Corrigendum: SARS-CoV-2 evolution among patients with immunosuppression in a nosocomial cluster of a Japanese medical center during the Delta (AY.29 sublineage) surge.

[This corrects the article DOI: 10.3389/fmicb.2023.944369.].

Serum Inflammatory Dynamics as Novel Biomarkers for Immune Checkpoint Inhibitors in Non-small-cell Lung Cancer With Bone Metastases.

BACKGROUND/AIM: The aim of the study was to develop a novel predictive scoring system based on the dynamics of serum inflammatory indicators in immune checkpoint inhibitor (ICI) treatment on non-small-cell lung cancer (NSCLC) with bone metastases. PATIENTS AND METHODS: Sixty patients with NSCLC and bone metastases treated with ICIs between January 2016 and March 2021 were included in the development cohort. Serum neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) levels were assessed before (pre-value) and 6 weeks after (post-value) ICI treatment, and a novel predictive score was developed: pre-value ≥ post-value, 0 points; pre-value < post-value, 1 point; total score: 0-2 points. The associations of these dynamics and the score with clinical outcomes, including overall survival (OS), progression-free survival (PFS), response rate (RR) of bone metastases, and disease control rate (DCR), were evaluated. Furthermore, cross-validation was performed with 23 patients after April 2021 using the same inclusion criteria. RESULTS: The patients with decreased serum inflammation levels had significantly better OS, PFS, and RR than those with increased levels. Applying the developed score to the development cohort, the patients with 0 points had significantly better OS, PFS, and RR than others. In multivariable analysis, the score independently predicted treatment response to ICI for bone metastasis and prognosis. Cross-validation showed that OS, PFS, and RR were significantly better in the patients in the 0-point group. CONCLUSION: The early NLR and CRP dynamics were associated with therapeutic responses to ICIs in NSCLC with bone metastases. Our novel scoring system based on these dynamics is simple and has a high predictive accuracy.

The Role of Microsurgery and Fluorescent-reporter Genes in Establishing Mouse Models for Real-Time Imaging of Metastatic Cancer-Cell Trafficking and Colony Formation: A Revolutionary and Disruptive Technology for Metastasis Research.

The field of experimental microsurgery was pioneered by the great microsurgeon Sun Lee, who developed the foundation of transplant surgery in the clinic. Dr Lee also played a seminal role in introducing microsurgery to establish mouse models of cancer. In 1990, at the age of 70, Dr Lee demonstrated microsurgery techniques to the mouse-model team at AntiCancer Inc., leading to the development of the surgical orthotopic implant (SOI) technique and the first orthotopic mouse models of cancer that metastasized in a pattern similar to clinical cancer. At the beginning of the present century, one of us (NY) from Kanazawa University School of Medicine became a visiting scientist at AntiCancer to learn SOI and develop mouse models of cancer using cancer cells expressing fluorescent reporter genes, such as green fluorescent protein (GFP) and red fluorescent protein (RFP), in order to image metastatic cancer cells trafficking in real time. Since then, a total of eight young surgeons from Kanazawa University have been visiting researchers at AntiCancer, developing SOI mouse models of cancer to visualize cancer cells in vivo, tracking all stages of metastasis in real time. The present perspective review summarizes this seminal work, which has revolutionized the field of metastasis research.

Risk factor analysis of medical litigation outcomes in obstetrics and gynecology: A retrospective cohort study of 344 claims in Japan.

