ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts.

Fibroblasts, the most abundant structural cells, exert homeostatic functions but also drive disease pathogenesis. Single-cell technologies have illuminated the shared characteristics of pathogenic fibroblasts in multiple diseases including autoimmune arthritis, cancer and inflammatory colitis. However, the molecular mechanisms underlying the disease-associated fibroblast phenotypes remain largely unclear. Here, we identify ETS1 as the key transcription factor governing the pathological tissue-remodeling programs in fibroblasts. In arthritis, ETS1 drives polarization toward tissue-destructive fibroblasts by orchestrating hitherto undescribed regulatory elements of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL) as well as matrix metalloproteinases. Fibroblast-specific ETS1 deletion resulted in ameliorated bone and cartilage damage under arthritic conditions without affecting the inflammation level. Cross-tissue fibroblast single-cell data analyses and genetic loss-of-function experiments lent support to the notion that ETS1 defines the perturbation-specific fibroblasts shared among various disease settings. These findings provide a mechanistic basis for pathogenic fibroblast polarization and have important therapeutic implications.

Diurnal Variation of Brain Activity in the Human Suprachiasmatic Nucleus.

The suprachiasmatic nucleus (SCN) is the central clock for circadian rhythms. Animal studies have revealed daily rhythms in the neuronal activity in the SCN. However, the circadian activity of the human SCN has remained elusive. In this study, to reveal the diurnal variation of the SCN activity in humans, we localized the SCN by employing an areal boundary mapping technique to resting-state functional images and investigated the SCN activity using perfusion imaging. In the first experiment (n = 27, including both sexes), we scanned each participant four times a day, every 6 h. Higher activity was observed at noon, while lower activity was recorded in the early morning. In the second experiment (n = 20, including both sexes), the SCN activity was measured every 30 min for 6 h from midnight to dawn. The results showed that the SCN activity gradually decreased and was not associated with the electroencephalography. Furthermore, the SCN activity was compatible with the rodent SCN activity after switching off the lights. These results suggest that the diurnal variation of the human SCN follows the zeitgeber cycles of nocturnal and diurnal mammals and is modulated by physical lights rather than the local time.

Inflammatory diseases causing joint and bone destruction: rheumatoid arthritis and hemophilic arthropathy.

Various diseases and conditions cause joint disorders. Osteoarthritis (OA) is characterized by the degeneration of articular cartilage, synovitis, and anabolic changes in surrounding bone tissues. In contrast, rheumatoid arthritis (RA) and hemophilic arthropathy (HA) display marked destruction of bone tissues caused by synovitis. RA is a representative autoimmune disease. The primary tissue of RA pathogenesis is the synovial membrane and involves various immune cells that produce catabolic cytokines and enzymes. Hemophilia is a genetic disorder caused by a deficiency in blood clotting factors. Recurrent intra-articular bleeding leads to chronic synovitis through excessive iron deposition and results in the destruction of affected joints. Although the triggers for these two joint diseases are completely different, many cytokines and enzymes are common in the pathogenesis of both RA and HA. This review focuses on the similarities between joint and bone destruction in RA and HA. The insights may be useful in developing better treatments for hemophilia patients with arthropathy and osteoporosis by leveraging advanced therapeutics for RA.

A crossover comparison of patient satisfaction with two teriparatide regimens: primary results of the Japanese Osteoporosis Intervention Trial 06 (JOINT-06).

