Close negative correlation of local and circulating Dickkopf-1 and Sclerostin levels during human fracture healing.

Wnt signaling is critically involved in fracture healing. Existing data predominantly relies on rodent models. Here, we explored local and circulating Dickkopf-1 (DKK1) levels in patients with respect to fracture healing and explore its association to sclerostin (SOST). 69 patients after surgical stabilization of long bone fractures of which six patients had impaired fracture healing were included in this study. Life-style and patient related factors with a known effect on DKK1 and SOST were recorded. DKK1 and SOST concentrations were measured using enzyme-linked immunosorbent assay (ELISA) at the fracture site and in circulation. DKK1 and SOST showed a close inverse correlation. In fracture hematoma and immediately after trauma DKK1 levels were significantly reduced while SOST levels were significantly increased, compared to healthy control. Postoperatively, DKK1 peaked at week 2 and SOST at week 8, again demonstrating a close negative correlation. Age and smoking status affected the balance of DKK1 and SOST, while type 2 diabetes and sex did not demonstrate a significant influence. Early postoperative elevation of SOST without compensatory DKK1 decrease was associated with fracture non-union in younger patients (< 50a). The close inverse correlation and very rapid dynamics of DKK1 and SOST locally as well as systemically suggest their critical involvement during human fracture healing. Importantly, as immediate compensatory feedback mechanism are apparent, we provide evidence that dual-blockade of DKK1 and SOST could be critical to allow for therapeutic efficiency of Wnt targeted therapies for fracture healing.

Deep Learning Estimation of Median Nerve Volume Using Ultrasound Imaging in a Human Cadaver Model.

Median nerve swelling is one of the features of carpal tunnel syndrome (CTS), and ultrasound measurement of maximum median nerve cross-sectional area is commonly used to diagnose CTS. We hypothesized that volume might be a more sensitive measure than cross-sectional area for CTS diagnosis. We therefore assessed the accuracy and reliability of 3-D volume measurements of the median nerve in human cadavers, comparing direct measurements with ultrasound images interpreted using deep learning algorithms. Ultrasound images of a 10-cm segment of the median nerve were used to train the U-Net model, which achieved an average volume similarity of 0.89 and area under the curve of 0.90 from the threefold cross-validation. Correlation coefficients were calculated using the areas measured by each method. The intraclass correlation coefficient was 0.86. Pearson's correlation coefficient R between the estimated volume from the manually measured cross-sectional area and the estimated volume of deep learning was 0.85. In this study using deep learning to segment the median nerve longitudinally, estimated volume had high reliability. We plan to assess its clinical usefulness in future clinical studies. The volume of the median nerve may provide useful additional information on disease severity, beyond maximum cross-sectional area.

The influence of M-CSF on fracture healing in a mouse model.

Macrophage colony-stimulating factor 1 (M-CSF) is known to play a critical role during fracture repair e.g. by recruiting stem cells to the fracture site and impacting hard callus formation by stimulating osteoclastogenesis. The aim of this experiment was to study the impact of systemic M-CSF application and its effect on bony healing in a mouse model of femoral osteotomy. Doing so, we studied 61 wild type (wt) mice (18-week-old female C57BL/6) which were divided into three groups: (1) femoral osteotomy, (2) femoral osteotomy + stabilization with external fixator and (3) femoral osteotomy + stabilization with external fixator + systemic M-CSF application. Further, 12 op/op mice underwent femoral osteotomy and served as proof of concept. After being sacrificed at 28 days bony bridging was evaluated ex vivo with µCT, histological and biomechanical testing. Systemic M-CSF application impacted osteoclasts numbers, which were almost as low as found in op/op mice. Regarding callus size, the application of M-CSF in wt mice resulted in significantly larger calluses compared to wt mice without systemic M-CSF treatment. We further observed an anabolic effect of M-CSF application resulting in increased trabecular thickness compared to wt animals without additional M-CSF application. Systemic M-CSF application did not alter biomechanical properties in WT mice. The impact of M-CSF application in a mouse model of femoral osteotomy was oppositional to what we were expecting. While M-CSF application had a distinct anabolic effect on callus size as well as trabecular thickness, this on bottom line did not improve biomechanical properties. We hypothesize that in addition to the well-recognized negative effects of M-CSF on osteoclast numbers this seems to further downstream cause a lack of feedback on osteoblasts. Ultimately, continuous M-CSF application in the absence of co-stimulatory signals (e.g. RANKL) might overstimulate the hematopoietic linage in favor of tissue macrophages instead of osteoclasts.

