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Study design: Retrospective multicenter study. Objectives: To evaluate how preoperative neck pain influences clinical outcomes following posterior decompression for cervical ossification of the posterior longitudinal ligament (OPLL). Setting: Fourteen medical institutions in Japan. Methods: We enrolled 90 patients with cervical OPLL who underwent posterior decompression and were followed for a minimum of two years. We collected demographic data, medical history, and imaging findings. Patients were divided into two groups based on preoperative neck pain presence (Pre-op. neck pain (−) and (+) groups), and their outcomes were compared. Results: There were no significant differences in patient demographics between the Pre-op. neck pain (−) and (+) groups. Both groups showed similar distributions of ossification types and K-line positivity. Perioperative complications were comparable between the two groups. Radiographic analysis revealed no significant differences in C2–7 angles or cervical range of motion, pre- and postoperatively. Both groups demonstrated significant improvement in postoperative Japanese orthopedic association (JOA) scores, but there were no significant differences in scores or recovery rates. In the Pre-op. neck pain (−) group, factors associated with appearance of postoperative neck pain included pre- and postoperative lower JOA scores and larger C2–7 angles in neutral and extension positions. Conclusions: It emerges that lower pre- and postoperative JOA scores or larger C2–7 angles in neutral and extension positions predispose to postoperative neck pain even in those patients without preoperative neck pain. Therefore, this is worth discussing at the time of consenting patients for surgical decompression and fixation.

The recent success of cancer immunotherapies has highlighted the benefit of harnessing the immune system for cancer treatment. Vaccines have a long history of promoting immunity to pathogens and, consequently, vaccines targeting cancer neoantigens have been championed as a tool to direct and amplify immune responses against tumours while sparing healthy tissue. In recent years, extensive preclinical research and more than one hundred clinical trials have tested different strategies of neoantigen discovery and vaccine formulations. However, despite the enthusiasm for neoantigen vaccines, proof of unequivocal efficacy has remained beyond reach for the majority of clinical trials. In this Review, we focus on the key obstacles pertaining to vaccine design and tumour environment that remain to be overcome in order to unleash the true potential of neoantigen vaccines in cancer therapy.

Study design: Retrospective multicenter study. Objective: To compare the surgical outcomes and complications of posterior decompression between individuals with cervical spondylotic myelopathy (CSM) and those with ossification of the posterior longitudinal ligament (OPLL). Setting: Seventeen medical institutions in Japan. Methods: This study included 814 individuals with CSM (n= 636) and OPLL (n= 178) who underwent posterior decompression. Propensity score matching of the baseline characteristics was performed to compare surgical outcomes and perioperative complications between the CSM and OPLL groups. Results: Before propensity score matching, the OPLL group had higher percentage of male individuals, body mass index, and number of stenosis levels and longer duration of symptoms (P< 0.01, P< 0.01, P< 0.01, and P< 0.01, respectively). After matching, the baseline characteristics were comparable between the CSM (n= 98) and OPLL (n= 98) groups. The postoperative Japanese Orthopaedic Association (JOA) scores, preoperative-to-postoperative changes in the JOA scores, and JOA score recovery rates were not significantly different between the groups (P= 0.42, P= 0.47, and P= 0.09, respectively). The postoperative visual analog scale (VAS) score for neck pain and preoperative-to-postoperative changes in the VAS score for neck pain were not significantly different between the groups (P= 0.25 and P= 0.50, respectively). The incidence of perioperative complications was comparable between groups. Conclusion: Neurological improvement and complication rates after surgery were comparable between individuals with CSM and those with OPLL, suggesting similar effectiveness and safety of posterior decompression for both conditions.

Study Design: Multicenter retrospective study.Objectives: We aim to investigate features of cervical spondylotic myelopathy (CSM) associated with anterior cervical spondylolisthesis (ACS) during posterior decompression surgery.Methods: A total of 732 patients with CSM were enrolled, who underwent posterior decompression surgery between July 2011 and November 2015 at 17 institutions. The patients with ACS (group A), defined as an anterior slippage of ≥2 mm on plain radiographs, were compared with those without ACS (group non-A). Also, the characteristics of patients with ACS progression (group P), defined as postoperative worsening of ACS ≥2 mm or newly developed ACS, were investigated. Moreover, kyphosis was defined as C2-C7 angle in neutral position ≤−5°. The Japanese Orthopedic Association (JOA) scoring system was used for clinical evaluation.Results: Group A consisting of 62 patients (8.5%) had worse preoperative clinical status but comparable surgical outcomes to group non-A. Furthermore, ACS was associated with greater age, and the degree of slippage did not affect myelopathy grades. Seventeen patients (2.3%) were observed in group P, and preoperative ACS was a significant predisposing factor for the progression without clinical impact. Among the patients in group A, preoperative cervical kyphosis was a risk factor for lower JOA recovery rate.Conclusions: Although the presence of ACS increases the risk of postoperative progression, it is not a contraindication for posterior decompression. However, surgeons need to consider the indication of fusion surgery for the patients who have ACS accompanied by kyphosis because of the poor surgical outcomes.

