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Objective: The incidence of postoperative complications, including dysphagia, increases as the population undergoing cardiovascular surgery ages. This study aimed to explore the potential of maximum phonation time (MPT) as a simple tool for predicting postextubation dysphagia (PED) and major adverse cardiac and cerebrovascular events (MACCEs). Methods: This retrospective study included 442 patients who underwent elective cardiac surgery at a university hospital. MPT was measured before surgery, and patients were stratified into 2 groups based on normal and abnormal MPTs. Postoperative complications, including PED and MACCEs, were also investigated. Swallowing status was assessed using the Food Intake Level Scale. Results: MPT predicted PED with prevalence of 11.0% and 18.0% in the normal and abnormal MPT groups, respectively (P = .01). During the follow-up period, MACCEs developed in 17.0% of patients. Frailty, European System for Cardiac Operative Risk Evaluation II score, PED, and MPT were markedly associated with MACCEs (adjusted hazard ratios: 2.25, 1.08, 1.96, and 0.96, respectively). Mediation analysis revealed that MPT positively influenced PED and MACCEs, whereas PED positively influenced MACCEs. The trend in restricted cubic spline analysis indicated that the hazard ratio for MACCEs increased sharply when MPT was

Objective To elucidate the patient characteristics and outcomes of emergency surgery for spinal metastases and identify risk factors for emergency surgery. Methods We prospectively analyzed 216 patients with spinal metastases who underwent palliative surgery from 2015 to 2020. The Eastern Cooperative Oncology Group performance status, Barthel index, EuroQol-5 dimension (EQ5D), and neurological function were assessed at surgery and at 1, 3, and 6 months postoperatively. Multivariate analysis was performed to identify risk factors for emergency surgery. Results In total, 146 patients underwent nonemergency surgery and 70 patients underwent emergency surgery within 48 hours of diagnosis of a surgical indication. After propensity score matching, we compared 61 patients each who underwent nonemergency and emergency surgery. Regardless of matching, the median performance status and the mean Barthel index and EQ5D score showed a tendency toward worse outcomes in the emergency than nonemergency group both preoperatively and 1 month postoperatively, although the surgery greatly improved these values in both groups. The median survival time tended to be shorter in the emergency than nonemergency group. The multivariate analysis showed that lesions located at T3–10 (p = 0.002; odds ratio [OR], 2.92; 95% confidence interval [CI], 1.48–5.75) and Frankel grades A–C (p < 0.001; OR, 4.91; 95% CI, 2.45–9.86) were independent risk factors for emergency surgery. Conclusion Among patients with spinal metastases, preoperative and postoperative subjective health values and postoperative survival are poorer in emergency than nonemergency surgery. Close attention to patients with T3–10 metastases is required to avoid poor outcomes after emergency surgery.

Background and Objectives: Changes in activities of daily living (ADL) and quality of life (QOL) of patients with bone metastasis who underwent surgical treatment through Bone Metastasis Cancer Boards (BMCBs), a recent multidisciplinary approach for managing bone metastases, have been reported; however, no reports exist on patients who undergo conservative treatment. In this study, we aimed to evaluate these patients’ ADL and QOL and examine the factors influencing changes in these parameters. Materials and Methods: We retrospectively reviewed 200 patients with bone metastases who underwent conservative therapy through BMCBs between 2013 and 2021. A reassessment was conducted within 2–8 weeks after the initial assessment. Patients’ background and changes in performance status (PS), Barthel Index (BI), EuroQol five-dimension (EQ-5D) scores, and Numerical Rating Scale (NRS) scores were initially assessed. Furthermore, we categorized patients into two groups based on improvements or deteriorations in ADL and QOL and performed comparative analyses. Results: Significant improvements in EQ-5D (0.57 ± 0.02 versus [vs.] 0.64 ± 0.02), NRS max (5.21 ± 0.24 vs. 3.56 ± 0.21), and NRS average (2.98 ± 0.18 vs. 1.85 ± 0.13) scores were observed between the initial assessment and reassessment (all p < 0.001). PS (1.84 ± 0.08 vs. 1.72 ± 0.08) and BI (83.15 ± 1.68 vs. 84.42 ± 1.73) also showed improvements (p = 0.06, and 0.054, respectively). In addition, spinal cord paralysis (odds ratio [OR]: 3.69, p = 0.049; OR: 8.42, p < 0.001), chemotherapy (OR: 0.43, p = 0.02; OR: 0.25, p = 0.007), and NRS average scores (OR: 0.38, p = 0.02; OR: 0.14, p < 0.001) were independent factors associated with ADL and QOL. Conclusions: Patients with bone metastases who underwent conservative treatment through BMCBs exhibited an increase in QOL without a decline in ADL. The presence of spinal cord paralysis, absence of chemotherapy, and poor pain control were associated with a higher risk of deterioration in ADL and QOL.

Abstract Body mass index (BMI) distribution and its impact on cardiovascular disease (CVD) vary between Asian and western populations. The study aimed to reveal time-related trends in the prevalence of obesity and underweight and safe ranges of BMI in Japanese patients with CVD. We analyzed 5,020,464 records from the national Japanese Registry of All Cardiac and Vascular Diseases—Diagnosis Procedure Combination dataset over time (2012–2019) and evaluated BMI trends and the impact on in-hospital mortality for six acute CVDs: acute heart failure (AHF), acute myocardial infarction (AMI), acute aortic dissection (AAD), ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). Patients were categorized into five groups using the WHO Asian-BMI criteria: underweight (

