Monitoring the COVID-19 immune landscape in Japan

[Objectives] COVID-19 vaccination in Japan started on February 17, 2021. Because the timing of vaccination and the risk of severe COVID-19 greatly varied with age, the present study aimed to monitor the age-specific fractions of the population who were immune to SARS-CoV-2 infection after vaccination. [Methods] Natural infection remained extremely rare, accounting for less than 5% of the population by the end of 2021; thus, we ignored natural infection-induced immunity and focused on vaccine-induced immunity. We estimated the fraction of the population immune to infection by age group using vaccination registry data from February 17, 2021, to October 17, 2021. We accounted for two important sources of delay: (i) reporting delay and (ii) time from vaccination until immune protection develops. [Results] At the end of the observation period, the proportion of individuals still susceptible to SARS-CoV-2 infection substantially varied by age and was estimated to be ≥90% among people aged 0–14 years, in contrast to approximately 20% among the population aged ≥65 years. We also estimated the effective reproduction number over time using a next-generation matrix while accounting for differences in the proportion immune to infection by age. [Conclusion] The COVID-19 immune landscape greatly varied by age, and a substantial proportion of young adults remained susceptible. Vaccination contributed to a marked decrease in the reproduction number

Evidence for the tonic inhibition of spinal pain by nicotinic cholinergic transmission through primary afferents

<p>Abstract</p> <p>Background</p> <p>We have proposed that nerve injury-specific loss of spinal tonic cholinergic inhibition may play a role in the analgesic effects of nicotinic acetylcholine receptor (nAChR) agonists on neuropathic pain. However, the tonic cholinergic inhibition of pain remains to be well characterized.</p> <p>Results</p> <p>Here, we show that choline acetyltransferase (ChAT) signals were localized not only in outer dorsal horn fibers (lamina I–III) and motor neurons in the spinal cord, but also in the vast majority of neurons in the dorsal root ganglion (DRG). When mice were treated with an antisense oligodeoxynucleotide (AS-ODN) against ChAT, which decreased ChAT signals in the dorsal horn and DRG, but not in motor neurons, they showed a significant decrease in nociceptive thresholds in paw pressure and thermal paw withdrawal tests. Furthermore, in a novel electrical stimulation-induced paw withdrawal (EPW) test, the thresholds for stimulation through C-, Aδ- and Aβ-fibers were all decreased by AS-ODN-pretreatments. The administration of nicotine (10 nmol i.t.) induced a recovery of the nociceptive thresholds, decreased by the AS-ODN, in the mechanical, thermal and EPW tests. However, nicotine had no effects in control mice or treated with a mismatch scramble (MS)-ODN in all of these nociception tests.</p> <p>Conclusion</p> <p>These findings suggest that primary afferent cholinergic neurons produce tonic inhibition of spinal pain through nAChR activation, and that intrathecal administration of nicotine rescues the loss of tonic cholinergic inhibition.</p

Involvement of LPA1 receptor signaling in the reorganization of spinal input through Abeta-fibers in mice with partial sciatic nerve injury

Lysophosphatidic acid receptor subtype LPA1 is crucial for the initiation of neuropathic pain and underlying changes, such as up-regulation of Ca2+ channel α2δ-1 subunit in dorsal root ganglia (DRG), up-regulation of PKCγ in the spinal dorsal horn, and demyelination of dorsal root fibers. In the present study, we further examined the involvement of LPA1 signaling in the reorganization of Aβ-fiber-mediated spinal transmission, which is presumed to underlie neuropathic allodynia. Following nerve injury, the phosphorylation of extracellular-signal regulated kinase (pERK) by Aβ-fiber stimulation was observed in the superficial layer of spinal dorsal horn, where nociceptive C- or Aδ-fibers are innervated, but not in sham-operated wild-type mice. However, the pERK signals were largely abolished in LPA1 receptor knock-out (Lpar1-/-) mice, further supported by quantitative analyses of pERK-positive cells. These results suggest that LPA1 receptor-mediated signaling mechanisms also participate in functional cross-talk between Aβ- and C- or Aδ-fibers

Pharmacological switch in Aβ-fiber stimulation-induced spinal transmission in mice with partial sciatic nerve injury

