Evaluation of crankshaft phenomenon after posterior fusion for early onset scoliosis using an inverse trigonometric function: a multicenter retrospective cohort study.

PURPOSE: The crankshaft phenomenon (CSP) is a corrective loss after posterior surgery for early onset scoliosis (EOS). However, an accurate method for CSP evaluation has yet to be developed. In this study, we evaluated pedicle screw (PS) length and rotation angle using an inverse trigonometric function and investigated the prevalence of the CSP. METHODS: Fifty patients from nine institutions (mean age 10.6 years, male/female ratio 4:46) who underwent early definitive fusion surgery at ≤ 11 years of age were included. The rotation angle was calculated as arctan (lateral/frontal PS length) using radiography. Measurements were taken at the apex and lower instrumented vertebra (LIV) immediate, 2-, and 5-year postoperatively. CSP was defined as a rotation angle progression ≥ 5°. We divided patients into CSP and non-CSP groups and measured the demographic parameters, Risser grade, state of the triradiate cartilage, major coronal Cobb angle, T1-T12 length, T1-S1 length, and presence of distal adding-on (DAO). We compared these variables between groups and investigated the correlation between the measured variables and vertebral rotation. Logistic regression analysis investigated factors associated with CSP. RESULTS: The rotation angle progressed by 2.4 and 1.3° over 5 years for the apex and LIV, respectively. CSP occurred in 15 cases (30%), DAO in 11 cases (22%), and CSP and DAO overlapped in 4 cases (8%). In the CSP group, the T1-T12 length was low immediate postoperatively. The rotation angle was negatively correlated with preoperative height (r = - 0.33), T1-T12 length (r = - 0.35), and T1-S1 length (r = - 0.30). A lower preoperative T1-T12 length was associated with CSP (odds ratio: 0.996, p = 0.048). CONCLUSIONS: CSP occurred in 30% of patients with EOS who underwent definitive fusion. The presence of CSP was associated with a lower preoperative T1-T12 length. LEVEL OF EVIDENCE: Diagnosis, level IV.

Instrumentation failure following pediatric spine deformity growth-sparing surgery using traditional growing rods or vertical expandable prosthetic titanium ribs.

BACKGROUND: Instrumentation failure (IF) is a major complication associated with growth-sparing surgery for pediatric spinal deformities; however, studies focusing on IF following each surgical procedure are lacking. We aimed to evaluate the incidence, timing, and rates of unplanned return to the operating room (UPROR) associated with IF following each surgical procedure in growth-sparing surgeries using traditional growing rods (TGRs) and vertical expandable prosthetic titanium ribs (VEPTRs). METHODS: We reviewed 1,139 surgical procedures documented in a Japanese multicenter database from 2015 to 2017. Of these, 544 TGR and 455 VEPTR procedures were included for evaluation on a per-surgery basis. IF was defined as the occurrence of an implant-related complication requiring revision surgery. RESULTS: The surgery-based incidences of IF requiring revision surgery in the TGR and VEPTR groups were 4.3% and 4.0%, respectively, with no significant intergroup difference. Remarkably, there was a negative correlation between IF incidence per surgical procedure and the number of lengthening surgeries in both groups. In addition, rod breakage in the TGR group and anchor-related complications in the VEPTR group tended to occur relatively early in the treatment course. The surgery-based rates of UPROR due to IF in the TGR and VEPTR groups were 2.0% and 1.5%, respectively, showing no statistically significant difference. CONCLUSIONS: We found that IF, such as anchor related-complications and rod breakage, occurs more frequently earlier in the course of lengthening surgeries. This finding may help in patient counseling and highlights the importance of close postoperative follow-up to detect IF and improve outcomes.

Development of an Immunochromatography Assay to Detect Marburg Virus and Ravn Virus.

The recent outbreaks of Marburg virus disease (MVD) in Guinea, Ghana, Equatorial Guinea, and Tanzania, none of which had reported previous outbreaks, imply increasing risks of spillover of the causative viruses, Marburg virus (MARV) and Ravn virus (RAVV), from their natural host animals. These outbreaks have emphasized the need for the development of rapid diagnostic tests for this disease. Using monoclonal antibodies specific to the viral nucleoprotein, we developed an immunochromatography (IC) assay for the rapid diagnosis of MVD. The IC assay was found to be capable of detecting approximately 102-4 50% tissue culture infectious dose (TCID50)/test of MARV and RAVV in the infected culture supernatants. We further confirmed that the IC assay could detect the MARV and RAVV antigens in the serum samples from experimentally infected nonhuman primates. These results indicate that the IC assay to detect MARV can be a useful tool for the rapid point-of-care diagnosis of MVD.

