Cancer risk assessment of premalignant breast tissues from patients with BRCA mutations by genome profiling.

Patients with germline pathogenic variants of BRCA1/2 genes have a particular predisposition to develop breast cancer. No clinical test has been developed to accurately and quantitatively evaluate their risk of developing breast cancer. We hypothesized that aberrant cell clonal expansion may be initiated in normal breast tissues without manifesting pathologic changes. To assess the prevalence of clonal expansion in the normal breast, we collected normal breast tissue from 24 breast cancer patients who had undergone surgical resection and 5 carriers of pathogenic BRCA1/2 variant who had undergone prophylactic mastectomy. Whole-exome sequencing (WES) was conducted in 97 specimens from 14 individuals, and TOP panel, a gene panel targeting 464 genes, was conducted in 321 specimens from 26 individuals, including 8 individuals with germline pathogenic variants of BRCA1/2 genes. Recurrent oncogenic mutations within PIK3CA, ARHGAP35, HRAS, and NF1 were identified in normal breast tissue at considerable variant allelic frequencies (VAF), suggesting clonal expansion. In addition, 937 normal breast tissues were evaluated using the Breast Cancer Panel (BCP) targeting 25 genes to determine the exact prevalence and distribution of clonal expansion. To assess the clonal expansion, we developed the clonality score, which is the mean value of clonal cell fractions for samples obtained from a given breast. The average clonality score in macroscopically normal breast tissue was 0.95 (0-2.46), with a significant difference between cases with and without a history of breast cancer of stage 2 or more advanced stage (p = 0.01). Additional WES on 42 samples with relatively large clone size (VAF > 3%) confirmed that these cell clones harbored multiple mutations (10.7 mutations/sample), and the number of existing mutations was consistent with the clone size (R = 0.50). The results suggest that clonal changes occur in normal breast tissue of women at high risk for breast cancer even before cancer is detected pathologically and/or radiologically, and the clonality score shows the potential to be a valid method of evaluating clonal expansion for cancer-risk assessment that provides appropriate preventive options for patients at high risk for breast cancer.

Radiographic factors affecting contralateral knee alignment in patients with dysplastic hip osteoarthritis.

INTRODUCTION: Patients with dysplastic hip arthritis (DHA) often present with abnormal knee alignment. We investigate the factors influencing varus and valgus knee alignment on the contralateral side in patients with unilateral DHA. METHODS: 123 patients with unilateral DHA were enrolled between 2018 and 2022. Based on the hip-knee-ankle angle (HKAA), patients were divided into three groups: neutral group (HKAA <3° varus and valgus), varus group (>3° varus), and valgus group (>3° valgus). Demographics, radiographic parameters, and functional scores were compared between the groups. RESULTS: There were 58, 44, and 21 patients in the neutral, varus, and valgus group, respectively. The varus group had a varus HKAA and hip adduction angle in the affected hip and a large femoral offset in the healthy hip. The valgus group had a valgus HKAA and large hip adduction angle in the affected hip and a small femoral offset in the healthy hip. In addition, the valgus group presented with pelvic obliquity, expressed as an upper pelvic tilt on the affected side. Multivariate analysis identified a varus HKAA in the affected hip (odds ratio [OR], 0.64; 95% confidence interval [CI]: 0.51-0.79; p < 0.01) as a factor associated with the varus group, while pelvic obliquity (OR, 0.69; 95% CI: 0.53-0.89; p = 0.01) was associated with the valgus group. The varus and valgus groups had significantly worse functional scores than the neutral group. CONCLUSIONS: This study demonstrated that varus and valgus alignments of the contralateral knee with unilateral DHA were associated with radiographic parameters and hip function.

Accelerometer-based portable navigation system shows no superior accuracy over pelvic alignment guide for acetabular cup placement in total hip arthroplasty in lateral decubitus position.