Study design: Retrospective multicenter study. Objectives: To identify the usefulness of the baseline severity of myelopathy for predicting surgical outcomes for cervical spondylotic myelopathy (CSM). Setting: Seventeen institutions in Japan. Methods: This study included 675 persons with CSM who underwent posterior decompression. According to baseline severity, the individuals were divided into the mild (Japanese Orthopaedic Association [JOA] score ≥ 14.5), moderate (JOA score = 10.5–14), and severe (JOA score ≤ 10) groups. Surgical outcomes and clinical variables were compared between the groups. Logistic regression analysis was used to develop a prediction model for unsatisfactory symptom state (postoperative JOA score ≤ 14, residual moderate or severe myelopathy). Results: The mean (±standard deviation) age was 67 ± 12 years. The participants in the severe group were older than those in the mild group. Postoperative JOA scores were higher in the mild group than in the severe group. According to multivariate logistic regression analysis, the prediction model included preoperative JOA scores (odds ratio [OR] 0.60; 95% confidence interval [CI] 0.55–0.67) and age (OR 1.06, 95% CI 1.04–1.08). On the basis of the model, a representative combination of the thresholds to maximize the value of “sensitivity − (1 − specificity)” demonstrated a preoperative JOA score of 11.5 as a predictor of postoperative unsatisfactory symptom state in people around the mean age of the study cohort (67 years). Conclusions: The combination of the baseline severity of myelopathy and age can predict postoperative symptom states after posterior decompression surgery for CSM.

Cholera toxin (CT), a bacterial exotoxin composed of one A subunit (CTA) and five B subunits (CTB), functions as an immune adjuvant. CTB can induce production of interleukin-1β (IL-1β), a proinflammatory cytokine, in synergy with a lipopolysaccharide (LPS), from resident peritoneal macrophages (RPMs) through the pyrin and NLRP3 inflammasomes. However, how CTB or CT activates these inflammasomes in the macrophages has been unclear. Here, we clarify the roles of inositol-requiring enzyme 1 alpha (IRE1α), an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1β production in RPMs. In RPMs, CTB is incorporated into the ER and induces ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1α-deficient RPMs show a significant impairment of CT- or CTB-induced IL-1β production, indicating that IRE1α is required for CT- or CTB-induced IL-1β production in RPMs. This study demonstrates the critical roles of IRE1α in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages.

mRNA vaccines such as those used to prevent COVID-19 owe part of their success to methylation that masks immunostimulatory properties of the mRNA, but the immunological mechanisms of adjuvanticity are unclear. Two new studies reveal distinct mechanisms for innate sensing of this hidden adjuvant.

Study design: Retrospective cohort study. Objectives: Although intramedullary astrocytoma is associated with a high mortality rate, the optimal treatment has not reached a consensus. This study aimed at evaluating neurologic function and overall survival rate (OSR) in the treatment of this tumor. Setting: The single institution in Japan. Methods: This study enrolled 67 subjects who underwent surgical treatment for intramedullary astrocytoma. Demographic, imaging, and surgical information were collected from each participant. Tumors were histologically categorized using the World Health Organization classification, and subjects were divided into low-grade (I and II; n= 40) and high-grade (III and IV; n= 27) groups. Neurologic status was evaluated using the modified McCormick scale (MMS). OSR was assessed using Kaplan–Meier methods. Results: The OSR decreased when the pathological grade increased (p< 0.01). Regarding the therapeutic efficacy for low-grade astrocytomas, subjects who underwent gross total resection (GTR) showed a higher OSR than those who did not (p= 0.02). GTR prevented worsening of MMS score, while non-GTR increased the MMS score (p< 0.01). In the high-grade group, 19 and 10 underwent radiation therapy and chemotherapy, respectively. However, both treatments did not improve OSR. Cordotomy was performed for subjects whose lesional area was at the thoracic level, but the OSR did not significantly increase. Conclusions: The most beneficial therapeutic strategy for low-grade astrocytomas was GTR, whereas that for the high-grade tumors was unclear. Further studies with a larger sample size are warranted to validate the effective treatment for malignant astrocytomas.

Background: Modified Bösch osteotomy (distal linear metatarsal osteotomy [DLMO]) is one of the minimally invasive correctional surgeries for hallux valgus. The 3-dimensional correctional angles and distances of the first metatarsal bone in DLMO have not been clarified. The purpose of this study was to analyze the 3-dimensional postoperative morphological changes of the first metatarsal bone in DLMO.Methods: Twenty patients (30 feet) who underwent DLMO were enrolled. Preoperative plain radiographs and computed tomography (CT) scans of the feet were examined. Postoperative radiographs and CT scans were also obtained after bone union. The surface data of the pre- and postoperative first metatarsals were reconstructed from the CT data. The positions of the distal ends of the first metatarsals described with respect to the proximal ends were calculated using CT surface-matching technique.Results: The distal end of the first metatarsal after DLMO was significantly supinated (10.2 ± 6.0 degrees, P< .001), adducted (6.0 ± 11.8 degrees, P= .004), dorsiflexed (11.1 ± 10.9, P< .001), shortened (7.4 ± 2.5 mm, P< .001), elevated (2.3 ± 3.1 mm, P= .001), and laterally shifted (8.2 ± 3.0 mm, P< .001) compared to the preoperative metatarsal distal end. Supination correction demonstrated a significant correlation with adduction correction (r= 0.659, P< .001) on correlation analyses between these parameters.Conclusion: The 3-dimensional corrections of the first metatarsal bone after DLMO were evaluated. Pronation and abduction were successfully corrected. Furthermore, adduction correction might be an important factor affecting correction of pronation.Level of Evidence: Level IV, retrospective case series.

