NDT-C11 as a viable novel detergent for single particle cryo-EM.

Single particle cryo electron microscopy (cryo-EM) is now the major method for the determination of integral membrane protein structure. For the success of a given project the type of membrane mimetic used for extraction from the native cell membrane, purification to homogeneity and finally cryo-grid vitrification is crucial. Although small molecule amphiphiles - detergents - are the most widely used membrane mimetic, specific tailoring of detergent structure for single particle cryo-EM is rare and the demand for effective detergents not satisfied. Here, we compare the popular detergent lauryl maltose-neopentyl glycol (LMNG) with the novel detergent neopentyl glycol-derived triglucoside-C11 (NDT-C11) in its behavior as free detergent and when bound to two types of multisubunit membrane protein complexes - cyanobacterial photosystem I (PSI) and mammalian F-ATP synthase. We conclude that NDT-C11 has high potential to become a very useful detergent for single particle cryo-EM of integral membrane proteins.

Epitopes of an antibody that neutralizes a wide range of SARS-CoV-2 variants in a conserved subdomain 1 of the spike protein.

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued, enabling the virus to escape from host immunity by changing its spike antigen, while biased toward the receptor-binding domain and N-terminal domain. Here, we isolated a novel pan-SARS-CoV-2 neutralizing antibody (which we named MO11) for even the recent dominators XBB.1.16 and EG.5.1, from a convalescent patient who had received three doses of an original mRNA COVID-19 vaccination. A cryo-electron microscopy analysis of the spike-MO11 complex at 2.3 Å atomic resolution revealed that it recognizes a conserved epitope hidden behind a glycan shield at N331 on subdomain 1 (SD1), holding both the N- and C-terminal segments comprising SD1. Our identification of MO11 unveiled the functional importance of SD1 for the spike's function, and we discuss the potential availability of a novel common epitope among the SARS-CoV-2 variants.IMPORTANCENovel severe acute respiratory syndrome coronavirus 2 variants with immune evasion ability are still repeatedly emerging, nonetheless, a part of immunity developed in responding to the antigen of earlier variants retains efficacy against recent variants irrespective of the numerous mutations. In exploration for the broadly effective antibodies, we identified a cross-neutralizing antibody, named MO11, from the B cells of the convalescent patient. MO11 targets a novel epitope in subdomain 1 (SD1) and was effective against all emerging variants including XBB.1.16 and EG.5.1. The neutralizing activity covering from D614G to EG.5.1 variants was explained by the conservation of the epitope, and it revealed the importance of the subdomain on regulating the function of the antigen for viral infection. Demonstrated identification of the neutralizing antibody that recognizes a conserved epitope implies basal contribution of such group of antibodies for prophylaxis against COVID-19.

Which patients do we need to consider augmentation of muscle active potentials regarding transcranial electrical stimulation motor-evoked potentials monitoring before spine surgery?

