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Kenji Inoue,1 Takayuki Fujimoto,1 Risako Higa,1 Ryo Moriyama,1 Hiromi Kohmoto,1 Haruka Nagumo,1 Masato Wakakura,1 Goji Tomita21Inouye Eye Hospital, Chiyoda-ku, Tokyo, 2Second Department of Ophthalmology, Toho University School of Medicine, Meguro-ku, Tokyo, JapanBackground: The purpose of this prospective study was to investigate the intraocular pressure (IOP)-lowering effect and safety of latanoprost 0.005% + timolol maleate 0.5% fixed combination eyedrops, now available in Japan.Materials and methods: Thirty-one patients diagnosed with primary open-angle glaucoma who had an insufficient intraocular pressure (IOP) decrease with latanoprost 0.005% eyedrop monotherapy were enrolled. The latanoprost 0.005% eyedrops were discontinued, and administration of latanoprost 0.005%/timolol maleate 0.5% fixed combination eyedrops was initiated without any washout period. IOP was compared before and at months 1, 3, and 6 after the switch. The incidence of adverse reactions was investigated at every follow-up visit.Results: Mean IOP was 17.3 ± 2.7 mmHg before the switch, 15.5 ± 2.6 mmHg one month after the switch, 14.9 ± 2.4 mmHg 3 months after the switch, and 15.1 ± 2.2 mmHg 6 months after the switch, indicating that IOP decreased significantly after the change. The IOP reduction rate was 9.9% ± 11.5% after one month, 13.1% ± 10.9% after 3 months, and 11.2% ± 11.8% after 6 months. Two patients (6.5%) discontinued therapy due to adverse reactions (one case each of itchiness and bradycardia).Conclusion: When latanoprost 0.005% eyedrop monotherapy was replaced by latanoprost 0.005% + timolol maleate 0.5% fixed combination eyedrops, IOP decreased significantly without increasing the frequency of administration, and safety was satisfactory.Keywords: latanoprost 0.005%, timolol maleate 0.5%, fixed combination, eyedrops, intraocular pressure, switch

Research is presented describing the study of data compression techniques using parallel algorithms.

Background: Reports of cases of bacterial infection due to transfusion of red blood cell (RBC) components (RBC-TTBI) are relatively rare. Hence, the possibility of undetectable bacterial contamination in RBCs, especially by psychrotrophic bacteria, must be clarified., Study Design and Methods: We assessed nine psychrotrophic bacterial species, including those implicated in bacteremia or RBC-TTBIs. They were cultured on plates from 4 to 37°C to determine their optimal growth temperatures. We also assessed the detection capabilities of the automated culture/alarm system BACT/ALERT VIRTUO (VIRTUO) using BPA (aerobic) and BPN (anaerobic) bottles. In addition, bacteria-inoculated RBCs were incubated at 4°C for 42 days, with samples assessed weekly for bacterial growth using plate culture, VIRTUO, visual inspection, and endotoxin production., Results: Two Psychrobacter species exhibited weak or no proliferation at temperatures ≥30°C in plate cultures. Three Pseudomonas species, one Psychrobacter species, and one psychrotrophic lactic acid bacteria proliferated in RBCs at 4°C, reaching 10 4 -10 8 colony-forming units/mL (growth count) and 15-39,230 pg/mL (endotoxin production) by day 14. VIRTUO, operating at 36°C, failed to consistently yield reliable results for any of the tested bacterial species. Notably, visual changes in bag appearance were observed from day 21 in four species that proliferated in RBCs., Discussion: Each psychrotrophic bacteria demonstrated a specific temperature preference for optimal proliferation. Standard culture tests, typically conducted at 35-37°C, often fail to detect the growth of such bacteria, suggesting they may be overlooked in the cultural analysis of suspected RBC-TTBI cases., (© 2025 AABB.)