Strategic Outlook toward 2030: Japan's Research for Allergy and Immunology(Strategy 2030) is the national research strategy based on Japan's Basic Law on Measures Against Allergic Diseases, a first of its kind worldwide. This strategy was established by a multi-disciplinary committee consisting of administrators of the Ministry of Health, Labour and Welfare of Japan, young and senior experts from various research societies and associations, and representatives of patient and public groups. Whereas the issues of transition, integration, and international collaboration have yet to be solved in this research realm in Japan, identification of unmet needs, digitization of information and transparent procedures, and strategic planning for complex problems (a process dubbed MIERUKAby the Toyota Way) are crucial to share and tackle the same vision and goals. The committee developed three specific actions focusing on preemptive treatment, interdisciplinarity and internationality, and life stage. The real success of Strategy 2030is made by the spontaneous contributions of doctors, dentists, veterinarians, and other medical professionals; basic and clinical research scientists, research supporters, and pharmaceutical/medical device companies; manufacturers of food, healthcare, and home appliances; and patients, their families, and the public. The hope is to establish a stable society in which people can live long, healthy lives, as free as possible from allergic and immunological diseases, at each individual life stage. This article is based on a Japanese review first reported in Arerugi, introduces the developmental process and details of Strategy 2030.

Study Design Retrospective multicenter study.Objectives To investigate surgical outcomes following posterior decompression for cervical ossification of the posterior longitudinal ligament (OPLL) when performed by board-certified spine (BCS) or non-BCS (NBCS) surgeons.Methods We included 203 patients with cervical OPLL who were followed for a minimum of 1 year after surgery. Demographic information, medical history, and imaging findings were collected. Clinical outcomes were assessed preoperatively and at the final follow-up using the Japanese Orthopedic Association (JOA) score and the visual analog scale (VAS) for the neck. We compared outcomes between BCS surgeons, who must meet several requirements, including experience in more than 300 spinal surgeries, and NBCS surgeons.Results BCS surgeons performed 124 out of 203 cases, while NBCS surgeons were primary in 79 cases, with 73.4% were directly supervised by a BCS surgeon. There was no statistically significant difference in surgical duration, estimated blood loss, and perioperative complication rates between the BCS and NBCS groups. Moreover, no statistically significant group differences were observed in each position of the C2-7 angle and cervical range of motion at preoperation and the final follow-up. Preoperative and final follow-up JOA scores, VAS for the neck, and JOA score recovery rate were comparable between the two groups.Conclusions Surgical outcomes, including functional recovery, complication rates, and cervical dynamics, were comparable between the BCS and NBCS groups. Consequently, posterior decompression for cervical OPLL is considered safe and effective when conducted by junior surgeons who have undergone training and supervision by experienced spine surgeons.

Leukotriene B4receptor 1 (BLT1) triggers the migration of granulocytes and activated T cells; however, its role in B-cell function remains unclear. Here we report that BLT1 is required to induce the production of antigen-specific IgA against oral vaccine through mediating innate immune signals from commensal bacteria. B cells acquire BLT1 expression during their differentiation to IgA+B cells and plasma cells in Peyer's patches and the small intestinal lamina propria, respectively. BLT1 KO mice exhibited impaired production of antigen-specific fecal IgA to oral vaccine despite normal IgG responses to systemically immunized antigen. Expression of MyD88 was decreased in BLT1 KO gut B cells and consequently led to diminished proliferation of commensal bacteria-dependent plasma cells. These results indicate that BLT1 enhances the proliferation of commensal bacteria-dependent IgA+plasma cells through the induction of MyD88 and thereby plays a key role in the production of antigen-specific intestinal IgA.

Study Design: Retrospective multicenter study.Objectives: To evaluate the outcomes of posterior cervical decompression for cervical spondylotic myelopathy (CSM) when performed by board-certified spine (BCS) or non-BCS (NBCS) surgeons.Methods: We reviewed outcomes for 675 patients who underwent surgery for CSM, were followed at least 1 year after surgery, and were assessed preoperatively and at final follow-up by Japanese Orthopaedic Association (JOA) scores and by the visual analog scale (VAS) for the neck. Cervical alignment was assessed on radiographs by C2-C7 angles, and range of motion (ROM) by extension minus flexion C2-C7 angles. We compared outcomes for BCS surgeons, who must meet several requirements, including experience in more than 300 spinal surgeries, and for NBCS surgeons.Results: BCS surgeons performed 432 of 675 laminoplasties. NBCS surgeons were primary in 243 surgeries, of which 187 were directly supervised by a BCS surgeon. BCS surgeons required significantly less time in surgery (98.0 ± 39.5 vs 108.1 ± 49.7 min; P< .01). BCS and NBCS surgeons had comparable perioperative complications rates, and preoperative-to-postoperative changes in JOA scores (2.9 ± 2.1 vs 3.1 ± 2.3; P= .40) and VAS (−1.5 ± 2.9 vs −1.4 ± 2.5; P= .96). Lordotic cervical alignment and ROM were maintained after operations by both groups.Conclusions: Surgical outcomes such as functional recovery, complication rates, and cervical dynamics were comparable between the BCS and NBCS groups. Thus, posterior cervical decompression for CSM is safe and effective when performed by junior surgeons who have been trained and supervised by experienced spine surgeons.

Abstract:We devised a simple and rapid technique for establishing axenic cultures of centric diatoms by sieving and washing resting stage cells. This technique is an effective means for establishing the axenic cultures of species that have endogenous resting spores. The primary advantage of this method is in the isolation of cells when the target species is absent from the water column.