INTRODUCTION: This study aimed to compare treatment satisfaction with two dosing regimens (two teriparatide [TPTD] self-injection systems) in osteoporosis patients at high risk of fracture. MATERIALS AND METHODS: In this open-label crossover randomized trial comparing self-injected once-daily (1/D)-TPTD with self-injected twice-weekly (2/W)-TPTD, three satisfaction variables were evaluated by questionnaire for 2 years. The primary endpoint was overall satisfaction and secondary endpoints were satisfaction with treatment effectiveness and with utility of the self-injection device. Changes in quality of life (QOL) assessed by EuroQol-5 Dimension, pain assessed by visual analogue scale (VAS), and anthropometric parameters were also analyzed. Safety was evaluated based on the incidence and severity of adverse events (AEs). RESULTS: The 1/D-TPTD and 2/W-TPTD groups consisted of 180 (75.9 ± 7.3 years) and 179 (age: 75.5 ± 6.9 years) patients, respectively. After 26 weeks of treatment, no significant between-group difference in the persistence rate (79.4% vs 72.6% in the 1/D-TPTD and 2/W-TPTD groups, respectively), distributions of overall satisfaction scores, and satisfaction with treatment (p > 0.05) were observed. However, several items of satisfaction with the utility of the injection device were significantly higher in the 2/W-TPTD group (p < 0.05). Statistical improvements from baseline values were observed in QOL and pain VAS in both groups (p < 0.05). No serious AEs were reported. CONCLUSION: The between-group similarity of overall treatment satisfaction and effectiveness scores and between-group difference in satisfaction with the utility of the self-injection device was useful information for real-world treatment of osteoporosis. Both medication regimens were well tolerated.

The 2023 Guidelines for the management and treatment of glucocorticoid-induced osteoporosis.

INTRODUCTION: Although synthetic glucocorticoids (GCs) are commonly used to treat autoimmune and other diseases, GC induced osteoporosis (GIOP) which accounts for 25% of the adverse reactions, causes fractures in 30-50% of patients, and markedly decreases their quality of life. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) published the revised guidelines for the management and treatment of steroid-induced osteoporosis, providing the treatment criteria based on scores of risk factors, including previous fractures, age, GC doses, and bone mineral density, for patients aged ≥18 years who are receiving GC therapy or scheduled to receive GC therapy for ≥3 months. MATERIALS AND METHODS: The Committee on the revision of the guidelines for the management and treatment of GIOP of the JSBMR prepared 17 clinical questions (CQs) according to the GRADE approach and revised the guidelines for the management and treatment of GIOP through systematic reviews and consensus conferences using the Delphi method. RESULTS: Bisphosphonates (oral and injectable formulations), anti-RANKL antibody teriparatide, eldecalcitol, or selective estrogen receptor modulators are recommended for patients who has received or scheduled for GC therapy with risk factor scores of ≥3. It is recommended that osteoporosis medication is started concomitantly with the GC therapy for the prevention of fragility fractures in elderly patients. CONCLUSION: The 2023 guidelines for the management and treatment of GIOP was developed through systematic reviews and consensus conferences using the Delphi method.

Factors associated with work sustainability in patients with bone metastasis.

BACKGROUND: Working while receiving cancer treatment is challenging for patients, with considerable impact on their quality of life (QOL). However, there have been no reports on the factors that prevent employment in patients with bone metastases. This study aimed to investigate the employment status and factors impacting the continued employment of patients with bone metastases. METHODS: We analyzed clinical data from new patients consulting The University of Tokyo Hospital team for bone metastasis treatment between June 2015 and September 2017. Patients who were working at the time of cancer diagnosis (n = 124) completed four QOL questionnaires. Factors associated with work sustainability were identified via univariate analysis and a chi-squared test. Multivariate logistic regression analysis was used for significant variables. Relationships between employment and QOL scales were investigated using the Wilcoxon rank-sum test, with P < .05 considered as statistically significant. RESULTS: Among the 124 patients, only 45 (36.3%) were still working when the questionnaire was administered. Multivariate analysis revealed temporary employment, lytic or mixed bone metastases, and lower limb or acetabular metastasis, as significant factors hindering work sustainability. The QOL scores were high in the continued employment group. However, the relationship between employment status and pain remains unclear. CONCLUSIONS: Lytic or mixed bone metastases and the lower limb and acetabular metastasis were significantly associated with employment resignation. Mobility difficulties may prevent patients with bone metastases from sustaining employment. Collaboration between rehabilitation professionals, oncologists, and workplaces is imperative to address this problem.

End-of-life walking ability in cancer patients with spinal metastases.