A Novel Method for Assessing the 3-dimensional Morphology of Cartilaginous Acetabulum Via Childhood Magnetic Resonance Imaging.

BACKGROUND: Periarticular cartilage is abundant in children, making evaluations of 3-dimensional (D) cartilaginous acetabular morphology using x-ray or computed tomography (CT) difficult. The study aimed to visualize the 3D cartilaginous acetabular morphology in normal children and patients with pediatric developmental dysplasia of the hip (DDH). METHODS: Magnetic resonance imaging (MRI) of 17 female children without acetabular dysplasia at 7.5 years and CT of 33 normal female adolescents with mature bones at 14.6 years were used as controls. Subjects were 26 female patients with unilateral DDH who underwent angulated Salter innominate osteotomy (A-SIO) at 5.5 years. Preoperative and postoperative MRIs were performed at 5.2 and 7.0 years, respectively. The MRI sequence was 3D-MEDIC. The medial intersection (point A) of the line connecting the centers of the bilateral femoral head and the femoral head were defined as point zero. The 3D coordinates (X, Y, Z) of the cartilaginous acetabular edge (point C) from anterior to posterior were calculated. Subsequently, a 3D scatter plot was created using 3D graph software. The subjects were divided into 6 groups, including control MRI, control CT, unaffected DDH before and after A-SIO, and affected DDH before and after A-SIO. The femoral head coverage ratio (FHCR: AC/AB) was used to quantify coverage and was compared in each group. RESULTS: In the control MRI group, the acetabular coverage was small anteriorly, largest anterolaterally, and gradually decreased posteriorly, similar to the bony acetabulum in adolescents. In the affected DDH before A-SIO group, the coverage was significantly lower than that of the control MRI and unaffected DDH groups. After A-SIO, the morphology improved beyond the unaffected DDH and the control MRI group. CONCLUSIONS: The global defect of the cartilaginous acetabulum in the affected DDH group was significantly improved to normal morphology after A-SIO. Evaluating the cartilaginous acetabulum using MRI was useful for assessing hip morphology in childhood. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Theoretical and experimental mechanistic study of water molecule involvement in the Prilezhaev reaction.

The Prilezhaev reaction produces epoxides using alkenes and peroxy acids such as m-chloroperoxybenzoic acid (mCPBA). The reaction proceeds via a concerted mechanism in one step. Although the mCPBA used in organic syntheses contains water because of its explosive nature, the effects of water on the reaction have not been considered. To investigate the effects of water on the reaction mechanism, we determined the thermodynamic parameters for the Prilezhaev reaction between styrene and mCPBA. The activation free energies, including solvent effects, were calculated using the SMD and QM/MC/FEP methods. The calculated thermodynamic parameters for the reaction directly involving two water molecules were in better agreement with the experimental data than those for the concerted mechanism. This result indicated that water molecules are involved in the progression of the mCPBA-mediated Prilezhaev reaction in solvents containing water molecules.

Outcomes of Linear Circumferential Skin Closure for Congenital Constriction Ring Syndrome.

Background: Congenital constriction ring syndrome (CCRS) is a rare condition diagnosed at birth characterised by deformation due to a constriction ring. The usual treatment for CCRS involves excision of the constriction ring and suture of the skin incorporating a Z-plasty to prevent scar contracture. A Z-plasty often results in an unsightly scar. In order to avoid this, we performed linear circumferential skin closure (LCSC). The aim of this paper is to report the outcomes of LCSC for CCRS. Methods: We retrospectively investigated all patients with CCRS who underwent LCSC between 2002 and 2020. Two linear incisions were placed proximal and distal to the constriction ring in parallel, and the constriction ring was excised carefully so as not to damage nerves or vessels. The deep subcutaneous and dermis layers were sutured. The skin was closed using adhesive tape. Two-stage surgery was performed in two patients with severe CCRS of the lower leg to avoid problems with distal circulation. Patients were followed up for at least 1 year and assessed for complications and quality of scar. Results: We performed LCSC for 31 sites in 19 patients, including one forearm, 14 fingers, 10 lower legs and six toes. The median age at the operation was 16 months (range: 4-175). The median follow-up period after surgery was 5.8 years (range: 1.9-16.0). The linear surgical scar had healed well in all patients and there were no complications. There was no recurrence of the constriction ring and no scar hypertrophy, though we did not perform fat mobilisation in all cases. None of the patients required additional surgery and the aesthetic outcome of the linear circumferential surgical scar was maintained at the final observation. Conclusions: Treatment for CCRS using LCSC resulted in no complications, no recurrence of constriction and an excellent aesthetic outcome. Level of Evidence: Level IV (Therapeutic).