AIM: Medical errors are critical in obstetrics and gynecology (OB/GYN) and contribute to high litigation risks. However, few studies have examined system and diagnostic errors as potential preventable problems. This study aimed to enhance medical safety and reduce litigation by identifying and addressing key contributory factors. METHODS: We retrospectively searched the national Japanese malpractice claims database for OB/GYN cases between 1961 and 2017. We evaluated provider characteristics and background information of the patients (plaintiffs). The main outcome was litigation (acceptance or rejection) in the final judgment. Using multivariable logistic regression models, we assessed the associations between medical malpractice variables (system and diagnostic errors, facility size, situation, place, time, and clinical outcomes) and litigation outcomes (acceptance). RESULTS: Overall, 344 malpractice claims were analyzed. Among these, 277 (80.5 %) were obstetric, and 67 (19.5 %) were gynecological. Of the obstetric cases, 193 were perinatal, and 84 were maternal. Malpractice claims were accepted (OB-GYN losses) in 185 cases (53.8 %). In multivariable analyses, system errors (odds ratio 97.4, 95 % confidence interval 35.2-270.0), diagnostic errors (odds ratio 4.5, 95 % confidence interval 1.8-11.3), and clinic (odds ratio 2.7, 95 % confidence interval 1.2-4.8) had a significant statistical association with accepted claims. CONCLUSION: System errors, diagnostic errors, and clinics were significantly associated with acceptance claims. These findings underscore the necessity of addressing modifiable factors at the physician level and within the healthcare management system to enhance patient safety and reduce litigation risks, thereby ensuring a safer and more reliable healthcare environment for patients and medical professionals.

Evaluation of a qualified MDCK cell line for virus isolation to develop cell-based influenza vaccine viruses with appropriate antigenicity.

We established a qualified Madin-Darby canine kidney cell line (qMDCK-Cs) and investigated its suitability for source virus isolation to develop cell-based seasonal influenza vaccine viruses using vaccine manufacturer cells (Manuf-Cs). When inoculated with 81 influenza-positive clinical specimens, the initial virus isolation efficiency of qMDCK-Cs was exceeded 70%. Among the qMDCK-C isolates, 100% of the A/H1N1pdm09, B/Victoria and B/Yamagata strains and >70% of the A/H3N2 strains showed antigenicity equivalent to that of the contemporary vaccine or relevant viruses in haemagglutination inhibition (HI) or virus neutralization (VN) tests using ferret antisera. These qMDCK-C isolates were propagated in Manuf-Cs (MDCK and Vero cells) (Manuf-C viruses) to develop vaccine viruses. In reciprocal antigenicity tests, ferret antisera raised against corresponding reference viruses and Manuf-C viruses recognized 29 of 31 Manuf-C viruses and corresponding reference viruses, respectively at HI or VN titres more than half of the homologous virus titres, which is the antigenicity criterion for cell culture seasonal influenza vaccine viruses specified by the World Health Organization. Furthermore, ferret antisera against these Manuf-C viruses recognized ≥95% of the viruses circulating during the relevant influenza season with HI or VN titres greater than one-quarter of the homologous virus titres. No cell line-specific amino acid substitutions were observed in the resulting viruses. However, polymorphisms at positions 158/160 of H3HA, 148/151 of N2NA and 197/199 of B/Victoria HA were occasionally detected in the qMDCK-C and Manuf-C viruses but barely affected the viral antigenicity. These results indicated that qMDCK-Cs are suitable for isolating influenza viruses that can serve as a source of antigenically appropriate vaccine viruses. The use of the qMDCK-C isolates will eliminates the need for clinical sample collection, virus isolation, and antigenicity analysis every season, and is expected to contribute to the promotion of vaccine virus development using manufacturer cells.

Recombinant Methioninase Increases Eribulin Efficacy 16-fold in Highly Eribulin-resistant HT1080 Fibrosarcoma Cells, Demonstrating Potential to Overcome the Clinical Challenge of Drug-resistant Soft-tissue Sarcoma.