In this study, we examined the proliferation capability and osteogenic and chondrogenic differentiation potential of non-hypertrophic nonunion cells (NHNCs), and the effect of Escherichia coli-derived BMP-2 (E-BMP-2) on them. We enrolled five patients with non-hypertrophic nonunion. NHNCs isolated from nonunion tissue sampled during surgery were cultured, passaged, counted every 14 days, and analyzed. NHNCs were homogenous fibroblastic adherent cells and long-lived through at least 10 passages, with a slight decline. The cells were consistently positive for mesenchymal stem cell-related markers CD73 and CD105, and negative for the hematopoietic markers CD14 and CD45. NHNCs could differentiate into osteoblast lineage cells; however, they did not have strong calcification or sufficient chondrogenic differentiation capability. E-BMP-2 did not affect the proliferative capability of the cells but improved their osteogenic differentiation capability by increasing alkaline phosphatase activity and upregulating the gene expression of osterix, bone sialoprotein, and osteocalcin. E-BMP-2 enhanced their chondrogenic differentiation capability by upregulating the gene expression of aggrecan and collagen type II. We showed, for the first time, that NHNCs have the capacity to differentiate into osteoblast-lineage cells, although the chondrogenic differentiation potential was poor. Local application of E-BMP-2 with preservation of nonunion tissue is a potential treatment option for non-hypertrophic nonunion.

Background and Objectives: Bone metastasis cancer boards (BMCBs) focusing on the management of bone metastases have been gathering much attention. However, the association of BMCBs with spinal surgery in patients with spinal metastases remains unclear. In this retrospective single-center observational study, we aimed to clarify the effect of a BMCB on spinal metastasis treatment. Materials and Methods: We reviewed consecutive cases of posterior decompression and/or instrumentation surgery for metastatic spinal tumors from 2008 to 2019. The BMCB involved a team of specialists in orthopedics, rehabilitation medicine, radiation oncology, radiology, palliative supportive care, oncology, and hematology. We compared demographics, eastern cooperative oncology group performance status (ECOGPS), Barthel index (BI), number of overall versus emergency surgeries, and primary tumors between patients before (2008–2012) and after (2013–2019) BMCB establishment. Results: A total of 226 patients including 33 patients before BMCB started were enrolled; lung cancer was the most common primary tumor. After BMCB establishment, the mean patient age was 5 years older (p = 0.028), the mean operating time was 34 min shorter (p = 0.025), the mean hospital stay was 34.5 days shorter (p < 0.001), and the mean BI before surgery was 12 points higher (p = 0.049) than before. Moreover, the mean number of surgeries per year increased more than fourfold to 27.6 per year (p < 0.01) and emergency surgery rates decreased from 48.5% to 29.0% (p = 0.041). Patients with an unknown primary tumor before surgery decreased from 24.2% to 9.3% (p = 0.033). Postoperative deterioration rates from 1 to 6 months after surgery of ECOGPS and BI after BMCB started were lower than before (p = 0.045 and p = 0.027, respectively). Conclusion: The BMCB decreased the emergency surgery and unknown primary tumor rate despite an increase in the overall number of spinal surgeries. The BMCB also contributed to shorter operation times, shorter hospital stays, and lower postoperative deterioration rates of ECOGPS and BI.

Abstract Background Few studies have addressed the impact of palliative surgery for cervical spine metastasis on patients’ performance status (PS) and quality of life (QOL). We investigated the surgical outcomes of patients with cervical spine metastasis and the risk factors for a poor outcome with a focus on the PS and QOL. Methods We prospectively analyzed patients with cervical spine metastasis who underwent palliative surgery from 2013 to 2018. The Eastern Cooperative Oncology Group PS (ECOGPS) and EuroQol 5-Dimension (EQ5D) score were assessed at study enrollment and 1, 3, and 6 months postoperatively. Neurological function was evaluated with Frankel grading. Univariate and multivariate analyses were performed to identify the risk factors for a poor surgical outcome, defined as no improvement or deterioration after improvement of the ECOGPS or EQ5D score within 3 months. Results Forty-six patients (mean age, 67.5 ± 11.7 years) were enrolled. Twelve postoperative complications occurred in 11 (23.9%) patients. The median ECOGPS improved from PS3 at study enrolment to PS2 at 1 month and PS1 at 3 and 6 months postoperatively. The mean EQ5D score improved from 0.085 ± 0.487 at study enrolment to 0.658 ± 0.356 at 1 month and 0.753 ± 0.312 at 3 months. A poor outcome was observed in 18 (39.1%) patients. The univariate analysis showed that variables with a P value of

Abstract Background Rich vascularity of the induced membrane (IM) is important for Masquelet reconstruction surgery. The factors affecting IM vascularity are not completely understood. This study aimed to investigate these factors using histological samples of human IMs. Methods We retrospectively evaluated 36 patients whose bone defects were treated using the Masquelet technique. Two clinical pathologists analyzed histological sections of IM pieces (1 cm2). The number of blood vessels per 1 mm2 was counted and compared among men and women, femur or tibia, with and without free flap surgery, antibiotic impregnation to the cement, osteogenesis inside the membrane, smoking, and diabetes mellitus. The number of blood vessels within the same patient was compared among different time points. Correlation analysis was performed among blood vessel numbers and patient age, duration of cement spacer placement, and histological grading scales (inflammation, foreign body reaction, and fibrosis). Results IM formation with rich vascularity and some inflammation, foreign body reaction, and fibrosis were histologically confirmed in all patients. We found 37.4 ± 19.1 blood vessels per 1 mm2. The number of blood vessels was significantly lower in patients with than in those without free flap surgery; it was higher in patients with osteogenesis inside the IM. No significant correlations were found in any of the analyses. Conclusion Sex, patient age, smoking, diabetes mellitus, femur or tibia, duration of cement spacer placement, and antibiotic impregnation to the cement did not affect IM vascularization. IM vascularization was reduced in patients with than in those without free flap surgery.