BACKGROUND: Total hip arthroplasty (THA) using a portable navigation system (PNS) incurs costs per procedure. However, it does not require a large console. This study aimed to compare the accuracy of acetabular cup placement using a pelvic alignment guide (PAG) attached to the pelvis and an accelerometer-based PNS in THA performed in the lateral decubitus position. METHODS: We retrospectively analyzed 100 hips that underwent primary THA in the lateral decubitus position between July 2018 and January 2021. The PAG was used in 50 hips, whereas the PNS was used in the other 50. Cup placement accuracy was measured using postoperative computed tomography scans, comparing errors in inclination and anteversion angles. The surgical time, blood loss, and complications were recorded. The follow-up period was at least 2 years in all cases. RESULTS: The mean absolute error of the inclination angle was similar between the groups (the PAG group: 3.7° ± 2.3° [range, 0.0-9.0]; the PNS group: 3.7° ± 2.3° [range, 0.2-10.5], p = 0.705). The mean absolute error of the anteversion angle was significantly smaller in the PAG group than in the PNS group (3.0° ± 2.4° [range, 0.0-9.7] vs. 6.5° ± 4.8° [range, 0.3-17.3], p < 0.001). The PAG group had a higher proportion of hips within 5° and 10° of the target angle (64 vs. 42%, P = 0.028, and 100 vs. 74%, p < 0.001, respectively). The PNS group had six hips with anteversion errors of 15° or more. Surgical time and blood loss were lower in the PAG group. The PNS group had one dislocation, whereas the PAG group did not. CONCLUSION: The accelerometer-based PNS did not demonstrate superior cup alignment accuracy compared to the PAG in THA performed in the lateral decubitus position. This finding informs surgeons that computer-assisted surgery is not necessarily superior to conventional THA using a PAG.

[Histiocytic sarcoma derived from the same origin as splenic marginal zone lymphoma revealed by exome analysis].

Histiocytic sarcoma (HS) is a rare aggressive hematological malignancy reported to occur secondary to B cell lymphoma. We report a case of HS secondary to splenic marginal zone lymphoma (SMZL) complicated by autoimmune hemolytic anemia (AIHA) in a 64-year-old man. He was referred to our department with anemia and was diagnosed as having AIHA. After starting treatment with prednisolone, atypical lymphocytes appeared in his blood tests, and a bone marrow biopsy revealed invasion by B cell lymphoma. A CT scan showed splenomegaly and a pancreatic mass, which confirmed the diagnosis of SMZL. The patient received bendamustine and rituximab as chemotherapy, which rapidly improved the anemia and splenomegaly and reduced atypical lymphocytes. However, left lumbar back pain appeared along with an increase in the pancreatic mass, and he died suddenly of acute renal failure. An autopsy revealed that the tumor had invaded several organs including the pancreas, and immunohistochemistry was positive for CD163, leading to the diagnosis of HS. Furthermore, the specimens of SMZL and HS were positive for IgH gene reconstitution, and exome analysis showed genetic abnormalities in 226 genes including CARD11, suggesting that the SMZL and HS had the same origin.

Bimodal machine learning model for unstable hips in infants: integration of radiographic images with automatically-generated clinical measurements.

Bimodal convolutional neural networks (CNNs) are frequently combined with patient information or several medical images to enhance the diagnostic performance. However, the technologies that integrate automatically generated clinical measurements within the images are scarce. Hence, we developed a bimodal model that produced automatic algorithm for clinical measurement (aaCM) from radiographic images and integrated the model with CNNs. In this multicenter research project, the diagnostic performance of the model was investigated with 813 radiographic hip images of infants at risk of developmental dysplasia of the hips (232 and 581 images of unstable and stable hips, respectively), with the ground truth defined by provocative examinations. The results indicated that the accuracy of aaCM was equal or higher than that of specialists, and the bimodal model showed better diagnostic performance than LightGBM, XGBoost, SVM, and single CNN models. aaCM can provide expert's knowledge in a high level, and our proposed bimodal model has better performance than the state-of-art models.

Characteristics of pelvic obliquity in dysplastic hip osteoarthritis.