BACKGROUND: Even terminal cancer patients desire to walk to the toilet by themselves until the very last day. This study aimed to describe the walking ability of patients with spinal metastases at the end-of-life stage and identify the factors affecting this ability. METHODS: Among 527 patients who first visited our multidisciplinary team for bone metastasis between 2013 and 2016, 56 patients who had spinal metastases with a Spinal Instability Neoplastic Score ≥7 and died during follow-up were included. We collected general clinical data, performance status, Frankel classification, epidural spinal cord compression scale and Spinal Instability Neoplastic Score at the first consultation. Patients' last day of walking and date of death were also examined. Univariate analyses (chi-squared tests) were performed to identify the factors that impacted walking ability 30 and 14 days before patients' death. RESULTS: A total of 56 patients were extracted, and 57.1% (32/56) and 32.7% (16/49) of patients were ambulatory 30 and 14 days before death, respectively. Their performance status (P = 0.0007), Frankel grade (P = 0.012) and epidural spinal cord compression grade (P = 0.006) at the first examination, and administration of bone modifying agents during follow-up period (P = 0.029) were significantly related to walking ability 30 days before death. Among ambulatory patients 30 days before death, those with Spinal Instability Neoplastic Score ≥10 (P = 0.005), especially with high scores of collapse (P = 0.002) and alignment (P = 0.002), were less likely to walk 14 days before death. The walking period in the last month of their life was significantly longer in patients with total Spinal Instability Neoplastic Score 7-9 (P = 0.009) and in patients without collapse (P = 0.040) by the Wilcoxon test. CONCLUSION: The progression of spinal metastasis, especially neurological deficit, at the initial consultation were associated with walking ability 30 days before death, and spinal stability might be crucial for preserving walking ability during the last month. Early diagnosis and implementation of appropriate bone management might be important for the end-of-life walking ability.

Extended curettage for tumour-induced osteomalacia in the bone.

BACKGROUND: extended curettage is generally used to treat infiltrative bone tumours. However, the extent of the curettage performed in previous studies remains unclear. This study aimed to investigate the efficacy of extended curettage for bone tumour-induced osteomalacia. METHODS: we included 12 patients with tumour-induced osteomalacia who underwent extended curettage at our hospital between 2000 and 2022. Extended curettage was applied in cases where tumour resection could cause functional impairment or necessitate complex reconstruction. We investigated patients' clinical and oncological outcomes. RESULTS: patients had a mean age of 55 (24-81) years, and the median follow-up duration after surgery was 3.9 (1.0-14.0) years. The causative tumours were located in the pelvis and lumbar spine. Imaging revealed the tumours to be of the sclerotic, intertrabecular, lytic and mixed types. Intraoperative 3D fluoroscopy was used in 10 patients. Extended curettage with high-speed burring and adjuvant therapy with cauterization using an electric scalpel and ethanol resulted in a remission rate of 83%; no recurrence or metastasis was observed in cases of early postoperative biochemical remission. In cases where the causative tumour was at the lumbar spine and ischium close to the acetabulum, no postoperative biochemical remission was observed, and conservative treatment was continued. Except for one patient with a tumour in the lumbar spine, all patients could walk without a cane. CONCLUSIONS: extended curettage for bone tumour-induced osteomalacia is oncologically and functionally favourable, especially in cases where resection of the causative tumour could cause functional impairment or necessitate complex reconstruction.

Embryonal and alveolar rhabdomyosarcoma in adolescents/young adults, adults and older adults: a population-based cohort study.