Carpal tunnel syndrome treatment and the subsequent alterations in tendon and connective tissue dynamics.

BACKGROUND: Carpal tunnel syndrome patients demonstrate diminished motion of the median nerve and fibrotic changes in the subsynovial connective tissue within the carpal tunnel. Currently, there are few prognostic factors to help predict the outcome of commonly performed treatments including surgical carpal tunnel release and corticosteroid injections. This study aimed to non-invasively assess the changes in the dynamic response of the subsynovial tissue relative to tendon motion after the intervention and to correlate this with disease severity. METHODS: A total of 145 patients with carpal tunnel syndrome were recruited into this study. Clinical and demographic data, electrophysiological severity and dynamic ultrasound images were collected before and after treatment, either by injection or surgery. The relative motion of the subsynovial tissue with the underlying middle finger flexor digitorum superficialis tendon was measured using a speckle tracking algorithm and was expressed as a shear index (SI). Baseline and follow-up data, the association between change in SI and severity, and the role of treatment modality were analyzed and statistically compared. FINDINGS: Overall, there was a significant increase (more relative motion) after treatment in the mean shear index from 79.9% (±15.4% SD) to 82.9% (±14.8% SD) (p = 0.03). Secondary analyses showed that this change was mostly present in those with mild disease severity undergoing surgery (p = 0.01). INTERPRETATION: This study shows that the relative subsynovial tissue movement increases in patients after intervention. The present study lays a foundation for future studies to non-invasively assess the role of carpal tunnel dynamics in response to treatment.

Risk of de novo severe carpal tunnel syndrome after bilateral oophorectomy: a population-based cohort study.

OBJECTIVE: The incidence of carpal tunnel syndrome (CTS) is higher in women, and peaks around the age of menopause. Therefore, we investigated whether bilateral oophorectomy is associated with an increased risk of severe CTS. METHODS: We included all of the 1,653 premenopausal women who underwent bilateral oophorectomy for a nonmalignant indication between 1988 and 2007, and a random sample of 1,653 age-matched referent women who did not undergo bilateral oophorectomy in Olmsted County, MN. Diagnoses of CTS assigned to women over their entire lifetime were identified in these two cohorts. The risk of de novo severe CTS after bilateral oophorectomy (or index date) was evaluated using Cox proportional hazards models adjusted for potential confounders. RESULTS: Bilateral oophorectomy was associated with an increased risk of severe CTS (adjusted hazard ratio 1.65, 95% confidence interval 1.20-2.25). The risk was suggestively greater in women with lower body mass index, nulliparity, and with a benign ovarian indication for oophorectomy (nonsignificant interactions). We did not observe a protective effect of estrogen therapy after the oophorectomy. The findings were similar in secondary analyses considering the incidence of CTS of any severity or idiopathic CTS. CONCLUSIONS: The risk of severe CTS, common in perimenopausal women, is increased after bilateral oophorectomy. The association may be causal or due to confounding. Therefore, the precise biological mechanisms explaining the association and the absence of a mitigating effect of estrogen therapy should be further investigated.

Carpal Tunnel Syndrome Treatment and the Subsequent Alterations in Median Nerve Transverse Mobility.

OBJECTIVES: The mobility (transverse movement) of the median nerve (MN) is decreased in patients with carpal tunnel syndrome and can be measured noninvasively by ultrasound. To date, there are few prognostic features to help predict the outcome of 2 commonly performed treatments: surgical carpal tunnel release and corticosteroid injection. This study aimed to assess the changes in nerve mobility after the intervention and to correlate this with treatment and the disease severity. METHODS: A total of 181 patients with carpal tunnel syndrome with different electrophysiologic severities were recruited and assessed by dynamic ultrasound scanning of the MN before and after treatment. The dynamic ultrasound images were collected while the patients performed finger and wrist flexion. RESULTS: For both injection and carpal tunnel release, the nerve displacement increased with wrist flexion, from a mean ± SD of 7.0 ± 2.4 to 7.9 ± 2.7 mm (P < .005). Patients who underwent surgery showed greater improvement (P < .005) in nerve mobility compared to those who underwent injection. We also observed that the increase in nerve mobility was predominantly in patients with more nerve damage at baseline. CONCLUSIONS: This study shows that the dynamic behavior of the MN changes in response to treatment and lays a foundation for future studies to assess the prognostic potential of nerve mobility measurement.