Background: Poor oral health status can lead to a deteriorated level of general health and is common among patients undergoing cardiovascular surgery. However, the effect of oral health status on postoperative outcomes in cardiovascular surgery patients remains unclear. Thus, we investigated the effect of preoperative oral health status on postoperative complications and functional recovery after cardiovascular surgery. Methods: This single-centre retrospective cohort study included 884 inpatients undergoing elective cardiovascular surgery. Oral health status was assessed based on the number of remaining teeth, use of dentures, occlusal support, and periodontal status. We investigated postoperative complications related to surgery and postoperative functional recovery by measuring the reacquisition of walking ability, activities of daily living, and length of postoperative hospital stay. Results: In this cohort (age 66.9 ± 13.4 years), the mean number of remaining teeth was 18.7 ± 9.4. Patients were grouped based on tertiles of the data distribution of remaining teeth: ≥ 20 teeth (470 patients); 10-19 teeth (137 patients); < 10 teeth (185 patients). The number of missing teeth was associated with age (P < 0.001). The prevalence of postoperative pneumonia and reintubation after surgery was 3.2% and 2.5%, respectively, which was significantly higher in patients with severe tooth loss (P < 0.05 for both). After adjusting for age and other confounding factors, the number of remaining teeth was a statistically significant predictor of functional recovery (P < 0.05). Conclusions: Preoperative oral health status was related to postoperative respiratory complications and independently associated with functional recovery. Preoperative oral intervention may improve functional recovery after cardiovascular surgery. Résumé: Contexte: Une mauvaise santé buccodentaire peut avoir des répercussions néfastes sur la santé générale et est fréquemment observée chez les patients subissant une intervention chirurgicale cardiovasculaire. Cependant, l’effet de l’état de santé buccodentaire sur les issues postopératoires chez les patients ayant subi une telle intervention est mal connu. Nous avons donc étudié l’effet de l’état de santé buccodentaire avant l’intervention sur les complications postopératoires et le rétablissement fonctionnel après une intervention chirurgicale cardiovasculaire. Méthodologie: Cette étude de cohorte rétrospective menée dans un seul centre réunissait 884 patients subissant une intervention chirurgicale cardiovasculaire non urgente. L’état de santé buccodentaire des patients a été évalué en fonction du nombre de dents restantes, du recours à des prothèses dentaires, de la présence d’appuis occlusaux et de la santé parodontale. Nous avons examiné les cas de complications postopératoires liées à l’intervention chirurgicale ainsi que le rétablissement fonctionnel après l’intervention en évaluant la réacquisition de la capacité de marcher, la capacité d’accomplir les activités de la vie quotidienne et la durée du séjour à l’hôpital après l’intervention. Résultats: Dans cette cohorte (âge moyen : 66,9 ± 13,4 ans), les sujets avaient en moyenne 18,7 ± 9,4 dents restantes. Les patients ont été répartis en trois groupes en fonction du nombre de dents restantes : ≥ 20 dents (470 patients); de 10 à 19 dents (137 patients); < 10 dents (185 patients). Il y avait un lien entre le nombre de dents manquantes et l’âge (p < 0,001). La prévalence des cas de pneumonie postopératoire et de réintubation après l’intervention s’établissait à 3,2 % et à 2,5 %, respectivement, et était significativement plus élevée chez les patients à qui il restait très peu de dents (p < 0,05 dans les deux cas). Après correction pour tenir compte de l’âge et d’autres facteurs de confusion, le nombre de dents restantes s’est révélé être un facteur de prédiction statistiquement significatif du rétablissement fonctionnel (p < 0,05). Conclusions: L’état de santé buccodentaire avant l’intervention chirurgicale était lié à des complications respiratoires postopératoires et associé de manière indépendante au rétablissement fonctionnel. Des soins buccodentaires préopératoires pourraient améliorer le rétablissement fonctionnel après une intervention chirurgicale cardiovasculaire.

Abstract Background MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate gene expression. There is increasing evidence that some miRNAs are involved in the pathology of diabetes mellitus (DM) and its complications. We hypothesized that the functions of certain miRNAs and the changes in their patterns of expression may contribute to the pathogenesis of impaired fractures due to DM. Methods In this study, 108 male Sprague–Dawley rats were divided into DM and control groups. DM rats were created by a single intravenous injection of streptozotocin. Closed transverse femoral shaft fractures were created in both groups. On post-fracture days 5, 7, 11, 14, 21, and 28, miRNA was extracted from the newly generated tissue at the fracture site. Microarray analysis was conducted with miRNA samples from each group on post-fracture days 5 and 11. The microarray findings were validated by real-time polymerase chain reaction (PCR) analysis at each time point. Results Microarray analysis revealed that, on days 5 and 11, 368 and 207 miRNAs, respectively, were upregulated in the DM group, compared with the control group. The top four miRNAs on day 5 were miR-339-3p, miR451-5p, miR-532-5p, and miR-551b-3p. The top four miRNAs on day 11 were miR-221-3p, miR376a-3p, miR-379-3p, and miR-379-5p. Among these miRNAs, miR-221-3p, miR-339-3p, miR-376a-3p, miR-379-5p, and miR-451-5p were validated by real-time PCR analysis. Furthermore, PCR analysis revealed that these five miRNAs were differentially expressed with dynamic expression patterns during fracture healing in the DM group, compared with the control group. Conclusions Our findings will aid in understanding the pathology of impaired fracture healing in DM and may support the development of molecular therapies using miRNAs for the treatment of impaired fracture healing in patients with DM.

