Complications after orthopaedic surgeries in patients with rheumatoid arthritis treated with Janus kinase inhibitors: A retrospective observational study.

OBJECTIVES: The current study compared the outcome after orthopaedic surgeries in patients with rheumatoid arthritis receiving Janus kinase inhibitors (JAKis) versus biologic disease-modifying anti-rheumatic drugs (bDMARDs). METHODS: This was a retrospective observational study of Japanese patients with rheumatoid arthritis. Sixty-two patients with rheumatoid arthritis using JAKi preoperatively underwent orthopaedic surgeries. Using propensity score matching, these 62 patients were matched with 62 patients using bDMARDs preoperatively. The number of adverse events was counted. We also examined whether the drug-withholding period in the JAKi-treated group was associated with the occurrence of major postoperative adverse events, namely inflammatory flares and delayed wound healing. RESULTS: JAKi-treated patients had a higher incidence of postoperative flares than bDMARD-treated patients (29% versus 12.1%, P = .01). The incidences of postoperative complications other than flares were not significantly different between the two groups. Among the JAKi-treated group, a longer perioperative drug-withholding period (≥11 days) was associated with a higher incidence of postoperative flares (P = .04). The incidences of delayed wound healing and surgical site infection were not associated with the duration of the JAKi-withholding period. CONCLUSIONS: JAKi-treated patients had a higher incidence of postoperative flares than bDMARD-treated patients. A total of ≥11 days of drug withdrawal was associated with postoperative flares.

Standardization of evaluation method and prognostic significance of histological response to preoperative chemotherapy in high-grade non-round cell soft tissue sarcomas.

BACKGROUND: Preoperative chemotherapy is widely applied to high-grade localized soft tissue sarcomas (STSs); however, the prognostic significance of histological response to chemotherapy remains controversial. This study aimed to standardize evaluation method of histological response to chemotherapy with high agreement score among pathologists, and to establish a cut-off value closely related to prognosis. METHODS: Using data and specimens from the patients who had registered in the Japan Clinical Oncology Group study, JCOG0304, a phase II trial evaluating the efficacy of perioperative chemotherapy with doxorubicin (DOX) and ifosfamide (IFO), we evaluated histological response to preoperative chemotherapy at the central review board. RESULTS: A total of 64 patients were eligible for this study. The percentage of viable tumor area ranged from 0.1% to 97.0%, with median value of 35.7%. Regarding concordance proportion between pathologists, the weighted kappa coefficient (κ) score in all patients was 0.71, indicating that the established evaluation method achieved substantial agreement score. When the cut-off value of the percentage of the residual tumor area was set as 25%, the p-value for the difference in overall survival showed the minimum value. Hazard ratio of the non-responder with percentage of the residual tumor < 25%, to the responder was 4.029 (95% confidence interval 0.893-18.188, p = 0.070). CONCLUSION: The standardized evaluation method of pathological response to preoperative chemotherapy showed a substantial agreement in the weighted κ score. The evaluation method established here was useful for estimating of the prognosis in STS patients who were administered perioperative chemotherapy with DOX and IFO. TRIAL REGISTRATION: UMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered).

Examining the Potential of Blockchain Technology to Meet the Needs of 21st-Century Japanese Health Care: Viewpoint on Use Cases and Policy.

Japan is undergoing a major population health transition as its society ages, and it continues to experience low birth rates. An aging Japan will bring new challenges to its public health system, highlighted as a model for universal health coverage (UHC) around the world. Specific challenges Japan's health care system will face include an increase in national public health expenditures, higher demand for health care services, acute need for elder and long-term care, shortage of health care workers, and disparities between health care access in rural versus urban areas. Blockchain technology has the potential to address some of these challenges, but only if a health blockchain is conceptualized, designed, localized, and deployed in a way that is compatible with Japan's centralized UHC-centric public health system. Blockchain solutions must also be adaptive to opportunities and barriers unique to Japan's national health and innovation policy, including its regulatory sandbox system, while also seeking to learn from blockchain adoption in the private sector and in other countries. This viewpoint outlines the major opportunities and potential challenges to blockchain adoption for the future of Japan's health care.

Positive correlation between the density of macrophages and T-cells in undifferentiated sarcoma.