BACKGROUND CONTEXT: Transcranial electrical stimulation motor-evoked potentials (Tc-MEPs) are the current trend and are important in preventing intraoperative neurological deficits. Post-tetanic Tc-MEPs (p-MEP) can augment the amplitudes of compound muscle active potentials (CMAPs), especially in the case of insufficient conventional Tc-MEPs (c-MEP). PURPOSE: To retrospectively investigate pre- and intraoperative factors necessitating p-MEP monitoring and to examine changes in the success rates of baseline Tc-MEP monitoring before and after tetanic stimulation in patients with such factors. STUDY DESIGN: Retrospective observational study. PATIENT SAMPLE: Patients (n=184) who underwent spinal surgery with Tc-MEP monitoring in our department between August 2020 and July 2022. OUTCOME MEASURES: Manual muscle testing (MMT) scores were calculated to identify patients with preoperative motor deficits. c-MEP and p-MEP amplitudes were recorded from the defined muscles. METHODS: We compared preoperative and intraoperative factors between the c-MEP and p-MEP groups (study 1). In cases where the factors were identified, we investigated the success rate of the baseline MEP measurement of each muscle before and after tetanic stimulation (study 2). RESULTS: One hundred fifty-seven patients were included. Of those, 87 showed sufficient CMAPs with c-MEP. Meanwhile, 70 needed p-MEP because of insufficient CMAPs. In univariate analysis, cervical/thoracic surgery (p<.001), preoperative MMT 3 or below (p=.009), shorter duration of illness (p=.037), previous cerebrovascular disease (p=.014), and dialysis (p=.031) were significantly associated with p-MEP group. Preoperative MMT 3 or below was the only factor requiring p-MEP (odds ratio, 3.34; 95% confidence interval, 1.28-8.73, p=.014) in multivariate analysis. In the p-MEP group, 24 patients had preoperative motor deficits; 16 patients with complete data were included in the analysis (study 2). The success rates of MEP monitoring before and after tetanic stimulation of the entire lower-extremity muscles were 42.7 and 57.3%, respectively (p<.001). The success rates for each muscle before and after tetanic stimulation were abductor pollicis brevis: 81.3% and 96.9%, tibialis anterior: 34.4% and 50.0%, gastrocnemius: 25% and 40.6%, and abductor hallucis: 68.8% and 81.3%, respectively. No significant differences were observed in success rates for any of the muscles. CONCLUSIONS: Patients with preoperative MMT 3 or below highly needed p-MEP. The success rate of baseline MEP monitoring increased with tetanic stimulation, even in patients with preoperative motor deficits. We believe that p-MEP monitoring can result in reliable CMAP recording, especially in cases of preoperative motor deficits with MMT scores of 3 or below.

Structural insights into thermophilic chaperonin complexes.

Group I chaperonins are dual heptamer protein complexes that play significant roles in protein homeostasis. The structure and function of the Escherichia coli chaperonin are well characterized. However, the dynamic properties of chaperonins, such as large ATPase-dependent conformational changes by binding of lid-like co-chaperonin GroES, have made structural analyses challenging, and our understanding of these changes during the turnover of chaperonin complex formation is limited. In this study, we used single-particle cryogenic electron microscopy to investigate the structures of GroES-bound chaperonin complexes from the thermophilic hydrogen-oxidizing bacteria Hydrogenophilus thermoluteolus and Hydrogenobacter thermophilus in the presence of ATP and AMP-PNP. We captured the structure of an intermediate state chaperonin complex, designated as an asymmetric football-shaped complex, and performed analyses to decipher the dynamic structural variations. Our structural analyses of inter- and intra-subunit communications revealed a unique mechanism of complex formation through the binding of a second GroES to a bullet-shaped complex.

Anterior Placement of Cages in Posterior Lumbar Interbody Fusion for Obtaining Good Lumbar Lordosis Formation.

Introduction: Posterior lumbar interbody fusion (PLIF) is a common treatment for nerve root disease associated with lumbar foraminal stenosis or lumbar spondylolisthesis. At our institution, PLIF is usually performed with high-angle cages and posterior column osteotomy (PLIF with HAP). However, not all patients achieve sufficient segmental lumbar lordosis (SLL). This study determined whether the location of PLIF cages affect local lumbar lordosis formation. Methods: A total of 59 patients who underwent L4/5 PLIF with HAP at our hospital, using the same titanium control cage model, were enrolled in this cohort study. The mean ratio of the distance from the posterior edge of the cage to the posterior wall of the vertebral body/vertebral length (RDCV) immediately after surgery was 16.5%. The patients were divided into two groups according to RDCV <16.5% (group P) and ≥16.5% (group G). The preoperative and 6-month postoperative slip rate (%slip), SLL, local disk angle (LDA), ratio of disk height/vertebral height (RDV), 6-month postoperative RDCV, ratio of cage length/vertebral length (RCVL), and ratio of posterior disk height/anterior disk height at the fixed level (RPA) were evaluated via simple lumbar spine X-ray. The preoperative and 6-month postoperative Japanese Orthopedic Association (JOA) and low back pain visual analog scale (VAS) scores were also evaluated. Results: Groups G and P included 31 and 28 patients, respectively. The preoperative %slip, SLL, LDA, RDV, JOA score, and low back pain VAS score were not significantly different between the groups. In groups G and P, 6-month postoperative %slip, SLL, LDA, RDV, RDCV, RCVL, and RPA were 3.3% and 7.9%, 18.6° and 15.4°, 9.7° and 8.0°, 36.6% and 40.3%, 21.1% and 10.1%, 71.4% and 77.0%, and 56.1% and 67.7%, respectively. The 6-month postoperative SLL, LDA, RDV, RDCV, RCVL, and RPA significantly differed (p=0.03, 0.02, 0.02, <0.001, <0.001, and <0.001, respectively). Conclusions: Anterior PLIF cage placement relative to the vertebral body is necessary for good SLL in PLIF.