ObjectivesThe objectives of this study were to investigate the incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) after anterior cruciate ligament reconstruction (ACLR) using ultrasonography (US) and contrast-enhanced CT (CECT) without pharmacological prophylaxis and to identify the risk factors for DVT.MethodsA prospective, observational study of 55 consecutive Japanese patients undergoing ACLR, including 10 revision surgeries, between April 2017 and September 2018 was performed. All operations were performed by the one experienced surgeon with the use of a tourniquet. Anterior cruciate ligaments were reconstructed using a single-bundle hamstring autograft. US of the leg veins was performed on the sixth or seventh postoperative day. When the patient was diagnosed with DVT, CECT was performed to detect PE. The patients were divided into two groups, those with and those without DVT. Clinical factors were compared between the two groups.ResultsAfter the ACLR, DVT was detected in nine (16.4%) patients, and CECT showed that four of them had PE (incidence, at least 7.3%). All of them were asymptomatic. The mean age was significantly higher in patients with DVT (41.9±15.7 years) than in patients without DVT (28.2±14.2 years, p=0.012). There were no significant differences in other clinical factors, including sex, body mass index, current smoker, preoperative Lysholm score, time interval from injury to ACLR, primary or revision ACLR, preoperative knee pain, operative and tourniquet times, and with or without meniscus repair between patients with DVT and those without DVT.ConclusionThe incidences of DVT and PE after ACLR were 16.4% and at least 7.3%, respectively. These incidences, especially PE, were unexpectedly high and might suggest a need for thromboprophylaxis. Since advanced age was identified as the risk factor for DVT in this study, patients with this risk factor should be considered for pharmacological prophylaxis after ACLR.Level of evidenceLevel IV.

Abstract:The distribution of resting stage cells of diatoms in the surface sediments and water samples collected in the Chukchi Sea was investigated using the most probable number (MPN) analysis to understand the mechanism underlying diatom blooms in the Arctic region. High densities (3.5 × 105to 6.8 × 106MPN cells cm−3wet sediment) of viable resting stage cells of typical Arctic diatom species were found in the surface sediments of the Chukchi Sea. Resting stage cells of the sea-ice–related diatom genus Fragilariopsiswere more abundant (2.6 × 106MPN cells cm−3wet sediment) than Chaetoceros(2.18 × 106MPN cells cm−3wet sediment) or Thalassiosira(1.76 × 106MPN cells cm−3wet sediment) in the southern Chukchi Sea. This reflected a previous bloom of Fragilariopsisahead of typical planktonic blooms of Chaetocerosand Thalassiosiraand suggests that sea-ice–related blooms are a substantial factor for primary production in this area. During the sampling period, diatom assemblages in the in situwater columns were dominated by Pseudo-nitzschia delicatissima, Cylindrotheca closterium, Proboscia alata, and Thalassionemaspp. After storage of water samples for 6 months in the dark, viable diatom resting stage cells of typical Arctic species such as Attheya longicornisand Chaetoceros socialiswere detected. These autochthonous species formed resting stage cells that remained viable in the dark for more than 6 months, while diatom species of Pacific origins could not survive under conditions of extremely limited light. The resting stage cells provide an advantage for autochthonous diatoms to endure the unfavourable light conditions of the Arctic winter. In the Chukchi Sea, resting stage cells of diatoms were supplied by current inflows from shallow sea areas. Densely distributed viable resting stages at the bottom are also a possible source for seeding the diatom cells into phytoplankton communities and ice assemblages in shallow marginal ice zones.

Alcaligenesare opportunistic commensal bacteria that reside in gut-associated lymphoid tissues such as Peyer’s patches (PPs); however, how they create and maintain their homeostatic environment, without inducing an excessive inflammatory response remained unclear. We show here that Alcaligenes-derived lipopolysaccharide (AlcaligenesLPS) acts as a weak agonist of toll-like receptor 4 and promotes IL-6 production from dendritic cells, which consequently enhances IgA production. The inflammatory activity of AlcaligenesLPS was weaker than that of Escherichia coli-derived LPS and therefore no excessive inflammation was induced by AlcaligenesLPS in vitroor in vivo. AlcaligenesLPS also showed adjuvanticity, inducing antigen-specific immune responses without excessive inflammation. These findings reveal the presence of commensal bacteria-mediated homeostatic inflammatory conditions within PPs that produce optimal IgA induction without causing pathogenic inflammation and suggest that AlcaligenesLPS could be a safe and potent adjuvant.

During blood-stage infections, Plasmodiumparasites infect erythrocytes and can cause a variety of acute and chronic complications, some of which can be fatal. Although malaria complications are often attributed to sepsis-like systemic inflammation, the parasites in the circulation reach and interact with host tissues locally and specifically.The brain, eye (retina), gastrointestinal tract, bones, lungs, kidneys and placenta are the organs that are specifically affected both during and even long after malaria infection. The unique anatomical structure of the vessels, parenchyma and lymphatics in each organ shapes the interaction with Plasmodiumparasites and their products.In the brain, unique areas such as the olfactory bulb, retina and perivascular spaces share similar anatomical and immunological features; Plasmodiumparasites and their associated inflammation cause blood–brain barrier disruption in these areas.The gastrointestinal tract microenvironment is a target of Plasmodiumparasites and related events. Malaria infection causes the disruption of blood vessels and epithelial barriers in the gut.Plasmodiumparasites can reside in the bone marrow. At this site, the parasites and their products, such as haemozoin, interact with bone marrow niches and with cells resident in the bone tissue, including osteoblasts and osteoclasts, causing long-term effects in the host, such as bone loss.The interactions that occur between Plasmodiumparasites and the specific host tissues alter the outcome of malaria disease. A better understanding of malaria pathology in the context of host–parasite interactions at the various tissue levels of each organ will allow for better diagnostics and treatments for malaria.