Abstract Background Clinicians have very limited options to improve fracture repair. Therefore, it is critical to develop a new clinically available therapeutic option to assist fracture repair biologically. We previously reported that the topical cutaneous application of carbon dioxide (CO2) via a CO2 absorption-enhancing hydrogel accelerates fracture repair in rats by increasing blood flow and angiogenesis and promoting endochondral ossification. The aim of this study was to assess the safety and efficacy of CO2 therapy in patients with fractures. Methods Patients with fractures of the femur and tibia were prospectively enrolled into this study with ethical approval and informed consent. The CO2 absorption-enhancing hydrogel was applied to the fractured lower limbs of patients, and then 100% CO2 was administered daily into a sealed space for 20 min over 4 weeks postoperatively. Safety was assessed based on vital signs, blood parameters, adverse events, and arterial and expired gas analyses. As the efficacy outcome, blood flow at the level of the fracture site and at a site 5 cm from the fracture in the affected limb was measured using a laser Doppler blood flow meter. Results Nineteen patients were subjected to complete analysis. No adverse events were observed. Arterial and expired gas analyses revealed no adverse systemic effects including hypercapnia. The mean ratio of blood flow 20 min after CO2 therapy compared with the pre-treatment level increased by approximately 2-fold in a time-dependent manner. Conclusions The findings of the present study revealed that CO2 therapy is safe to apply to human patients and that it can enhance blood flow in the fractured limbs. Trial registration This study has been registered in the UMIN Clinical Trials Registry (Registration number: UMIN000013641, Date of registration: July 1, 2014).

Abstract Background Bone defects may occur because of severe trauma, nonunion, infection, or tumor resection. However, treatments for bone defects are often difficult and have not been fully established yet. We previously designed an efficient system of topical cutaneous application of carbon dioxide (CO2) using a novel hydrogel, which facilitates CO2 absorption through the skin into the deep area within a limb. In this study, the effect of topical cutaneous application of CO2 on bone healing was investigated using a rat femoral defect model. Methods In this basic research study, an in vivo bone defect model, fixed with an external fixator, was created using a rat femur. The affected limb was shaved, and CO2 was applied for 20 min/day, 5 days/week. In the control animals, CO2 gas was replaced with air. Radiographic, histological, biomechanical, and genetic assessments were performed to evaluate bone healing. Results Radiographically, bone healing rate was significantly higher in the CO2 group than in the control group at 4 weeks (18.2% vs. 72.7%). The degree of bone healing scored using the histopathological Allen grading system was significantly higher in the CO2 group than in the control group at 2 weeks (1.389 ± 0.334 vs. 1.944 ± 0.375). The ultimate stress, extrinsic stiffness, and failure energy were significantly greater in the CO2 group than in the control group at 4 weeks (3.2 ± 0.8% vs. 38.1 ± 4.8%, 0.6 ± 0.3% vs. 41.5 ± 12.2%, 2.6 ± 0.8% vs. 24.7 ± 5.9%, respectively.). The volumetric bone mineral density of the callus in micro-computed tomography analysis was significantly higher in the CO2 group than in the control group at 4 weeks (180.9 ± 43.0 mg/cm3 vs. 247.9 ± 49.9 mg/cm3). Gene expression of vascular endothelial growth factor in the CO2 group was significantly greater than that in the control group at 3 weeks (0.617 ± 0.240 vs. 2.213 ± 0.387). Conclusions Topical cutaneous application of CO2 accelerated bone healing in a rat femoral defect model. CO2 application can be a novel and useful therapy for accelerating bone healing in bone defects; further research on its efficacy in humans is warranted.

Background: Skeletal related events due to metastatic bone tumors markedly affect the activities of daily living (ADL) and quality of life (QOL) in cancer patients. We focused on multidisciplinary therapy for metastatic bone tumors. This study aimed to evaluate the outcomes of surgical treatment for metastatic bone tumors in the extremities. Methods: We retrospectively reviewed 114 patients who underwent surgical treatment for metastatic bone tumors of the extremities between 2008 and 2019 and 69 patients were reassessed for more than 6 months after surgery. The most common primary tumor was renal, followed by lung, thyroid, and breast cancers. We assessed 69 patients’ performance status (PS), Barthel Index (BI) for ADL, EuroQol 5 Dimensions (EQ-5D) for QOL, and numerical rating scale (NRS) for pain and analyzed these postoperative values relative to preoperative values using Friedman’s test. The postoperative overall survival and the prognostic factors were evaluated using the Kaplan-Meier method, the log-rank test and Cox proportional hazards analysis. Results: The 1-year overall survival rate was 59%, and the median survival time after surgery was 20 months. Primary tumor, visceral metastasis, and surgical procedure were risk factors correlated with overall survival. PS, BI, EQ-5D, and NRS improved at 3 months after surgery and these improvements were maintained for 6 months after surgery regardless of the surgical procedure. Conclusions: The significant factors affecting survival after surgical treatment for bone metastases included the primary tumor, presence of visceral metastases, and internal fixation without tumor resection or curettage. Surgical treatment for metastatic bone tumors effectively reduced pain and improved PS, ADL, and QOL postoperatively after 3 months.

Introduction Diabetes mellitus (DM) negatively affects fracture repair by inhibiting endochondral ossification, chondrogenesis, callus formation, and angiogenesis. We previously reported that transcutaneous CO2 application accelerates fracture repair by promoting endochondral ossification and angiogenesis. The present study aimed to determine whether CO2 treatment would promote fracture repair in cases with type I DM.Research design and methods A closed femoral shaft fracture was induced in female rats with streptozotocin-induced type I DM. CO2 treatment was performed five times a week for the CO2 group. Sham treatment, where CO2 was replaced with air, was performed for the control group. Radiographic, histologic, genetic, and biomechanical measurements were taken at several time points.Results Radiographic assessment demonstrated that fracture repair was induced in the CO2 group. Histologically, accelerated endochondral ossification and capillary formation were observed in the CO2 group. Immunohistochemical assessment indicated that early postfracture proliferation of chondrocytes in callus was enhanced in the CO2 group. Genetic assessment results suggested that cartilage and bone formation, angiogenesis, and vasodilation were upregulated in the CO2 group. Biomechanical assessment revealed enhanced mechanical strength in the CO2 group.Conclusions Our findings suggest that CO2 treatment accelerates fracture repair in type I DM rats. CO2 treatment could be an effective strategy for delayed fracture repair due to DM.