Severe type of segmental spinal dysgenesis with complete disconnection of the spinal cord and vertebra associated with open neural tube defect.

Background: Severe type of segmental spinal dysgenesis (SSD) is a rare and complex anomaly in which the spinal cord completely disconnects at the portion of the spinal dysgenesis. Although closed spinal dysraphisms have been associated with SSD, to the best of our knowledge, the association between open neural tube defect (ONTD) and SSD is significantly rare, with only one case being reported to date. Case Description: We report a case of an infant with severe SSD and a disconnected spinal cord and spinal column at the thoracolumbar junction associated with myelomeningocele (MMC) in the lumbosacral region. The patient presented severe neurological deficits in the legs and impaired bowel function. The spinal column of L1-L3 was absent. The lower spinal segment consisted of neural placode at the L5-S1 level and no connecting structure between the upper and lower spinal cords. A repair surgery for MMC, including cord untethering and dura plasty, was performed. Histopathological findings revealed a neural placode consisting of a neuroglial tissue and leptomeninges. Conclusion: The management of severe SSD during the perinatal period is more challenging when it is associated with ONTD. We report detailed neuroradiological, intraoperative, and histological findings of such a case and discuss the embryopathogenesis of the associated ONTD and the treatment strategies.

Does Flexion Varus Osteotomy Improve Radiographic Findings Compared With Patients Treated in a Brace for Late-onset Legg-Calvé-Perthes Disease?