BACKGROUND: The clinical characteristics, outcomes, and prognostic factors of adult embryonal rhabdomyosarcomas (ERMS) and alveolar rhabdomyosarcomas (ARMS), particularly the differences among adolescents/young adults (AYA), adults, and older adults, remain unclear. We assessed the clinicopathological features and survival outcomes of adult patients with ERMS and ARMS in Japan and to compare these features among AYA, adult, and older adult patients. METHODS: We retrospectively analyzed data from the Bone and Soft Tissue Tumor Registry of Japan and enrolled patients aged ≥15 years with ERMS and ARMS. Disease-specific overall survival (DOS) was estimated using the Kaplan-Meier method, and a Cox regression model was used to identify prognostic factors. RESULTS: Among 184 patients with ERMS and ARMS (median age, 27 years; interquartile range, 18-49 years), a high rate of distant and regional nodal metastases was initially observed in 65 (35%) and 66 (36%) cases, respectively. Older age and distant metastasis at first presentation were statistically poor prognostic factors, and histological subtype and site of tumor origin were not associated with DOS. In patients with localized ERMS and ARMS, older age and nodal metastasis were poor prognostic factors; the 5-year DOS rates of patients with and without nodal metastasis were 23% and 72%, respectively. CONCLUSIONS: Older patients with rhabdomyosarcoma had a dismal prognosis, and distant metastasis was a poor prognostic factor. The prognostic factors differed between adult and pediatric patients with rhabdomyosarcoma; biological analyses, such as genome analysis of adult rhabdomyosarcoma and clinical trials with pediatric oncologists, are needed to improve the prognosis of adult rhabdomyosarcoma.

Prognostic factors and treatment outcomes in patients with pleomorphic rhabdomyosarcoma: a population-based cohort study.

BACKGROUND: Pleomorphic rhabdomyosarcoma is a rare sarcoma in adults. The clinical characteristics, outcomes and prognostic factors associated with pleomorphic rhabdomyosarcoma remain unclear. METHODS: We retrospectively analyzed data from the Bone and Soft Tissue Tumor Registry of Japan, and enrolled patients with pleomorphic rhabdomyosarcoma. Disease-specific overall survival, local recurrence-free survival and distant metastasis-free survival were estimated using the Kaplan-Meier method; Cox regression model was used to identify prognostic factors. RESULTS: In total, 182 patients with pleomorphic rhabdomyosarcoma were included. Median age was 63 (range 20-95) years. The lower extremity (48%) was the most frequent tumor origin site, while head and neck were rare (4%). A total of 43 patients (24%) had distant or regional nodal metastases at first presentation. In all cases, the 2-year and 5-year survival rates were 66.3% and 54.1%, respectively. Distant metastasis was a significant poor prognostic factor (Hazard ratio 6.65; 95% confidence intervals, 3.00-14.75, P < 0.0001), with median survival of such patients being 9.4 (95% confidence intervals: 5.3-12.2) months. In 134 localized cases, the 2-year and 5-year survival rates were 91.5% and 68.3%, respectively. Large tumor size and older age were associated with poorer prognosis. Through data from localized and locally curative cases extracted and adjusted by propensity score matching, we found that perioperative chemotherapy did not improve disease-specific overall survival, distant metastasis-free survival or local recurrence-free survival. CONCLUSIONS: Clinical characteristics and outcomes of pleomorphic rhabdomyosarcoma are similar to those of other high-grade soft tissue sarcomas. Pleomorphic rhabdomyosarcoma may be less chemosensitive, and a strategy other than the standard cytotoxic chemotherapy is required to improve its prognosis.

Reduced gray matter volume in the default-mode network associated with insulin resistance.

Insulin resistance may lead to structural and functional abnormalities of the human brain. However, the mechanism by which insulin resistance impairs the brain remains elusive. In this study, we used two large neuroimaging databases to investigate the brain regions where insulin resistance was associated with the gray matter volume and to examine the resting-state functional connectivity between these brain regions and each hypothalamic nucleus. Insulin resistance was associated with reduced gray matter volume in the regions of the default-mode and limbic networks in the cerebral cortex in older adults. Resting-state functional connectivity was prominent between these networks and the paraventricular nucleus of the hypothalamus, a hypothalamic interface connecting functionally with the cerebral cortex. Furthermore, we found a significant correlation in these networks between insulin resistance-related gray matter volume reduction and network paraventricular nucleus of the hypothalamus resting-state functional connectivity. These results suggest that insulin resistance-related gray matter volume reduction in the default-mode and limbic networks emerged through metabolic homeostasis mechanisms in the hypothalamus.