<p>Abstract</p> <p>Background</p> <p>We have previously demonstrated that different spinal transmissions are involved in the nociceptive behavior caused by electrical stimulation of Aβ-, Aδ- or C-fibers using a Neurometer^®in naïve mice. In this study, we attempted to pharmacologically characterize the alteration in spinal transmission induced by partial sciatic nerve injury in terms of nociceptive behavior and phosphorylation of extracellular signal-regulated kinase (pERK) in the spinal dorsal horn.</p> <p>Results</p> <p>Aβ-fiber responses (2000-Hz), which were selectively blocked by the AMPA/kainate antagonist CNQX in naïve mice, were hypersensitized but blocked by the NMDA receptor antagonists MK-801 and AP-5 in injured mice in an electrical stimulation-induced paw withdrawal (EPW) test. Although Aδ-fiber responses (250-Hz) were also hypersensitized by nerve injury, there was no change in the pharmacological characteristics of Aδ-fiber responses through NMDA receptors. On the contrary, C-fiber responses (5-Hz) were hyposensitized by nerve injury. Moreover, Aδ- and C-, but not Aβ-fiber stimulations significantly increased the number of pERK-positive neurons in the superficial spinal dorsal horns of naïve mice, and corresponding antagonists used in the EPW test inhibited this increase. In mice with nerve injury, Aβ- as well as Aδ-fiber stimulations significantly increased the number of pERK-positive neurons in the superficial spinal dorsal horn, whereas C-fiber stimulation decreased this number. The nerve injury-specific pERK increase induced by Aβ-stimulation was inhibited by MK-801 and AP-5, but not by CNQX. However, Aβ- and Aδ-stimulations did not affect the number or size of pERK-positive neurons in the dorsal root ganglion, whereas C-fiber-stimulation selectively decreased the number of pERK-positive neurons.</p> <p>Conclusion</p> <p>These results suggest that Aβ-fiber perception is newly transmitted to spinal neurons, which originally receive only Aδ- and C-fiber-mediated pain transmission, through NMDA receptor-mediated mechanisms, in animals with nerve injury. This pharmacological switch in Aβ-fiber spinal transmission could be a mechanism underlying neuropathic allodynia.</p

Characterization of three different sensory fibers by use of neonatal capsaicin treatment, spinal antagonism and a novel electrical stimulation-induced paw flexion test

In the present study, we first report an in vivo characterization of flexor responses induced by three distinct sine-wave stimuli in the electrical stimulation-induced paw flexion (EPF) test in mice. The fixed sine-wave electric stimulations of 5 Hz (C-fiber), 250 Hz (Aδ-fiber) and 2000 Hz (Aβ-fiber) to the hind paw of mice induced a paw-flexion response and vocalization. The average threshold for paw flexor responses by sine-wave stimulations was much lower than that for vocalization. Neonatally (P3) pretreatment with capsaicin to degenerate polymodal substance P-ergic C-fiber neurons increased the threshold to 5 Hz (C-fiber) stimuli, but not to 250 Hz (Aδ-fiber) and 2000 Hz (Aβ-fiber). The flexor responses to 5 Hz stimuli were significantly blocked by intrathecal (i.t.) pretreatment with both CP-99994 and MK-801, an NK1 and NMDA receptor antagonist, respectively, but not by CNQX, an AMPA/kainate receptor antagonist. On the other hand, the flexor responses induced by 250 Hz stimuli were blocked by MK-801 (i.t.) but not by CP-99994 or CNQX. In contrast, flexor responses induced by 2000 Hz stimuli were only blocked by CNQX treatment. These data suggest that we have identified three pharmacologically different categories of responses mediated through different primary afferent fibers. Furthermore, we also carried out characterization of the in vivo functional sensitivity of each of the sensory fiber types in nerve-injured mice using the EPF test, and found that the threshold to both 250 Hz and 2000 Hz stimulations were markedly decreased, whereas the threshold to 5 Hz stimulations was significantly increased. Thus we found opposing effects on specific sensory fiber-mediated responses as a result of nerve injury in mice. These results also suggest that the EPF analysis is useful for the evaluation of plasticity in sensory functions in animal disease models

Detail Measurement of Pre-Prandial and Post-Prandial Blood Glucose during Imeglimin (Twymeeg) Treatment

Background: Among oral hypoglycemic agents (OHAs), imeglimin (Twymeeg) would be in focus. Case Presentation: The patient in this case is a 58-year-old female with a history of obesity and previous operations for posterior longitudinal ligament ossification. In early September 2022, she developed dizziness and a general feeling of unwellness, leading to a diagnosis of Type 2 Diabetes (T2D) with an HbA1c level of 11.1%. Result: The patient was treated with a low carbohydrate diet (LCD) and Twymeeg, resulting in a significant decrease in HbA1c levels from 11.1% to 9.0%, 6.7%, and 5.9% over the course of three months. Pre-prandial and post-prandial blood glucose levels were measured with great accuracy. Discussion and Conclusion: The administration of Twymeeg was found to be effective in reducing the patient's HbA1c levels, and the relationship between HbA1c and glucose variability could be further investigated based on these results

A Case of Bilateral Adrenal and Pleural Metastases from Prostate Cancer

Our case was 65 years old. At check-up, a high PSA level of 515 ng/ml was observed, the patient was diagnosed with having clinical stage D prostate cancer and a Maximum Androgen Blockade (MAB therapy) was started. In response to the exacerbated prostate cancer, we started a therapy involving the administration of 8 mg/kg body weight of dexamethasone and 55 mg/m2 of docetaxel every 3 weeks. After completing 8 courses, an enlargement of the bilateral adrenal tumor was observed, and after completing 12 courses, a pleural tumor was discovered and the PSA level was also increased. The patient was therefore diagnosed with having bilateral adrenal metastasis and pleural metastasis of prostate cancer through diagnostic imaging. So far, there have been no reports of multiple occurrences of prostate cancer in the adrenal glands and the pleura, thus making this case the first such case