Boric acid intercepts 80S ribosome migration from AUG-stop by stabilizing eRF1.

In response to environmental changes, cells flexibly and rapidly alter gene expression through translational controls. In plants, the translation of NIP5;1, a boric acid diffusion facilitator, is downregulated in response to an excess amount of boric acid in the environment through upstream open reading frames (uORFs) that consist of only AUG and stop codons. However, the molecular details of how this minimum uORF controls translation of the downstream main ORF in a boric acid-dependent manner have remained unclear. Here, by combining ribosome profiling, translation complex profile sequencing, structural analysis with cryo-electron microscopy and biochemical assays, we show that the 80S ribosome assembled at AUG-stop migrates into the subsequent RNA segment, followed by downstream translation initiation, and that boric acid impedes this process by the stable confinement of eukaryotic release factor 1 on the 80S ribosome on AUG-stop. Our results provide molecular insight into translation regulation by a minimum and environment-responsive uORF.

Reliability of the Risser+ grade for assessment of bone maturity in pediatric scoliosis cases: Investigation using standing and supine whole-spine radiograph.

BACKGROUND: Although several radiography-based systems for assessing skeletal maturity are available to clinicians, the classical Risser grading system remains a clinical gold standard. For scoliosis follow-up, a standing whole-spine radiograph is usually used. However, in our clinical practice, we have occasionally encountered cases in which ossification of the iliac crest is seen differently in the standing and supine whole-spine radiography. Here, we aimed to clarify the reliability of the Risser+ grading system for supine versus standing position radiographs. METHODS: This study recruited patients with all types of scoliosis who had been radiographed in both the standing and supine positions. We retrospectively evaluated the Risser+ grade of standing and supine whole-spine radiographs taken consecutively. Kappa statistics were computed to investigate the agreement between standing and supine Risser+ grades for this study. RESULTS: We evaluated 111 patients (age: 12.6 ± 2.0; male-to-female = 23:88). The Kappa value for the standing and supine Risser+ grade systems was 0.74. The degree of agreement between the two positions for each Risser+ grade revealed high agreement for grades 0 and 5 in all cases, whereas grades 2 and 3 had low agreement. CONCLUSIONS: Overall, there was substantial agreement between the Risser+ grades assigned to standing and supine position radiographs. However, disagreement was observed between standing and supine position radiographs assigned Risser+ grades of 2 or 3. Therefore, we have found a wide range in the visibility of iliac apophysis ossification of the iliac depending on the posture, and there are limitations in assessing bone maturity using the Risser+ grade alone. Clinicians should use other evaluation systems, in addition to the Risser+ system, to achieve a more accurate bone maturity assessment, especially for cases with standing position radiographs assigned Risser grades of 2 or 3.

Recurrence of kyphotic deformity following implant removal in pediatric pure discoligamentous Chance-type injury: A case report.

Pediatric pure discoligamentous Chance-type injury is relatively rare and the appropriate surgical method has not yet been established, particularly, whether spinal fixation with fusion or without fusion is more effective. This case report describes a 10-year-old-boy who sustained an L2-3 pure discoligamentous Chance-type injury following a car accident and underwent an L2-3 posterior fixation without fusion. The implants were removed after eight months of an uneventful postoperative course. However, four months later, the kyphotic deformity recurred. Although the deformity gradually progressed over nine months, the patient remained neurologically intact and asymptomatic. This report suggests that fixation without fusion may not be appropriate in pediatric patients with pure discoligamentous Chance-type injuries. Spinal fixation with fusion may be recommended to prevent loss of correction and ensure secure stabilization.