Undifferentiated sarcoma (US) is a frequent soft tissue sarcoma. Although the 10-year survival rate is around 60%, advanced US is highly resistant to chemo/radiotherapy. The tumor microenvironment (TME) is closely associated with tumor progression. However, few studies of infiltrated immune cells in US have been published. In this study, we evaluated tumor-associated macrophages (TAMs) and CD8-positive cytotoxic T lymphocytes (CTLs) in 28 cases of US. Iba1, CD163, and CD204 were used as markers for TAMs. The density of CTLs was positively correlated with the density of TAMs. However, a negative correlation was seen between the density of CTLs and the percentage of CD204-positive TAMs. We found no significant association between the density of Iba1-/CD204-/CD8-positive cells and clinicopathological factors. No significant correlation between immune cell infiltration and clinical outcome was observed. Although we found no significant association between immune cells and clinicopathological factors, these findings may provide new insight into the characterization of immune cells in the TME of US.

Phosphorylation of STAT3 in Undifferentiated Pleomorphic Sarcoma Is Correlated with a Favorable Prognosis.

OBJECTIVE: The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a role in various biological processes. Phosphorylated STAT3 (p-STAT3) functions as a transcriptional factor, and suppressor of cytokine signaling 3 (SOCS3) is a potential inhibitor of STAT3. Here, we analyzed the status of the JAK-STAT pathway in undifferentiated pleomorphic sarcoma (UPS). METHODS: We performed immunohistochemistry in 79 samples of UPS and Western blotting in 10 frozen samples. We also examined alterations in protein expression in the JAK-STAT pathway after the inhibition of phosphorylated Akt (p-Akt) or extracellular signal-regulated kinase (p-Erk) in vitro. RESULTS: Immunohistochemically, p-STAT3 and SOCS3 were positive in 59.7 and 55.8%, respectively. Positivity for p-STAT3 was significantly correlated with a better prognosis (p = 0.0006) and negatively with SOCS3 expression (p = 0.0223). Positivity for SOCS3 was significantly correlated with a worse prognosis (p = 0.0001). Western blotting analysis revealed that p-STAT3 expression was lower in tumor than in normal tissue. In vitro results demonstrated that there was no detectable change in the expression of p-STAT3 regardless of the status of p-Akt or p-Erk. CONCLUSION: p-STAT3 may be a useful prognostic factor for UPS.

Soft tissue sarcomas: From a morphological to a molecular biological approach.

Recently developed molecular genetic techniques have led to the elucidation of tumor-specific genomic alterations and thereby the reclassification of tumor entities of soft tissue sarcoma. A solitary fibrous tumor-mimicking tumor with the AHRR-NCOA2 gene has been isolated as angiofibroma of soft tissue. As for small round cell sarcomas, novel fusion genes such as CIC-DUX4 and BCOR-CCNB3 have been identified in these tumor groups. SMARCB1/INI1 deficient tumors with round cell morphology are also expected to be reclassified in three types, based on the combination of their morphology and genotype. The identification of the MDM2 gene amplification in pleomorphic sarcomas has extended the entity of dedifferentiated liposarcoma (DDLS). Our recent molecular investigations elucidated candidates for novel therapeutic strategies. Activation of the Akt-mTOR pathway was correlated with poor prognosis or tumor grade in spindle cell sarcomas including malignant peripheral nerve sheath tumor. In vitro and in vivo studies of transcription factor Forkhead Box M1 (FOXM1) demonstrated the close correlation between aggressive biological behavior or chemosensitivity and FOXM1 expression in synovial sarcoma, so far. Finally, in regard to the investigation of cancer-testis antigens, myxoid/round cell liposarcoma and synovial sarcoma showed frequent and high expression of PRAME and NY-ESO-1.

Histological spectrum of angiofibroma of soft tissue: histological and genetic analysis of 13 cases.

