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Facilitates chromatin transcription (FACT) interacts with nucleosomes to promote gene transcription by regulating the dissociation and reassembly of nucleosomes downstream and upstream of RNA polymerase II (Pol II). A previous study reported that herpes simplex virus 1 (HSV-1) regulatory protein ICP22 interacted with FACT and was required for its recruitment to the viral DNA genome in HSV-1-infected cells. However, the biological importance of interactions between ICP22 and FACT in relation to HSV-1 infection is unclear. Here, we mapped the minimal domain of ICP22 required for its efficient interaction with FACT to a cluster of five basic amino acids in ICP22. A recombinant virus harboring alanine substitutions in this identified cluster led to the decreased accumulation of viral mRNAs from UL54, UL38, and UL44 genes, reduced Pol II occupancy of these genes in MRC-5 cells, and impaired HSV-1 virulence in mice following ocular or intracranial infection. Furthermore, the treatment of mice infected with wild-type HSV-1 with CBL0137, a FACT inhibitor currently being investigated in clinical trials, significantly improved the survival rate of mice. These results suggested that the interaction between ICP22 and FACT was required for efficient HSV-1 gene expression and pathogenicity. Therefore, FACT might be a potential therapeutic target for HSV-1 infection.IMPORTANCEICP22 is a well-known regulatory factor of HSV-1 gene expression, but its mechanism(s) are poorly understood. Although the interaction of FACT with ICP22 was reported previously, its significance in HSV-1 infection is unknown. Given that FACT is involved in gene transcription, it is of interest to investigate this interaction as it relates to HSV-1 gene expression. To determine a direct link between the interaction and HSV-1 infection, we mapped a minimal domain of ICP22 required for its efficient interaction with FACT and generated a recombinant virus carrying mutations in the identified domain. Using the recombinant virus, we obtained evidence suggesting that the interaction between ICP22 and FACT promoted Pol II transcription from HSV-1 genes and viral virulence in mice. In addition, CBL0137, an inhibitor of FACT, effectively protected mice from lethal HSV-1 infection, suggesting FACT might be a potential target for the development of novel anti-HSV drugs., Competing Interests: The authors declare no conflict of interest.

Background: Thyroid storm (TS), a life-threatening condition that can damage multiple organs, has limited therapeutic options. Hypercytokinemia is a suggested background, but the pathological condition is unclear and there are no appropriate animal models. We aimed to develop a TS mouse model by administration of triiodothyronine and lipopolysaccharide, and then to examine the effects of ghrelin on this model., Methods: We evaluated the use of serum IL-6 levels as a representative marker of hypercytokinemia in patients with TS. To establish the mouse model, preliminary experiments were conducted to determine the non-lethal doses of triiodothyronine and lipopolysaccharide when administered individually. As a TS model, C57BL/6 mice were administered with triiodothyronine 1.0 mg/kg (subcutaneously, once daily for seven consecutive days) and lipopolysaccharide 0.5 mg/kg (intraperitoneally, on day 7) to develop a lethal model with approximately 30% survival on day 8. We assessed the survival ratio, mouse sepsis scores and blood biomarkers (IL-6, metanephrine, alanine aminotransferase) and evaluated the effects of ghrelin 300 µg/kg on these parameters in TS model., Results: Serum IL-6 was increased in patients with TS compared with those with Graves' disease as the diseased control (18.2 vs. 2.85 pg/mL, P < .05, n = 4 each). The dosage for the murine TS model was triiodothyronine 1.0 mg/kg and lipopolysaccharide 0.5 mg/kg. The TS model group had increased mouse sepsis score, serum IL-6, metanephrine and alanine aminotransferase. In this model, the ghrelin improved the survival rate to 66.7% (P < .01, vs. 0% [saline-treated group]) as well as the mouse sepsis score, and it decreased the serum IL-6 and metanephrine., Conclusion: We established an animal model of TS that exhibits pathophysiological states similar to human TS with induction of serum IL-6 and other biomarkers by administration of T3 and LPS. The results suggest the potential effectiveness of ghrelin for TS in humans., (© 2024. The Author(s).)