ObjectiveAlthough HCV is a major cause of chronic liver disease worldwide, there is currently no prophylactic vaccine for this virus. Thus, the development of an HCV vaccine that can induce both humoural and cellular immunity is urgently needed. To create an effective HCV vaccine, we evaluated neutralising antibody induction and cellular immune responses following the immunisation of a non-human primate model with cell culture-generated HCV (HCVcc).DesignTo accomplish this, 10 common marmosets were immunised with purified, inactivated HCVcc in combination with two different adjuvants: the classically used aluminum hydroxide (Alum) and the recently established adjuvant: CpG oligodeoxynucleotide (ODN) wrapped by schizophyllan (K3-SPG).ResultsThe coadministration of HCVcc with K3-SPG efficiently induced immune responses against HCV, as demonstrated by the production of antibodies with specific neutralising activity against chimaeric HCVcc with structural proteins from multiple HCV genotypes (1a, 1b, 2a and 3a). The induction of cellular immunity was also demonstrated by the production of interferon-γ mRNA in spleen cells following stimulation with the HCV core protein. These changes were not observed following immunisation with HCVcc/Alum preparation. No vaccination-related abnormalities were detected in any of the immunised animals.ConclusionsThe current preclinical study demonstrated that a vaccine included both HCVcc and K3-SPG induced humoural and cellular immunity in marmosets. Vaccination with this combination resulted in the production of antibodies exhibiting cross-neutralising activity against multiple HCV genotypes. Based on these findings, the vaccine created in this study represents a promising, potent and safe prophylactic option against HCV.

Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type–dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.

Study Design: Retrospective study of registry data.Objectives: Aging of society and recent advances in surgical techniques and general anesthesia have increased the demand for spinal surgery in elderly patients. Many complications have been described in elderly patients, but a multicenter study of perioperative complications in spinal surgery in patients aged 80 years or older has not been reported. Therefore, the goal of the study was to analyze complications associated with spine surgery in patients aged 80 years or older with cervical, thoracic, or lumbar lesions.Methods: A multicenter study was performed in patients aged 80 years or older who underwent 262 spinal surgeries at 35 facilities. The frequency and severity of complications were examined for perioperative complications, including intraoperative and postoperative complications, and for major postoperative complications that were potentially life threatening, required reoperation in the perioperative period, or left a permanent injury.Results: Perioperative complications occurred in 75 of the 262 surgeries (29%) and 33 were major complications (13%). In multivariate logistic regression, age over 85 years (hazard ratio [HR] = 1.007, P= 0.025) and estimated blood loss ≥500 g (HR = 3.076, P= .004) were significantly associated with perioperative complications, and an operative time ≥180 min (HR = 2.78, P= .007) was significantly associated with major complications.Conclusions: Elderly patients aged 80 years or older with comorbidities are at higher risk for complications. Increased surgical invasion, and particularly a long operative time, can cause serious complications that may be life threatening. Therefore, careful decisions are required with regard to the surgical indication and procedure in elderly patients.

Study Design: Retrospective database analysis.Objective: Spine surgeries in elderly patients have increased in recent years due to aging of society and recent advances in surgical techniques, and postoperative complications have become more of a concern. Postoperative delirium is a common complication in elderly patients that impairs recovery and increases morbidity and mortality. The objective of the study was to analyze postoperative delirium associated with spine surgery in patients aged 80 years or older with cervical, thoracic, and lumbar lesions.Methods: A retrospective multicenter study was performed in 262 patients 80 years of age or older who underwent spine surgeries at 35 facilities. Postoperative complications, incidence of postoperative delirium, and hazard ratios of patient-specific and surgical risk factors were examined.Results: Postoperative complications occurred in 59 of the 262 spine surgeries (23%). Postoperative delirium was the most frequent complication, occurring in 15 of 262 patients (5.7%), and was significantly associated with hypertension, cerebrovascular disease, cervical lesion surgery, and greater estimated blood loss (P< .05). In multivariate logistic regression using perioperative factors, cervical lesion surgery (odds ratio = 4.27, P< .05) and estimated blood loss ≥300 mL (odds ratio = 4.52, P< .05) were significantly associated with postoperative delirium.Conclusions: Cervical lesion surgery and greater blood loss were perioperative risk factors for delirium in extremely elderly patients after spine surgery. Hypertension and cerebrovascular disease were significant risk factors for postoperative delirium, and careful management is required for patients with such risk factors.

Supplemental Digital Content is available in the text.

Minimodeling is a type of focal bone formation that is characterized by the lack of precedent bone erosion by osteoclasts. Although this form of bone formation has been described for more than a decade, how anti-osteoporotic agents that are currently used in clinical practice affect the kinetics of minimodeling is not fully understood. We performed a bone morphometric analysis using human vertebral specimens collected from postmenopausal patients who underwent spinal surgery. Patients were divided into three groups according to osteoporosis medication; non-treated, Eldecalcitol (ELD, a vitamin D derivative that has recently been approved to treat patients with osteoporosis in Japan)-treated, and bisphosphonate-treated groups. Five to six patients were enrolled in each group. There was a trend toward enhanced minimodeling in ELD-treated patients and suppressed of it in bisphosphonate-treated patients compared with untreated patients. The differences of minimodeling activity between ELD-treated and bisphosphonate-treated patients were statistically significant. The present study suggests that ELD and bisphosphonates have opposite effects on minimodeling from one another, and show that minimodeling also takes place in vertebrae as has been described for the ilium and femoral head in humans.