AIMS: Angiofibroma of soft tissue (AFST) is a rare soft tissue neoplasm characterized by a fibroblastic cytomorphology and a prominent vascular structure. AFSTs possess a novel fusion gene, i.e. NCOA2-AHRR/AHRR-NCOA2 or GTF2I-NCOA2, providing a useful approach to diagnosing AFST. Morphologically, AFSTs span a wide spectrum, making diagnosis a challenge. The aim of this study was to review AFST cases and to report previously unknown histological features, which we confirmed by genetic analysis. METHODS AND RESULTS: We reviewed 276 cases diagnosed as solitary fibrous tumours/haemangiopericytomas (232 cases), unclassified tumours of fibroblastic differentiation (36 cases), and recently diagnosed AFSTs (eight cases), and retrieved 13 cases compatible with AFST. Immunohistochemical staining was performed for these cases, all 13 of which were analysed by reverse transcription polymerase chain reaction and fluorescence in-situ hybridization. The histological findings were as follows: amianthoid fibres, extravasation of red blood cells, haemosiderin deposition, aggregates of foamy histiocytes, cystic change, necrosis, and haemorrhage. Immunohistochemically, the tumour cells were positive for epithelial membrane antigen (four of 13 cases), desmin (six of 13 cases), CD163 (13 of 13 cases), CD68 (seven of 13 cases), oestrogen receptor (13 of 13 cases), progesterone receptor (three of 13 cases), and STAT6 (one of 13 cases, weak nuclear staining), but they were negative for CD34, α-smooth muscle actin, muscle-specific actin, S100, pan-cytokeratin, MDM2, and CDK4. The AHRR-NCOA2 fusion gene was detected in eight cases, and NCOA2 gene rearrangement in nine cases. CONCLUSION: We revealed the previously unreported histological variation and immunohistochemical findings of AFST, and confirmed them by using genetic methods. The results suggested that AFST should be considered in the diagnosis of fibrous or fibrohistiocytic tumours with the above histological features.

Activation of the Akt-mTOR and MAPK pathways in dedifferentiated liposarcomas.

The Akt/mTOR and MAPK pathways play important roles in modulating cellular function in response to extracellular signals, and they are known to be activated in certain kinds of sarcomas. Few investigations have examined these pathways in dedifferentiated liposarcoma (DDLS), in relation to clinicopathological features. Clinicopathological and immunohistochemical analyses were conducted using 99 DDLS specimens. An in vitro study was also conducted to examine the antitumor effects of an mTOR inhibitor and a MEK inhibitor on two DDLS cell lines. The clinicopathological analyses revealed that the AJCC staging was a significant prognostic factor for overall survival and that the tumor size, depth, and location were significant prognostic factors for event-free survival. Phosphorylated Akt (pAkt), pmTOR, pS6RP, p4E-BP1, pMEK, and pERK expressions were positive in 57.4, 52.4, 71.4, 57.1, 84.1, and 50.8 % of the dedifferentiated component of the 63 primary DDLSs. Positive staining for pmTOR was significantly more frequent in the dedifferentiated component than the well-differentiated component. A univariate prognostic analysis revealed that pmTOR expression was associated with poor prognosis in the tumors in the retroperitoneum/ventral body cavity. The mTOR and MEK inhibitors dose-dependently inhibited the cell proliferation of both DDLS cell lines and decreased the expression of downstream pS6RP and pERK, respectively. The combined use of the two inhibitors enhanced antiproliferative activity. In conclusion, the Akt/mTOR and MAPK pathways were activated in DDLS specimens, and the inhibition of these pathways decreased cell proliferation in DDLS cell lines. Our findings suggest that these pathways could be a therapeutic target for patients with DDLS.

Elevated expression of HSP90 and the antitumor effect of an HSP90 inhibitor via inactivation of the Akt/mTOR pathway in undifferentiated pleomorphic sarcoma.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a heterogeneous tumor group, and little is known about molecular target therapy for UPS. Heat shock protein 90 (HSP90) is an expressed chaperone that refolds certain denatured proteins under stress conditions. One of these proteins is Akt. The disruption of Akt signaling plays an important role in tumor progression. The present study's purpose was to analyze the HSP90 expression, Akt/mTOR pathway activation and the correlation between HSP90 expression and its pathway activation in UPS. METHODS: The status of HSP90 and the profiles of the Akt/ mTOR pathway were assessed by immunohistochemistry in 79 samples of UPS, and these data were compared with clinicopathological and histopathological findings. The expressions of indicated proteins were assessed by Western blotting in five frozen samples. After treating UPS cells with the HSP90 inhibitor, we assessed the antitumor effect of the inhibitor. RESULTS: Immunohistochemically, phosphorylated Akt (p-Akt), p-mTOR, p-S6RP and p-4EBP were positive in 57.3, 51.9, 54.5 and 57.1% of the UPS samples, respectively. The expressions of those phosphorylated proteins were correlated with each other. HSP90 expression was elevated in 56.4% of the samples and was correlated with p-Akt, p-mTOR and p-S6RP. The immunohistochemical results were confirmed by Western blotting. The HSP90 inhibitor led to decreased viability and invasiveness of the cells and inactivated the AKT/mTOR pathway in vitro. CONCLUSION: Elevated expression of HSP90 is a poor-prognosis factor and is involved in the activation of the Akt/mTOR pathway in UPS. HSP90 inhibition is a potential treatment option for UPS.

