be implemented into daily practice.