Abstract Background Effects of methotrexate (MTX) on the proliferation of rheumatoid arthritis (RA) synovial fibroblasts are incompletely understood. We explored actions of MTX in view of circadian transcriptions of synovial fibroblasts. Methods Under treatment with MTX, expression of core circadian clock genes, circadian transcriptional factor proline and acidic amino acid-rich basic leucine zipper (PAR bZIP), and proapoptotic molecule Bcl-2 interacting killer (Bik) was examined by real-time polymerase chain reaction. Protein expression of circadian clock gene PERIOD2 (PER2) and CYTOCHROME C was also examined by western blotting and ELISA. Promoter activities of Per2 and Bik were measured by Luciferase assay. Expression of PER2, BIK, and CYTOCHROME C and morphological changes of the nucleus were observed by fluorescent immunostaining. Synovial fibroblasts were transfected with Per2/Bik small interfering RNA, and successively treated with MTX to determine cell viabilities. Finally, synovial fibroblasts were treated with MTX according to the oscillation of Per2/Bik expression. Results MTX (10 nM) significantly decreased cell viabilities, but increased messenger RNA expression of Per2, Bik, and PAR ZIP including D site of the albumin promoter binding protein (Dbp), hepatic leukemia factor (Hlf), and thyrotroph embryonic factor (Tef). MTX also increased protein expression of PER2 and CYTOCHROME C, and promoter activities of Per2 and Bik via D-box. Under fluorescent observations, expression of PER2, BIK, and CYTOCHROME C was increased in apoptotic cells. Cytotoxicity of MTX was attenuated by silencing of Per2 and/or Bik, and revealed that MTX was significantly effective in situations where Per2/Bik expression was high. Conclusions We present here novel unique action of MTX on synovial fibroblasts that upregulates PAR bZIP to transcribe Per2 and Bik, resulting in apoptosis induction. MTX is important in modulating circadian environments to understand a new aspect of pathogenesis of RA.

Background: After cardiac valve surgery, postoperative exercise capacity and psychosocial parameters of patients change significantly and both affect prognosis. This study aimed to analyze and clarify the relationship between changes in perioperative exercise capacity and psychosocial factors in the early phase after valvular surgery. Materials and Methods: We enrolled 48 consecutive patients who underwent valvular surgery and studied their exercise capacity, health-related quality of life (HRQOL), anxiety disorders, depression symptoms, blood samples, and echocardiograms preoperatively and 14-day postoperatively. Results: At the preoperative evaluation, the peak maximal oxygen consumption was 17.7 ± 5.9 ml/kg/min and decreased by 14.3 ± 4.4 ml/kg/min after the surgery (P < 0.0001). With regard to the HRQOL, the physical component summary (PCS) score and the role component summary scores decreased significantly after surgery (P < 0.05 for each). However, the mental component summary score increased significantly after surgery (51.9 ± 11.6 to 55.2 ± 10.4; P = 0.04). The ratios of the above the cut-off value for postoperative anxiety and depression scores were 29.1%, and 43.7%, respectively. Postoperative changes in exercise capacity were associated with variations in right ventricular function, chronotropic response during exercise, and the PCS score (P < 0.05 for each). Conclusions: Exercise capacity was reduced approximately 20% during the postoperative period in patients who underwent valvular surgery, and changes in exercise capacity were related to changes in psychosocial factors, not only cardiac functions. Therefore, it is important to evaluate not only perioperative exercise capacity but also psychosocial indicators during postoperative cardiac rehabilitation programs.

Background: Data of vitamin D sufficiency in Asian patients with osteoporotic fragility hip fractures are limited. This study aimed to obtain data from the Japanese population. Methods: Patients aged 60 years or older with hip fractures were prospectively enrolled. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured. Levels were compared between patients receiving and not receiving treatment for osteoporosis, those with and without previous contralateral hip fractures, and those with femoral neck versus trochanteric fractures. Sex-based differences were also assessed. The serum levels in patients younger than 60 years with extremity fractures were assessed, and differences between elderly and younger patients were evaluated. The individual correlation between 25(OH)D levels and the ultraviolet (UV) index and age was analyzed in elderly patients with hip fractures. Results: The data of 360 patients (aged 84.7 ± 8.2 years), comprising 80 men and 280 women, were analyzed. The mean 25(OH)D level was 16.5 ± 7.2 ng/mL. The prevalence of vitamin D insufficiency (25(OH)D

ABSTRACT Improving patient health‐related quality of life (HRQOL) and prevention of bone fracture are important components of the treatment of osteoporosis. Our aim in this study was to evaluate the effect of denosumab treatment in improving HRQOL among patients with osteoporosis. Our analysis was based on 332 patients with osteoporosis, followed for 24 months. All patients received denosumab (60 mg) subcutaneously every 6 months. Bone mineral density (BMD) was assessed at the distal radius, with serum concentration of calcium, phosphate, P1NP, and TRACP5b also measured. HRQOL assessment included pain (visual analogue scale [VAS]) and the EQ‐5D questionnaire. A multivariate analysis was performed to identify the possible confounders associated with deterioration in the EQ‐5D utility score in response to denosumab treatment. Denosumab treatment yielded a 3.4% increase in BMD at 24 months. Serum levels of TRACP5b and P1NP decreased significantly, from baseline, at 6 months, with no effect on calcium and phosphate levels. Pain VAS and EQ‐5D utility score improved significantly, from baseline, at 6 months, with the EQ‐5D utility score correlating with the BMD at all time points of measurement over the 24‐month period of observation. Knee osteoarthritis and multiple comorbidities were significantly associated with a worse HRQOL in response to denosumab treatment. Denosumab treatment increased BMD, with improvements in BMD correlating with improved HRQOL, supporting a possible benefit of using denosumab for the treatment of osteoporosis. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Purpose: Patients with fractures of the pelvis and/or lower extremities are at a high risk of developing postoperative venous thromboembolism (VTE). The purpose of this study was to determine whether the thrombin–antithrombin III complex (TAT) tests could be used for postoperative screening of VTE in patients with lower limb or pelvic fractures. Methods: We enrolled 133 patients who underwent surgical treatment for fracture of the pelvis or lower extremities. TAT and D-dimer levels were compared in patients with and without VTE. Receiver operating characteristic (ROC) curve analysis was done and the appropriate TAT and D-dimer cutoff levels were determined for VTE screening. Results: VTE was diagnosed in 41 patients (30.8%). Patients with VTE had significantly higher levels of TAT and D-dimer on postoperative days 1, 3, and 7 than those without VTE, respectively. ROC curve analysis suggested that TAT test at postoperative day 7 had the highest accuracy for predicting postoperative VTE. With the optimal cutoff TAT level of 3.0 ng/mL, sensitivity and specificity were 93.3% and 70.1%, respectively. With the optimal cutoff D-dimer level of 7.4 µg/mL, sensitivity and specificity were 93.3% and 57.0%, respectively. Conclusion: TAT levels measured at postoperative day 7 could be the most useful parameter for screening postoperative VTE. TAT can be used as a screening tool for screening postoperative VTE in patients with lower limb and pelvic fractures.