The Expression of Insulin-Like Growth Factor II Messenger RNA-Binding Protein 3 Upregulated in Intradural Extramedullary Schwannomas.

Introduction: Tumor size is an important factor in determining the appropriate clinical management of intradural-extramedullary schwannoma. A tumor volume reduction may be achieved by conservative targeted therapy instead of invasive surgery if a molecular event related to tumor size is discovered. Insulin-like growth factor II messenger RNA-binding protein 3 (IMP3), an oncofetal tumor-associated antigen that is expected to be a target for immunotherapy, was focused on in this study. Methods: The IMP3 status was assessed by immunohistochemistry in 64 samples of intradural-extramedullary schwannoma, and the correlation between IMP3 expression and tumor size was evaluated. Results: Immunohistochemically, high IMP3 expression was observed in ～85% of schwannomas. The maximum tumor diameter of the high IMP3 expression group was significantly larger than that of the low IMP3 expression group (34.3 mm vs 18.5 mm, p=0.002). The receiver operating characteristic curve demonstrated that a maximum tumor diameter of 24 mm was a predictable factor for IMP3 expression (sensitivity, 0.7; 1-specificity, 0.2; area under the curve, 0.82). Conclusions: Upregulated IMP3 expression was associated with large tumor size, suggesting a possible therapeutic approach.

Comparison of Microendoscopic Laminotomy (MEL) Versus Spinous Process-Splitting Laminotomy (SPSL) for Multi Segmental Lumbar Spinal Stenosis.

Aims  This study was aimed to compare the perioperative and postoperative outcomes of patients who underwent posterior decompression for multi-segmental lumbar spinal stenosis by microendoscopic laminotomy (MEL) versus spinous process-splitting laminotomy (SPSL) retrospectively. Methods We retrospectively reviewed 73 consecutive patients who underwent two or three levels MEL (n=51) or SPSL (n=22) for lumbar spinal stenosis between 2012 and 2018. The perioperative outcomes were operative time, intraoperative blood loss, length of postoperative hospital stay, complications, and reoperation rate. The postoperative outcomes were evaluated using a visual analog scale (VAS) and the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) scores at one year postoperatively. Results The mean follow-up time was 26.6 months in MEL and 35.6 months in SPSL. The mean operative time was significantly longer in MEL than SPSL (two levels, 183.6 ± 43.2 versus 134.8 ± 26.7 min, respectively; three levels: 241.6 ± 47.8 versus 179.9 ± 28.8 min, respectively). MEL's mean postoperative hospital stay was significantly shorter than SPSL (12.3 ± 5.9 versus 15.5 ± 7.2 days, respectively). There was no significant difference in the mean intraoperative blood loss, complication rate, reoperation rate, and postoperative outcomes between the two groups. Conclusions This study suggests that both techniques are effective in treating multi-segmental lumbar spinal stenosis. There was no significant difference between the two procedures in intraoperative blood loss (IBL), complications rate, reoperation rate, or improvement in VAS and Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) scores. MEL had an advantage in the postoperative hospital stay.

Factors Affecting Postoperative Spinal Epidural Hematoma and the Optimal Order of Vertebral Body Decompression in Multivertebral Microendoscopic Laminectomy.