BACKGROUND/AIM: A major challenge in treating soft-tissue sarcoma is the development of drug resistance. Eribulin, an anti-tubulin agent, is used as a second-line chemotherapy for patients with unresectable or metastatic soft-tissue sarcoma. However, most patients with advanced soft-tissue sarcoma are resistant to eribulin and do not survive. Recombinant methioninase (rMETase) targets the fundamental and general hallmark of cancer, methionine addiction, termed the Hoffman Effect. The present study aimed to show how much rMETase could increase the efficacy of eribulin on eribulin-resistant fibrosarcoma cells in vitro. MATERIALS AND METHODS: HT1080 human fibrosarcoma cells were exposed to step-wise increasing concentrations of eribulin from 0.15-0.4 nM to establish eribulin-resistant HT1080 (ER-HT1080). ER-HT1080 cells were cultured in vitro and divided into four groups: untreated control; eribulin treated (0.15 nM); rMETase treated (0.75 U/ml); and eribulin (0.15 nM) plus rMETase (0.75 U/ml) treated. RESULTS: The IC50 of eribulin on ER-HT1080 cells was 0.95 nM compared to the IC50 of 0.15 nM on HT1080 cells, a 6-fold increase. The IC50 of rMETase on ER-HT1080 and HT1080 was 0.87 U/ml and 0.75 U/ml, respectively. The combination of rMETase (0.75 U/ml) and eribulin (0.15 nM) was synergistic on ER-HT1080 cells resulting in an inhibition of 80.1% compared to eribulin alone (5.0%) or rMETase alone (47.1%) (p<0.05). rMETase thus increased the efficacy of eribulin 16-fold on eribulin-resistant fibrosarcoma cells. CONCLUSION: The present study showed that the combination of eribulin and rMETase can overcome high eribulin resistance of fibrosarcoma. The present results demonstrate that combining rMETase with first- or second-line therapy for soft-tissue sarcoma has the potential to overcome the intractable clinical problem of drug-resistant soft-tissue sarcoma.

Diagnostic accuracy of chest X-ray and CT using artificial intelligence for osteoporosis: systematic review and meta-analysis.

INTRODUCTION: Artificial intelligence (AI)-based systems using chest images are potentially reliable for diagnosing osteoporosis. METHODS: We performed a systematic review and meta-analysis to assess the diagnostic accuracy of chest X-ray and computed tomography (CT) scans using AI for osteoporosis in accordance with the diagnostic test accuracy guidelines. We included any type of study investigating the diagnostic accuracy of index test for osteoporosis. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and IEEE Xplore Digital Library on November 8, 2023. The main outcome measures were the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) for osteoporosis and osteopenia. We described forest plots for sensitivity, specificity, and AUC. The summary points were estimated from the bivariate random-effects models. We summarized the overall quality of evidence using the Grades of Recommendation, Assessment, Development, and Evaluation approach. RESULTS: Nine studies with 11,369 participants were included in this review. The pooled sensitivity, specificity, and AUC of chest X-rays for the diagnosis of osteoporosis were 0.83 (95% confidence interval [CI] 0.75, 0.89), 0.76 (95% CI 0.71, 0.80), and 0.86 (95% CI 0.83, 0.89), respectively (certainty of the evidence, low). The pooled sensitivity and specificity of chest CT for the diagnosis of osteoporosis and osteopenia were 0.83 (95% CI 0.69, 0.92) and 0.70 (95% CI 0.61, 0.77), respectively (certainty of the evidence, low and very low). CONCLUSIONS: This review suggests that chest X-ray with AI has a high sensitivity for the diagnosis of osteoporosis, highlighting its potential for opportunistic screening. However, the risk of bias of patient selection in most studies were high. More research with adequate participants' selection criteria for screening tool will be needed in the future.

Overcoming High Trabectedin Resistance of Soft-tissue Sarcoma With Recombinant Methioninase: A Potential Solution of a Recalcitrant Clinical Problem.

BACKGROUND/AIM: Drug resistance has been a recalcitrant problem for sarcoma patients for many decades. Trabectedin is a second-line chemotherapy for soft-tissue sarcoma that often leads to resistance and death of the patients. The objective of the present study was to address the issue of trabectedin-chemoresistance in HT1080 fibrosarcoma cells by combining recombinant methioninase (rMETase) with trabectedin and examining their efficacy on trabectedin-resistant fibrosarcoma cells in vitro. MATERIALS AND METHODS: Trabectedin-resistant HT1080 (TR-HT1080) cells were generated by subjecting HT1080 human fibrosarcoma cells to increasing trabectedin concentrations (3.3-8 nM). IC50 values for trabectedin and rMETase were compared for HT1080 and TR-HT1080 cells. TR-HT 1080 cells were placed into four groups to determine synergy of rMETase and trabectedin on TR-HT1080 cells: a control group with no treatment; a group treated with trabectedin (3.3 nM); a group treated with rMETase (0.75 U/ml); and a group treated with both trabectedin (3.3 nM) and rMETase (0.75 U/ml). RESULTS: The IC50 value of trabectedin- on TR-HT1080 cells was 42.9 nM, whereas the IC50 value of trabectedin on the parental HT1080 cells was 3.3 nM, indicating a 13-fold increase. The combination of rMETase (0.75 U/ml) and trabectedin (3.3 nM) was synergistic on TR-HT1080 cells resulting in an inhibition of 64.2% compared to trabectedin alone (5.7%) or rMETase alone (50.5%) (p<0.05). rMETase increased the efficacy of trabectedin 11-fold on trabectedin-resistant fibrosarcoma cells. CONCLUSION: The combined administration of trabectedin and rMETase was synergistic on the viability of TR-HT1080 cells in vitro. The combination of rMETase and trabectedin has promising clinical potential for overcoming chemo-resistance of soft-tissue sarcoma.

