Issues with infectious disease vaccine introduction into routine vaccination in Japan, and considerations for accelerating the process.

Routine vaccinations help prevent the outbreak and spread of infectious diseases; however, it can take up to ten years from vaccine approval to introduction into routine vaccination schedules in Japan. Here, we investigate the information required to introduce an approved vaccine into routine vaccination schedules and the reasons why it takes so long. Based on the published data of the Immunization and Vaccine Committee of the Health Science Council, we set out to explore ways to facilitate discussion on this topic. The following issues were identified as discussion points: disease burden, efficacy and safety, and cost-effectiveness. Until now, epidemiological information has been used to evaluate the efficacy of vaccines, and also to evaluate the safety in the presence of notable adverse reactions. However, in some cases, it took a long time to obtain epidemiological information regarding the frequency of rare but serious adverse reactions and the need for a booster dose. Given the risk of spreading infectious diseases due to delays in decision-making, vaccines may have to be introduced into routine vaccination schedules based on the results of clinical trials that can be obtained in a relatively short period. In contrast, epidemiological information is necessary to evaluate the disease burden, frequency of adverse reactions, and the necessity of booster doses. Therefore, developing an epidemiological information collection system is urgently required.

Proposal for the revision of guidelines for clinical trials of vaccines to prevent infectious diseases in Japan.

The development of vaccines against infectious diseases requires a different approach from that of therapeutics, because vaccines are inoculated into healthy individuals and have a preventive effect by activating the immunity of the inoculated human. In Japan, "The Guideline for Clinical Trials of Vaccines for the Prevention of Infectious Diseases" was published in 2010 before changes occurred in the vaccine development environment in Japan, such as the introductions of foreign vaccines and simultaneous global development. This study aimed to identify current challenges in vaccine development through a questionnaire-based survey of pharmaceutical companies in Japan and by comparing the domestic and international guidelines and surveying review reports of 35 vaccines approved in Japan between April 2010 and December 2020. Identified challenges included the requirement for protective efficacy trials, efficacy evaluation of combination vaccines, development of multiregional and foreign clinical trials, and immunization of older adults and immunocompromised patients. We propose that new vaccines against infectious diseases should be evaluated for the protective efficacy, preferably through multiregional clinical trials. Additionally, differences in the incidence of infectious diseases or in epidemic virus strains between regions may affect the trials, when multiregional clinical trials are conducted, but immunogenicity-based studies can be conducted if a correlation between protective efficacy and immunogenicity has been established. We suggest that licensed combination vaccines can be used as comparators when an antigen is added to a licensed combination vaccine. We also proposed that the efficacy of a vaccine in non-major subjects, such as older adults or immunocompromised patients could be evaluated by comparing immunogenicity in major subjects with the confirmed protective effects of the vaccine. It is expected that these revisions will lead to the rapid advancement of vaccine development, which should contribute to the improvement of public health.

Proposal for the revision of the guidelines for Non-clinical studies of vaccines for the prevention of infectious diseases in Japan.

The efficacy and safety of vaccines for the prevention of infectious diseases are mostly evaluated based on the induction of an immune response against antigens, and do not necessarily depend on the dose administered. Therefore, there are some specific aspects that need to be considered in the development of vaccines and have been described in "The Guidelines for the non-clinical studies of vaccines for the prevention of infectious disease" in Japan. Recent changes in the vaccine development field, such as the introduction of vaccines developed overseas in Japan and vaccine development on a global scale have increased the need for revision of these guidelines. In this study, we identified the current challenges in the development of vaccines through comparison of Japanese and international guidelines. We conducted a questionnaire-based survey of pharmaceutical industries in Japan, and found issues related to non-clinical studies, such as the necessity of safety pharmacology studies and repeated-dose toxicity studies for each route of administration. We examined international guidelines on these issues as well as review reports by regulatory authorities, and determined that the results of repeated-dose toxicity studies can be used to decide whether safety pharmacology studies are required, and that studies to evaluate toxicity due to systemic effects may not be necessary for both intramuscular and subcutaneous administration. We propose revision of the guidelines for the non-clinical studies of vaccines in Japan taking international harmonizaion into account. We expected that the revised guidelines will promote smooth and rational vaccine development.