Purpose Symptomatic postoperative spinal epidural hematoma (POSEH) is a complication of spine surgery that occurs infrequently but may cause ongoing serious neurological damage. Due to the narrow entry portal, the risk of hematoma is increased after microendoscopic laminectomy (MEL) compared with conventional open surgery, and the risk might be even higher for multivertebral MEL (m-MEL). The purpose of this study was to clarify the factors affecting the development of POSEH after m-MEL and identify the optimal order for the decompression of vertebral bodies. Methods A total of 313 patients who underwent m-MEL from 2016 to 2020 were retrospectively assessed. The cohort comprised 238 patients who underwent two-level MEL, 67 who underwent three-level MEL, and eight who underwent four-level MEL. Symptomatic POSEH was defined as the presence of an epidural hematoma at the surgical site on MRI with symptoms such as lower extremity pain or muscle weakness. We elucidated the incidence of POSEH at each vertebral level and investigated the relationship between POSEH and possible risk factors such as clinical and operative variables. Results There were 41 patients in the POSEH group and 272 patients in the non-POSEH group. Seven patients in the POSEH group underwent reoperation. The occurrence of POSEH was related to the number of decompressed vertebral bodies. Patients who underwent L2/3 and L3/4 decompression at the end of the procedure also showed a higher incidence of POSEH at the surgical level. Conclusion In patients undergoing m-MEL, treatment of the upper lumbar vertebrae at the end of decompression surgery might be a risk factor for symptomatic POSEH. The incidence of POSEH was particularly increased at L2/3, suggesting that L2/3 decompression should not be performed at last and that careful hemostasis should be applied.

Risk Factors for Incidence of Postoperative Spinal Epidural Hematoma Following Multilevel Microendoscopic Laminectomy.

INTRODUCTION: Due to the narrow portal of entry, microendoscopic laminectomy (MEL) is associated with a risk of postoperative spinal epidural hematoma (POSEH). This risk might be higher when performing multiple-level (m-) MEL. The purpose of this study is to clarify the incidence rate of POSEH following single-level (s-) and m-MEL by each interlaminar level and identify the risk factors for POSEH following m-MEL. METHODS: A total of 379 patients underwent MEL of the lumbar spine (s-MEL, n=141; m-MEL, n=238). We determined the incidence of POSEH following s-MEL and m-MEL by each interlaminar level. For m-MEL, we clarified the correlation between POSEH and possible risk factors, such as operative findings, the sequence of operated interlaminar levels, and the preoperative cross-sectional dural area (CSA) on magnetic resonance imaging. RESULTS: The incidence rate at L2/3 was significantly higher than that at L3/4 and L4/5. Patients who underwent L2/3 decompression at the end of the procedure showed a higher incidence of POSEH at the L2/3 level. Preoperative spinal stenosis was associated with POSEH at the L2/3 level, and CSA of 56 mm2 was a predictive factor for POSEH. Logistic regression analysis revealed that both were significant risk factors. CONCLUSIONS: In patients undergoing m-MEL, the incidence of POSEH is highest at the L2/3 level, and treatment of the L2/3 level at the end of the procedure and the presence of spinal stenosis are risk factors for POSEH.

Risk factor analysis of perioperative complications in patients with rheumatoid arthritis undergoing primary cervical spine surgery.

BACKGROUND: Rheumatoid arthritis (RA) often causes cervical spine lesions as the disease condition progresses, which induce occipital neuralgia or cervical myelopathy requiring surgical interventions. Meanwhile, patients with RA are susceptible to infection or other complications in the perioperative period because they frequently have comorbidities and use immunosuppressive medications. However, the risk factors or characteristics of patients with RA who experience perioperative complications after cervical spine surgery remain unknown. A risk factor analysis of perioperative complications in patients with RA who underwent primary cervical spine surgery was conducted in the present study. METHODS: A total of 139 patients with RA who underwent primary cervical spine surgery from January 2001 to March 2020 were retrospectively investigated. Age and height, weight, serum albumin, serum C-reactive protein, American Society of Anesthesiologists Physical Status (ASA-PS), Charlson comorbidity index, medications used, cervical spine lesion, surgery time, bleeding volume, and procedures were collected from medical records to compare the patients with complications to those without complications after surgery. The risk factors for perioperative complications were assessed by univariate and multivariate logistic regression analysis. RESULTS: Twenty-eight patients (20.1%) had perioperative complications. Perioperative complications were significantly associated with the following factors [data presented as odds ratio]: lower height [0.928, p=0.007], higher ASA-PS [2.296, p=0.048], longer operation time [1.013, p=0.003], more bleeding volume [1.004, p=0.04], higher rates of vertical subluxation [2.914, p=0.015] and subaxial subluxation (SAS) [2.507, p=0.036], occipito-cervical (OC) fusion [3.438, p=0.023], and occipito-cervical/thoracic (long) fusion [8.021, p=0.002] in univariate analyses. In multivariate analyses, lower height [0.915, p=0.005], higher ASA-PS [2.622, p=0.045] and long fusion [7.289, p=0.008] remained risk factors. High-dose prednisolone use [1.247, p=0.028], SAS [6.413, p=0.018], OC fusion [17.93, p=0.034], and long fusion [108.1, p<0.001] were associated with severe complications. CONCLUSIONS: ASA-PS and long fusion could be indicators predicting perioperative complications in patients with RA after cervical spine surgery. In addition, cervical spine lesions requiring OC fusion or long fusion and high-dose prednisolone use were suggested to be risk factors for increasing severe complications.