Utility of desflurane as an anesthetic in motor-evoked potentials in spine surgery and the facilitating effect in tetanic stimulation of bilateral median nerves.

Although desflurane is a safe and controllable inhalation anesthetic used in spinal surgery, to our knowledge, there have been no reports of successful motor-evoked potential (MEP) recordings under general anesthesia with desflurane alone. A high desflurane concentration may reduce the risk of intraoperative awareness but can also reduce the success of MEP recording. Therefore, we aimed to evaluate the reliability of MEP monitoring and investigate whether tetanic stimulation can augment MEP amplitude under general anesthesia with high-concentration desflurane during spinal surgery. We prospectively evaluated 46 patients who were scheduled to undergo lumbar surgery at a single center between 2018 and 2020. Anesthesia was maintained with an end-tidal concentration of 4% desflurane and remifentanil. Compound muscle action potentials were recorded bilaterally from the abductor pollicis brevis, abductor hallucis, tibialis anterior, gastrocnemius, and quadriceps. For post-tetanic MEPs (p-MEPs), tetanic stimulation was applied to the median nerves (p-MEPm) and tibial nerves (p-MEPt) separately before transcranial stimulation. The average success rates for conventional MEP (c-MEP), p-MEPm, and p-MEPt were 77.9%, 80%, and 79.3%, respectively. The p-MEPm amplitudes were significantly higher than the c-MEP amplitudes in all muscles (P < 0.05), whereas the p-MEPt amplitudes were not significantly different from the c-MEP amplitudes. The MEP recording success rates for the gastrocnemius and quadriceps were inadequate. However, bilateral median nerve tetanic stimulation can effectively augment MEPs safely under general anesthesia with high-concentration desflurane in patients who undergo spinal surgery.

Ultrasound-guided disc pain induction test for diagnosis of discogenic lumbar pain: a cross-sectional study.

BACKGROUND: Several methods can be used to diagnose discogenic pain, but only discoblock can diagnose discogenic pain definitively. This study aimed to examine the usefulness of an ultrasound-guided disc pain induction test for a simple and accurate diagnosis of the culprit lesion. METHODS: We included 41 patients with lumbar pain in whom pain was induced by an ultrasound-guided disc pain induction test. All patients had confirmed pain at L1/2 to L5/S1 based on an ultrasound-guided disc pain induction test and underwent X-ray photography and magnetic resonance imaging. Seventeen patients who required injection due to severe pain underwent discoblock procedures for discs with the most intense pain, and visual analogue scale (VAS) scores were obtained before and after the procedure for these patients. We analysed the association between painful discs and radiological findings. RESULTS: Pain induction was noted in a total of 65 discs, and the pain was induced in 23 patients in only one disc. All patients had disc degeneration of Pfirrmann classification grade 1 or higher, with more significant disc degeneration in painful discs than in painless discs. There was no significant relationship between the presence or absence of pain and Modic type. The average VAS measurements improved significantly from 9.5 (pre-procedure) to 2.5 (post-procedure). These results suggest that the most painful discs were the causes of discogenic lumbar pain. CONCLUSIONS: Our ultrasound-guided disc pain induction test may help diagnose disc degeneration and identify culprit lesions, even when multiple discs exhibit findings of degeneration.

Does a Positive Response to Transforaminal Epidural Steroid Injection Identify Patients Who Can Avoid Surgery for Two Years?