Impact of pathogenic FBN1 variant types on the development of severe scoliosis in patients with Marfan syndrome.

BACKGROUND: Among the several musculoskeletal manifestations in patients with Marfan syndrome, spinal deformity causes pain and respiratory impairment and is a great hindrance to patients' daily activities. The present study elucidates the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome. METHODS: We retrospectively evaluated 278 patients with pathogenic or likely pathogenic FBN1 variants. The patients were divided into those with (n=57) or without (n=221) severe scoliosis. Severe scoliosis was defined as (1) patients undergoing surgery before 50 years of age or (2) patients with a Cobb angle exceeding 50° before 50 years of age. The variants were classified as protein-truncating variants (PTVs), which included variants creating premature termination codons and inframe exon-skipping, or non-PTVs, based on their location and predicted amino acid alterations, and the effect of the FBN1 genotype on the development of severe scoliosis was examined. The impact of location of FBN1 variants on the development of severe scoliosis was also investigated. RESULTS: Univariate and multivariate analyses revealed that female sex, PTVs of FBN1 and variants in the neonatal region (exons 25-33) were all independent significant predictive factors for the development of severe scoliosis. Furthermore, these factors were identified as predictors of progression of existing scoliosis into severe state. CONCLUSIONS: We elucidated the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome. Patients harbouring pathogenic FBN1 variants with these genetic risk factors should be monitored carefully for scoliosis progression.

Prevalence and distribution of Schmorl node and endplate signal change, and correlation with disc degeneration in a population-based cohort: the Wakayama Spine Study.

PURPOSE: Degenerative spinal conditions, including disc degeneration (DD), Schmorl nodes (SN), and endplate signal changes (ESC), are pervasive age-associated phenomena that critically affect spinal health. Despite their prevalence, a comprehensive exploration of their distribution and correlations is lacking. This study examined the prevalence, distribution, and correlation of DD, SN, and ESC across the entire spine in a population-based cohort. METHODS: The Wakayama Spine Study included 975 participants (324 men, mean age 67.2 years; 651 women, mean age 66.0 years). Magnetic resonance imaging (MRI) was used to evaluate the intervertebral space from C2/3 to L5/S1. DD was classified using Pfirrmann's system, ESC was identified by diffuse high-intensity signal changes on the endplates, and SN was defined as a herniation pit with a hypointense signal. We assessed the prevalence and distribution of SN, ESC, and DD across the entire spine. The correlations among these factors were examined. RESULTS: Prevalence of ≥ 1 SN over the entire spine was 71% in men and 77% in women, while prevalence of ≥ 1 ESC was 57.9% in men and 56.3% in women. The prevalence of ESC and SN in the thoracic region was the highest among the three regions in both sexes. Positive linear correlations were observed between the number of SN and DD (r = 0.41, p < 0.001) and the number of ESC and DD (r = 0.40, p < 0.001), but weak correlations were found between the number of SN and ESC (r = 0.29, p < 0.001). CONCLUSION: The prevalence and distribution of SN and ESC over the entire spine were observed, and correlations between SN, ESC, and DD were established. This population-based cohort study provides a comprehensive analysis of these factors.

A longitudinal population-based study identifies THBS2 as a susceptibility gene for intervertebral disc degeneration.

PURPOSE: Intervertebral disc degeneration (IDD) is a common degenerative disease associated with ageing. Additionally, IDD is recognized as one of the leading causes of low back pain and disability in the working-age population and is the first step in the process leading to degenerative spinal changes. However, the genetic factors and regulatory mechanisms of IDD remain unknown. Therefore, we selected eight single nucleotide polymorphisms of genes to reveal the progression of IDD in a 7-year longitudinal study of the general population in Japan. METHODS: IDD was evaluated in the Wakayama Spine Study (WSS), which is a population-based cohort study. Overall, 574 participants from the general population cohort who underwent whole spine magnetic resonance imaging and provided clinical information were included in this longitudinal survey. RESULTS: The progression of IDD was affected only by THBS2 at the lumbar region, T12-L1 (p = 0.0044) and L3-4 (p = 0.0045). The significant interaction between THBS2 and age with IDD negatively affected the thoracic spines and passively influenced both the thoracolumbar junction and thoracic spines. The higher progression per year of Pfirrmann's score was rapid in young people with age; however, this decelerated the IDD progression per year in different ages. CONCLUSION: Our longitudinal study found the genes associated with IDD progression and that genetic factors' impact on IDD differs depending on disc level and age.