PURPOSE: Factors affecting direction of pelvic obliquity (PO) in dysplastic hip osteoarthritis (DHOA) remains unclear. This retrospective cohort study evaluates morphological characteristics, spinal alignment, and hip function in patients with unilateral DHOA. METHODS: Between 2018 and 2022, 104 patients with unilateral DHA were enrolled. Patients were categorized into flat PO (F-PO group; PO < 2°), affected side PO (A-PO group; PO downward by ≥ 2°), and unaffected side PO (U-PO group; PO upward by ≥ 2°). Demographics, radiographic hip and lower limb parameters, spinal parameters, and functional scores were compared between the groups. RESULTS: There were 39, 44, and 21 patients in the F-PO, A-PO, and U-PO group, respectively. The subluxation percentage of Crowe classification showed a significant difference among the three groups. The femoral head lateralization distance was significantly greater in the U-PO group than in the F-PO and A-PO groups. Furthermore, the hip adduction angle was significantly lower in the A-PO group than in the F-PO and U-PO groups. The lumbar scoliosis angle was significantly different between the groups. In multivariate analysis, hip adduction angle was extracted as an independent factor associated with the A-PO. Age, subluxation percentage, and hip adduction angle were identified as independent factors associated with the U-PO. Harris hip score was significantly poorer in U-PO group than in F-PO group. CONCLUSIONS: Hip adduction angle influenced A-PO, while age, subluxation percentage, and hip adduction angle influenced U-PO; lumbar scoliosis angle was associated with PO direction. U-PO patients had poorer functional scores, indicating the impact of hip contracture and subluxation on PO direction in DHOA.

Preoperative Sarcopenia Severity and Clinical Outcomes after Total Hip Arthroplasty.

The outcome of total hip arthroplasty (THA) in patients with end-stage arthritis of the hip is associated with preoperative physical status. This study was performed to examine the relationship between the preoperative severity of sarcopenia and clinical outcomes after THA. This retrospective cohort study was performed among 306 consecutive patients (mean age: 63.7 ± 12.9 years, 222 women) undergoing THA at a university hospital. The severity of sarcopenia was determined based on the skeletal muscle mass index (SMI), handgrip strength, and gait speed according to the criteria of the Asian Working Group for Sarcopenia 2019. The severe sarcopenia prevalence rate was 10.6%. Severe sarcopenia was significantly associated with the risk of delayed functional recovery (adjusted odds ratio, 2.82; 95% confidence interval, 1.03-7.72; p = 0.043) compared with the non-sarcopenia group after adjusting for pre-existing risk factors, including preoperative hip function and physical activity. The addition of SMI, handgrip strength, and gait speed to the model for risk of functional recovery delay significantly increased the area under the receiver operating characteristic curve (p = 0.038). Severe sarcopenia was significantly associated with poorer hip function and patient-reported outcomes at 6 months after surgery compared with the non-sarcopenia group. Severe sarcopenia was adversely associated with postoperative clinical outcomes in patients undergoing THA.

Virological characteristics of the SARS-CoV-2 Omicron EG.5.1 variant.

In middle to late 2023, a sublineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. We performed multiscale investigations, including phylogenetic analysis, epidemic dynamics modeling, infection experiments using pseudoviruses, clinical isolates, and recombinant viruses in cell cultures and experimental animals, and the use of human sera and antiviral compounds, to reveal the virological features of the newly emerging EG.5.1 variant. Our phylogenetic analysis and epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T are critical to its increased viral fitness. Experimental investigations on the growth kinetics, sensitivity to clinically available antivirals, fusogenicity, and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 are comparable to those of XBB.1.5. However, cryo-electron microscopy revealed structural differences between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible in our experimental setup. Our multiscale investigations provide knowledge for understanding the evolutionary traits of newly emerging pathogenic viruses, including EG.5.1, in the human population.

Virological characteristics of a SARS-CoV-2-related bat coronavirus, BANAL-20-236.