Background: Transforaminal epidural steroid injection (TFESI) is widely used to manage lumbar radiculopathy. In clinical settings, patients often undergo repeated transforaminal epidural injections with or without steroid administration. Objectives: To examine whether a positive response to TFESI at the first month, can in clinical settings, identify patients with radiculopathy who can avoid surgery for two years. Study Design/Setting. This prospective observational study was conducted at an academic medical center. Methods: Individuals aged ≥20 years who had been referred to our pain center by spine surgeons were enrolled. All patients were assessed using the Numerical Rating Scale (NRS) at baseline and 1 month after the first TFESI. Patients were divided into two groups according to the NRS decrement: the positive response (PR) group achieved a ≥2.0 decrease on the NRS 1 month after the first TFESI compared to baseline and the no response (NR) group achieved a <2.0 decrease on the NRS. The incidence rates of surgery over two years were compared between the two groups. In addition, we calculated the hazard ratio of the PR group to the NR group regarding the incidence of surgery over two years using the Cox proportional hazard model, adjusting for baseline NRS. Results: Seventy-six patients completed the two-year follow-up. In total, 8 and 68 patients had bilateral and unilateral radiculopathy, respectively. The PR and NR groups included 35 and 41 patients, respectively. The rate of surgery avoidance was 85.7% and 73.2% in the PR and NR groups, respectively. This difference was not statistically significant (p=0.26). After adjusting for baseline NRS, the hazard ratio of the PR group to the NR group regarding the incidence of surgery within two years was 0.35 (95% confidence interval: 0.11-1.11, p=0.08). Conclusion: A positive response to TFESI may not identify patients who can avoid surgery for two years.

Deep learning driven de novo drug design based on gastric proton pump structures.

Existing drugs often suffer in their effectiveness due to detrimental side effects, low binding affinity or pharmacokinetic problems. This may be overcome by the development of distinct compounds. Here, we exploit the rich structural basis of drug-bound gastric proton pump to develop compounds with strong inhibitory potency, employing a combinatorial approach utilizing deep generative models for de novo drug design with organic synthesis and cryo-EM structural analysis. Candidate compounds that satisfy pharmacophores defined in the drug-bound proton pump structures, were designed in silico utilizing our deep generative models, a workflow termed Deep Quartet. Several candidates were synthesized and screened according to their inhibition potencies in vitro, and their binding poses were in turn identified by cryo-EM. Structures reaching up to 2.10 Å resolution allowed us to evaluate and re-design compound structures, heralding the most potent compound in this study, DQ-18 (N-methyl-4-((2-(benzyloxy)-5-chlorobenzyl)oxy)benzylamine), which shows a Ki value of 47.6 nM. Further high-resolution cryo-EM analysis at 2.08 Å resolution unambiguously determined the DQ-18 binding pose. Our integrated approach offers a framework for structure-based de novo drug development based on the desired pharmacophores within the protein structure.

Impact of Preoperative Motor Status for the Positive Predictive Value of Transcranial Motor-Evoked Potentials Alerts in Thoracic Spine Surgery: A Prospective Multicenter Study by the Monitoring Committee of the Japanese Society for Spine Surgery and Related Research.

STUDY DESIGN: Prospective multicenter study. OBJECTIVE: To investigate the validity of transcranial motor-evoked potentials (Tc-MEP) in thoracic spine surgery and evaluate the impact of specific factors associated with positive predictive value (PPV). METHODS: One thousand hundred and fifty-six cases of thoracic spine surgeries were examined by comparing patient backgrounds, disease type, preoperative motor status, and Tc-MEP alert timing. Tc-MEP alerts were defined as an amplitude decrease of more than 70% from the baseline waveform. Factors were compared according to preoperative motor status and the result of Tc-MEP alerts. Factors that showed significant differences were identified by univariate and multivariate analysis. RESULTS: Overall sensitivity was 91.9% and specificity was 88.4%. The PPV was significantly higher in the preoperative motor deficits group than in the preoperative no-motor deficits group for both high-risk (60.3% vs 38.3%) and non-high-risk surgery groups (35.1% vs 12.8%). In multivariate logistic analysis, the significant factors associated with true positive were surgical maneuvers related to ossification of the posterior longitudinal ligament (odds ratio = 11.88; 95% CI: 3.17-44.55), resection of intradural intramedullary spinal cord tumor (odds ratio = 8.83; 95% CI: 2.89-27), preoperative motor deficit (odds ratio = 3.46; 95% CI: 1.64-7.3) and resection of intradural extramedullary spinal cord tumor (odds ratio = 3.0; 95% CI: 1.16-7.8). The significant factor associated with false positive was non-attributable alerts (odds ratio = .28; 95% CI: .09-.85). CONCLUSION: Surgeons are strongly encouraged to use Tc-MEP in patients with preoperative motor deficits, regardless of whether they are undergoing high-risk spine surgery or not. Knowledge of PPV characteristics will greatly assist in effective Tc-MEP enforcement and minimize neurological complications with appropriate interventions.