Patients with a large ossification of the posterior longitudinal ligament have a higher incidence of arteriosclerosis in the carotid artery.

PURPOSE: This study aimed to investigate the impact of the severity of cervical ossification of the posterior longitudinal ligament (OPLL) on the incidence of arteriosclerosis in the carotid artery. METHODS: Patients with OPLL-induced cervical myelopathy were prospectively enrolled. The study involved analyzing patient characteristics, blood samples, computed tomography scans of the spine, and intima-media thickness (IMT) measurements of the common carotid artery. Patients were divided into two groups based on the size of the cervical OPLL to compare demographic data, comorbidities, and the presence of thickening of the carotid intima-media (max IMT ≥ 1.1 mm). RESULTS: The study included 96 patients (mean age: 63.5 years; mean body mass index: 26.9 kg/m2; 71.8% male; 35.4% with diabetes mellitus). The mean maximum anteroposterior (AP) diameter of the OPLL was 4.9 mm, with a mean occupancy ratio of 43%. The mean maximum IMT was 1.23 mm. Arteriosclerosis of the carotid artery was diagnosed in 62.5% of the patients. On comparing the two groups based on OPLL size, the group with larger OPLL (≥ 5 mm) had a higher BMI and a greater prevalence of carotid intima-media thickening. This significant difference in the prevalence of carotid intima-media thickening persisted even after adjusting for patient backgrounds using propensity score matching. CONCLUSIONS: Patients with a larger cervical OPLL showed a higher frequency of intima-media thickening in the carotid artery.

Post-operative shift in pain profile following fusion surgery for adult spinal deformity: a cluster analysis.

PURPOSE: Adult spinal deformity (ASD) is associated with a combination of back and leg pain of various intensities. The objective of the present study was to investigate the diverse reaction of pain profiles following ASD surgery as well as post-operative patient satisfaction. METHODS: Multicenter surveillance collected data for patients ≥ 19 years old who underwent primary thoracolumbar fusion surgery at > 5 spinal levels for ASD. Two-step cluster analysis was performed utilizing pre-operative numeric rating scale (NRS) for back and leg pain. Radiologic parameters and patient-reported outcome (PRO) scores were also obtained. One-year post-operative outcomes and satisfaction rates were compared among clusters, and influencing factors were analyzed. RESULTS: Based on cluster analysis, 191 ASD patients were categorized into three groups: ClusterNP, mild pain only (n = 55); ClusterBP, back pain only (n = 68); and ClusterBLP, significant back and leg pain (n = 68). ClusterBLP (mean NRSback 7.6, mean NRSleg 6.9) was the oldest 73.4 years (p < 0.001) and underwent interbody fusion (88%, p < 0.001) and sacral/pelvic fixation (69%, p = 0.001) more commonly than the other groups, for the worst pelvis incidence-lumbar lordosis mismatch (mean 43.7°, p = 0.03) and the greatest sagittal vertical axis (mean 123 mm, p = 0.002). While NRSback, NRSleg and PRO scores were all improved postoperatively in ClustersBP and BLP, ClusterBLP showed the lowest satisfaction rate (80% vs. 80% vs. 63%, p = 0.11), which correlated with post-operative NRSback (rho = -0.357). CONCLUSIONS: Cluster analysis revealed three clusters of ASD patients, and the cluster with the worst pain back and leg pain had the most advanced disease and showed the lowest satisfaction rate, affected by postoperative back pain.