Postoperative delirium (POD) is a common and critical complication after cardiac surgery. However, the relationship between POD and postoperative physical frailty and the effect of both on long-term clinical outcomes have not been fully explored.We aimed to examine the associations among POD, postoperative frailty, and major adverse cardiac events (MACE).This was a prospective cohort study.We studied 329 consecutive patients undergoing elective cardiac surgery. The intensive care delirium screening checklist was used to assess POD. Postoperative frailty was defined by handgrip strength and walking speed. Patients were subsequently followed-up to detect MACE.POD was present in 13.2%, while the incidence of postoperative frailty was 27.0%. POD was independently associated with development of postoperative frailty (adjusted odds ratio = 2.98). During follow-up, MACE occurred in 14.1% of all participants. On multivariate Cox proportional hazard analysis, POD (adjusted hazard ratio (HR) = 3.36), postoperative frailty (HR = 2.21), postoperative complications (HR = 1.54), and left ventricular ejection fraction (HR = 0.95) were independently associated with increased risk of MACE.It is a single-center study with a risk of bias. We did not investigate follow up cognitive function.POD was a predictor of postoperative frailty after cardiac surgery. Both postoperative frailty and POD were associated with the incidence of MACE, while POD was the stronger predictor of MACE. Thus, POD and frailty play critical roles in the risk stratification of patients undergoing cardiac surgery.

Purpose. To evaluate the rate of venous thromboembolism (VTE) after complex lower-limb fracture surgery without pharmacological prophylaxis. Methods. Between July 2005 and April 2009, 11 men and 6 women (mean age, 45 years) underwent temporary external fixation followed by internal fixation for a total of 3 femoral and 20 tibial fractures. Patients were screened for VTE using contrast-enhanced computed tomography (CT) when the D-dimer value was beyond normal range. Between May 2009 and December 2012, 18 men and 4 women (mean age, 45 years) underwent temporary external fixation followed by internal fixation for a total of 8 femoral and 20 tibial fractures. Patients were routinely screened for deep vein thrombosis (DVT) using ultrasonography and for pulmonary embolism (PE) using contrast-enhanced CT (in high-risk patients with multiple injuries or pelvic and acetabular fractures). In both groups, pharmacological prophylaxis was not used; only mechanical prophylaxis was used. Results. The 2 groups were comparable in terms of age, sex, and proportion of bilateral external fixation, open fracture, and associated injury, except that the duration of external fixation was longer in the early group (29.8±28.0 vs. 11.6±4.0 days, p=0.001). Of the 17 patients in the early group, 5 developed VTEs (3 DVTs and 2 PEs) at a mean of 13.6 (range, 6–20) days after injury; 2 of whom developed VTE during the external fixation period. Of the 22 patients in the later period, 10 developed VTEs (10 DVTs and 4 PEs) at a mean of 13 (range, 5–33) days after injury; 7 of whom developed VTE during the external fixation period. Conclusion. The rate of VTE was high in patients undergoing complex lower-limb fracture surgery without pharmacological prophylaxis.

The potential relationship between cell cycle checkpoint control and tissue regeneration has been indicated. Despite considerable research being focused on the relationship between p21 and myogenesis, p21 function in skeletal muscle regeneration remains unclear. To clarify this, muscle injury model was recreated by intramuscular injection of bupivacaine hydrochloride in the soleus of p21 knockout (KO) mice and wild type (WT) mice. The mice were sacrificed at 3, 14, and 28 days post-operation. The results of hematoxylin-eosin staining and immunofluorescence of muscle membrane indicated that muscle regeneration was delayed in p21 KO mice. Cyclin D1 mRNA expression and both Ki-67 and PCNA immunohistochemistry suggested that p21 deficiency increased cell cycle and muscle cell proliferation. F4/80 immunohistochemistry also suggested the increase of immune response in p21 KO mice. On the other hand, both the mRNA expression and western blot analysis of MyoD, myogenin, and Pax7 indicated that muscular differentiation was delayed in p21KO mice. Considering these results, we confirmed that muscle injury causes an increase in cell proliferation. However, muscle differentiation in p21 KO mice was inhibited due to the low expression of muscular synthesis genes, leading to a delay in the muscular regeneration. Thus, we conclude that p21 plays an important role in the in vivo healing process in muscular injury.

We report a case of chronic calcaneal osteomyelitis in a diabetic patient who was successfully treated with radical debridement and gentamycin-impregnated calcium phosphate cement. At 1.5-year follow-up, the patient could walk without any assistance. Calcium phosphate cement is an effective local antibiotic delivery system and a biocompatible material for filling the debrided space to facilitate bone formation.