Protein or peptide cancer vaccines usually include immune potentiators, so-called adjuvants. However, it remains challenging to identify structurally simple, chemically accessible synthetic molecules that are effective and safe as vaccine adjuvant. Here, we present cholicamideβ (6), a self-assembling small-molecule vaccine adjuvant with an improved toxicity profile and proven efficacy in vivo. We demonstrate that cholicamideβ (6), which is less cytotoxic than its parent compound, forms virus-like particles to potently activate dendritic cells with the concomitant secretion of cytokines. When combined with a peptide antigen, cholicamideβ (6) potentiated the antigen presentation on dendritic cells to induce antigen-specific T cells. As a therapeutic cancer vaccine adjuvant in mice, a mixture of cholicamideβ (6) and a peptide antigen protected mice from the challenges of malignant cancer cells without overt toxicity. Cholicamideβ (6) may offer a translational opportunity as an unprecedented class of small-molecule cancer vaccine adjuvants.

A retrospective multicenter study. Body mass index (BMI) is recognized as an important determinant of osteoporosis and spinal postoperative outcomes; however, the specific impact of BMI on surgery for osteoporotic vertebral fractures (OVFs) remains inconclusive. This retrospective multicenter study investigated the impact of BMI on clinical outcomes following fusion surgery for OVFs. 237 OVF patients (mean age, 74.3 years; 48 men and 189 women) with neurological symptoms who underwent spinal fusion were included in this study. Patients were grouped by World Health Organization BMI categories: low BMI (<18.5 kg/m2), normal BMI (≥18.5 and <25 kg/m2), and high BMI (≥25 kg/m2). Patients’ backgrounds, surgical method, radiological findings, pain measurements, activities of daily living (ADL), and postoperative complications were compared after a mean follow-up period of 4 years. As results, the proportion of patients able to walk independently was significantly smaller in the low BMI group (75.0%) compared with the normal BMI group (89.9%; P = .01) and the high BMI group (94.3%; P = .04). Improvement in the visual analogue scale for leg pain was significantly less in the low BMI group than the high BMI group (26.7 vs 42.8 mm; P = .046). Radiological evaluation, the Frankel classification, and postoperative complications were not significantly different among all 3 groups. Improvement of pain intensity and ADL in the high BMI group was equivalent or non-significantly better for some outcome measures compared with the normal BMI group. Leg pain and independent walking ability after fusion surgery for patients with OVFs improved less in the low versus the high BMI group. Surgeons may want to carefully evaluate at risk low BMI patients before fusion surgery for OVF because poor clinical results may occur.

Lung CD8+memory T cells play central roles in protective immunity to respiratory viruses, such as influenza A virus (IAV). Here, we find that alveolar macrophages (AMs) function as antigen-presenting cells that support the expansion of lung CD8+memory T cells. Intranasal antigen administration to mice subcutaneously immunized with antigen results in a rapid expansion of antigen-specific CD8+T cells in the lung, which is dependent on antigen cross-presentation by AMs. AMs highly express interleukin-18 (IL-18), which mediates subsequent formation of CD103+CD8+resident memory T (TRM) cells in the lung. In a mouse model of IAV infection, AMs are required for expansion of virus-specific CD8+T cells and CD103+CD8+TRMcells and inhibiting virus replication in the lungs during secondary infection. These results suggest that AMs instruct a rapid expansion of antigen-specific CD8+T cells in lung, which protect the host from respiratory virus infection.

Many people suffer from metal allergy, and the recently demonstrated presence of naturally occurring metal nanoparticles in our environment could present a new candidate for inducing metal allergy. Here, we show that mice pretreated with silver nanoparticles (nAg) and lipopolysaccharides, but not with the silver ions that are thought to cause allergies, developed allergic inflammation in response to the silver. nAg-induced acquired immune responses depended on CD4+T cells and elicited IL-17A-mediated inflammation, similar to that observed in human metal allergy. Nickel nanoparticles also caused sensitization in the mice, whereas gold and silica nanoparticles, which are minimally ionizable, did not. Quantitative analysis of the silver distribution suggested that small nAg (≤10 nm) transferred to the draining lymph node and released ions more readily than large nAg (>10 nm). These results suggest that metal nanoparticles served as ion carriers to enable metal sensitization. Our data demonstrate a potentially new trigger for metal allergy.

Oxidative stress has been reported to be involved in numerous human diseases, including musculoskeletal disorders such as osteoarthritis. However, the interaction between intervertebral disc (IVD) degeneration and oxidative stress is not well understood. The purpose of the present study was to elucidate the contribution of oxidative stress to IVD degeneration and the efficacy of antioxidant treatment for degenerative discs. The expression level of an oxidative stress marker, nitrotyrosine, was assessed by immunohistochemistry and Western blotting. For evaluating intracellular reactive oxygen species (ROS) levels and oxidative stress in rat annulus fibrosus (AF) cells, flow cytometry and luciferase assay with an OKD48 construct were performed. The grade of IVD degeneration was assessed by magnetic resonance imaging and histological analysis. A high frequency of nitrotyrosine-positive cells was observed in rat and human degenerative discs. mRNA expression of catabolic factors such as tumor necrosis factor-alpha (TNF-alpha), matrix metalloprotease-3 (MMP-3), and cyclooxygenase-2 (COX-2) was significantly induced by treatment with H2O2or buthionine sulfoximine, whereas that of aggrecan, an important chondrogenic proteoglycan, was reduced in a dose-dependent manner. Treatment with mitogen-activated protein kinase (MAPK) inhibitors blocked the inductive effect of excessive ROS on COX-2 mRNA expression. Western blotting confirmed the phosphorylation of MAPKs in H2O2and BSO-treated AF cells. Conversely, we showed that TNF-α induced oxidative stress with increased intracellular ROS levels in AF cells. Treatment with the antioxidant N-acetyl cysteine (NAC) abrogated the catabolic effect of excessive ROS and TNF-alpha in vitro. Finally, we showed that oral administration of NAC prevented IVD degeneration in rat degenerative model. A positive feedback loop was formed between excessive ROS and TNF-alpha in AF cells. Thus, oxidative stress contributes to the progression of IVD degeneration and NAC can be a therapeutic option for IVD degeneration.