Incidence and severity of electric scooter related injuries after introduction of an urban rental programme in Vienna: a retrospective multicentre study.

PURPOSE: Electric scooters (e-scooters) are an emerging way of mobility in cities around the world. Despite quickly rising numbers of e-scooters, limited studies report on incidence and severity of e-scooter-associated injuries. The aim of our study was to report on these injuries and identify potential protective measures to ultimately decrease e-scooter-associated morbidity. METHODS: We performed a retrospective multicentre study including all patients, who were admitted to three major trauma departments in Vienna from May 2018 to September 2019. We analysed patients' data, including demographics, injury pattern, types of injury and subsequent treatment. RESULTS: A total number of 175 patients (115 males, 60 females) sustained e-scooter-associated injuries. Patients' mean age was 34.4 years [4-74]. While the mean Injury Severity Score (ISS) was 3.4, 11 patients presented with an ISS ≥ 9 and 2 patients with an ISS ≥ 16. ISS increased with age. Older patients (≥ 40 years) presented a significantly higher ISS than younger patients (< 40 years) (P = 0.011). Seventy-one patients (40.6%) sustained major injuries affecting head (35.2%) and upper extremities (36.6%). Twenty-three patients (13.1%) required surgery leading to hospitalization of 11 days on average [1-115]. E-scooter-associated injuries increased during late afternoon plateauing at 8.00 pm. However, the largest share of patients (39.2%) sustained their injuries during early night (8.00 pm to 1.59 am) with especially young adults (19-39 years) being at risk. CONCLUSION: The popularity of rideshare e-scooters across cities worldwide seems to be on the rise, so are e-scooter-associated injuries. These injuries should be considered high-energy trauma affecting primarily head and upper extremity; indeed, 17.7% sustained major head injuries. Therefore, the mandatory use of a helmet seems to be adequate to decrease head injury-associated morbidity. Ultimately, given the remarkably high rates of nighttime injuries, an e-scooter ban during night could further cut injury numbers in half.

Bisegmental posterior stabilisation of thoracolumbar fractures with polyaxial pedicle screws: Does additional balloon kyphoplasty retain vertebral height?

We retrospectively evaluated single-level compression fractures (T12-L3) scheduled for a short-segment POS (posterior-only stabilization) using polyaxial screws. Patients averaged 55.7 years (range, 19-65). Patients received either POS or, concomitantly, BK (balloon kyphoplasty) of the fractured vertebrae as well. Primary endpoint was the radiological outcome at the last radiographic follow-up prior to implant removal. POS together with BK of the fractured vertebrae resulted in a significant improvement of the local kyphosis angle and vertebral body compression rates immediately post-OP. During the further course of FU, a considerable loss of correction was observed post-OP in both groups. (Local KA: pre-OP/ post-OP/ FU: 12.6±4.8/ 3.35±4.8/ 11.6±6.0; anterior vertebral body compression%: pre-OP/post-OP/ FU: 71.94±12.3/ 94.78±19.95/ 78.17±14.74). VAS was significantly improved from 7.2±1.3 pre-OP to 2.7±1.3 (P<0.001) at FU. We found a significant restoration of the vertebral body height by BK. Nevertheless, follow-up revealed a noticeable loss of reduction. Given the fact that BK used together with polyaxial screws did not maintain intra-operative reduction, our data do not support this additional maneuver when used together with bi-segmental polyaxial pedicle screw fixation.

The impact of nonosteogenic factors on the expression of osteoprotegerin and RANKL during human fracture healing.

OBJECTIVES: The osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) balance is of the utmost importance in fracture healing. The aim of this study was therefore to investigate the impact of nonosteogenic factors on OPG and RANKL levels. METHODS: Serum obtained from 51 patients with long bone fractures was collected over 48 weeks. The OPG and serum sRANKL (soluble RANKL) concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Smoking habit, diabetes, and alcohol consumption were recorded. RESULTS: Age and sex greatly influenced preoperative serum levels of OPG and sRANKL but differences were even more pronounced during fracture healing. Statistical significance was observed for overall serum levels of OPG (p = 0.001) and sRANKL (p < 0.001) in older men and women (age greater than 50 years). Interestingly, OPG levels increased over time in older women but decreased over time in older men. CONCLUSION: These data suggest that nonosteogenic factors, most significantly age and sex, have a major impact on sRANKL and OPG levels. Given the established association of OPG and sRANKL levels and nonunion, these findings seem to be of clinical relevance.Cite this article: J. Starlinger, G. Kaiser, A. Thomas, K. Sarahrudi. The impact of nonosteogenic factors on the expression of osteoprotegerin and RANKL during human fracture healing. Bone Joint Res 2019;8:349-356. DOI: 10.1302/2046-3758.87.BJR-2018-0116.R3.