Assessment of two entry points for S2 alar-iliac screw in a Japanese cohort using three-dimensional computed tomography scan.

BACKGROUND CONTEXT: Lumbosacral fusion supplemented with sacropelvic fusion has recently been increasingly employed for correcting spinal deformity and is associated with lower incidence of pseudarthrosis and implant failure. To date, few studies have evaluated anatomical parameters and technical feasibility between different entry points for S2 alar-iliac screws. PURPOSE: To compare anatomical parameters and technical feasibility of two entry points for the S2 alar-iliac screw (S2AIS) in a Japanese cohort using three-dimensional (3D) computed tomography (CT). STUDY DESIGN/SETTING: Retrospective cohort study. PATIENT SAMPLE: Fifteen men and 15 women aged 50-79 years who underwent pelvic CT at our hospital in 2013. OUTCOME MEASURES: Screw length, lateral angulation, caudal angulation, angle range, distance from the entry point to the sacroiliac joint, distance from the S2AIS to the acetabular roof, distance from the S2AIS to the sciatic notch, and insertion difficulty. METHODS: We used 30 pelvic CT images (15 men and 15 women). We selected two entry points from previous studies: one was 1 mm distal and 1 mm lateral to the S1 dorsal foramen (A group) and the other was the midpoint between the S1 and S2 dorsal foramen (B group). We resliced the plane in which the pelvis was sectioned obliquely from these entry points to the anterior inferior iliac spine in the sagittal plane. We placed the shortest and longest virtual S2AISs bilaterally in this plane using a 4-mm margin. We measured screw length, lateral angulation, caudal angulation, angle range, distance from the entry point to the sacroiliac joint, distance from the S2AIS to the acetabular roof, distance from the S2AIS to the sciatic notch, and insertion difficulty. These measurements were compared between Groups A and B. RESULTS: In group A, the angle in the sagittal plane was significantly smaller and the distance from the entry point to the sciatic notch was significantly longer than in group B. Group B demonstrated a significantly longer screw length, longer distance from the entry point to the sacroiliac joint, and longer distance from the entry point to the acetabular roof than group A. The rate of insertion difficulty of S2AIS was much higher in group A. CONCLUSIONS: Insertion of S2AIS from the midpoint between the S1 and S2 dorsal foramen compared with the entry at distal and lateral to S1 foramen enables insertion of longer screws with low insertion difficulty.

Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study.

Introduction: Adolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested. However, the causal relationship between AIS and BMI remains to be elucidated. Material and methods: Mendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWASs) of AIS (Japanese cohort, 5,327 cases, 73,884 controls; US cohort: 1,468 cases, 20,158 controls) and BMI (Biobank Japan: 173430 individual; meta-analysis of genetic investigation of anthropometric traits and UK Biobank: 806334 individuals; European Children cohort: 39620 individuals; Population Architecture using Genomics and Epidemiology: 49335 individuals). In MR analyses evaluating the effect of BMI on AIS, the association between BMI and AIS summary statistics was evaluated using the inverse-variance weighted (IVW) method, weighted median method, and Egger regression (MR-Egger) methods in Japanese. Results: Significant causality of genetically decreased BMI on risk of AIS was estimated: IVW method (Estimate (beta) [SE] = -0.56 [0.16], p = 1.8 × 10-3), weighted median method (beta = -0.56 [0.18], p = 8.5 × 10-3) and MR-Egger method (beta = -1.50 [0.43], p = 4.7 × 10-3), respectively. Consistent results were also observed when using the US AIS summary statistic in three MR methods; however, no significant causality was observed when evaluating the effect of AIS on BMI. Conclusions: Our Mendelian randomization analysis using large studies of AIS and GWAS for BMI summary statistics revealed that genetic variants contributing to low BMI have a causal effect on the onset of AIS. This result was consistent with those of epidemiological studies and would contribute to the early detection of AIS.