Hydroxyapatite (HAp) is one of components of bone and teeth, and has an osteoconductivity. Thus, the HAp has been used as biomaterials for bone graftings. We have succeeded in development of the novel chelate-setting calcium-phosphate cement (CPC) using pure HAp particles surface-modified with inositol phosphate (IP6). While, biological apatite presented in bone and teeth of mammals contains various ions: Na+, K+, Mg2+, Cl-, F- and CO32-, in addition to Ca2+ and PO43- ions. In this work, in order to create the chelate-setting CPC with enhanced osteoconductivity, the above-mentioned biological apatite powder (hereafter, bone HAp), instead of pure HAp, was used as a starting powder for fabrication of the chelate-setting cement. The biocompatibility of the resulting chelate-setting bone HAp cement (hereafter, IP6-bone HAp cement) was examined using a rabbit’s tibia model. When the living reaction to hard tissue was histologically examined after 4 weeks implantation, we could observe that newly-formed bone directly bonded to the surface of the specimen. The newly-formed bone was also present around the cement specimen. The amounts of newly-formed bone around IP6-bone HAp cement was about 1.5 times those around IP6-pure HAp cement without bone minerals. The above findings demonstrate that the present IP6-bone HAp cements are one of the promising candidates as novel CPC with enhanced osteoconductivity.

Magnetic resonance imaging (MRI) findings of a tram-track appearance and celery stalk appearance in mucoid degeneration of the cruciate ligament are valuable; however, their pathological basis is unclear. Because these appearances are generally seen throughout the entire ligament, the association between MRI findings and pathological findings must be verified in specimens of the whole degenerated ligament, including the ligamentous attachments to bone. We herein report two cases of mucoid degeneration of the posterior cruciate ligament with osteoarthritis of the knee requiring total knee arthroplasty. The entire degenerated ligament, including the ligamentous attachments to bone, was removed and pathologically evaluated. On pathological examination, the central portion of the lesion showed typical mucoid degeneration, whereas the marginal and adherent portions showed normal ligament tissue, consistent with a tram-track appearance on T2-weighted MRI. The fibrous normal ligament tissues in the longitudinal direction in regions of mucoid degeneration were consistent with a celery stalk appearance on T2-weighted MRI. No mucoid degeneration was found in the attachment area. The tram-track appearance and celery stalk appearance of mucoid degeneration on MRI can be explained by the pathological findings.

The germinal center (GC) is a site where somatic hypermutation and clonal selection are coupled for antibody affinity maturation against infections. However, how GCs are formed and regulated is incompletely understood. Here, we identified an unexpected role of Tank-binding kinase-1 (TBK1) as a crucial B cell–intrinsic factor for GC formation. Using immunization and malaria infection models, we show that TBK1-deficient B cells failed to form GC despite normal Tfh cell differentiation, although some malaria-infected B cell–specific TBK1-deficient mice could survive by GC-independent mechanisms. Mechanistically, TBK1 phosphorylation elevates in B cells during GC differentiation and regulates the balance of IRF4/BCL6 expression by limiting CD40 and BCR activation through noncanonical NF-κB and AKTT308 signaling. In the absence of TBK1, CD40 and BCR signaling synergistically enhanced IRF4 expression in Pre-GC, leading to BCL6 suppression, and therefore failed to form GCs. As a result, memory B cells generated from TBK1-deficient B cells fail to confer sterile immunity upon reinfection, suggesting that TBK1 determines B cell fate to promote long-lasting humoral immunity.

Since the introduction of DNA vaccines two decades ago, this attractive strategy has been hampered by its low immunogenicity in humans. Studies conducted to improve the immunogenicity of DNA vaccines have shown that understanding the mechanism of action of DNA vaccines might be the key to successfully improving their immunogenicity. Our current understanding is that DNA vaccines induce innate and adaptive immune responses in two ways: (1) encoded protein (or polypeptide) antigen(s) by the DNA plasmid can be expressed in stromal cells (i.e., muscle cells) as well as DCs, where these antigens are processed and presented to naïve CD4 or CD8 T cells either by direct or cross presentation, respectively; and (2) the transfected DNA plasmid itself may bind to an un-identified cytosolic DNA sensor and activate the TBK1-STING pathway and the production of type I interferons (IFNs) which function as an adjuvant. Recent studies investigating double-stranded cytosolic DNA sensor(s) have highlighted new mechanisms in which cytosolic DNA may release secondary metabolites, which are in turn recognized by a novel DNA sensing machinery. Here, we discuss these new metabolites and the possibilities of translating this knowledge into improved immunogenicity for DNA vaccines.

A retrospective case series.