BACKGROUND: Although several SARS-CoV-2-related coronaviruses (SC2r-CoVs) were discovered in bats and pangolins, the differences in virological characteristics between SARS-CoV-2 and SC2r-CoVs remain poorly understood. Recently, BANAL-20-236 (B236) was isolated from a rectal swab of Malayan horseshoe bat and was found to lack a furin cleavage site (FCS) in the spike (S) protein. The comparison of its virological characteristics with FCS-deleted SARS-CoV-2 (SC2ΔFCS) has not been conducted yet. METHODS: We prepared human induced pluripotent stem cell (iPSC)-derived airway and lung epithelial cells and colon organoids as human organ-relevant models. B236, SARS-CoV-2, and artificially generated SC2ΔFCS were used for viral experiments. To investigate the pathogenicity of B236 in vivo, we conducted intranasal infection experiments in hamsters. FINDINGS: In human iPSC-derived airway epithelial cells, the growth of B236 was significantly lower than that of the SC2ΔFCS. A fusion assay showed that the B236 and SC2ΔFCS S proteins were less fusogenic than the SARS-CoV-2 S protein. The infection experiment in hamsters showed that B236 was less pathogenic than SARS-CoV-2 and even SC2ΔFCS. Interestingly, in human colon organoids, the growth of B236 was significantly greater than that of SARS-CoV-2. INTERPRETATION: Compared to SARS-CoV-2, we demonstrated that B236 exhibited a tropism toward intestinal cells rather than respiratory cells. Our results are consistent with a previous report showing that B236 is enterotropic in macaques. Altogether, our report strengthens the assumption that SC2r-CoVs in horseshoe bats replicate primarily in the intestinal tissues rather than respiratory tissues. FUNDING: This study was supported in part by AMED ASPIRE (JP23jf0126002, to Keita Matsuno, Kazuo Takayama, and Kei Sato); AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers "UTOPIA" (JP223fa627001, to Kei Sato), AMED SCARDA Program on R&D of new generation vaccine including new modality application (JP223fa727002, to Kei Sato); AMED SCARDA Hokkaido University Institute for Vaccine Research and Development (HU-IVReD) (JP223fa627005h0001, to Takasuke Fukuhara, and Keita Matsuno); AMED Research Program on Emerging and Re-emerging Infectious Diseases (JP21fk0108574, to Hesham Nasser; JP21fk0108493, to Takasuke Fukuhara; JP22fk0108617 to Takasuke Fukuhara; JP22fk0108146, to Kei Sato; JP21fk0108494 to G2P-Japan Consortium, Keita Matsuno, Shinya Tanaka, Terumasa Ikeda, Takasuke Fukuhara, and Kei Sato; JP21fk0108425, to Kazuo Takayama and Kei Sato; JP21fk0108432, to Kazuo Takayama, Takasuke Fukuhara and Kei Sato; JP22fk0108534, Terumasa Ikeda, and Kei Sato; JP22fk0108511, to Yuki Yamamoto, Terumasa Ikeda, Keita Matsuno, Shinya Tanaka, Kazuo Takayama, Takasuke Fukuhara, and Kei Sato; JP22fk0108506, to Kazuo Takayama and Kei Sato); AMED Research Program on HIV/AIDS (JP22fk0410055, to Terumasa Ikeda; and JP22fk0410039, to Kei Sato); AMED Japan Program for Infectious Diseases Research and Infrastructure (JP22wm0125008 to Keita Matsuno); AMED CREST (JP21gm1610005, to Kazuo Takayama; JP22gm1610008, to Takasuke Fukuhara; JST PRESTO (JPMJPR22R1, to Jumpei Ito); JST CREST (JPMJCR20H4, to Kei Sato); JSPS KAKENHI Fund for the Promotion of Joint International Research (International Leading Research) (JP23K20041, to G2P-Japan Consortium, Keita Matsuno, Takasuke Fukuhara and Kei Sato); JST SPRING (JPMJSP2108 to Shigeru Fujita); JSPS KAKENHI Grant-in-Aid for Scientific Research C (22K07103, to Terumasa Ikeda); JSPS KAKENHI Grant-in-Aid for Scientific Research B (21H02736, to Takasuke Fukuhara); JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (22K16375, to Hesham Nasser; 20K15767, to Jumpei Ito); JSPS Core-to-Core Program (A. Advanced Research Networks) (JPJSCCA20190008, to Kei Sato); JSPS Research Fellow DC2 (22J11578, to Keiya Uriu); JSPS Research Fellow DC1 (23KJ0710, to Yusuke Kosugi); JSPS Leading Initiative for Excellent Young Researchers (LEADER) (to Terumasa Ikeda); World-leading Innovative and Smart Education (WISE) Program 1801 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to Naganori Nao); Ministry of Health, Labour and Welfare (MHLW) under grant 23HA2010 (to Naganori Nao and Keita Matsuno); The Cooperative Research Program (Joint Usage/Research Center program) of Institute for Life and Medical Sciences, Kyoto University (to Kei Sato); International Joint Research Project of the Institute of Medical Science, the University of Tokyo (to Terumasa Ikeda and Takasuke Fukuhara); The Tokyo Biochemical Research Foundation (to Kei Sato); Takeda Science Foundation (to Terumasa Ikeda and Takasuke Fukuhara); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Terumasa Ikeda); The Naito Foundation (to Terumasa Ikeda); Hokuto Foundation for Bioscience (to Tomokazu Tamura); Hirose Foundation (to Tomokazu Tamura); and Mitsubishi Foundation (to Kei Sato).