BACKGROUND: Legg-Calvé-Perthes disease (LCPD) is a childhood hip disease characterized by osteonecrosis of the femoral head. Because severe deformity of the femoral head can cause secondary osteoarthritis in adulthood, progressive collapse should be prevented in children with a necrotic epiphysis. The prognosis of patients with LCPD generally worsens as the age at disease onset increases, and the appropriate treatment for late-onset LCPD remains unclear. Based on the limited effect of nonoperative treatment using a nonweightbearing brace, flexion varus osteotomy (FVO) was introduced in 2010 as an initial treatment for late-onset LCPD in place of brace treatment, which we used in our institution before that time. QUESTIONS/PURPOSES: We asked, (1) Which treatment, FVO or a nonweightbearing brace, is associated with a lower likelihood of progressive femoral head collapse in children whose diagnosis of LCPD was made at the age of ≥ 8 years and who were followed for a minimum of 3 years after their intervention? (2) What proportion of patients in the brace group had surgery despite the treatment, and what percentage of children in the FVO group had a second operation to remove hardware and/or additional operations? METHODS: The initial treatment was applied in 181 patients with LCPD between 1995 and 2018 in our institution. Patients whose disease onset was at ≥ 8 years old (late-onset LCPD) with complete clinical and radiologic data were considered potentially eligible. In 2010, treatment for these patients changed from brace treatment to FVO for all patients. A total of 35% (42 of 121) of patients who were treated with a nonweightbearing brace between 1995 and 2009 and 40% (24 of 60) of patients who were treated with FVO between 2010 and 2018 were eligible. Among patients treated with a brace, 21% (nine of 42 patients) were excluded because of hospital transfer (three patients), short-term follow-up (three), the period from onset to the first visit was ≥ 7 months (two), and inability to use the brace because of mental incapacity (one patient). In patients treated with FVO, 12% (three of 24 patients) were excluded (two patients with a period from onset to the first visit ≥ 7 months and one with a comorbidity and multiple-epiphyseal dysplasia). Among the remaining patients, 79% (33 of 42 patients) were classified into the brace group and 88% (21 of 24 patients) were classified into the FVO group for analyses. There were no overlapping patients at the timepoint when the treatment strategy for late-onset LCPD changed. In the FVO group, subtrochanteric osteotomy with 35° to 40° of flexion and 15° to 20° of varus was performed using a locking compression plate for pediatric use. Patient demographics, radiographic parameters, and the assessment of femoral head deformity using the Stulberg classification were compared between the two groups. There was a greater proportion of boys than girls in both groups (brace: 88% and FVO: 86%), and there were no differences in the distribution of genders between the groups (p = 0.82). The right side was more frequently treated in the brace group, but there was no difference in laterality between the groups (brace: 58% right and FVO: 62% left; p = 0.16). There was no difference between groups in the median age at disease onset (9.0 years [range 8.0 to 12.5 years] in the brace group and 9.6 years [range 8.0 to 12.4 years] in the FVO group; p = 0.26). There was no difference between the groups in the period of treatment from onset (1.7 ± 1.9 months in the brace group and 1.5 ± 1.5 months in the FVO group; p = 0.73) or the follow-up period (6.7 ± 2.1 years in the brace group and 6.2 ± 2.1 years in the FVO group; p = 0.41). The LCPD stage at the first visit was assessed using the modified Waldenström classification. The intraobserver and interobserver values of the modified Waldenström classification, evaluated using kappa statistics, were excellent (kappa value 0.89 [95% CI 0.75 to 0.97]; p < 0.01) and good (kappa value 0.65 [95% CI 0.43 to 0.87]; p < 0.01). The radiographic degree of collapse at the maximum fragmentation stage was assessed using the lateral pillar classification. The intraobserver and interobserver reliabilities of the lateral pillar classification were excellent (kappa value 0.84 [95% CI 0.73 to 0.94]; p < 0.01) and excellent (kappa value 0.83 [95% CI 0.71 to 0.94]; p < 0.01). The degree of femoral head deformity at the most recent follow-up examination was compared between the groups in terms of the Stulberg classification, in which Classes I and II were classified as good and Classes III through V were classified as poor. The intraobserver and interobserver reliabilities of the Stulberg classification were good (kappa value 0.74 [95% CI 0.55 to 0.92]; p < 0.01) and good (kappa value 0.69 [95% CI 0.50 to 0.89]; p < 0.01). The evaluators were involved in the patients' clinical care as part of the treating team. RESULTS: Good radiographic results (Stulberg Class I or II) were obtained more frequently in the FVO group (76% [16 of 21 patients]) than in the brace group (36% [12 of 33 patients]), with an odds ratio of 5.6 (95% CI 1.7 to 18.5; p < 0.01). In the brace group, a subsequent femoral varus osteotomy was performed in 18% (six of 33) of patients with progressive collapse and hinge abduction, and implant removal surgery was performed approximately 1 year after the first procedure. This traditional varus osteotomy was occasionally performed in patients who were considered for conversion from nonoperative treatment before 2009 because FVO had not yet been introduced. In the FVO group, all patients (n = 21) had a second procedure to remove the implant at a mean of 10.5 ± 1.2 months postoperatively. Additional procedures were performed in 24% (five of 21) of patients, including a second FVO for progressive collapse (one patient), guided growth for a limb length discrepancy (one patient), and flexion valgus osteotomy for coxa vara in patients with a limb length discrepancy (three patients). CONCLUSION: Our historical control study found that FVO may increase the possibility of obtaining good radiographic results (Stulberg Class I or II) compared with brace treatment for patients with late-onset LCPD, although surgical interventions after the first and second implant removal procedures may be indicated. Surgeons can consider FVO if they encounter patients with late-onset LCPD, which is a challenging condition. A larger study with long-term follow-up is needed to confirm the efficacy of FVO. LEVEL OF EVIDENCE: Level III, therapeutic study.

First Approval of Generic Mometasone Furoate Nasal Suspension Spray in Japan: Similarities and Differences Between Japan and the USA.

The Ministry of Health, Labour and Welfare (MHLW) in Japan approved the first generic version of Nasonex in February 2018. The Pharmaceuticals and Medical Devices Agency requires in vitro, pharmacokinetic, and pharmacodynamic or clinical endpoint data to approve generic nasal spray drug products. However, the MHLW has not published basic principle for approving nasal generic drug products. Therefore, this article summarizes the data used for the approval of the first generic Nasonex based on publicly available data. Additionally, we compare the bioequivalence evaluations regarding the human studies based on the generic version of Nasonex between Japan and the USA.