Implementation of Electrical Auricular Acupuncture and Low Frequency Modulated Electric Current Therapy in Pain Management of Patients with Knee Osteoarthritis: A Randomized Pilot Trial.

BACKGROUND: Knee osteoarthritis is a major cause of knee pain. Conservative therapy resources are limited due to adverse effects. Therefore, alternative non-invasive therapy approaches to reduce pain medications are gaining importance. The current study analyses if electrical auricular acupuncture (EAA) or low frequency modulated electric current therapy (LFMECT) could support analgesic treatment. METHODS: In a randomized pilot trial patients with painful knee OA were treated with EAA (group 1) or LFMECT (group 2) additional to standard pharmacological analgesic treatment. In total 19 female and 10 male patients with a mean age of 59.1 years (standard deviation ± 13.6) and a mean BMI of 28.9 kg/m2 (± 5.2) were included. Patients were randomly assigned to one of the groups stratified for age, gender and BMI. Before starting of the active study period and collecting of the initial data on day 1, all patients received a pharmacological analgesic baseline therapy for one week. At the next study stage patients started their randomly assigned treatment protocol for 42 days and final follow-up was set on day 70. Patients recorded their pain intensity (numerical rating scale; NRS) using a standardized patient diary. The pain free walking time in min was recorded and range of motion was assessed. RESULTS: Rescue medication intake was comparable between both groups on day 42 (p = 0.55) and day 70 (p = 0.35). After the active study period (day 42) pain scores decreased significantly in both groups (group 1 p = 0.02; group 2 p = 0.0006). At follow up median pain scores further decreased in group 1 (p = 0.0002) and remained at a low level in group 2 (p = 0.001). Level of pain decreased in about 50% in both groups and was comparable during the study period. Total mean range of motion (ROM) increased in both groups (group 1 p = 0.0003; group 2 p = 0.02). Group 1 had more improvement of mean total ROM compared to group 2 (p = 0.034). Pain-free walking time increased in both groups and was comparable between both groups (p = 0.31). Any adverse effects due to EAA or LFMECT were not observed. CONCLUSIONS: Data of the current study indicates that implementation of EAA or LFMECT seems to be beneficial to reduce knee pain and improve knee function in patients with knee osteoarthritis.

Post-operative retransfusion of unwashed filtered shed blood reduces allogenic blood demand in hip hemiarthroplasty in traumatic femoral neck fractures-a prospective randomized trial.

PURPOSE: Patients who undergo hip hemiarthroplasty (HHA) due to traumatic femoral neck fracture frequently require red blood cell (RBC) transfusion. Although post-operative autologous blood transfusion (ABT) is well established in elective arthroplasty, its role in trauma patients remains unclear. METHODS: Two hundred twenty-nine patients with a traumatic femoral neck fracture that underwent HHA at our level-I trauma centre between 2005 and 2009 were prospectively randomized to a high-vacuum drainage or an ABT device. In this single-institution analysis, the number of RBC units as well as the amount of retransfused shed blood were recorded and compared according to study groups. Additionally, the significance of confounding factors for allogenic blood demand such as age, gender, pre-operative Hb level, surgical approach, type of prosthesis and amount of intra-operative RBC units were evaluated using multivariate analysis. RESULTS: One hundred thirty-five patients were randomized in the high-vacuum group while 94 patients received an ABT device. Intention to treat analysis revealed no significant difference in post-operative RBC demand (ABT: 0.87 RBC, high-vacuum drainage: 1.01 RBC; P = 0.374). However, patients that actually received retransfusion (N = 35) had a reduced post-operative RBC demand (0.49 RBC units, P = 0.014). CONCLUSION: While only one third of trauma patients treated with an ABT device during HHA actually receive retransfusion, retransfused patients seem to significantly benefit from this treatment as reflected by a reduced pos-toperative RBC demand.