Changes in a Single Institution's Orthopedic Hospitalization Service in Japan Owing to COVID-19 in 2020.

Introduction The coronavirus disease 2019 (COVID-19) pandemic has had immense impact on people and institutions, including the number of admissions to hospitals for surgery. Our aim in this study was to determine the impact of the pandemic on surgeries in a single institution located in Fukuoka, Japan, between 2019 and 2020. Methods We quantified the numbers of surgeries in both years according to three sites of injury (indoor, outdoor, and unknown), 14 disease categories, and 9 primary diseases using patients' medical records. We also compared the hospital cost per day in each month from March to November in both 2019 and 2020 and compared the change in these costs between the two years. Results The number of admissions in 2020 was 1,187 cases vs 1,282 cases in 2019. The average patients' age was higher in 2020 vs 2019 (69.7 ± 0.5 vs 67.5 ± 0.5 years, respectively; p = 0.004), with no gender differences (2020: 705 women and 482 men; 2019: 716 women and 566 men). We found no significant differences in the number of admissions by month between 2019 and 2020. The percentages of outdoor injuries were significantly lower in 2020 vs 2019 (29.8% vs 37.9%, respectively; p = 0.004), and we found significantly different rates when comparing 2020 and 2019 for degenerative disease (42.6% vs 37.4%; p = 0.007), trauma related to falls (34.4% vs 30.2%; p = 0.02), chronic disease (1.9% vs 3.7%; p = 0.005), and sports injuries (0.8% vs 3.7%; p < 0.0001). The rate of sports-related injury was significantly lower in 2020 (1.6%) than in 2019 (7.7%) (p < 0.0001). The daily hospital charge was $10,517.09 (US dollars) in 2020 vs $11,225.32 in 2019, and the charges in the months of April and June were significantly higher in 2020 vs 2019 (p = 0.003 and p = 0.001, for April and June, respectively). Both the number and rate of upper limb fractures were higher in 2020. Conclusions The COVID-19 pandemic is affecting some hospitals' revenue. Although the charges per day were sufficient in our institution in 2020, compared with 2019, some hospital beds were unused during this phase of the pandemic. Hospitals may increase the revenue by mixing both short-term and long-term patients' hospital stays effectively.

Association of Postoperative Neutrophil Lymphocyte Ratio (NLR) and Monocyte Lymphocyte Ratio (MLR) with the Presence of Osteoporosis in Japanese Patients after Hip Fracture Surgery: A Retrospective Cohort Study.

BACKGROUND: The diagnosis of osteoporosis is based on bone mineral density measurements expressed as a percentage of the young adult mean (YAM) in Japan. Osteoporosis is defined as YAM <70%, and intervention is recommended at this cutoff. Because osteoporosis has a strong association with systemic metabolic disorders, we postulated that patients with YAM <70% had higher inflammatory biomarker concentrations owing to the higher systemic stress compared with YAM >70%. METHOD: We retrospectively reviewed 94 patients with low-trauma hip fractures. Blood examinations were performed on postoperative day (POD) 1 and POD 7. We used neutrophil lymphocyte ratio (NLR) and monocyte lymphocyte ratio (MLR) to evaluate postoperative recovery. After dividing the 94 patients into two groups according to a YAM cutoff of 70%, we compared the differences in NLR and MLR. RESULTS: On POD 1, patients with YAM >70% had a median NLR of 5.7 and a median MLR of 0.66, which were significantly lower than for patients with YAM <70% (8.8 and 0.9, respectively). Similarly, on POD 7, patients with YAM >70% had a median NLR of 2.0 and a median MLR of 0.31, which were significantly lower than for patients with YAM <70% (3.5 and 0.43, respectively). CONCLUSION: A YAM cutoff of 70% is an appropriate intervention threshold regarding postoperative recovery after hip fracture surgery. Mini-Abstract. Patients with YAM >70% showed lower NLR and MLR on POD 1 and POD 7. A YAM cuffoff of 70% is an appropriate intervention threshold regarding postoperative recovery after hip fracture surgery.