Purpose. To review the outcomes of 102 consecutive patients who underwent fixation for nonunion of extremities. Methods. Medical records of 71 men and 31 women aged 16 to 82 (mean, 45; standard deviation [SD], 19) years who underwent fixation for nonunion of the upper (n=31) and lower (n=71) extremities were reviewed. The nonunion types included oligotrophic (n=47), hypertrophic (n=22), atrophic (n=17), defect (n=12), and comminuted (n=4). 13 of the nonunions were infected. 10 patients had concomitant injuries of the brain (n=2), abdomen (n=5), chest (n=1), and spine (n=2). 43 patients were smokers, and 19 had diabetes mellitus. 80 patients had had previous surgery, and 3 had undergone previous radiotherapy. The mean time from injury to nonunion surgery was 19 (SD, 25.6; range, 6–180) months. Outcome measures included bone union, ability to return to original work, pain, gait, and loss of range of motion. Results. The mean follow-up period was 26.6 (SD, 19.9; range, 8–121) months. 100 patients achieved bone union. 83 of them achieved bone union after a single surgery in a mean of 5.6 (SD, 2.9) months. The remaining 17 patients underwent multiple surgeries, 13 of whom had infected nonunions. Two patients did not achieve bone union. Of 64 patients who had work, 47 returned to their original work and 17 did not. Outcome was unsatisfactory in 5 patients who had persistent pain and/or no improvement in gait. Conclusion. Bone union is not necessarily associated with adequate recovery of function.

Squamous cell carcinoma (SCC) is the main histological type of oral cancer. Its growth rate and incidence of metastasis to regional lymph nodes is influenced by various factors, including hypoxic conditions. We have previously reported that transcutaneous CO2 induces mitochondrial apoptosis and decreases lung metastasis by reoxygenating sarcoma cells. However, previous studies have not determined the sequential mechanism by which transcutaneous CO2 suppresses growth of epithelial tumors, including SCCs. Moreover, there is no report that transcutaneous CO2 suppresses lymphogenous metastasis using human cell lines xenografts. In this study, we examined the effects of transcutaneous CO2 on cancer apoptosis and lymphogenous metastasis using human SCC xenografts. Our results showed that transcutaneous CO2 affects expressions of PGC-1α and TFAM and protein levels of cleavage products of caspase-3, caspase-9 and PARP, which relatives mitochondrial apoptosis. They also showed that transcutaneous CO2 significantly inhibits SCC tumor growth and affects expressions of HIF-1α, VEGF, MMP-2 and MMP-9, which play essential roles in tumor angiogenesis, invasion and metastasis. In conclusion, transcutaneous CO2 suppressed tumor growth, increased mitochondrial apoptosis and decreased the number of lymph node metastasis in human SCC by decreasing intra-tumoral hypoxia and suppressing metastatic potential with no observable effect in vivo. Our findings indicate that transcutaneous CO2 could be a novel therapeutic tool for treating human SCC.

Among the symptoms of patients with rheumatoid arthritis (RA), joint stiffness is influenced by diurnal rhythm and reaches peak in the morning, which is a common complaint and reflects the circadian nature of disease manifestation. In addition, inflammatory cytokines, which reach peak secretion early in the morning are major players causing the morning stiffness. In this review, we explore the link between the circadian clock and inflammation, focusing on the interactions of various clock genes with the immune-pathways underlying the pathology of rheumatoid arthritis.

Bicondylar coronal plane fracture, eponymically named Hoffa fractures, is an extremely rare injury. We present a case of isolated unilateral bicondylar Hoffa fracture that was successfully treated with open reduction and internal fixation using headless compression screws with satisfactory results. We inserted posteroanteriorly oriented Acutrak screws perpendicular to the fracture plane via lateral parapatellar arthrotomy, which provided excellent compression across the fracture.

The use of intramedullary nails to treat trochanteric fractures of the femur has increased with the increasing size of the elderly population. The third generation Gamma nail is currently one of the most popular devices for the treatment of trochanteric fractures. Nail breakage is a rare complication, possibly resulting from fatigue fracture of the implant. We present the first reported case of breakage of a third generation Gamma nail that was not used to treat a pathological fracture. An 83-year-old woman with an unstable trochanteric fracture of the femur was treated using a third generation Gamma nail. She was referred to our hospital 14 months postoperatively with nail breakage at the opening for the lag screw. The breakage was secondary to nonunion, which was thought to be mainly due to insufficient reduction of the fracture. The broken nail was removed, and the patient underwent cemented bipolar hemiarthroplasty. At followup 18 months later, she was mobile with a walker and asymptomatic with no complications. This case shows that inadequate operation such as insufficient reduction of the trochanteric fracture may result in nonunion and implant breakage, even when using a high-strength, well-designed implant.

We describe a rare case with breakage of gamma nail accompanied by nonunion of the original fracture and a subsequent new fracture in the ipsilateral femur. A 73-year-old woman suffered a subtrochanteric fracture of the femur, and the fracture was fixed with gamma nail at a previous hospital. However, fracture reduction was not adequately achieved and a large gap remained between the fracture fragments. The fracture demonstrated atrophic nonunion 10 months after surgery, and autologous bone grafting was performed at the same hospital. Two months after the second surgery, a breakage of the nail at the distal screw hole was observed. Twenty-six months after the second surgery, the patient fell and a fracture occurred at the level of the nail breakage. The atrophic nonunion site and fresh fracture site were very close thus demonstrating a segmental fracture. We exchanged the original gamma nail with a long gamma nail and performed autologous bone grafting at the nonunion site. Both the fresh fracture site and the nonunion site obtained bony union. This tragic chain of events was caused by inappropriate initial treatment and replacing the nail to a longer nail and autologous bone grafting were effective as salvage surgery.