Automatic estimation of hallux valgus angle using deep neural network with axis-based annotation.

OBJECTIVES: We developed the deep neural network (DNN) model to automatically measure hallux valgus angle (HVA) and intermetatarsal angle (IMA) on foot radiographs. The objective is to assess the accuracy of the model by comparing to the manual measurement of foot and ankle surgeons. MATERIALS AND METHODS: A DNN was developed to predict the bone axes of the first proximal phalanx and all metatarsals from the first to the fifth in foot radiographs. The dataset used for model development consisted of 1798 radiographs collected from a population-based cohort and patients at our foot and ankle clinic. The retrospective validation cohort comprised of 92 radiographs obtained from 92 consecutive patients visiting our foot and ankle clinic. The mean absolute error (MAE) between automatic measurements by the model and the median of manual measurements by three foot and ankle surgeons was compared to 3° using one-tailed t-test and was also compared to the inter-rater difference in manual measurements among the three surgeons using two-tailed paired t-test. RESULTS: The MAE for HVA was 1.3° (upper limit of 95% CI 1.6°), and this was significantly smaller than the inter-rater difference of 2.0 ± 0.2° among the surgeons, demonstrating the superior accuracy of the model. In contrast, the MAE for IMA was 0.8° (upper limit of 95% CI 1.0°) that showed no significant difference from the inter-rater difference of 1.0 ± 0.1° among the surgeons. CONCLUSION: Our model demonstrated the ability to measure the HVA and IMA with an accuracy comparable to that of specialists.

In Vivo Kinematics and Cruciate Ligament Tension Are Not Restored to Normal After Bicruciate-Preserving Arthroplasty.

BACKGROUND: Whether cruciate ligament forces in cruciate-preserving designs, such as unicompartmental knee arthroplasty (UKA) or bi-cruciate-retaining total knee arthroplasty (BCR-TKA), differ from those in normal knees remains unknown. The purpose of this study was to compare the in vivo kinematics and cruciate ligament force in knees before and after UKA or BCR-TKA to those in normal knees during high-flexion activity. METHODS: Overall, twenty normal knees, 17 knees with medial UKA, and 15 knees with BCR-TKA were fluoroscopically examined while performing a squatting activity. A 2-dimensional or 3-dimensional registration technique was employed to measure tibio-femoral kinematics. Ligament strains and tensions in the anteromedial bundle of the anterior cruciate ligament and posterolateral bundle of the anterior cruciate ligament and the anterolateral bundle of the posterior cruciate ligament (aPCL) and posteromedial bundle of the posterior cruciate ligament (pPCL) during knee flexion were analyzed. RESULTS: Tension in both bundles of the anterior cruciate ligament decreased with flexion. At 60° of flexion, anteromedial bundle of the anterior cruciate ligament tension in postoperative UKA knees was greater than that in normal knees. At 30° of flexion, posterolateral bundle of the anterior cruciate ligament tension in postoperative UKA knees was greater than that in normal knees. On the other hand, aPCL and pPCL tensions increased with flexion. From 40 to 110° of flexion, the postoperative aPCL tension in UKA knees was greater than that in normal knees. At 110° of flexion, the preoperative pPCL tension in UKA knees was greater than that in normal knees. In addition, the postoperative pPCL tension in UKA knees was larger than that in normal knees beyond 20° of flexion. Furthermore, the pPCL tension of postoperative BCR-TKA knees was larger than that in normal knees from 20 to 50° and beyond 90° of flexion. CONCLUSIONS: The cruciate ligament tensions, especially posterior cruciate ligament tension in knees after UKA, were greater than those in the normal knees. Surgeons performing bi-cruciat-preserving knee arthroplasties should therefore balance cruciate ligament tension more carefully in flexion and extension.

Anti-osteoporotic drug efficacy for periprosthetic bone loss after total hip arthroplasty: A systematic review and network meta-analysis.

