Efficacy and safety of single-dose ivermectin in mild-to-moderate COVID-19: the double-blind, randomized, placebo-controlled CORVETTE-01 trial

BackgroundTo investigate whether ivermectin inhibits SARS-CoV-2 proliferation in patients with mild-to-moderate COVID-19 using time to a negative COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) test.MethodsCORVETTE-01 was a double-blind, randomized, placebo-controlled study (August 2020–October 2021) conducted in Japan. Overall, 248 patients diagnosed with COVID-19 using RT-PCR were assessed for eligibility. A single oral dose of ivermectin (200  μg/kg) or placebo was administered under fasting. The primary outcome was time to a negative COVID-19 RT-PCR test result for SARS-CoV-2 nucleic acid, assessed using stratified log-rank test and Cox regression models.ResultsOverall, 112 and 109 patients were randomized to ivermectin and placebo, respectively; 106 patients from each group were included in the full analysis set (male [%], mean age: 68.9%, 47.9 years [ivermectin]; 62.3%, 47.5 years [placebo]). No significant difference was observed in the occurrence of negative RT-PCR tests between the groups (hazard ratio, 0.96; 95% confidence interval [CI] 0.70–1.32; p = 0.785). Median (95% CI) time to a negative RT-PCR test was 14.0 (13.0–16.0) and 14.0 (12.0–16.0) days for ivermectin and placebo, respectively; 82.1% and 84% of patients achieved negative RT-PCR tests, respectively.ConclusionIn patients with COVID-19, single-dose ivermectin was ineffective in decreasing the time to a negative RT-PCR test.Clinical Trial RegistrationClinicalTrials.gov, NCT04703205

グリア細胞に焦点を当てたマウス顔面神経切断モデルの検討

金沢大学医薬保健研究域保健学系The effect of Nicotinamide adenine dinucleotide (NAD+) on nerve injury was investigated using a CD38 knockout mouse with a high NAD + concentration and a model in which the concentration was increased by administering a NAD+ precursor. No neuroprotective effect was observed in the facial nerve nucleus after nerve transection, but degeneration of peripheral nerves was delayed. From this, it was found that a high concentration of NAD+ has an effect of protecting nerves from nerve injury, and that the effect can be obtained by administering a NAD+ precursor.神経傷害に対するNicotinamide adenine dinucleotide（NAD+）の作用につきNAD+濃度の高いCD38ノックアウトマウス並びにNAD+前駆体を投与し濃度を高めたモデルを用いて検討を行なった。神経切断後の顔面神経核では神経保護効果は認めなかったが、末梢神経の変性が遅延した。このことから、NAD+濃度が高いことは神経傷害から神経を保護する作用があり、NAD+前駆体を投与することでもその効果が得られることがわかった。研究課題/領域番号:20K18274, 研究期間(年度):2020-04-01 – 2022-03-31出典：研究課題「グリア細胞に焦点を当てたマウス顔面神経切断モデルの検討」課題番号20K18274（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-20K18274/20K18274seika/）を加工して作

Macrophage depletion attenuates degeneration of spiral ganglion neurons in kanamycin-induced unilateral hearing loss model

Abstract Pathological conditions in cochlea, such as ototoxicity, acoustic trauma, and age-related cochlear degeneration, induce cell death in the organ of Corti and degeneration of the spiral ganglion neurons (SGNs). Although macrophages play an essential role after cochlear injury, its role in the SGNs is limitedly understood. We analyzed the status of macrophage activation and neuronal damage in the spiral ganglion after kanamycin-induced unilateral hearing loss in mice. The number of ionized calcium-binding adapter molecule 1 (Iba1)-positive macrophages increased 3 days after unilateral kanamycin injection. Macrophages showed larger cell bodies, suggesting activation status. Interestingly, the number of activating transcription factor 3 (ATF3)-positive-neurons, an indicator of early neuronal damage, also increased at the same timing. In the later stages, the number of macrophages decreased, and the cell bodies became smaller, although the number of neuronal deaths increased. To understand their role in neuronal damage, macrophages were depleted via intraperitoneal injection of clodronate liposome 24 h after kanamycin injection. Macrophage depletion decreased the number of ATF3-positive neurons at day 3 and neuronal death at day 28 in the spiral ganglion following kanamycin injection. Our results suggest that suppression of inflammation by clodronate at early timing can protect spiral ganglion damage following cochlear insult