Caging Bioactive Triarylimidazoles: An Approach to Create Visible Light-Activatable Drugs.

Imidazoles are crucial structural components in a variety of small-molecule inhibitors designed to target different kinases in anticancer treatment. However, the effectiveness of such inhibitors is often hampered by nonspecific effects and the development of resistance. Photopharmacology provides a compelling solution by enabling external control over drug activity with spatiotemporal precision. Herein, we introduce a novel strategy for caging bioactive triarylimidazole-based drug molecules. This approach involves introducing a dialkylamino group as a photoremovable group on the carbon atom of the imidazole ring, which intrinsically modulates the core structure from planar imidazole to tetrahedral 2H-imidazole, enabling the caged compound to be selectively uncaged upon visible light exposure. We applied this innovative caging technique to SB431542, a triarylimidazole-based small-molecule inhibitor that targets the pivotal TGF-ß signaling pathway, the dysregulation of which is linked to several human diseases, including cancer. Our results demonstrated the selective inhibition of human breast cancer cell migration in vitro upon light activation, highlighting the potential of our approach to transform triarylimidazole-based drug molecules into visible light-activatable drugs, thereby facilitating spatiotemporal regulation of their pharmacological activity.

Involvement of SARS-CoV-2 accessory proteins in immunopathogenesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the largest single-stranded RNA virus known to date. Its genome contains multiple accessory protein genes that act against host immune responses but are not required for progeny virus production. The functions of the accessory proteins in the viral life cycle have been examined, but their involvement in viral pathogenicity remains unclear. Here, we investigated the roles of the accessory proteins in viral immunopathogenicity. To this end, recombinant SARS-CoV-2 possessing nonsense mutations in the seven accessory protein open reading frames (ORFs) (ORF3a, ORF3b, ORF6, ORF7a, ORF8, ORF9b, and ORF10) was de novo generated using an early pandemic SARS-CoV-2 strain as a backbone. We confirmed that the resultant virus (termed ORF3-10 KO) did not express accessory proteins in infected cells and retained the desired mutations in the viral genome. In cell culture, the ORF3-10 KO virus exhibited similar virus growth kinetics as the parental virus. In hamsters, ORF3-10 KO virus infection resulted in mild weight loss and reduced viral replication in the oral cavity and lung tissue. ORF3-10 KO virus infection led to mild inflammation, indicating that an inability to evade innate immune sensing because of a lack of accessory proteins impairs virus growth in vivo and results in quick elimination from the body. Overall, we showed that SARS-CoV-2 accessory proteins are involved in immunopathogenicity.

Clinical outcome, radiological findings, and genetic features of IDH-mutant brainstem glioma in adults.

BACKGROUND: With the recent advent of genetic testing, IDH-mutant glioma has been found among adult brainstem gliomas. However, the clinical outcome and prognosis of IDH-mutant brainstem gliomas in adults have not been elucidated. This study aimed to investigate the clinical outcome, radiological findings, and genetic features of adult patients with IDH-mutant diffuse brainstem gliomas. METHODS: Data from adult patients with brainstem glioma at Hokkaido University Hospital between 2006 and 2022 were retrospectively analyzed. Patient characteristics, treatment methods, genetic features, and prognosis were evaluated. RESULTS: Of 12 patients with brainstem glioma with proven histopathology, 4 were identified with IDH mutation. All patients underwent local radiotherapy with 54 Gray in 27 fractions combined with chemotherapy with temozolomide. Three patients had IDH1 R132H mutation and one had IDH2 R172G mutation. The median progression-free survival and overall survival were 68.4 months and 85.2 months, respectively, longer than that for IDH-wildtype gliomas (5.6 months and 12.0 months, respectively). At the time of initial onset, contrast-enhanced lesions were observed in two of the four cases in magnetic resonance imaging. CONCLUSION: As some adult brainstem gliomas have IDH mutations, and a clearly different prognosis from those with IDH-wildtype, biopsies are proactively considered to confirm the genotype.

Regulation of cytokine and chemokine expression by histone lysine methyltransferase MLL1 in rheumatoid arthritis synovial fibroblasts.