The SE36 antigen, derived from serine repeat antigen 5 (SERA5) of Plasmodium falciparum, is a promising blood stage malaria vaccine candidate. Ongoing clinical trials suggest the efficacy of the SE36 vaccine could be increased by the incorporation of more effective adjuvants into the vaccine formulation. In this study, we assessed the safety, immunogenicity and protective efficacy of SE36/AHG formulated with TLR9 ligand adjuvants K3 CpG oligodeoxyribonucleotides (CpG ODNs) (K3 ODN), D3 ODN or synthetic hemozoin, in two non-human primate models. SE36/AHG with or without each adjuvant was administrated to cynomolgus monkeys. A combination of TLR9 ligand adjuvant with SE36/AHG induced higher humoral and cellular immune response compared with SE36/AHG alone. Administration of a crude extract of P. falciparumparasite resulted in the induction of more SE36-specific IgG antibodies in monkeys vaccinated with a combination of SE36/AHG and adjuvant, as opposed to vaccination with SE36/AHG alone. The most effective TLR9 ligand, K3 ODN, was chosen for further vaccine trials in squirrel monkeys, in combination with SE36/AHG. All monkeys immunized with the combined SE36/AHG and K3 ODN formulation effectively suppressed parasitemia and symptoms of malaria following challenge infections. Furthermore, no serious adverse events were observed. Our results show that the novel vaccine formulation of K3 ODN with SE36/AHG demonstrates safety, potent immunogenicity and efficacy in nonhuman primates, and this vaccine formulation may form the basis of a more effective malaria vaccine.

We have developed novel calcium-phosphate cements (CPCs) based on the chelate-setting mechanism of inositol phosphate (IP6) using hydroxyapatite (HAp), β-tricalcium phosphate (β-TCP) and α-TCP as starting materials. These cements (IP6-HAp, IP6-β-TCP and IP6-α-TCP cements) have different bioresorbability due to the chemical composition of starting materials. In the present study, biocompatibility and bioresorbability of the above three cements and commercially available cement (Biopex®-R) was histologically evaluated in vivo using rabbit model for 4, 8, and 24 weeks, in addition to their dissolution in vitro. The dissolution of these cements increased in the order of IP6-HAp, IP6-β-TCP and IP6-α-TCP cements. The newly-formed bones were directly in contact with both the IP6-HAp and Biopex®-R cement specimens. As for the IP6-β-TCP and IP6-α-TCP cements, newly-formed bones were formed time-dependently slightly apart from the cement specimens. Resorption rate for Biopex®-R, IP6-HAp, IP6-β-TCP, and IP6-α-TCP cements after 24 weeks implantation were of 7.2, 5.0, 13.7, and 16.2%, respectively, compared to original cements. The present chelate-setting cements with different bioresorbability are promising candidates for application as the novel CPCs.

Despite numerous articles on the use of artificial nerve conduits, autologous nerve transplants remain the most effective for nerve repair. To improve this technique, the authors examined conduits containing gelatin hydrogel as a carrier enabling the sustained release of basic fibroblast growth factor (bFGF).

DNA vaccines can induce both humoral and cellular immune responses in animals. Some DNA vaccines are already licensed for infectious diseases such as West Nile virus encephalitis in horses. When used in humans, however, DNA vaccines suffer from lower immunogenicity profiles. Although the reasons for this are poorly understood, various hypotheses have been proposed. This review aims to provide better understanding of the molecular and immunological mechanisms by which DNA vaccines work and how such knowledge can be used to bring about improvements in their efficacy. Recent studies have provided evidence that the ‘adjuvant effect’ of plasmid DNA is mediated by its doublestranded structure. This structure activates stimulator of interferon genes/TANK-binding kinase 1 (STING/TBK1)- dependent innate immune signaling pathways in the absence of Toll-like receptors. Indeed, type-I interferons (IFNs), induced in vivo via the STING/TBK1 pathway, were found to be crucial for both direct- and indirect-antigen presentation via distinct cell types (i.e. dendritic cells (DC) and muscle cells, respectively). Importantly, incorporation of TBK1 into a DNA vaccine was found to enhance the antigen-specific humoral immune responses targeting the Plasmodium falciparum serine repeat antigen (SERA), a candidate vaccine antigen expressed in the blood-stages of human malaria parasites. Thus, the results of these studies may offer new ways to develop DNA vaccines, as well as delivering novel vaccine adjuvants against infectious diseases.

Osteomyelitis remains a serious problem in the orthopedic field. There are only a few animal models in which the quantity and distribution of bacteria can be reproducibly traced. Here, we established a real-time quantitative mouse model of osteomyelitis using bioluminescence imaging (BLI) without sacrificing the animals. A bioluminescent strain of Staphylococcus aureus was inoculated into the femurs of mice. The bacterial photon intensity (PI) was then sequentially measured by BLI. Serological and histological analyses of the mice were performed. The mean PI peaked at 3 days, and stable signals were maintained for over 3 months after inoculation. The serum levels of interleukin-6, interleukin-1β, and C-reactive protein were significantly higher in the infected mice than in the control mice on day 7. The serum monocyte chemotactic protein 1 level was also significantly higher in the infected group at 12 h than in the control group. A significantly higher proportion of granulocytes was detected in the peripheral blood of the infected group after day 7. Additionally, both acute and chronic histological manifestations were observed in the infected group. This model is useful for elucidating the pathophysiology of both acute and chronic osteomyelitis and to assess the effects of novel antibiotics or antibacterial implants.