Intraoperative Blood Loss at Different Surgical-Procedure Stages during Posterior Spinal Fusion for Idiopathic Scoliosis

Background and Objectives: Several predictive factors have been reportedly associated with intraoperative total blood loss (TBL) during posterior spinal fusion (PSF) for idiopathic scoliosis (IS). To reduce TBL, preoperative factors and interoperative factors are considered important. However, there are few reports that have evaluated bleeding patterns according to surgical stages. This study aimed to elucidate bleeding patterns at different surgical stages and determine the predictive factors for TBL during PSF surgery in patients with IS. Materials and Methods: Preoperative data, radiographic parameters, and intraoperative data of patients undergoing PSF for IS were retrospectively collected. We divided the patients into six stages: stage 1, exposure; stage 2, implant placement; stage 3, release; stage 4, correction; stage 5, bone grafting; and stage 6, closure; then we reviewed the blood loss and bleeding speed. Multiple-regression analysis was performed to generate a predictive formula for blood loss using preoperative and intraoperative factors, including blood loss at stage 1, as explanatory variables. Results: Forty-five patients (mean age: 17.6 years) were included. The mean operative time and TBL were 287.9 min and 756.5 mL, respectively. Blood loss was the highest at stage 3, followed by stage 4. Bleeding speed was the highest at stage 4, followed by stage 3. Bleeding speeds at stages 3 and 4 were significantly higher than those at stages 1 and 2. Preoperative Cobb angle, activated partial thromboplastin time (aPTT), number of fused vertebrae, and blood loss at stage 1 were significant contributing factors. Conclusions: Blood loss and bleeding speed during the release and correction stages were high. Specifically, bleeding speed significantly increased during and after the release procedure. The preoperative Cobb angle, aPTT, number of fixed vertebrae, and blood-loss volume during PSF were significantly associated with TBL. Our findings would be helpful for reducing TBL in patients undergoing PSF for IS

Posterior Spinal Fusion Surgery for Neuromuscular Disease Patients with Severe Scoliosis Whose Cobb Angle Was over 100 Degrees

Background and objectives: Patients with neuromuscular diseases usually have progressive neuromuscular scoliosis (NMS), requiring invasive surgery. Some patients present with severe scoliosis at the time of consultation and are difficult to treat. Posterior spinal fusion (PSF) surgery combined with anterior release and pre- or intraoperative traction would be effective for severe spinal deformities but would be invasive. This study aimed to evaluate the outcomes of PSF-only surgery for patients with severe NMS with a Cobb angle > 100°. Materials and Methods: Thirty NMS patients (13 boys and 17 girls; mean age 13.8 years) who underwent PSF-only surgery for scoliosis with a Cobb angle > 100° were included. We reviewed the lower instrumented vertebra (LIV), duration of surgery, blood loss, perioperative complications, preoperative clinical findings, and radiographic findings, including Cobb angle and pelvic obliquity (PO) in the sitting position pre- and postoperatively. The correction rate and correction loss of the Cobb angle and PO were also calculated. Results: The mean duration of surgery was 338 min, intraoperative blood loss was 1440 mL, preoperative %VC was 34.1%, FEV1.0 (%) was 91.5%, and EF was 66.1%. There were eight cases of perioperative complications. The Cobb angle and PO correction rates were 48.5% and 42.0%, respectively. We divided the patients into two groups: the L5 group, in which the LIV was L5, and the pelvis group, in which the LIV was the pelvis. The duration of surgery and PO correction rate in the pelvis group were significantly higher than those in the L5 group. Conclusions: Patients with severe NMS demonstrated severe preoperative restrictive ventilatory impairments. PSF surgery without anterior release or any intra-/preoperative traction showed satisfactory outcomes, including acceptable scoliosis correction and improved clinical findings, even in patients with extremely severe NMS. Instrumentation and fusion to the pelvis for severe scoliosis in patients with NMS showed good PO correction and low correction loss of Cobb angle and PO, but a longer duration of surgery

A High Body Mass Index and the Vacuum Phenomenon Upregulate Pain-Related Molecules in Human Degenerated Intervertebral Discs