Prevalence of fracture progression in fragility fractures of the pelvis: Systematic review and meta-analysis.

BACKGROUND: Fragility fractures of the pelvis (FFP) are a growing problem in aging populations. Fracture progression (FP) occasionally occurs during FFP treatment; however, its prevalence remains unclear. This systematic review and meta-analysis aimed to assess the prevalence of FP among patients with FFP. METHODS: We performed a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. All cohort studies that reported the prevalence of FP in patients with FFP were included. FP was defined as the appearance of additional pelvic fractures after the initial FFP. We searched the CENTRAL, MEDLINE, and EMBASE databases until April 2024. The pooled prevalence was generated using a random-effects model and presented as a 95 % confidence interval (CI) and prediction interval (PI). We assessed the risk of bias in each study using the Joanna Briggs Institute's Prevalence Critical Appraisal Tool. RESULTS: This review included eight studies (925 patients). The pooled prevalence of FP in patients with FFP was 11 % (95 % CI, 5-19 %; 95 % PI, 0-44 %). Subgroup analysis showed that the pooled prevalence of FP in patients with FFP (conservative treatment vs. surgery for initial FFP) was 16 % (95 % CI, 9-24 %) and 2 % (95 % CI, 0-11 %), respectively (test for subgroup difference, P = 0.03). Additional analysis showed that in patients with FP, the pooled prevalence of the fractured site (ipsilateral site, contralateral site, and both sites) was 66 %, 12 %, and 19 %, respectively. The pooled prevalence of fractured bone (pubis, ischium, ilium, and sacrum) was 25 %, 0 %, 15 %, and 68 %, respectively. The risk of bias in the patient sampling method and sufficient data analysis in all included studies was high. CONCLUSION: This review suggests that the prevalence of FP in patients with FFP is relatively high. Clinicians should recognize FP as a possible diagnosis in patients experiencing additional pain after FFP. However, further prospective studies with adequate patient sampling are required to confirm the true prevalence.

Significant influence of prelingual deafness but less impact of elderly age at implantation on long-term psychoacoustic CI programming parameters.

OBJECTIVE: This study aimed to elucidate the long-term impact of prelingual deafness and elderly age at cochlear implantation on cochlear implant (CI) programming parameters and CI thresholds METHODS: We retrospectively reviewed patients who underwent cochlear implantation less than 5 years (Prelingual group) and equal and more than 18 years in our institute. The latter group was further divided into Adult and Elderly groups according to whether the patient was younger or older than 65 at implantation. From 152, 69, and 55 patients in the Prelingual, Adult, and Elderly groups, 242, 92, and 58 ears were included. We compared CI thresholds and CI programming parameters, including impedances, T/C levels, and dynamic ranges for 8 years after implantation between the Prelingual, Adult, and Elderly groups. RESULTS: The Prelingual group showed consistently lower CI thresholds than the Adult and Elderly groups during the postoperative 2-8 years, but no difference was detected between the Elderly and Adult groups, except at the postoperative 4 years. The elderly group's CI thresholds did not deteriorate until postoperative 8 years. The Prelingual group showed consistently larger T/C levels (minimum/maximum current strength from CI), especially C levels, than the other two groups. At the same time, there was no significant difference between the Elderly and Adult groups except for smaller dynamic ranges in the Elderly group until postoperative 2 years. These results in the CI programming parameters might explain the lower CI thresholds in the Prelingual group than in the other groups. Focusing on CI maps 1 and 3 years after implantation, the strength of the T/C levels was similar for all channels in the Prelingual group, but the Adult and Elderly groups showed larger electrical stimuli in channels responsible for the middle frequencies than those for the lower or higher frequencies. CONCLUSIONS: Our results suggest a significant influence of prelingual deafness but less impact of elderly age at implantation on long-term CI programming parameters and CI thresholds. The larger C levels and lower CI thresholds in the Prelingual group than in the Adult and Elderly groups implied that CI children with prelingual deafness tolerate and prefer larger CI stimuli, which may reflect the CI-dependent development of their auditory system before the critical period. No age-related reduction in hearing thresholds was observed in the Elderly group, probably because the CI compensates for age-related dysfunction of the peripheral auditory system.