Objectives: Cement penetration (CP) plays a key role in implant stability for cemented total knee arthroplasty (TKA), and the radiolucent line (RLL) >2 ​mm is a preliminary sign for loosening of components. However, the direct relationship between CP and the frequency of RLL >2 ​mm is unclear, and the best cut-off value for CP to prevent RLL >2 ​mm also remains unclear. This study aimed to investigate this relationship between CP and RLL and to determine the clinical cut-off value for tibial CP in patients 2 years after TKA., Methods: This retrospective study investigated 157 knees from 123 patients with osteoarthritis who underwent cemented TKA. The CP and RLL immediately after TKA and the RLL 2 years after TKA were measured for the medial, lateral, anterior, and posterior tibial baseplate zones. Receiver operating characteristic (ROC) curves were constructed to determine the best cut-off values for CP., Results: RLL >2 ​mm was not observed just after TKA. An RLL >2 ​mm was observed in any tibial baseplate zone in 22 knees from 20 patients (RLL+ group) and was not observed in the remaining (RLL- group) 2 years after TKA. The mean CP for all zones was significantly higher in the RLL- group (2.5 ​± ​1.1 ​mm) than in the RLL+ group (1.7 ​± ​0.6 ​mm; P ​< ​0.001). An RLL >2 ​mm was seen in 21 knees in the medial zone, 9 knees in the lateral zone, 8 knees in the anterior zone, and 3 knees in the posterior zone. CP values with RLL >2 ​mm were significantly lower than those without the RLL at the medial, anterior, and posterior tibial baseplate zones. The best cut-off values from the ROC curve of CP in each zone were between 1.1 ​mm and 2.1 ​mm., Conclusions: The depth of the CP directly affects the incidence of an RLL >2 ​mm. The best cut-off value for tibial CP to prevent an RLL >2 ​mm is 2.1 ​mm., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with hallux valgus are known to alter lower limb joint kinematics during gait. However, little information is available about gait changes following hallux valgus surgery. We aimed to longitudinally investigate lower limb kinematic changes at the mid and terminal stances of gait after hallux valgus surgery., Methods: This prospective observational study included 11 female patients (17 feet), who underwent first metatarsal osteotomy. Gait analyses were performed preoperatively and 1- and 2-year postoperatively using a three-dimensional motion capture system. Toe-out angle, ankle, knee, and hip joint angles during gait were calculated from the recorded data. The spatiotemporal parameters and these angles at the mid and terminal stances of gait were statistically compared between preoperative and postoperative periods., Findings: All spatiotemporal parameters remained unchanged postoperatively. The toe-out angle was significantly greater at 1- and 2-year postoperatively. The ankle pronation angle, the knee abduction angle, and the hip adduction angle at the mid and terminal stances of gait were smaller postoperatively compared to the preoperative. These angular changes showed a similar trend at 1 and 2 years postoperatively. However, the postoperative changes of the sagittal joint angles were relatively small., Interpretation: Hallux valgus surgery can affect the toe-out angle and the lower limb coronal kinematics at the mid and terminal stances of gait in patients with hallux valgus. However, surgical correction of hallux valgus deformity did not directly improve the gait characteristics in patients with hallux valgus., Competing Interests: Declaration of competing interest The author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: None declared.

Although the herpes simplex virus type 1 (HSV-1) genome was thought to contain approximately 80 different protein coding sequences (CDSs), recent multi-omics analyses reported HSV-1 encodes more than 200 potential CDSs. However, few of the newly identified CDSs were confirmed to be expressed at the peptide or protein level in HSV-1-infected cells. Furthermore, the impact of the proteins they encode on HSV-1 infection is largely unknown. This study focused on a newly identified CDS, UL31.6. Re-analyzation of our previous chemical proteomics data verified that UL31.6 was expressed at the peptide level in HSV-1-infected cells. Antisera raised against a viral protein encoded by UL31.6 (pUL31.6) reacted with a protein with an approximate molecular mass of 37  kDa in lysates of Vero cells infected with each of three HSV-1 strains. pUL31.6 was efficiently dissociated from virions in high-salt solution. A UL31.6-null mutation had a minimal effect on HSV-1 gene expression, replication, cell-to-cell spread, and morphogenesis in Vero cells; in contrast, it significantly reduced HSV-1 cell-to-cell spread in three neural cells but not in four non-neural cells including Vero cells. The UL31.6-null mutation also significantly reduced the mortality and viral replication in the brains of mice after intracranial infection, but had minimal effects on pathogenic manifestations in and around the eyes, and viral replication detected in the tear films of mice after ocular infection. These results indicated that pUL31.6 was a tegument protein and specifically acted as a neurovirulence factor by potentially promoting viral transmission between neuronal cells in the central nervous system.IMPORTANCERecent multi-omics analyses reported the herpes simplex virus type 1 (HSV-1) genome encodes an additional number of potential coding sequences (CDSs). However, the expressions of these CDSs at the peptide or protein levels and the biological effects of these CDSs on HSV-1 infection remain largely unknown. This study annotated a cryptic orphan CDS, termed UL31.6, an HSV-1 gene that encodes a tegument protein with an approximate molecular mass of 37  kDa, which specifically acts as a neurovirulence factor. Our study indicates that HSV-1 proteins important for viral pathogenesis remain to be identified and a comprehensive understanding of the pathogenesis of HSV-1 will require not only the identification of cryptic orphan CDSs using emerging technologies but also step-by-step and in-depth analyses of each of the cryptic orphan CDSs., Competing Interests: The authors declare no conflict of interest.