Ascending Aortic Calcification as a Potential Predictor for Low Bone Mineral Density: A Pilot Study.

BACKGROUND: Identifying the factors related to low bone mineral density (BMD) can have significant implications for preventing hip fractures. The correlation between ascending aortic calcification and BMD has never been reported. Therefore, the purpose of the current study is to confirm the hypothesis that ascending aortic calcification can be used as a predictive factor for low BMD and to find a radiographic sign to show it. METHOD: Plain film and computed tomography (CT) images of the thorax were obtained from 91 patients with hip fractures. Using the images, the calcification line of the ascending aorta adjacent to the aortic arch was evaluated. A prominent calcification line confirmed by both plain film and CT was classified as +2. A line which was ambiguous on plain film but confirmed by CT was classified as +1. Cases with no calcification were categorized as 0 (control). We compared the classified score with the BMD and calculated the kappa coefficient to measure intraobserver reliabilities for this radiographic finding. RESULTS: Twenty-eight patients showed a +2 line, twenty-four patients showed a +1 line, and thirty-nine patients showed 0 lines. The median BMD of each group was 0.37 for the +2 line, 0.45 for the +1 line, and 0.51 for the 0 line. The BMD for the +2 group was significantly lower than the others. The kappa coefficient was approximately 0.6 (p < 0.01). CONCLUSION: The imaging finding of calcification of the ascending aorta might be considered as a potential surrogate marker of low BMD. In such subjects, BMD might be ordered for the confirmation of diagnosis of osteoporosis. Mini-Abstract. The Aortic Arch Tail Sign, a calcification line on the ascending aorta, was relevant to low BMD in the current study. BMD can be ordered for the confirmation of diagnosis of osteoporosis in a subject incidentally found to have ascending aorta calcification on X-ray or CT.

Genome-Wide Occupancy Profiling Reveals Critical Roles of FoxO1 in Regulating Extracellular Matrix and Circadian Rhythm Genes in Human Chondrocytes.

OBJECTIVE: Osteoarthritis (OA) is the most common age-related joint disease. With aging and in OA, the expression of FoxO transcription factors is reduced, diminishing their chondroprotective actions. In order to elucidate the molecular mechanisms by which FoxO1 protects chondrocytes, we sought to identify the genome-wide occupancy profile of FoxO1. METHODS: We performed FoxO1 chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) on human primary chondrocytes. ChIP-Seq data were integrated with RNA sequencing (RNA-Seq) data sets. Bioinformatics results were confirmed in primary chondrocytes that were treated with a FoxO1 inhibitor. RESULTS: Analysis of FoxO1 ChIP-Seq on human primary chondrocytes showed that pathways implicated in OA pathogenesis are mainly regulated by FoxO1 binding to tissue-specific enhancers with suboptimal binding sites (20% of the peaks), while more ubiquitous FoxO1 pathways are regulated at the promoter level through interaction with its canonical binding motif (7% of the peaks). Integrating FoxO1 occupancy data with RNA-Seq data comparing OA and healthy human cartilage revealed 428 putative FoxO1 target genes that are dysregulated in OA. Pathway analysis showed enrichment for genes belonging to the senescence pathway (logP = -6.73), extracellular matrix (ECM) pathway (logP = -12.97), and circadian clock pathway (logP = -6.30), which suggests that FoxO1 dysregulation plays an important role in their abnormal expression in OA. Using an inhibitor of FoxO1, we confirmed that FoxO1 regulates these pathways in cultured human chondrocytes. CONCLUSION: FoxO1 regulates ubiquitous and cartilage-specific genes in chondrocytes by using different mechanisms. The FoxO1 transcriptional network is a key player in regulating homeostasis, ECM, and circadian clock genes and plays an important role in the abnormal expression of these pathways observed in OA pathogenesis.