Incidence and causes of instrument-related complications after primary definitive fusion for pediatric spine deformity.

OBJECTIVE: Various complications have been reported in the treatment of pediatric spinal deformities. Among these, instrument-related complications could be critical concerns and risks of reoperation. This study aimed to identify the incidence and causes of complications after primary definitive fusion for pediatric spine deformities. METHODS: The authors retrospectively collected data from 14 institutions about patients who underwent primary definitive fusion between 2015 and 2017. There were 1490 eligible patients (1184 female and 306 male), with a mean age of 13.9 years. The incidence, causes, and reoperation rates were analyzed according to 4 etiologies of pediatric spine deformity (congenital, neuromuscular, syndromic, idiopathic). The complications were also categorized as screw-, hook-, or rod-related complications, implant loosening or backout, and junctional problems. RESULTS: The incidence of overall instrument-related complications was 5.6% (84 cases). Regarding etiology, the incidence rates were 4.3% (idiopathic), 6.8% (syndromic), 7.9% (congenital), and 10.4% (neuromuscular) (p < 0.05). The most common causes were pedicle screw malposition (60.7%), followed by implant backout or loosening (15.4%), junctional problems (13.1%), rod breakage (4.8%), and other complications (6.0%). Univariate analysis showed that etiology, type of deformity (kyphosis), surgical procedure, operation time, and estimated blood loss were significant factors. Multivariate analysis revealed that etiology (neuromuscular), surgical procedure (combined approach), and operation time (> 5 hours) remained as significant risk factors. Among all patients with instrument-related complications, 45% (38/84) required revision surgery. Of these cases, > 50% were related to pedicle screw malposition. Medial breach was the most common complication regardless of location, from upper thoracic to lumbar spine. CONCLUSIONS: Pedicle screw malposition was the primary cause of overall complications and subsequent reoperation. In addition to more precise screw insertion techniques, meticulous confirmation of pedicle screw placement, especially of medial breach, may reduce the overall instrument-related complications and revision rates.

A Case of Lupus Enteritis in Which Multiple Colorectal Ulcers Were the Only Signs of Relapse.

The patient was a 62-year-old woman. She had been treated for systemic lupus erythematosus (SLE) for 15 years and had a stable clinical course with cyclosporine, prednisolone, and ticlopidine. She experienced anal pain, diarrhea, and bloody stools for four months. Colonoscopy showed scattered large and small punchedout ulcers in the colon and deep longitudinal ulcers in the sigmoid colon. Blood test results indicated low SLE activity. Culture of mucosal biopsy did not reveal any findings. Computed tomography showed intestinal membrane arteriovenous dilatation (comb sign), therefore lupus enteritis was suspected. After initiating endoxan pulse therapy, symptoms improved rapidly. Disappearance of ulcers was confirmed by endoscopic images.

The recent bacterial etiology of childhood osteoarticular infections focusing on the vaccine initiation for Streptococcus pneumoniae and Haemophilus influenzae: A single-center retrospective analysis in Japan.

Background: Pediatric acute osteomyelitis and septic arthritis can destroy growth plate cartilage and joint cartilage, causing permanent deformities and growth disorders. Preventing the contraction of osteoarticular infections is important. Various types of bacteria cause osteoarticular infections in children. Since 2013, when routine vaccination against Streptococcus pneumoniae and Haemophilus influenzae was initiated in Japan, diseases caused by these bacteria (other than osteoarticular infection) are reported to decrease. In this study, we aimed to re-confirm the actual situation including the presence of pathogenic bacteria of pediatric bone and joint infections. Methods: The subjects were patients of 15 years old or younger who had been diagnosed with acute osteomyelitis or septic arthritis and received initial treatment in our hospital from April 1995 to March 2019. We obtained information from the medical records and analyzed them statistically. Results: There were 65 patients with 65 bones with acute osteomyelitis, and 120 patients with 124 joints with septic arthritis. The pathogenic bacteria were identified in 26 (40.0%) osteomyelitis patients and 59 (49.2%) septic arthritis patients. Staphylococcus aureus was the most common pathogenic bacterium, and S. pneumoniae and H. influenzae were identified in four and seven patients respectively, frequently in younger patients. After routine vaccination against S. pneumoniae and H. influenzae, these bacteria were no longer detected in patients under five years old. Conclusions: The efficacy of the S. pneumoniae and H. influenzae vaccine against orthopedic infectious diseases in Japan was indicated.