Objectives Our hospital was newly opened in the spring of 2020 in a rural area of Japan, with a remarkably developing aging society and population decline. This study aimed to clarify and evaluate the practice of osteoporosis care in our hospital for three years since its establishment. We report a retrospective review of therapeutic interventions for osteoporosis for patients who underwent surgical treatment for non-vertebral fragility fractures in our hospital. Methods We evaluated the practice of osteoporosis intervention in patients who underwent surgery for proximal humerus fractures (PHFs), distal radius fractures (DRFs), or proximal femoral fractures (PFFs) from April 2020 to the end of March 2023. Results There were 115 surgical cases with non-vertebral fractures (10 patients with PHF, 41 patients with DRF, and 64 with PFF). Among the patients who had received osteoporosis treatment at other hospitals before the injury, only 15 (13.0%) patients had been administered therapeutic intervention for osteoporosis by other clinics or hospitals. Also, 82 (71.3%) patients were newly diagnosed with osteoporosis in our hospital after surgery according to the Japanese osteoporosis guideline. New postoperative osteoporosis interventions were administered to 39 (47.0%) patients, of which the rate was higher than the previous reports in Japan. While there was no significant difference between upper limb fracture and PFF in the percentage per young adult mean of spine areal bone marrow density (aBMD), the femoral neck aBMDs in the upper limb fracture group were significantly higher than in the PFF group. The serum total P1NP levels were significantly lower and the 25(OH)D levels were also greater in the upper limb fracture group than in the PFF group, whereas the serum TRACP-5b levels were not significantly different between the two groups. Two (1.7%) patients were affected with secondary fractures during the study period. Conclusions The rates of therapeutic intervention for osteoporosis of patients with non-vertebral fractures, especially in those with upper limb fractures, in our hospital were considered to be greater than those in the previous reports. However, the intervention rate for patients with PFFs was not much, and there was still room for improvement in our hospital concerning osteoporosis diagnosis and treatment., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Ethical Committee of International University of Health and Welfare issued approval 20-Nr-014. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nakayama et al.)

Aim: Whether serum concentration of procalcitonin (PCT), brain natriuretic peptide (BNP) and albumin (Alb) have an association with the outcome of hospitalized older patients is unclear. We investigated clinical outcomes and any predictive factors in hospitalized Japanese older patients with a risk of infection., Methods: In the retrospective study, 820 Japanese patients were followed up for 30 days or until death. During the observation period, 656 patients survived and 164 patients died. The predictive factors of death were analyzed according to demographic and clinical variables., Results: The survival rate was decreased as the serum PCT increased from <0.5 to ≥10 ng/mL, as was also the case with BNP from <300 to ≥300 pg./mL, whereas low Alb (<2.5 g/dL) showed a lower survival rate than high Alb (≥2.5 g/dL; P < 0.01). Using the Cox regression model, the multivariable-adjusted hazard ratios (95% confidence interval) were as follows: PCT 0.5-2 versus <0.5 ng/mL: 1.61(1.04-2.49), PCT 2-10 versus <0.5 ng/mL: 1.91(1.15-3.16), PCT ≥10 versus <0.5 ng/mL: 2.90(1.84-4.59), high BNP 1.26 (0.89-1.76) and low Alb 0.68 (0.52-0.87). The mortality rate increased as the number of scores (PCT + BNP + Alb) increased., Conclusions: Concentration-dependent high PCT, high BNP and low Alb were positive risk factors associated with poor prognosis in hospitalized older patients with a risk of infection. Geriatr Gerontol Int 2024; 24: 571-576., (© 2024 Japan Geriatrics Society.)