GRK5 Inhibition Attenuates Cartilage Degradation via Decreased NF-κB Signaling.

OBJECTIVE: NF-κB-dependent signaling is an important modulator in osteoarthritis (OA), and G protein-coupled receptor kinase 5 (GRK5) regulates the NF-κB pathway. This study was undertaken to investigate the functional involvement of GRK5 in OA pathogenesis. METHODS: GRK5 expression in normal and OA human knee joints was analyzed immunohistochemically. Gain- or loss-of-function experiments were performed using human and mouse chondrocytes. OA was induced in GRK5-knockout mice by destabilization of the medial meniscus, and histologic examination was performed. OA was also induced in wild-type mice, which were then treated with an intraarticular injection of amlexanox, a selective GRK5 inhibitor, every 5 days for 8 weeks. RESULTS: GRK5 protein expression was increased in human OA cartilage. In vitro, expression levels of OA-related factors and NF-κB transcriptional activation were down-regulated by suppression of the GRK5 gene in human OA chondrocytes (3.49-fold decrease in IL6 [P < 0.01], 2.43-fold decrease in MMP13 [P < 0.01], and 2.66-fold decrease in ADAMTS4 [P < 0.01]). Conversely, GRK5 overexpression significantly increased the expression of OA-related catabolic mediators and NF-κB transcriptional activation. On Western blot analysis, GRK5 deletion reduced IκBα phosphorylation (up to 4.4-fold decrease [P < 0.05]) and decreased p65 nuclear translocation (up to 6.4-fold decrease [P < 0.01]) in mouse chondrocytes. In vivo, both GRK5 deletion and intraarticular amlexanox protected mouse cartilage against OA. CONCLUSION: Our results suggest that GRK5 regulates cartilage degradation through a catabolic response mediated by NF-κB signaling, and is a potential target for OA treatment. Furthermore, amlexanox may be a major compound in relevant drugs.

Which Side-Bending X-ray Position is Better to Evaluate the Preoperative Curve Flexibility in Adolescent Idiopathic Scoliosis Patients, Supine or Prone?

STUDY DESIGN: Prospective cohort study. PURPOSE: The present study aimed to evaluate the difference in the preoperative curve flexibility between the supine and prone positions in patients with adolescent idiopathic scoliosis (AIS). OVERVIEW OF LITERATURE: In AIS, a side-bending view is necessary to differentiate a structural curve from a nonstructural curve using the Lenke classification system. However, there are no published studies about which position, supine or prone, is more effective when evaluating preoperative curve flexibility using side-bending X-ray images in AIS patients. METHODS: Radiographs were analyzed for 32 AIS patients (26 females, six males) who underwent posterior correction and fusion of their main thoracic (MT) curves. Cobb angles of MT, proximal thoracic (PT), and thoracolumbar/lumbar (TL/L) curves were measured preoperatively using upright, supine (anteroposterior and side-bending), and prone (posteroanterior and side-bending) X-rays. RESULTS: The average Cobb angles of PT, MT, and TL/L curves on preoperative upright/supine/prone X-rays were 29.1°/26.7°/26.6°, 60.7°/48.5°/48.2°, and 41.0°/32.6°/33.1°, respectively. The average Cobb angles of PT, MT, and TL/L curves on supine/prone sidebending X-rays were 19.2°/20.3°, 36.3°/36.4°, and 13.9°/15.7°, respectively. The flexibility rates of PT, MT, and TL/L curves in supine/prone positions were 35.3%/32.5%, 40.6%/40.2%, and 71.7%/68.2%, respectively. Comparing flexibility rates in the prone position with those in the supine position in each case, the average ratios of PT, MT, and TL/L curves were found to be 1.0, 1.0, and 0.9, respectively. There were no statistically significant differences between supine and prone side-bending X-ray measurements. However, the Lenke classification in six of 32 patients (18.8%) differed between supine and prone positions because the TL/L curve in the supine position was slightly more flexible than in the prone position. CONCLUSIONS: Supine side-bending films may be suitable for the evaluation of preoperative curve flexibility in AIS, especially for lumbar modifier C.