Introduction: Pharmacological treatment of unresectable hepatocellular carcinoma (uHCC) includes sorafenib and lenvatinib, a tyrosine kinase inhibitor, which are linked to low serum levels of carnitine and reduced skeletal muscle volume. Nowadays, atezolizumab plus bevacizumab (Atezo/Bev) combination therapy is recommended as the first-line treatment for patients with uHCC. However, the association with decreased muscle mass or cardiac function is unknown. Therefore, this study aimed to evaluate the effects of Atezo/Bev on skeletal muscle volume and cardiac function in patients with uHCC., Methods: This retrospective study included 55 adult Japanese patients with chronic liver diseases and uHCC treated with Atezo/Bev. Patients were divided into three groups according to age: middle, preold, and old. Serum levels of carnitine and cardiac function were measured before and after 3 weeks of treatment. The psoas muscle index (PMI) was measured before and after 6 weeks of treatment., Results: After treatment, the global longitudinal strain was significantly lower in the old group, whereas the PMI and ejection fraction were significantly lower in the preold and old groups. However, no significant difference in serum levels of total carnitine and those fractions with treatment in each group was found. Cardiac function decreased in the preold and old groups., Conclusion: When treating patients with uHCC by Atezo/Bev, caution should be taken in preold and old patients because they are vulnerable to decreased skeletal muscle mass and deterioration of cardiac function. Strength training and regular monitoring of cardiac function are encouraged in these groups., (© 2024 S. Karger AG, Basel.)

Introduction: In atezolizumab plus bevacizumab (Atezo/Bev) combination treatment, both drugs act on the immune system. Previously, we reported that immunological changes after Atezo/Bev administration for unresectable hepatocellular carcinoma (uHCC) revealed significant alterations in interleukin (IL)-6, soluble IL-2 receptor, tumor necrosis factor-alpha, and programmed cell death-1 levels. Among these variable factors, serum levels of IL-6 can be easily measured on a commercial basis. Therefore, this study aimed to investigate the utility of serum IL-6 as a predictor of tumor response to Atezo/Bev treatment for uHCC., Method: The study included 44 patients with HCC treated with Atezo/Bev. Blood samples were collected before and 3 weeks after treatment, and tumor response was assessed using contrast-enhanced computed tomography 6 weeks after treatment., Results: Significant changes in serum IL-6 levels were observed in patients treated with Atezo/Bev as first-line therapy but not in those treated with it as second-line or later-line therapy. In patients treated with Atezo/Bev as first-line therapy, serum IL-6 levels increased significantly after treatment in patients with a complete or partial response but not in patients with stable or progressive disease. Furthermore, compared to other tumor markers such as alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein, and des-gamma-carboxyprothrombin, serum IL-6 levels exhibited the highest sensitivity in predicting tumor response during the treatment period., Conclusion: In patients with uHCC treated with Atezo/Bev, serum IL-6 levels could serve as a potential predictor of tumor response. Elevated levels after treatment may indicate a favorable tumor response and prognosis., (© 2024 S. Karger AG, Basel.)

A 51-year-old man presented with sudden-onset palpitations and dyspnea that had started 8 h earlier. The patient was restless and tachypneic and had persistent vomiting upon arrival. His sensorium and oxygen saturation levels rapidly declined three hours after arrival, and he was placed on a ventilator. On hospitalization day 2, he was removed from the ventilator and claimed that he had consumed a large amount of energy drinks (oral caffeine intake, approximately 1 g). The theophylline level on arrival had been elevated (9.0 μg/mL). Caffeine intoxication should be considered in patients presenting with restlessness, tachypnea, frequent vomiting, lactic acidosis, and electrolyte abnormalities.

[Purpose] When fabricating metal strut ankle-foot orthoses, previous studies have reported that shape acquisition is more efficient with a plastic cast than with a plaster of Paris bandage; however, this has not been quantitatively evaluated. This study aimed to clarify the usefulness of plastic casts by quantitatively evaluating the time spent and body shape accuracy among different methods of shape acquisition. [Participants and Methods] We compared the time spent and acquired shapes among the plaster of Paris bandage, plastic cast, and trace methods in 30 limbs of 15 healthy participants. Three-dimensional scans of the lower legs of participants were used as references to compare the three methods. [Results] The plastic cast method required less time than the plaster of Paris bandage method and provided a more accurate shape than the trace method did. However, the plastic cast method resulted in an increased overall width and circumferential diameter owing to the thickness of the stockinette and plastic cast. [Conclusion] The plastic cast method may be useful in reducing the time and burden of fabricating metal strut ankle-foot orthoses. The use of slightly narrow dimensions during the metal strut bending process can account for the increased width and diameter., Competing Interests: The authors declare no conflicts of interest., (2024©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Video 1How to use an endoscopic hand-suturing device (video version)., Competing Interests: The authors disclosed no financial relationships relevant to this publication., (© 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc.)