Tactile Evaluation Feedback System for Multi-Layered Structure Inspired by Human Tactile Perception Mechanism.

Tactile sensation is one type of valuable feedback in evaluating a product. Conventionally, sensory evaluation is used to get direct subjective responses from the consumers, in order to improve the product's quality. However, this method is a time-consuming and costly process. Therefore, this paper proposes a novel tactile evaluation system that can give tactile feedback from a sensor's output. The main concept of this system is hierarchically layering the tactile sensation, which is inspired by the flow of human perception. The tactile sensation is classified from low-order of tactile sensation (LTS) to high-order of tactile sensation (HTS), and also to preference. Here, LTS will be correlated with physical measures. Furthermore, the physical measures that are used to correlate with LTS are selected based on four main aspects of haptic information (roughness, compliance, coldness, and slipperiness), which are perceived through human tactile sensors. By using statistical analysis, the correlation between each hierarchy was obtained, and the preference was derived in terms of physical measures. A verification test was conducted by using unknown samples to determine the reliability of the system. The results showed that the system developed was capable of estimating preference with an accuracy of approximately 80%.

Repair of cervical esophageal perforation using longus colli muscle flap: a case report of a patient with cervical spinal cord injury.

BACKGROUND CONTEXT: Perforation of the esophagus after anterior cervical spine surgery is a rare, but well-recognized complication. The management of esophageal perforation is controversial, and either nonoperative or operative treatment can be selected. PURPOSE: Several reports have described the use of a sternocleidomastoid muscle flap for esophageal repair. In this case report, we describe a longus colli muscle flap as a substitute for a sternocleidomastoid flap in a patient with an esophageal perforation. STUDY DESIGN: Case report. PATIENT SAMPLE: A 20-year-old man sustained cervical spinal cord injury, on diving and hitting his head against the bottom of a pool. A C6 burst fracture was observed with posterior displacement of a bone fragment into the spinal canal. The patient exhibited complete paralysis below the C8 spinal segment level. METHODS: The patient underwent subtotal corpectomy of the sixth cervical vertebra with the iliac bone graft and augmented posterior spinal fixation (C5-7) with pedicle screws. After the primary operation, the patient showed signs of infection such as throat pain, a high fever, and osteolytic change of the grafted bone by cervical radiograph. A second operation was performed to replace the graft bone using fibula. On the day after the operation, food residue was confirmed in the suction drainage tube, suggesting esophagus perforation. A third operation was immediately performed to confirm and treat esophagus perforation, although apparent esophageal perforation could not be detected at the second operation. Because the erosion around the perforation of the esophageal posterior wall was extensive, a longus colli muscle flap transposition was accordingly performed into the interspace between the esophageal posterior wall and the grafted bone in addition to simple suturing of the perforation. RESULTS: Neither high fever nor pharyngeal pain has recurred at latest follow-up, 5 years after surgery. CONCLUSIONS: To the best of our knowledge, this is the first report concerning the use of a longus colli muscle flap for esophageal perforation after anterior cervical spine surgery.

Surgical strategy for cervical myelopathy due to ossification of the posterior longitudinal ligament: Part 1: Clinical results and limitations of laminoplasty.

STUDY DESIGN: Retrospective study of 66 patients who underwent laminoplasty for treatment of cervical myelopathy due to ossification of the posterior longitudinal ligament (OPLL). OBJECTIVES: The present study describes surgical results of laminoplasty for treatment of cervical myelopathy due to OPLL and aims to clarify 1) factors predicting outcome and 2) limitations of laminoplasty. SUMMARY OF BACKGROUND DATA: During the period 1986 and 1996, laminoplasty was the only surgical treatment selected for cervical myelopathy at our institutions. METHODS: We reviewed data obtained in 66 patients who underwent laminoplasty for treatment of cervical myelopathy due to OPLL. Mean duration of follow-up was 10.2 years (range, 5-20 years). Surgical outcomes were assessed using the Japanese Orthopaedic Association (JOA) scoring system for cervical myelopathy. RESULTS: Surgical outcome was significantly poorer in patients with occupying ratio greater than 60%. Multiple regression analysis showed that the most significant predictor of poor outcome after laminoplasty was hill-shaped ossification, followed by lower preoperative JOA score, postoperative change in cervical alignment, and older age at surgery. CONCLUSIONS: Laminoplasty is effective and safe for most patients with occupying ratio of OPLL less than 60% and plateau-shaped ossification. However, neurologic outcome of laminoplasty for cervical OPLL was poor or fair in patients with occupying ratio greater than 60% and/or hill-shaped ossification.