Absence of Radial Spokes in Mouse Node Cilia Is Required for Rotational Movement but Confers Ultrastructural Instability as a Trade-Off

SummaryDetermination of left-right asymmetry in mouse embryos is established by a leftward fluid flow that is generated by clockwise rotation of node cilia. How node cilia achieve stable unidirectional rotation has remained unknown, however. Here we show that brief exposure to the microtubule-stabilizing drug paclitaxel (Taxol) induces randomly directed rotation and changes the ultrastructure of node cilia. In vivo observations and a computer simulation revealed that a regular 9+0 arrangement of doublet microtubules is essential for stable unidirectional rotation of node cilia. The 9+2 motile cilia of the airway, which manifest planar beating, are resistant to Taxol treatment. However, the airway cilia of mice lacking the radial spoke head protein Rsph4a undergo rotational movement instead of planar beating, are prone to microtubule rearrangement, and are sensitive to Taxol. Our results suggest that the absence of radial spokes allows node cilia to rotate unidirectionally but, as a trade-off, renders them ultrastructurally fragile

Bilateral herpes simplex keratitis in a patient with chronic graft-versus-host disease

Takahiko Hayashi1, Misaki Ishioka2, Norihiko Ito1, Yoko Kato1, Hisashi Nakagawa3, Hiroshi Hatano4, Nobuhisa Mizuki11Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan; 2Ryogoku Eye Clinic, Tokyo, Japan; 3Tokushima Eye Clinic, Higashimurayama-shi, Tokyo, Japan; 4Lumine Hatano Eye Clinic, Fujisawa, Fujisawa-shi, Kanagawa, JapanPurpose: To describe a case of bilateral herpes simplex keratitis accompanying chronic graft-versus-host disease (GVHD).Design: Observational case report.Case report: An 11-year-old boy with myelocytic leukemia underwent allogeneic bone marrow transplantation. He developed symptoms of the skin, eyes, and mouth, and lip biopsy indicated chronic GVHD. Persistent keratitis with corneal filaments and neovascularization was noted in both eyes. Sodium hyaluronate, autoserum, and 0.1% fluorometholone eyedrops were instilled for approximately 2 years to treat this keratitis, and there were no other ocular changes. Bilateral herpes simplex keratitis developed with geographic ulcers after topical betamethasone therapy, but responded to acyclovir ointment.Conclusions: Herpes keratitis should be considered in the differential diagnosis of bilateral keratitis in patients with reduced immunocompetence. During the course of chronic GVHD, corneal herpes may occur, so ocular treatment with topical corticosteroids should be managed by an ophthalmologist to monitor sight-threatening conditions such as corneal herpes.Keywords: chronic graft-versus-host disease, bone marrow transplant, corneal herpes, bilateral herpes simplex keratitis, dry eye

Number of averted COVID-19 cases and deaths attributable to reduced risk in vaccinated individuals in Japan

Background: In Japan, vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initiated on 17 February 2021, mainly using messenger RNA vaccines and prioritizing health care professionals. Whereas nationwide vaccination alleviated the coronavirus disease 2019 (COVID-19)-related burden, the population impact has yet to be quantified in Japan. We aimed to estimate the numbers of COVID-19 cases and deaths prevented that were attributable to the reduced risk among vaccinated individuals via a statistical modeling framework. Methods: We analyzed confirmed cases registered in the Health Center Real-time Information-sharing System on COVID-19 (3 March–30 November 2021) and publicly reported COVID-19-related deaths (24 March–30 November 2021). The vaccination coverage over this time course, classified by age and sex, was extracted from vaccine registration systems. The total numbers of prevented cases and deaths were calculated by multiplying the daily risk differences between unvaccinated and vaccinated individuals by the population size of vaccinated individuals. Findings: For both cases and deaths, the averted numbers were estimated to be the highest among individuals aged 65 years and older. In total, we estimated that 564, 596 (95% confidence interval: 477, 020–657, 525) COVID-19 cases and 18, 622 (95% confidence interval: 6522–33, 762) deaths associated with SARS-CoV-2 infection were prevented owing to vaccination during the analysis period (i.e., fifth epidemic wave, caused mainly by the Delta variant). Female individuals were more likely to be protected from infection following vaccination than male individuals whereas more deaths were prevented in male than in female individuals. Interpretation: The vaccination program in Japan led to substantial reductions in the numbers of COVID-19 cases and deaths (33% and 67%, respectively). The preventive effect will be further amplified during future pandemic waves caused by variants with shared antigenicity. Funding: This project was supported by the Japan Science and Technology Agency; the Japan Agency for Medical Research and Development; the Japan Society for the Promotion of Science; and the Ministry of Health, Labour and Welfare