A 66-year-old man presented to the gastroenterology department with anal pain. For >10 years, he had used an electric bidet toilet while defecating for >5 min at a time, because of constipation. Two weeks prior to his visit, he became aware of discomfort in his anal area and had used an enema 1 week previously. He had persistent diarrhea and began to use the electric bidet toilet at the highest water pressure for long periods. As a result, his anal pain worsened. A colonoscopy revealed circumferential inflammation and ulceration extending from the anal canal to the lower rectum. Approximately half of the Japanese population washes their anuses before and after defecation. Cleaning the anus after defecation using a bidet contributes to hand hygiene and local comfort, and may be effective against constipation. However, excessive bidet use may cause rectal disorders, such as rectal mucosal prolapse syndrome and solitary rectal ulcers. Herein, we report a rare case of a patient with advanced rectal ulceration caused by electric bidet toilet usage., Competing Interests: None., (© 2024 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Introduction: Atezolizumab plus bevacizumab (AteBev) combination treatment is widely used as first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC). We aimed to clarify therapeutic issues regarding serum cytokines and the immune reaction in patients with uHCC treated with AteBev., Methods: We analyzed preserved serum from a previous prospective study on adult Japanese patients with chronic liver disease and uHCC who received AteBev treatment at our hospital. In that study, AteBev was administered intravenously every 3 weeks, and blood samples were collected before and after 3 weeks' treatment. Dynamic computed tomography was performed after 6 weeks of treatment to assess response., Results: In the prospective study, 21 of the 59 patients showed partial response (PR) and 19 patients showed stable disease, but 19 patients showed progressive disease (PD). We found that serum levels of tumor necrosis factor-alpha, interleukin (IL)-6, and soluble IL-2 receptor (IL-2R) increased significantly in the PR group, but only soluble IL-2R increased significantly in the PD group. Regulatory T cells decreased significantly in the PD group, but there was no significant change in Th1 or Th2 cells from before to after treatment in any group. As regards soluble MHC-class I, pre-treatment levels were significantly lower in the PD group than in the PR group, and serum levels increased significantly with treatment in the PD group., Conclusion: These findings reveal a need to further improve T-cell priming and to further make T cells recognize tumor antigens in uHCC., (© 2024 S. Karger AG, Basel.)

Background: Dyspnea is an unpleasant subjective symptom and is associated with decreased physical activity level (PAL). Effect of blowing air toward the face has received a great deal of attention as a symptomatic therapy for dyspnea. However, little is known about the duration of its effect and its impact on PAL. Therefore, this study aimed to measure dyspnea severity and changes in dyspnea and PALs with air blasts to the face., Methods: The trial conducted was open-label, randomized, and controlled. This study included out-patients with dyspnea caused by chronic respiratory deficiency. Subjects were provided a small fan and instructed to blow air toward their faces either twice a day or when having trouble breathing. Subsequently, severity of dyspnea and PALs was measured using visual analog scale and physical activity scale for the elderly (PASE), respectively, before and after 3-week treatment. Amounts of changes in dyspnea and PALs before and after treatment were compared using analysis of covariance., Results: Overall, 36 subjects were randomized, and 34 were analyzed. Mean age was 75.4 y (26 males [76.5%] and 8 females [23.5%]). Visual analog scale score for dyspnea (SD) before treatment was 33 (13.9) mm and 42 (17.5) mm in the control and intervention groups, respectively. PASE score before treatment was 78.0 (45.1) and 57.7 (38.0) in the control and intervention groups, respectively. No significant difference in changes in dyspnea severity and PAL was observed between the 2 groups., Conclusions: No significant difference was observed for dyspnea and PALs in subjects after blowing air toward their own faces with a small fan for 3 weeks at home. Disease variability and impact of protocol violations were high due to small number of cases. Further studies with a design focused on subject protocol adherence and measurement methods are required to understand impact of air flow on dyspnea and PAL., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

Small extracellular vesicles (sEVs) such as exosomes can efficiently deliver nucleic acids into the cytosol of recipient cells. However, the molecular mechanism of the subsequent fusion with an endosome is not well understood. In this study, we developed an in vitro lipid-mixing assay using an endosomal-mimicking anionic liposome to investigate the fusion between sEVs and endosomes. We observed that the particle number ratio between the sEVs and the anionic liposomes, the diameter of the liposomes, and the buffer pH were all important for fusion activity. Furthermore, we optimized the liposomal lipid composition and demonstrated that incorporating the anionic lipid bis(monooleoylglycero) phosphate and cholesterol was important for efficient and reliable fusion. Our in vitro assay suggested that a decrease in pH increased the fusion activity. Additionally, it was suggested that this pH-dependent increase in the fusion activity was predominantly due to a change in the sEVs. sEVs possess a larger fusion activity than artificial liposomes that mimic the physicochemical properties of exosomes. These results are consistent with those of previous in vivo studies, supporting the physiological relevance of our system. This study provides an important platform for further research to clarify the molecular mechanisms of fusion between sEVs and endosomes., 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 © 2023 Elsevier Inc. All rights reserved.)