Histone lysine methylation is thought to play a role in the pathogenesis of rheumatoid arthritis (RA). We previously reported aberrant expression of the gene encoding mixed-lineage leukemia 1 (MLL1), which catalyzes methylation of histone H3 lysine 4 (H3K4), in RA synovial fibroblasts (SFs). The aim of this study was to elucidate the involvement of MLL1 in the activated phenotype of RASFs. SFs were isolated from synovial tissues obtained from patients with RA or osteoarthritis (OA) during total knee joint replacement. MLL1 mRNA and protein levels were determined after stimulation with tumor necrosis factor α (TNFα). We also examined changes in trimethylation of H3K4 (H3K4me3) levels in the promoters of RA-associated genes (matrix-degrading enzymes, cytokines, and chemokines) and the mRNA levels upon small interfering RNA-mediated depletion of MLL1 in RASFs. We then determined the levels of H3K4me3 and mRNAs following treatment with the WD repeat domain 5 (WDR5)/MLL1 inhibitor MM-102. H3K4me3 levels in the gene promoters were also compared between RASFs and OASFs. After TNFα stimulation, MLL1 mRNA and protein levels were higher in RASFs than OASFs. Silencing of MLL1 significantly reduced H3K4me3 levels in the promoters of several cytokine (interleukin-6 [IL-6], IL-15) and chemokine (C-C motif chemokine ligand 2 [CCL2], CCL5, C-X-C motif chemokine ligand 9 [CXCL9], CXCL10, CXCL11, and C-X3-C motif chemokine ligand 1 [CX3CL1]) genes in RASFs. Correspondingly, the mRNA levels of these genes were significantly decreased. MM-102 significantly reduced the promoter H3K4me3 and mRNA levels of the CCL5, CXCL9, CXCL10, and CXCL11 genes in RASFs. In addition, H3K4me3 levels in the promoters of the IL-6, IL-15, CCL2, CCL5, CXCL9, CXCL10, CXCL11, and CX3CL1 genes were significantly higher in RASFs than OASFs. Our findings suggest that MLL1 regulates the expression of particular cytokines and chemokines in RASFs and is associated with the pathogenesis of RA. These results could lead to new therapies for RA.

Retrospective study comparing the accuracies of handheld infrared stereo camera and augmented reality-based navigation systems for total hip arthroplasty.

BACKGROUND: The use of portable navigation systems (PNS) in total hip arthroplasty (THA) has become increasingly prevalent, with second-generation PNS (sPNS) demonstrating superior accuracy in the lateral decubitus position compared to first-generation PNS. However, few studies have compared different types of sPNS. This study retrospectively compares the accuracy and clinical outcomes of two different types of sPNS instruments in patients undergoing THA. METHODS: A total of 158 eligible patients who underwent THA at a single institution between 2019 and 2022 were enrolled in the study, including 89 who used an accelerometer-based PNS with handheld infrared stereo cameras in the Naviswiss group (group N) and 69 who used an augmented reality (AR)-based PNS in the AR-Hip group (group A). Accuracy error, navigation error, clinical outcomes, and preparation time were compared between the two groups. RESULTS: Accuracy errors for Inclination were comparable between group N (3.5° ± 3.0°) and group A (3.5° ± 3.1°) (p = 0.92). Accuracy errors for anteversion were comparable between group N (4.1° ± 3.1°) and group A (4.5° ± 4.0°) (p = 0.57). The navigation errors for inclination (group N: 2.9° ± 2.7°, group A: 3.0° ± 3.2°) and anteversion (group N: 4.3° ± 3.5°, group A: 4.3° ± 4.1°) were comparable between the groups (p = 0.86 and 0.94, respectively). The preparation time was shorter in group A than in group N (p = 0.036). There were no significant differences in operative time (p = 0.255), intraoperative blood loss (p = 0.387), or complications (p = 0.248) between the two groups. CONCLUSION: An Accelerometer-based PNS using handheld infrared stereo cameras and AR-based PNS provide similar accuracy during THA in the lateral decubitus position, with a mean error of 3°-4° for both inclination and anteversion, though the AR-based PNS required a shorter preparation time.

Humoral responses are enhanced by facilitating B cell viability by Fcrl5 overexpression in B cells.