Identification and Analysis of Monoclonal Antibodies with Neutralizing Activity against Diverse SARS-CoV-2 Variants.

We identified neutralizing monoclonal antibodies against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) variants (including Omicron variants BA.5 and BA.2.75) from individuals who received two doses of mRNA vaccination after they had been infected with the D614G virus. We named them MO1, MO2, and MO3. Among them, MO1 showed particularly high neutralizing activity against authentic variants: D614G, Delta, BA.1, BA.1.1, BA.2, BA.2.75, and BA.5. Furthermore, MO1 suppressed BA.5 infection in hamsters. A structural analysis revealed that MO1 binds to the conserved epitope of seven variants, including Omicron variants BA.5 and BA.2.75, in the receptor-binding domain of the spike protein. MO1 targets an epitope conserved among Omicron variants BA.1, BA.2, and BA.5 in a unique binding mode. Our findings confirm that D614G-derived vaccination can induce neutralizing antibodies that recognize the epitopes conserved among the SARS-CoV-2 variants. IMPORTANCE Omicron variants of SARS-CoV-2 acquired escape ability from host immunity and authorized antibody therapeutics and thereby have been spreading worldwide. We reported that patients infected with an early SARS-CoV-2 variant, D614G, and who received subsequent two-dose mRNA vaccination have high neutralizing antibody titer against Omicron lineages. It was speculated that the patients have neutralizing antibodies broadly effective against SARS-CoV-2 variants by targeting common epitopes. Here, we explored human monoclonal antibodies from B cells of the patients. One of the monoclonal antibodies, named MO1, showed high potency against broad SARS-CoV-2 variants including BA.2.75 and BA.5 variants. The results prove that monoclonal antibodies that have common neutralizing epitopes among several Omicrons were produced in patients infected with D614G and who received mRNA vaccination.

Role of Transcranial Motor Evoked Potential Monitoring During Traumatic Spinal Injury Surgery: A Prospective Multicenter Study of the Monitoring Committee of the Japanese Society for Spine Surgery and Related Research.

STUDY DESIGN: A prospective multicenter observational cohort study. OBJECTIVE: This study aimed to investigate the role of transcranial motor evoked potential (TcMEP) monitoring during traumatic spinal injury surgery, the timing of TcMEP alerts, and intervention strategies to avoid intraoperative neurological complications. SUMMARY OF BACKGROUND DATA: Intraoperative neuromonitoring, including TcMEP monitoring, is commonly used in high-risk spinal surgery to predict intraoperative spinal cord injury; however, little information is available on its use in traumatic spinal injury surgery. METHODS: The TcMEP monitoring data of 350 consecutive patients who underwent traumatic spinal injury surgery (mean age, 69.3 y) between 2017 and 2021 were prospectively reviewed. In this study, a TcMEP amplitude reduction ≥70% was established as a TcMEP alert. A rescue case was defined as a case with the recovery of TcMEP amplitudes after certain procedures and without postoperative neurological complications. RESULTS: Among the 350 patients who underwent traumatic spinal injury surgery (TcMEP derivation rate 94%), TcMEP monitoring revealed seven true-positive (TP) (2.0%), three rescues (0.9%; rescue rate 30%), 31 false-positive, one false-negative, and 287 true-negative cases, resulting in 88% sensitivity, 90% specificity, 18% positive predictive value, and 99% negative predictive value. The TP rate in patients with preoperative motor deficits was 2.9%, which was higher than that in patients without preoperative motor deficits (1.1%). The most common timing of TcMEP alerts was during decompression (40%). During decompression, suspension of surgery with intravenous steroid injection was ineffective (rescue rate, 0%), and additional decompression was effective. CONCLUSION: Given the low prevalence of neurological complications (2.3%) and the low positive predictive value (18.4%), single usage of TcMEP monitoring during traumatic spinal injury surgery is not recommended. Further efforts should be made to reduce FP alert rates through better interpretation of multimodal Intraoperative neuromonitorings and the incorporation of anesthesiology to improve the positive predictive value. LEVEL OF EVIDENCE: 3.