Patients with Werner’s syndrome frequently develop chronic leg ulcers that heal poorly. We present a patient who suffered from this rare syndrome and developed typical heel ulcers. Treatment of the ulcer is challenging, as flap options are limited over the lower third of the leg and skin grafting is not easy as there is a lack of healthy granulations. We successfully treated the ulcer with osteomyelitis by drilling the bone and applying an ultrathin split thickness skin graft with the thigh skin as the donor site.

Nonunion of a sacral fracture is a rare but serious clinical condition which can cause severe chronic pain, discomfort while sitting, and significant restriction of the level of activities. Fracture nonunions reportedly occur most often after nonoperative initial treatment or inappropriate operative treatment. We report a case of fracture nonunion of the sacrum and pubic rami that resulted from non-operative initial treatment, which was treated successfully using bone grafting through a posterior approach and CT-guided percutaneous iliosacral screw fixation combined with anterior external fixation. Although autologous bone grafting has been the gold standard for the treatment of pelvic fracture nonunions, little has been written describing the approach. We utilized a posterior approach for bone grafting, which could allow direct visualization of the nonunion site and preclude nerve root injury. By this procedure, we were able to obtain the healing of fracture nonunion, leading to pain relief and functional recovery.

Mitochondria play an essential role in cellular energy metabolism and apoptosis. Previous studies have demonstrated that decreased mitochondrial biogenesis is associated with cancer progression. In mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) regulates the activities of multiple nuclear receptors and transcription factors involved in mitochondrial proliferation. Previously, we showed that overexpression of PGC-1α leads to mitochondrial proliferation and induces apoptosis in human malignant fibrous histiocytoma (MFH) cells in vitro. We also demonstrated that transcutaneous application of carbon dioxide (CO(2)) to rat skeletal muscle induces PGC-1α expression and causes an increase in mitochondrial proliferation. In this study, we utilized a murine model of human MFH to determine the effect of transcutaneous CO(2) exposure on PGC-1α expression, mitochondrial proliferation and cellular apoptosis. PGC-1α expression was evaluated by quantitative real-time PCR, while mitochondrial proliferation was assessed by immunofluorescence staining and the relative copy number of mitochondrial DNA (mtDNA) was assessed by real-time PCR. Immunofluorescence staining and DNA fragmentation assays were used to examine mitochondrial apoptosis. We also evaluated the expression of mitochondrial apoptosis related proteins, such as caspases, cytochorome c and Bax, by immunoblot analysis. We show that transcutaneous application of CO(2) induces PGC-1α expression, and increases mitochondrial proliferation and apoptosis of tumor cells, significantly reducing tumor volume. Proteins involved in the mitochondrial apoptotic cascade, including caspase 3 and caspase 9, were elevated in CO(2) treated tumors compared to control. We also observed an enrichment of cytochrome c in the cytoplasmic fraction and Bax protein in the mitochondrial fraction of CO(2) treated tumors, highlighting the involvement of mitochondria in apoptosis. These data indicate that transcutaneous application of CO(2) may represent a novel therapeutic tool in the treatment of human MFH.

We describe a case of radiation-associated fracture nonunion of the clavicle, which was treated by locking plate fixation and autologous bone grafting. The patient was a 67-year old man who received 70 Gy radiation therapy to treat nasopharyngeal carcinoma. Eight years later, he suffered a pathological fracture of the right clavicle. One year after the fracture, surgical treatment was performed due to persistent pain and weakness. Radiographs demonstrated atrophic nonunion. Bone scan demonstrated hot uptake at both ends of the fractured bone. MRI demonstrated a formation of pseudoarthrosis with fluid collection and suggested bone marrow edema at both ends of the fracture fragments. In surgery, fibrous pseudoarthrosis tissue was excised and both ends of the fracture fragments were refreshed to identify bleeding. Open reduction and internal fixation using a 7-hole locking plate and autologous bone grafting were performed. Successful bony union was obtained 1 year postoperatively, and no adverse events were observed up to 52 months after the operation. Our case suggests that a locking plate provides sufficient fixation and autologous bone grafting is effective in enhancing bone healing in a radiation-associated fracture nonunion of the clavicle in which it is difficult to achieve bony union.

BACKGROUND: Carbon dioxide (CO(2)) therapy refers to the transcutaneous administration of CO(2) for therapeutic purposes. This effect has been explained by an increase in the pressure of O(2) in tissues known as the Bohr effect. However, there have been no reports investigating the oxygen dissociation of haemoglobin (Hb) during transcutaneous application of CO(2)in vivo. In this study, we investigate whether the Bohr effect is caused by transcutaneous application of CO2 in human living body. METHODS: We used a novel system for transcutaneous application of CO(2) using pure CO(2) gas, hydrogel, and a plastic adaptor. The validity of the CO(2) hydrogel was confirmed in vitro using a measuring device for transcutaneous CO(2) absorption using rat skin. Next, we measured the pH change in the human triceps surae muscle during transcutaneous application of CO(2) using phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) in vivo. In addition, oxy- and deoxy-Hb concentrations were measured with near-infrared spectroscopy in the human arm with occulted blood flow to investigate O2 dissociation from Hb caused by transcutaneous application of CO(2). RESULTS: The rat skin experiment showed that CO(2) hydrogel enhanced CO(2) gas permeation through the rat skin. The intracellular pH of the triceps surae muscle decreased significantly 10 min. after transcutaneous application of CO(2). The NIRS data show the oxy-Hb concentration decreased significantly 4 min. after CO(2) application, and deoxy-Hb concentration increased significantly 2 min. after CO(2) application in the CO(2)-applied group compared to the control group. Oxy-Hb concentration significantly decreased while deoxy-Hb concentration significantly increased after transcutaneous CO(2) application. CONCLUSIONS: Our novel transcutaneous CO(2) application facilitated an O(2) dissociation from Hb in the human body, thus providing evidence of the Bohr effect in vivo.