Surgical strategy for cervical myelopathy due to ossification of the posterior longitudinal ligament: Part 2: Advantages of anterior decompression and fusion over laminoplasty.

STUDY DESIGN: Retrospective study of 27 patients who underwent anterior decompression and fusion (ADF) for treatment of cervical myelopathy due to ossification of the posterior longitudinal ligament (OPLL). OBJECTIVES: To compare surgical outcome of ADF with that of laminoplasty. SUMMARY OF BACKGROUND DATA: During the period 1986 and 1996, laminoplasty was the only surgical treatment selected for cervical myelopathy at our institutions. According to surgical results of laminoplasty performed during this period, we have performed either laminoplasty or ADF for patients with OPLL since 1996. METHODS: We reviewed clinical data obtained in 27 patients who underwent ADF between 1996 and 2003. Mean duration of follow-up was 6.0 years (range, 2-10 years). Surgical outcomes were assessed using the Japanese Orthopedic Association (JOA) scoring system for cervical myelopathy. Surgical results of ADF were compared with those of laminoplasty, which was performed in 66 patients during the period 1986 and 1996. RESULTS: ADF yielded a better neurologic outcome at final follow-up than laminoplasty in patients with occupying ratio > or =60%, although graft complications occurred in 15% and additional surgical intervention was required in 26%. Neither occupying ratio of OPLL, sagittal shape of ossification, nor cervical alignment was found to be related to surgical outcome of ADF. CONCLUSIONS: Although ADF is technically demanding and has a higher incidence of surgery-related complications, it is preferable to laminoplasty for patients with occupying ratio of OPLL > or =60%.

Large cell neuroendocrine carcinoma of the uterine cervix with cytogenetic analysis by comparative genomic hybridization: a case study.

Large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is a newly introduced category of the revised World Health Organization classification. We reported a case of cervical LCNEC with cytogenetic analysis by comparative genomic hybridization (CGH). The cervical tumor showed moderately increased mitotic activity (8-14 mitotic figures per 10 high-power fields) and focal necrosis, which made it problematic to differentiate from atypical carcinoid. CGH analysis failed to detect chromosome 11q loss that has been reported to be characteristic of pulmonary atypical carcinoids. Furthermore, chromosome 3q amplification, which has been detected frequently in pulmonary small cell carcinomas and LCNECs but not in pulmonary typical and atypical carcinoids, was the most remarkable chromosomal aberration. Although CGH reports are extremely rare in neuroendocrine tumors of the uterine cervix, specific chromosomal aberrations may be useful in their distinction.

Risk factors for adjacent segment degeneration after PLIF.