Animal studies suggest that pain-related-molecule upregulation in degenerated intervertebral discs (IVDs) potentially leads to low back pain (LBP). We hypothesized that IVD mechanical stress and axial loading contribute to discogenic LBP’s pathomechanism. This study aimed to elucidate the relationships among the clinical findings, radiographical findings, and pain-related-molecule expression in human degenerated IVDs. We harvested degenerated-IVD samples from 35 patients during spinal interbody fusion surgery. Pain-related molecules including tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, calcitonin gene-related peptide (CGRP), microsomal prostaglandin E synthase-1 (mPGES1), and nerve growth factor (NGF) were determined. We also recorded preoperative clinical findings including body mass index (BMI), Oswestry Disability Index (ODI), and radiographical findings including the vacuum phenomenon (VP) and spinal instability. Furthermore, we compared pain-related-molecule expression between the VP (−) and (+) groups. BMI was significantly correlated with the ODI, CGRP, and mPGES-1 levels. In the VP (+) group, mPGES-1 levels were significantly higher than in the VP (−) group. Additionally, CGRP and mPGES-1 were significantly correlated. Axial loading and mechanical stress correlated with CGRP and mPGES-1 expression and not with inflammatory cytokine or NGF expression. Therefore, axial loading and mechanical stress upregulate CGRP and mPGES-1 in human degenerated IVDs, potentially leading to chronic discogenic LBP

Prevalence and Characteristics of Spinal Sagittal Malalignment in Patients with Osteoporosis

Spinal sagittal malalignment due to vertebral fractures (VFs) induces low back pain (LBP) in patients with osteoporosis. This study aimed to elucidate spinal sagittal malalignment prevalence based on VF number and patient characteristics in individuals with osteoporosis and spinal sagittal malalignment. Spinal sagittal alignment, and VF number were measured in 259 patients with osteoporosis. Spinal sagittal malalignment was defined according to the SRS-Schwab classification of adult spinal deformity. Spinal sagittal malalignment prevalence was evaluated based on VF number. In patients without VFs, bone mineral density, bone turnover markers, LBP scores and health-related quality of life (HRQoL) scores of normal and sagittal malalignment groups were compared. In 205 of the 259 (79.2%) patients, spinal sagittal malalignment was detected. Sagittal malalignment prevalence in patients with 0, 1, or ≥2 VFs was 72.1%, 86.0%, and 86.3%, respectively. All LBP scores and some subscale of HRQoL scores in patients without VFs were significantly worse for the sagittal malalignment group than the normal alignment group (p < 0.05). The majority of patients with osteoporosis had spinal sagittal malalignment, including ≥70% of patients without VFs. Patients with spinal sagittal malalignment reported worse LBP and HRQoL. These findings suggest that spinal sagittal malalignment is a risk factor for LBP and poor HRQoL in patients with osteoporosis

Muscle strength rather than appendicular skeletal muscle mass might affect spinal sagittal alignment, low back pain, and health-related quality of life

Abstract Sarcopenia is defined as decreasing in muscle strength and mass, and dynapenia is defined as decreasing in muscle strength and maintained muscle mass. This study elucidated the prevalence and characteristics of sarcopenia and dynapenia and evaluate in elderly spinal disorders patients. 1039 spinal disorders patients aged ≥ 65 years were included. We measured age, grip strength, muscle mass, spinal sagittal alignment parameters, low back pain (LBP) scores and health-related quality of life (HR-QoL) scores. Based on the previous reports, patients were categorised into normal group: NG, pre-sarcopenia group: PG, dynapenia group: DG, and sarcopenia group: SG. Pre-sarcopenia, dynapenia, and sarcopenia were found in 101 (9.7%), 249 (19.2%), and 91 (8.8%) patients, respectively. The spinal sagittal alignment parameters, trunk muscle mass, LBP, and HR-QoL scores were significantly worse in DG and SG compared with those in PG and NG. Spinal alignment, trunk muscle mass, and clinical outcomes, including LBP and HR-QoL scores, were maintained in the PG and poor in the DG and SG. Thus, intervention for muscle strength may be a treatment option for changes of spinal sagittal alignment and low back pain