Recombinant Methioninase Is Selectively Synergistic With Doxorubicin Against Wild-type Fibrosarcoma Cells Compared to Normal Cells and Overcomes Highly-Doxorubicin-resistant Fibrosarcoma.

BACKGROUND/AIM: Doxorubicin is first-line therapy for soft-tissue sarcoma, but patients can develop resistance which is usually fatal. As a novel therapeutic strategy, the present study aimed to determine the synergy of recombinant methioninase (rMETase) and doxorubicin against HT1080 fibrosarcoma cells compared to Hs27 normal fibroblasts, and rMETase efficacy against doxorubicin-resistant HT1080 cells in vitro. MATERIALS AND METHODS: The 50% inhibitory concentrations (IC50) of doxorubicin and rMETase, as well as their combination efficacy, against HT1080 human fibrosarcoma cells, Hs27 normal human fibroblasts and doxorubicin-resistant HT1080 (DR-HT1080) cells were determined. Dual-color HT1080 cells which expressed red fluorescent protein (RFP) in the cytoplasm and green fluorescent protein (GFP) in the nuclei were used to visualize nuclear fragmentation during treatment. Nuclear fragmentation was observed with an IX71 fluorescence microscope. RESULTS: The IC50 for doxorubicin was 3.3 µM for HT1080 cells, 12.4 µM for DR-HT1080 cells, and 7.25 µM for Hs27 cells. The IC50 for rMETase was 0.75 U/ml for HT1080 cells, 0.42 U/ml for DR-HT1080 cells, and 0.93 U/ml for Hs27 cells. The combination of rMETase and doxorubicin was synergistic against fibrosarcoma cells but not against normal fibroblasts. The combination of doxorubicin plus rMETase also caused more fragmented nuclei than either treatment alone in HT1080 cells. rMETase alone was highly effective against the DR-HT1080 cells as well as the parental HT1080 cells. CONCLUSION: The present results indicate the future clinical potential of rMETase in combination with doxorubicin for fibrosarcoma, including doxorubicin-resistant fibrosarcoma.

Membrane Formed Around Liquid Nitrogen-treated Bone Promotes Osteogenesis and Revitalization in a Rat Model.

BACKGROUND/AIM: This study aimed to investigate the structure and functions of the membrane formed around liquid nitrogen-treated bones in the osteogenesis and revitalization of frozen bone using a rat model. MATERIALS AND METHODS: Segmental defects were created in femurs of rats, and resected bones treated with liquid nitrogen [frozen bone (FB) group, n=20] or polymethylmethacrylate (PMMA group; n=20) were implanted as spacers. Histological analysis and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) of the membrane around each spacer were performed for bone morphogenetic protein 2 (BMP2), transforming growth factor (TGF)-ß1, and vascular endothelial growth factor (VEGF). Furthermore, in week 2, spacers were removed from both groups (n=5 each), and autologous cancellous bone (ACB) harvested from the ilium was grafted into the defect. Radiological analysis was performed until bone union was observed. RESULTS: In week 2, similar two-layered membrane structures were observed in both groups; these matured into fibrous tissues over time. At each evaluation point, qRT-PCR showed higher expression of all factors in the FB than in the PMMA group. In the ACB graft model, the mean period to bone union and new bone volume were significantly shorter and greater, respectively, in the FB. Chondrocytes invaded the osteotomy site from the membrane in the FB, suggesting that endochondral ossification may occur and be related to osteogenesis. Additionally, fibroblasts and capillaries in the membrane invaded the surface of treated bone in week 2, and osteocytes were observed around them in weeks 6 and 8. CONCLUSION: Fibrous membranous tissue formed around liquid nitrogen-treated bones may be vital for osteogenesis and revitalization of frozen bones.