The clinical role of preoperative fulcrum-bending and supine side-bending radiographs on the prediction of curve correction in adolescent idiopathic scoliosis.

PURPOSE: Preoperative curve assessment is important in adolescent idiopathic scoliosis (AIS). Our objective is to clarify the role of side-bending radiographs (SBR) and fulcrum-bending radiographs (FBR) in predicting postoperative Cobb angle in nonstructural and structural curves. METHODS: Twenty-five consecutive patients with AIS who underwent correction surgery were included. The Cobb angles of structural and nonstructural curves were determined. Cobb angles were measured based on pre- and postoperative standing anteroposterior radiographs of the whole spine. The Cobb angles of SBR and FBR were measured preoperatively. The difference between the Cobb angle at each bending and the preoperative Cobb angle was defined as the predicted correction angle, whereas the difference between the preoperative Cobb angle and postoperative Cobb angle was defined as the surgical correction angle. The correction index was calculated by dividing the surgical correction angle by the predicted correction angle. The difference between the predicted correction angle and surgical correction angle was defined as the prediction error. We compared SBR and FBR for both structural and nonstructural curves in these terms. RESULTS: For both curves, the predicted correction angle of FBR was significantly higher than that of SBR, and the correction index of FBR was significantly lower than that of SBR. Patients with a correction index close to 1 and small prediction error had undergone FBR in the structural curve and SBR in the nonstructural curve. CONCLUSION: FBR is predictive of postoperative correction angle of the structural curve, whereas SBR is predictive of postoperative correction angle of the nonstructural curve.

Current Trends in Intraoperative Spinal Cord Monitoring: A Survey Analysis among Japanese Expert Spine Surgeons.

Introduction: Although intraoperative spinal neuromonitoring (IONM) is recommended for spine surgeries, there are no guidelines regarding its use in Japan, and its usage is mainly based on the surgeon's preferences. Therefore, this study aimed to provide an overview of the current trends in IONM usage in Japan. Methods: In this web-based survey, expert spine surgeons belonging to the Japanese Society for Spine Surgery and Related Research were asked to respond to a questionnaire regarding IONM management. The questionnaire covered various aspects of IONM usage, including the preferred modality, operation of IONM, details regarding muscle-evoked potential after electrical stimulation of the brain (Br(E)-MsEP), and need for consistent use of IONM in major spine surgeries. Results: Responses were received from 134 of 186 expert spine surgeons (response rate, 72%). Of these, 124 respondents used IONM routinely. Medical staff rarely performed IONM without a medical doctor. Br(E)-MsEP was predominantly used for IONM. One-third of the respondents reported complications, such as bite injuries caused by Br(E)-MsEP. Interestingly, two-thirds of the respondents did not plan responses to alarm points. Intramedullary spinal cord tumor, scoliosis (idiopathic, congenital, or neuromuscular in pediatric), and thoracic ossification of the posterior longitudinal ligament were representative diseases that require IONM. Conclusions: IONM has become an essential tool in Japan, and Br(E)-MsEP is a predominant modality for IONM at present. Although we investigated spine surgeries for which consistent use of IONM is supported, a cost-benefit analysis may be required.

TLR3 forms a laterally aligned multimeric complex along double-stranded RNA for efficient signal transduction.

Toll-like receptor 3 (TLR3) is a member of the TLR family, which plays an important role in the innate immune system and is responsible for recognizing viral double-stranded RNA (dsRNA). Previous biochemical and structural studies have revealed that a minimum length of approximately 40-50 base pairs of dsRNA is necessary for TLR3 binding and dimerization. However, efficient TLR3 activation requires longer dsRNA and the molecular mechanism underlying its dsRNA length-dependent activation remains unknown. Here, we report cryo-electron microscopy analyses of TLR3 complexed with longer dsRNA. TLR3 dimers laterally form a higher multimeric complex along dsRNA, providing the basis for cooperative binding and efficient signal transduction.