STUDY DESIGN: A retrospective study of 87 patients who underwent posterior lumbar interbody fusion (PLIF) at L4-L5 for L4 degenerative spondylolisthesis. OBJECTIVE: To clarify: 1) the correlation between radiologic degeneration of cranial adjacent segment and clinical results, 2) risk factors for radiologic degeneration of cranial adjacent segment, and 3) preoperative radiologic features of patients who underwent additional surgery with cranial adjacent segment degeneration. SUMMARY OF BACKGROUND DATA: Whereas PLIF with pedicle screw fixation has shown satisfactory clinical results, a solid fusion has been reported to accelerate a degenerative change at unfused adjacent levels, especially in the cranial level. Although several authors have reported the adjacent segment degeneration after PLIF, there are no previous reports of risk factors for adjacent segment degeneration after PLIF. MATERIALS AND METHODS: Eighty-seven patients who underwent PLIF for L4 degenerative spondylolisthesis and could be followed for at least 2 years were included in this study. We measured lumbar lordosis, scoliosis, laminar inclination angle at L3, facet sagittalization at L3-L4, facet tropism at L3-L4, preexisting disc degeneration at L3-L4, and lordosis at the fused segment. Progression of L3-L4 segment degeneration was defined as a condition in which disc narrowing, posterior opening, and progress of slippage in comparison with preoperative dynamic lateral radiographs. Patients were divided into three groups according to postoperative progression of L3-L4 degeneration: Group 1 with neither progression of L3-L4 degeneration nor neurologic deterioration, Group 2 with progression of L3-L4 degeneration but no neurologic deterioration, and Group 3 with an additional surgery required for neurologic deterioration. Correlation between clinical results and radiologic progression of L3-L4 degeneration, and risk factors for progression of radiologic degeneration were investigated. Further, preoperative radiologic features of Group 3 were studied to detect risk factors for clinical deterioration. RESULTS: There were 58 (67%) patients classified into Group 1, 25 (29%) patients into Group 2, and 4 (4%) patients into Group 3. There was no significant difference in average age in each group. No obvious difference was observed in recovery rate between Groups 1 and 2. Laminar inclination angle and facet tropism in Group 3 were more significant than those in Groups 1 and 2. Further, apparent lamina inclination and facet tropism coexisted in Group 3. There were no obvious differences in other factors between each group. CONCLUSION: 1) There was no correlation between radiologic degeneration of cranial adjacent segment and clinical results. 2) Risk factors for postoperative radiologic degeneration could not be detected in terms of each preoperative radiologic factor. 3) Coexistence of horizontalization of the lamina at L3 and facet tropism at L3-L4 may be one of the risk factors for neurologic deterioration resulting from accelerated L3-L4 degenerative change after L4-L5 PLIF.

Mechanical stress-induced apoptosis of endplate chondrocytes in organ-cultured mouse intervertebral discs: an ex vivo study.

STUDY DESIGN: Various amounts of static mechanical load were applied to mouse intervertebral discs in organ cultures. The apoptosis then was examined using nick end labeling. Two mitogen-activated protein kinase (MAPK) inhibitors were added to the medium. OBJECTIVES: To establish an experimental model for detecting factors regulating chondrocyte apoptosis induced by mechanical stress, and to determine the role of MAPK and p38 in the stress-induced apoptotic pathway of endplate chondrocytes. SUMMARY OF BACKGROUND DATA: The cause of degenerative change in the cartilaginous endplate (CEP) remains unclear. The authors' previous findings using a mouse model suggested that apoptosis in the cartilaginous endplate may play a role in intervertebral disc degeneration, and that mechanical stress may induce apoptosis. If apoptosis of endplate chondrocytes is involved in the cascade of intervertebral disc degeneration, then how apoptosis is induced by mechanical stress should be important in preventing disc degeneration. However, the mechanism of apoptosis induced by mechanical stress remains unclear. METHODS: Mouse coccygeal discs were harvested and organ cultured. Various static compression loads (0, 0.2, 0.4, 0.8, and 1.0 MPa) were applied on intervertebral discs placed in culture bottles for 24 hours. Paraffin-embedded sections of the harvested discs were stained using Safranin-O and the nick end labeling procedure. The apoptotic cells were counted in the cartilaginous endplate and junctional anulus fibrosus of each intervertebral disc. In addition, U0126 (MAPK inhibitor) and SB202190 (p38 inhibitor) were added to the culture medium to determine their regulatory roles in the apoptosis of endplate chondrocytes induced by mechanical load. RESULTS: Histologically, loaded discs became bulged, and the disc space became narrow. Apoptosis was absent in discs without load, but was particularly noticeable in loaded discs (load weight, 1.0 MPa). The number of apoptotic cells increased depending on the weight of the load. The two MAPK inhibitors significantly increased the number of apoptotic cells. CONCLUSIONS: Chondrocyte apoptosis was induced using a static mechanical load especially in the cartilaginous endplate in an organ culture. Apoptosis occurred similarly to previous findings using an in vivo model. This culture system thus reflected the apoptosis demonstrated in vivo. Because biologically active reagents such as MAPK inhibitors can be simply added to culture media, this system may be a useful method for detecting factors that influence apoptosis induced by mechanical stress. Both MAPK inhibitors increased the occurrence of apoptosis. This suggests that these two MAPKs can counteract the apoptotic pathway induced by mechanical stress.