Introduction: Atezolizumab, an immune checkpoint inhibitor, plus bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor (VEGF), is an approved first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). Immune checkpoint inhibitors are more effective in patients with HCC when administered with anti-VEGF drugs; however, these drugs affect host immunity. Lenvatinib is an anti-VEGF agent used to treat HCC; therefore, this study evaluated the effect of treatment of HCC with lenvatinib on host immunity in patients with chronic liver disease (CLD)., Methods: We studied adult Japanese patients with CLD and unresectable HCC treated with lenvatinib at our hospital. Lenvatinib was administered for 4 weeks (8 mg/day for bodyweight <60 kg; 12 mg/day for bodyweight >60 kg). Blood samples were collected at baseline and at 4 weeks of treatment and examined for immune-related changes., Results: Forty-three patients were enrolled in this study. We found a significant increase in T helper (Th) 1 cells following 4 weeks of lenvatinib treatment, although there was no significant difference in Th2 cells and regulatory T cells. We also found a significant increase in serum levels of TNF-alpha, soluble TNF-alpha receptor I, and endothelial growth factor following 4 weeks of lenvatinib treatment. Furthermore, an increase in Th1 cells and serum levels of TNF-alpha was found in patients with partial response., Conclusion: Lenvatinib might induce Th1-dominant host immunity in patients with CLD and unresectable HCC treatment in patients who showed a partial response. These changes in host immunity may be a biomarker in HCC patients treated with lenvatinib., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Previously, we reported that the tyrosine kinase inhibitor (TKI) sorafenib decreases serum levels of carnitine and reduces skeletal muscle volume. Moreover, others reported that TKIs might lead to cardiomyopathy or heart failure. Therefore, this study aimed to evaluate the effects of lenvatinib (LEN) on skeletal muscle volume and cardiac function in patients with hepatocellular carcinoma (HCC)., Methods: This retrospective study included 58 adult Japanese patients with chronic liver diseases and HCC treated with LEN. Blood samples were collected before and after 4 weeks of treatment, and serum carnitine fraction and myostatin levels were measured. Before and after 4-6 weeks of treatment, the skeletal muscle index (SMI) was evaluated from computed tomography images and cardiac function was assessed by ultrasound cardiography., Results: After treatment, SMI, serum levels of total carnitine, and global longitudinal strain were significantly lower, but serum levels of myostatin were significantly higher. Left ventricular ejection fraction showed no significant change., Conclusion: In patients with HCC, LEN decreases serum levels of carnitine, skeletal muscle volume, and worsens cardiac function., (© 2023 S. Karger AG, Basel.)

Objectives: In July 2017, supplementary guidelines on anticoagulants, including direct oral anticoagulants, were published in Japan. We investigated the changes in endoscopic submucosal dissection (ESD) of gastric mucosal lesions after the publication of the supplement, examined the risk factors, and developed a predictive model for post-ESD bleeding., Methods: We included 2272 gastric ESD cases from our hospital between May 2003 and June 2021 and classified them into two groups: 1789 cases before and 483 after the publication of the supplementary guidelines. A predictive model for post-ESD bleeding was developed using the pre-publication cohort data., Results: The proportion of patients receiving warfarin decreased (5.0% vs. 1.4%) and those receiving direct oral anticoagulants increased (1.2% vs. 6.8%) after the publication of the supplementary guidelines. Post-ESD bleeding occurred in 61 patients, but there was no significant difference in the bleeding rate between the groups (50 [2.8%] vs. 11 [2.3%] patients, respectively). Five risk factors (number of antithrombotic agents, dialysis, heparin replacement, resection specimen size, and procedure time) were identified for model development. The C-statistic for the model and post-publication cohorts were 0.83 and 0.72, respectively. In the model, each risk factor for postoperative bleeding was scored, and the risk was classified into three levels according to the total score. Bleeding rates at low, intermediate, and high risks were 1.6%, 10.3%, and 38.9%, respectively., Conclusion: Despite changes in patient characteristics and clinical practice regarding ESD before and after the publication of the supplementary guidelines, we could still develop a simple and useful predictive model., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