An Infection Model for SARS-CoV-2 Using Rat Transplanted with hiPSC-Airway Epithelial Cells.

Investigating the infection mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the airway epithelium and developing effective defense strategies against infection are important. To achieve this, establishing appropriate infection models is crucial. Therefore, various in vitro models, such as cell lines and primary cultures, and in vivo models involving animals that exhibit SARS-CoV-2 infection and genetically humanized animals have been used as animal models. However, no animal model has been established that allows infection experiments with human cells under the physiological environment of airway epithelia. Therefore, we aimed to establish a novel animal model that enables infection experiments using human cells. Human induced pluripotent stem cell-derived airway epithelial cell-transplanted nude rats (hiPSC-AEC rats) were used, and infection studies were performed by spraying lentiviral pseudoviruses containing SARS-CoV-2 spike protein and the GFP gene on the tracheae. After infection, immunohistochemical analyses revealed the existence of GFP-positive-infected transplanted cells in the epithelial and submucosal layers. In this study, a SARS-CoV-2 infection animal model including human cells was established mimicking infection through respiration, and we demonstrated that the hiPSC-AEC rat could be used as an animal model for basic research and the development of therapeutic methods for human-specific respiratory infectious diseases.

Individual Bilateral Difference of Femur, Tibia, and Leg Rotation: A Clinical Study of 141 Healthy Japanese Individuals Using Computed Tomography.

Background The malrotation of a femur and tibial fracture after surgery has been described in many articles. However, these studies have not considered individual bilateral differences (IBDs). The IBD of femur and tibial rotation has been identified via computed tomography (CT) in recent American studies. The IBD in rotation should be considered during femur and tibial surgery. However, IBDs in femur and tibial rotation remain unknown in the Japanese population. This study aimed to evaluate the rotation of the femur, knee, tibia, and leg, sex differences, and IBD in rotation among Japanese individuals with healthy bones by using CT analysis. Materials and methods In total,141 patients who underwent CT angiography or venography were included (70 men, 71 women; mean age, 44.7 years). The bilateral axial femur, knee, tibia, and leg rotation alignment were independently measured. The distribution, sex, and IBD were analyzed. The IBD in rotation had two statistical factors: absolute bilateral difference (ABD) and relative bilateral difference (RBD). Results The mean ABD of femur rotation was 6.5°, and the distribution of ABD of femur rotation ≤15° was 95%. The mean ABD of tibia rotation was 5.1°, and the distribution of ABD of tibia rotation ≤10° was 89%. The RBD of femur rotation was not significantly different between the right and left sides. The RBD of tibia rotation showed a higher mean external rotation of 3.3° on the right side (<0.001). The Pearson correlation coefficients of the femur, knee, tibia, and leg rotation between the right and left sides were high (r= 0.702-0.81; all, p<0.001). All elements of rotation showed significant differences between men and women, whereas the ABD and RBD of all elements showed no significant difference. Conclusion The distributions of ABD in femur and tibia rotation supported the previous definition of an acceptable rotation difference between the normal and fractured femur and tibia of ≤15°and ≤10°, respectively. The possibility of higher external rotation on the right side needs to be taken into account during tibial surgery.

Combination therapy with immune checkpoint inhibitors and denosumab improves clinical outcomes in non-small cell lung cancer with bone metastases.