Hip Prognosis in Patients With Congenital Diastasis of the Pubic Symphysis.

BACKGROUND: Congenital diastasis of the pubic symphysis (CDPS) is a rare musculoskeletal malformation in the exstrophy-epispadias complex that is potentially associated with the development of hip dysplasia. The purpose of this study was to investigate the incidence and prognostic factors of hip dysplasia in patients with CDPS. METHODS: Fifty-four hips in 27 patients with CDPS initially evaluated between 1983 and 2016 were retrospectively reviewed. The mean age at the first visit was 2.3 (0 to 8) years. The mean follow-up duration was 10.5 (1 to 36) years. Patient characteristics at the first visit, the clinical course at the most recent follow-up, and radiologic parameters on pubic malformation and hip dysplasia during at least 2 time points (first visit or age 1, and either the most recent visit or before hip surgery) were evaluated. Prognostic factors associated with the development of hip dysplasia were analyzed using univariate/multivariate analysis. The Kaplan-Meier survival curves were generated and compared based on these factors. RESULTS: Nine of 27 patients (33%) and 13 of 54 hip joints (24%) with CDPS developed hip dysplasia. Paraplegia (odds ratio, 10.0; 95% confidence interval, 1.7-76.6) and center-edge angle of <5 degrees at the first visit or age 1 (P<0.001) were independent predictors of the development of hip dysplasia. Patients with CDPS and either paraplegia or center-edge angle <5 degrees at the first visit or age 1 were significantly more likely to develop hip dysplasia than other patients (hazard ratio, 29.3; 95% confidence interval, 3.4-250). CONCLUSIONS: Approximately one third of patients with CDPS develop hip dysplasia. Paraplegia and center-edge angle of <5 degrees at the first visit are independent risk factors. LEVEL OF EVIDENCE: Level III.

Evaluation of Fluorescence Intensity and Antitumor Effect Using Real-Time Imaging in Photoimmunotherapy.

Photoimmunotherapy (PIT) is a promising tumor-selective treatment method that uses light-absorbing dye-conjugated antibodies and light irradiation. It has been reported that IR700 fluorescence changes with light irradiation. The purpose of this study was to investigate the fluorescence intensity and antitumor effect of PIT using real-time fluorescence observation of tumors and predict the required irradiation dose. The near-infrared camera system LIGHTVISION was used to image IR700 during PIT treatment. IR700 showed a sharp decrease in fluorescence intensity in the early stage of treatment and almost reached a plateau at an irradiation dose of 40 J/cm. Cetuximab-PIT for A431 xenografts was performed at multiple doses from 0-100 J/cm. A significant antitumor effect was observed at 40 J/cm compared to no irradiation, and there was no significant difference between 40 J/cm and 100 J/cm. These results suggest that the rate of decay of the tumor fluorescence intensity correlates with the antitumor effect by real-time fluorescence imaging during PIT. In addition, when the fluorescence intensity of the tumor plateaued in real-time fluorescence imaging, it was assumed that the laser dose was necessary for treatment.

Generic Drug Product Development in Japan: Regulatory Updates During 2014-2019 and the Future.

The growth of healthcare cost is a serious issue in many countries. Generic drug products play an essential role in reducing healthcare costs because they are less costly than the innovator drug products. The regulatory review of generic drug products in Japan is conducted by the Pharmaceuticals and Medical Devices Agency (PMDA). This report introduces the activities of the PMDA from fiscal years 2014-2019. The number of approvals of new generic drug products and partial changes was trending downward. Alternatively, the PMDA conducted six types of consultation meetings to advise on development and application; the number of consultation meetings was increasing. Moreover, during this period, the Ministry of Health, Labour and Welfare issued two basic principles for ophthalmic dosage forms and dry powder inhaler drug products and revised the guidelines for bioequivalence. Finally, the future of generic drug product development and considerations to improve their regulation were discussed. More efforts will continue to enable a more efficient and rational generic drug product development and shortening of the review period for partial change approval.