B cell initial activity is regulated through a balance of activation and suppression mediated by regulatory molecules expressed in B cells; however, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the function of the Fc receptor-like (Fcrl) family molecule Fcrl5, which is constitutively expressed in naive B cells, in humoral immune responses. Our study demonstrated that B cell-specific overexpression of Fcrl5 enhanced antibody (Ab) production in both T cell-independent type 1 (TI1) and T cell-dependent (TD) responses. Additionally, it promoted effector B cell formation under competitive conditions in TD responses. Mechanistically, in vitro ligation of Fcrl5 by agonistic Abs reduced cell death and enhanced proliferation in lipopolysaccharide-stimulated B cells. In the presence of anti-CD40 Abs and IL-5, the Fcrl5 ligation not only suppressed cell death but also enhanced differentiation into plasma cells. These findings reveal a novel role of Fcrl5 in promoting humoral immune responses by enhancing B cell viability and plasma cell differentiation.

The impact of goal-directed prehabilitation therapy on functional capacity in patients undergoing hepatobiliary and pancreatic surgery: A randomized clinical trial.

BACKGROUND: Emerging evidence has supported the idea that goal-directed prehabilitation is a promising approach to boost functional capacity in preoperative patients. However, its usefulness has not been tested in the hepatobiliary and pancreatic fields. The objective of this trial was to investigate the efficacy of goal-directed prehabilitation for improving functional capacity in patients who were planned to undergo major hepatobiliary and pancreatic operations. METHODS: This assessor-blinded, parallel-arm, randomized clinical trial recruited patients who were scheduled for major hepatobiliary and pancreatic surgeries for malignancy. Patients were randomly allocated into the step goal-directed prehabilitation group as the test group and into the conventional prehabilitation group as the control group. Patients in the goal-directed prehabilitation group participated in a walking prehabilitation program with an intergrading goal of the step count. Patients in the conventional prehabilitation group received standard physical and nutritional prehabilitation. The primary outcome was change in the 6-minute walking distance, which ranged from the time before starting prehabilitation (baseline) to the time after completing prehabilitation (immediately before surgery). RESULTS: Among 180 randomized patients, 144 patients were included in the primary analysis (73 patients in the conventional prehabilitation group and 71 patients in the goal-directed prehabilitation group). The mean change in the 6-minute walking distance was 27 meters in the conventional prehabilitation group and 31 meters in the goal-directed prehabilitation group (P = .633). CONCLUSION: In patients undergoing major hepatobiliary and pancreatic surgeries for malignancies, a goal-directed prehabilitation program did not result in a significantly greater increase in functional capacity than did conventional prehabilitation. REGISTRATION NUMBER: UMIN000038791 (https://www.umin.ac.jp/).

Association between advanced glycation end-products and fall risk in older adults: The Yakumo Study.

AIM: Advanced glycation end-products (AGEs) are irreversibly and heterogeneously formed compounds during the non-enzymatic modification of macromolecules, such as proteins. Aging and lifestyle habits, such as high-fat and high-protein diets, and smoking, promote AGEs accumulation. This study aimed to investigate the relationship between fall risk and AGEs in community-dwelling older adults. METHODS: This cross-sectional study included patients from the 2022 Yakumo Study who were evaluated for fall risk index 5-items version, locomotive syndrome stage and AGEs. AGEs were evaluated using Skin autofluorescence (SAF) measured by the AGE reader (DiagnOptics Technologies BV, Groningen, the Netherlands). We divided the participants into two groups according to the presence or absence of fall risk (fall risk index 5-items version ≥6 or not), and investigated the factors associated with fall risk. RESULTS: The fall risk group had a higher age and SAF, and a higher proportion of locomotive syndrome stage >2 than the without fall risk group in patients aged ≥65 years (P < 0.01). The multivariate logistic regression analysis after adjustment of age, sex and body mass index showed that locomotive syndrome stage ≥2 and SAF were independent associators of fall risk in older adults (odds ratio 3.26, P < 0.01, odds ratio 2.96, P < 0.05, respectively). The optimal cutoff value of the SAF for fall risk was 2.4 (area under the curve 0.631; 95% CI 0.53-0.733; sensitivity 0.415; specificity 0.814; P < 0.05). CONCLUSION: The accumulation of AGEs in skin tissues can be used to screen for fall risk comprehensively. Geriatr Gerontol Int 2024; 24: 517-522.