BACKGROUND: The concomitant use of denosumab and immune checkpoint inhibitor (ICI) treatment may have synergistic effects and enhance antitumor activity; however, this has not been fully evaluated. This study aimed to evaluate the clinical outcomes of non-small cell lung cancer (NSCLC) patients with bone metastases receiving combination therapy and to identify the best combination regimen. METHODS: Eighty-six NSCLC patients with bone metastases who received ICI treatment were enrolled in this study. The patients were divided into two groups; a denosumab combination group (D + ICI group; n = 47) and a non-combination group (non-D + ICI group; n = 39). The response rate (RR) for bone metastases, disease control rate (DCR), overall survival (OS), real world progression-free survival (rwPFS), and the incidence of immune-related adverse events (irAEs) were evaluated. Additionally, the time when denosumab treatment should commence and concomitant treatment duration were evaluated. RESULTS: The D + ICI group showed significantly better RR (40.4 % vs. 20.5 %, p = 0.01), DCR (67.3 % vs. 38.7 %, p = 0.02), OS (14.2 vs. 8.6 months, p = 0.02), and rwPFS (7.4 vs. 3.6 months, p < 0.01) than the non-D + ICI group; however, incidence of irAEs showed no difference (29.7 % vs. 12.8 %, p = 0.07). Although clinical outcomes did not differ regardless of whether denosumab was initiated before or after ICI treatment, the group that received concomitant denosumab for more than four months had significantly better RR (46.2 % vs. 17.4 %, p = 0.03), OS (20.3 vs. 3.8 months, p < 0.01), and rwPFS (10.9 vs. 2.8 months, p < 0.01) than the group that received concomitant denosumab for less than four months. However, the landmark analysis showed no significant differences in OS (20.4 vs. 12.7 months, p = 0.11) and rwPFS (22.8 vs. 11.2 months, p = 0.21), and the results of denosumab duration were influenced by long-term survivors. CONCLUSION: Denosumab showed favorable synergistic effects with ICI treatment and may significantly improve the response to bone metastasis and prognosis without increasing the incidence of irAEs.

Mutations in the SARS-CoV-2 spike proteins affected the ACE2-binding affinity during the development of Omicron pandemic variants.

Mutations in SARS-CoV-2 caused multiple waves of pandemics. To identify the function of such mutations, we investigated the binding affinity of the S protein with its receptor, ACE2. Omicron BA.1 showed significantly lower binding affinity with human ACE2 than prototype SARS-CoV-2 and Alpha strain, indicating that pre-Omicron to Omicron transition was not mediated by increasing the ACE2-binding affinity. Meanwhile, the later Omicron variants, BA.5 and XBB.1.5, showed significantly higher ACE2-binding affinity, suggesting that the increased ACE2-binding could be involved in the variant transition within Omicron strains. Furthermore, Alpha and Omicron variants, but not prototype SARS-CoV-2, bound mouse ACE2, which lead to a hypothesis that early Omicron strains evolved from Alpha strain by acquiring multiple mutations in mice.

Association between a history of major osteoporotic fractures and subsequent hip fracture: a systematic review and meta-analysis.

PURPOSE: A history of fractures involving the distal radius, proximal humerus, spine, and hip may be associated with the incidence of subsequent hip fractures in older people. However, a comprehensive summary of this association using a rigorous methodology is lacking. Our objective was to systematically review the literature and examine the association between four major osteoporotic fractures and subsequent hip fractures in individuals aged ≥ 50 years. METHODS: We searched MEDLINE, Embase, CENTRAL, ICTRP, and ClinicalTrials.gov on February 15, 2023. The search included cohort or case-control studies investigating the association between these four types of osteoporotic fractures and subsequent hip fractures. We pooled the hazard ratios (HRs) with 95% confidence intervals (CI) using the random-effects model. We used the Quality In Prognosis Studies tool to assess the risk of bias in the included studies, and the grading of recommendations assessment, development, and evaluation approach to determine the certainty of evidence. RESULTS: The selection process identified 48 studies for qualitative synthesis and 23 studies (2,239,217 participants) for meta-analysis. The overall methodological quality had a low risk of bias in 65% of the included studies. The association between a history of major osteoporotic fractures and subsequent hip fracture varied, with a high certainty of evidence for a history of proximal humerus and hip fractures (HR 2.02, 95% CI 1.75-2.33 and 2.86, 95% CI 1.92-4.25, respectively), moderate certainty for distal radius fractures (HR 1.66, 95% CI 1.53-1.81), and low certainty for spine fractures (HR 1.53, 95% CI 1.38-1.69). CONCLUSIONS: In conclusion, a history of major osteoporotic fractures, particularly distal radius, proximal humerus, and hip fractures, is associated with subsequent hip fractures in older adults. Further research is needed to verify the association between a history of spine fracture and subsequent hip fractures. PROTOCOL REGISTRATION: Open Science Framework ( https://osf.io/7fjuc ).