Hyperpolarized 13 C Magnetic Resonance Imaging of Fumarate Metabolism by Parahydrogen-induced Polarization: A Proof-of-Concept in†vivo Study.

The front cover artwork is provided by the group of Dr. Neil J. Stewart, Prof. Hiroshi Hirata, and Dr. Shingo Matsumoto (Hokkaido University, Japan) as well as Dr. Takuya Hashimoto (Chiba University, Japan). The image shows hyperpolarized 13 C fumarate metabolism to hyperpolarized 13 C malate, which is released into the extracellular space in regions of necrotic cell death, where the cell membrane is disrupted. Read the full text of the Article at 10.1002/cphc.202001038.

Hyperpolarized 13 C Magnetic Resonance Imaging of Fumarate Metabolism by Parahydrogen-induced Polarization: A Proof-of-Concept in†vivo Study.

Hyperpolarized [1-13 C]fumarate is a promising magnetic resonance imaging (MRI) biomarker for cellular necrosis, which plays an important role in various disease and cancerous pathological processes. To demonstrate the feasibility of MRI of [1-13 C]fumarate metabolism using parahydrogen-induced polarization (PHIP), a low-cost alternative to dissolution dynamic nuclear polarization (dDNP), a cost-effective and high-yield synthetic pathway of hydrogenation precursor [1-13 C]acetylenedicarboxylate (ADC) was developed. The trans-selectivity of the hydrogenation reaction of ADC using a ruthenium-based catalyst was elucidated employing density functional theory (DFT) simulations. A simple PHIP set-up was used to generate hyperpolarized [1-13 C]fumarate at sufficient 13 C polarization for ex vivo detection of hyperpolarized 13 C malate metabolized from fumarate in murine liver tissue homogenates, and in vivo 13 C MR spectroscopy and imaging in a murine model of acetaminophen-induced hepatitis.

Surgical Site Infection Following Primary Definitive Fusion for Pediatric Spinal Deformity: A Multicenter Study of Rates, Risk Factors, and Pathogens.

STUDY DESIGN: A retrospective multicenter study. OBJECTIVE: To determine the surgical site infection (SSI) rate, associated risk factors, and causative pathogens in pediatric patients with spinal deformity. SUMMARY OF BACKGROUND DATA: There have been no extensive investigations of the risk factors for SSI in Japan. METHODS: Demographic data, radiographic findings, and the incidence of SSI were retrospectively analyzed in 1449 pediatric patients who underwent primary definitive fusion surgery for spinal deformity at any of 15 institutions from 2015 to 2017. SSI was defined according to the US Centers for Disease Control and Prevention guideline. RESULTS: The incidence of all SSIs was 1.4% and that of deep SSIs was 0.76%. The most common pathogenic microbes were methicillin-resistant staphylococci (n = 5) followed by gram-negative rods (n = 4), methicillin-sensitive staphylococci (n = 1), and others (n = 10). In univariate analysis, younger age, male sex, a diagnosis of kyphosis, type of scoliosis, American Society of Anesthesiologists (ASA) class ≥3, mental retardation urinary incontinence, combined anterior-posterior fusion, greater magnitude of kyphosis, three-column osteotomy, use of blood transfusion, and number of antibiotic administration were associated with the likelihood of SSI (all P < 0.05). Multivariate logistic regression analysis identified the following independent risk factors for SSI: syndromic scoliosis etiology (vs. idiopathic scoliosis; adjusted odds ratio [OR] 16.106; 95% confidence interval [CI] 2.225-116.602), neuromuscular scoliosis etiology (vs. idiopathic scoliosis; adjusted OR 11.814; 95% CI 1.109-125.805), ASA class 3 (vs. class 2; adjusted OR 15.231; 95% CI 1.201-193.178), and administration of antibiotic therapy twice daily (vs. three times daily; adjusted OR 6.121; 95% CI 1.261-29.718). CONCLUSION: The overall infection rate was low. The most common causative bacteria were methicillin-resistant followed by gram-negative rods. Independent risk factors for SSI in pediatric patients undergoing spinal deformity surgery were scoliosis etiology, ASA class 3, and administration of antibiotic therapy twice daily.Level of Evidence: 3.