The BacT/Alert system has been used for detecting the presence of bacteria in various clinical settings as well as in blood services, but it is associated with a relatively high incidence of false-positive results. We analyzed the results of our quality control sterility testing of blood products by BacT/Alert 3D to understand the mechanism of false-positive results. Anaerobic and aerobic bottles were inoculated with 10 mL of samples and cultured in BacT/Alert 3D for 10 days. Positive-reaction cases were classified as true positive if any bacterium was identified or false positive if the identification test had a negative result. The detection algorithm and the bottle graph pattern of the positive reaction cases were investigated. Among the 43,374 samples, 25 true positives (0.06%) and 29 false positives (0.07%) were observed. Although the detection algorithm of all true positives and 25 of 29 false positives was accelerating production of CO 2 , a steep rise in the bottle graph was observed only in the true positives, and it was not observed in either of the false positives. Four of 29 false positives were dependent on high baseline scatter reflections. Furthermore, evaluating the bottle graph pattern of Streptococcus pneumoniae, a bacterium known to autolyze, we confirmed that no viable bacterium was detected even if a steep rise was observed. In conclusion, the bottle graph pattern of positive reactions allows the differentiation between true positives and false positives. In case of a steep rise without bacterium detection, the bacterium might have autolyzed. Moreover, positive reactions with high baseline scatter reflections, despite immediate loading of bottles after sampling, are potentially false positive. IMPORTANCE In clinical settings, false-positive results are treated as positive until bacterial identification. It may result in the discarding of blood products in blood centers or affect clinical decisions in hospitals or testing facilities. Moreover, the management of these samples is usually time- and labor-consuming. The results of our study may help clinicians and laboratory staff in making a more precise evaluation of positive reactions in BacT/Alert.

A 71-year-old Japanese man was treated with 200 mg of pembrolizumab for lung adenocarcinoma with multiple bone metastases at the Department of Respiratory Medicine of Kameda General Hospital. After 19 treatment courses, he complained of epigastric pain before meals. Upper gastrointestinal endoscopy showed multiple erosions in the gastric antrum, and antacids were administered at follow-up. After 27 treatment courses, the patient underwent another endoscopy because of anorexia. The erosions were enlarged and had increased from the gastric antrum to the greater curvature of the body. Histological biopsy showed lymphocytic infiltration with a predominance of CD8-positive T cells. The patient had previously been treated for Helicobacter pylori infection, and we suspected drug-induced gastritis due to the administration of immune checkpoint inhibitors in the course of the disease. Pembrolizumab was discontinued, and the patient's symptoms gradually improved. Endoscopic examinations were performed 2, 5, and 9 months after discontinuation of pembrolizumab, and improvement in mucosal findings and decreased lymphocyte infiltration were confirmed each time. The patient has remained without any relapse of symptoms for more than 1 year after discontinuing treatment., (© 2022. The Author(s).)

Phosphatidylserine (PS) is a unique lipid that is recognized by the endogenetic receptor, T-cell immunoglobulin mucin protein 4 (Tim4), and PS-containing liposomes have potential use in therapeutic applications. We prepared PS-containing liposomes of various lipid compositions and examined how lipid membrane fluidity affects PS recognition by Tim4 and the resulting endocytosis efficiency into Hela cells. Surface plasmon resonance and laurdan studies showed that increasing lipid membrane fluidity increased the stability of the PS-Tim4 interaction but hampered the entry of liposomes into cells. These results show that endocytosis efficiency is determined by balancing opposing forces induced by membrane fluidity. We found that inclusion of the zwitterionic helper lipid, 1,2-dipalmitoyl- sn -glycero-3-phosphocholine, into liposomes ensured efficient cellular internalization because the presence of this lipid provides an ideal balance of lipid fluidity and Tim4 affinity. The results showed that PS recognition by Tim4 and the resulting endocytosis efficiency can be maximized by modulating the membrane fluidity of liposomes by selecting a zwitterionic helper lipid. This study improves our understanding of how to rationally optimize nanotechnology for targeted drug delivery.