BACKGROUND: Periprosthetic bone loss following total hip arthroplasty (THA) threatens prosthesis stability. This systematic review and network meta-analysis aimed to compare the efficacy of anti-osteoporotic drugs for measures of hip function according to functional outcomes, periprosthetic femoral bone mineral density loss in each Gruen zone, and revision surgery after THA. METHODS: The systematic search of six literature databases was conducted in December 2021 in accordance with PRISMA guidelines. Adult participants who underwent primary THA were included. A random-effects network meta-analysis was performed within a frequentist framework, and the confidence in the evidence for each outcome was evaluated using the CINeMA tool, which assessed the credibility of results from the network meta-analysis. We included 22 randomized controlled trials (1243 participants) comparing the efficacy and safety of bisphosphonates (including etidronate, clodronate, alendronate, risedronate, pamidronate, and zoledronate), denosumab, selective estrogen receptor modulator, teriparatide, calcium + vitamin D, calcium, and vitamin D. We defined the period for revision surgery as the final follow-up period. RESULTS: Raloxifene, bisphosphonate, calcium + vitamin D, and denosumab for prosthetic hip function might have minimal differences when compared with placebos. The magnitude of the anti-osteoporotic drug effect on periprosthetic femoral bone loss varied across different Gruen zones. Bisphosphonate, denosumab, teriparatide might be more effective than placebo in Gruen zone 1 at 12 months after THA. Additionally, bisphosphonate might be more effective than placebo in Gruen zones 2, 5, 6, and 7 at 12 months after THA. Denosumab was efficacious in preventing bone loss in Gruen zones 6 and 7 at 12 months after THA. Teriparatide was likely to be efficacious in preventing bone loss in Gruen zone 7 at 12 months after THA. Raloxifene was slightly efficacious in preventing bone loss in Gruen zones 2 and 3 at 12 months after THA. Calcium was slightly efficacious in preventing bone loss in Gruen zone 5 at 12 months after THA. None of the studies reported revision surgery. CONCLUSIONS: Bisphosphonate and denosumab may be effective anti-osteoporotic drugs for preventing periprosthetic proximal femoral bone loss due to stress shielding after THA, particularly in cementless proximal fixation stems, which are the most commonly used prostheses worldwide.

BRAF mutations and concurrent alterations in patients with soft tissue sarcoma.

BRAF alterations, including V600E and non-V600E mutations and fusions, in soft tissue sarcoma (STS) have been identified in a limited case series. Here, we aimed to evaluate the frequency of BRAF mutations and concurrent alterations in STS to understand their therapeutic action. In this retrospective analysis, we included data from 1964 patients with advanced STS who underwent comprehensive genomic profiling tests at hospitals in Japan between June 2019 and March 2023. The prevalence of BRAF and recurrent concurrent gene alterations were also investigated. BRAF mutations were detected in 24 (1.2%) of 1964 STS patients, with a median age of 47 (range 1-69) years. BRAF V600E was detected in 11 (0.6%) of the 1964 patients with STS, BRAF non-V600E mutations in 9 (4.6%), and BRAF fusions were detected in 4 (0.2%). BRAF V600E was identified in 4 (0.2%) cases of malignant peripheral nerve sheath tumors. The most common concurrent alteration was CDKN2A (11 cases, 45.8%), and the frequency was equivalent to that of the BRAF V600E (5/11 cases, 45.5%) and non-V600E (5/9 cases, 55.6%) groups. Recurrent concurrent alterations, such as TERT promoter mutations (7 cases, 29.2%), were detected at the same frequency in the V600E and non-V600E groups. In contrast, TP53 alterations (4/9 cases, 44.4%) and mitogen-activated protein kinase (MAPK)-activating genes, including NF1, GNAQ, and GNA11 (3/9 cases, 33.3%), were identified as relatively higher in the non-V600E group than in the V600E group (each 1/11 case, 9.1%). We identified BRAF alterations at a rate of 1.2% in all patients with advanced STS. Among them, BRAF V600E and BRAF fusions account for 45.8% and 16.7%, respectively. Collectively, our findings support the clinical characteristics and therapeutic strategies for patients with BRAF-altered advanced STS.