A longitudinal study for the prediction of the mature acetabular morphology using childhood magnetic resonance imaging.

BACKGROUND: Although acetabular dysplasia is a common etiology of osteoarthritis of the hip regardless of the history of developmental dysplasia of the hip (DDH), whether or not corrective surgeries are beneficial for the childhood asymptomatic acetabular dysplasia remains controversial due to a lack of evidence. We conducted a longitudinal study to compare the cartilaginous morphology on childhood magnetic resonance imaging (MRI) and the mature hip morphology of the same patient and to assess the predictive indicators for future acetabular dysplasia. METHODS: A total of 92 unaffected hips (47 unilateral DDH and 45 unilateral Legg-Calvé-Perthes disease) were reviewed for X-ray and MRI findings on childhood (mean age: 6.0 years) and X-ray findings from a skeletally mature age with a mean follow-up period of 15.1 years. The following parameters were measured and compared: the immature-acetabular index (AI) and center edge angle (CE) on immature X-ray; the cartilage- and bone- AI, CE, Sharp and acetabular head index (AHI) on childhood MRI; and the mature-acetabular roof obliquity (ARO), CE, Sharp and AHI on skeletally mature X-ray. The prognostic factors on childhood MRI for acetabular dysplasia, defined by a CE of <20° on skeletally mature X-ray were also assessed. RESULTS: Positive correlations were shown between the cartilage-AI and mature-ARO (7.6°/6.3°; r = 0.44), the cartilage-CE and mature-CE (27.8°/28.0°; r = 0.62), the cartilage-Sharp and mature-Sharp (44.4°/41.8°; r = 0.52) and the cartilage-AHI and mature-AHI (78.7%/80.3%; r = 0.46). A multivariate analysis indicated cartilage-CE to be an independent predictor for acetabular dysplasia with a cut-off value of 22°. Children with a cartilage-CE <22° developed more frequently acetabular dysplasia compared to the others (52.4% vs. 1.4%). CONCLUSIONS: Childhood MRI findings are useful for the prediction of acetabular dysplasia without a DDH history. Children with a cartilage-CE ≥23° are likely to achieve a non-dysplastic hip without the need for surgical intervention.

Incidence and Risk Factors for Unplanned Return to the Operating Room Following Primary Definitive Fusion for Pediatric Spinal Deformity: A Multicenter Study with Minimum 2-year Follow-Up.

STUDY DESIGN: A retrospective multicenter cohort study. OBJECTIVE: The aim of this study was to identify the incidence and risk factors for UPROR within minimum 2-year follow-up in primary definitive fusion for pediatric spinal deformity. SUMMARY OF BACKGROUND DATA: Several previous reports have elucidated the incidence of complications after pediatric scoliosis surgery; however, there has been no study that described the incidence and risk factors for unplanned return to the operating room (UPROR) with long-term follow-up in surgery for pediatric scoliosis with every etiology. METHODS: We retrospectively extracted data of patients aged <19 years, from 14 institutes in Japan, who underwent primary definitive fusion surgery for spinal deformity between January 1, 2015 and December 31, 2017. The primary outcomes were the incidence of UPROR within the minimum 2-year follow-up period for any reason. Univariate and multivariate logistical analyses were conducted to identify potential risk factors associated with UPROR. RESULTS: We identified 1417 eligible patients (287 males and 1130 females) with a mean age of 13.9 years. UPROR for any reason within minimum 2-year follow-up was identified in 68 patients (4.8%). The most frequent cause for UPROR was implant failure found in 29 patients, followed by surgical site infection in 14 patients, junctional problems in 10 patients, and neurological complications in six patients. The multivariate logistic regression analysis revealed that a diagnosis of kyphosis (odds ratio [OR], 2.65; 95% confidence interval [CI] 1.16-6.04), etiology of congenital or structural type (OR 2.21; 95% CI 1.08-4.53), etiology of syndromic type (OR 2.67; 95% CI 1.27-5.64), and increased operation time of ≥300 minutes (OR 1.81; 95% CI 1.07-3.07) were the risk factors for the incidence of UPROR. CONCLUSION: The present multicenter study identified for the first time the incidence and risk factors for UPROR with minimum 2-year follow-up after primary definitive fusion surgery for pediatric spinal deformity with every etiology.Level of Evidence: 3.