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Background: The association between symptom interpretation and prognosis has not been investigated well among patients with acute coronary syndrome (ACS). As such, the present study evaluated the effect of heart disease awareness among patients with ACS on in-hospital mortality., Methods and results: We performed a post hoc analysis of 1,979 consecutive patients with ASC with confirmed symptom interpretation on admission between 2014 and 2018, focusing on patient characteristics, recanalization time, and clinical outcomes. Upon admission, 1,264 patients interpreted their condition as cardiac disease, whereas 715 did not interpret their condition as cardiac disease. Although no significant difference was observed in door-to-balloon time between the 2 groups, onset-to-balloon time was significantly shorter among those who interpreted their condition as cardiac disease (254 vs. 345 min; P<0.001). Moreover, the hazard ratio (HR) for in-hospital mortality was significantly higher among those who did not interpret their condition as cardiac disease based on the Cox regression model adjusted for established risk factors (HR 1.73; 95% confidence interval 1.08-2.76; P=0.022)., Conclusions: This study demonstrated that prehospital symptom interpretation was significantly associated with in-hospital clinical outcomes among patients with ACS. Moreover, the observed differences in clinical prognosis were not related to door-to-balloon time, but may be related to onset-to-balloon time.

The area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) - guided approach is recommended for vancomycin therapeutic drug monitoring in severe methicillin-resistant Staphylococcus aureus (MRSA) infection. However, evidence regarding the efficacy of vancomycin AUC-guided strategies for the treatment of systemic infections is limited. This case report describes the successful treatment of MRSA meningitis, with vancomycin using a higher AUC/MIC target. A 61-year-old woman who underwent ventriculoperitoneal (VP) shunt placement for subarachnoid hemorrhage, developed MRSA meningitis due to shunt infection. Vancomycin was administered intravenously, with concurrent monitoring of serum and cerebrospinal fluid (CSF) vancomycin concentrations and AUC/MIC. On post-operative day (POD) 24 of VP shunt placement, the vancomycin trough concentration and AUC/MIC were 12.0 μg/mL and 515, respectively, with persistently positive CSF culture. On POD 28, the trough concentration and AUC/MIC were 18.6 μg/mL and 610, respectively. There were no major adverse events, and CSF culture turned negative on POD 30. The vancomycin CSF-to-serum ratio was approximately 41 %. For patients with MRSA meningitis, we suggest an optimal therapeutic range with a vancomycin AUC/MIC target near the upper limit of the therapeutic window., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Authors.)

Background: Although much progress has been made in diagnosis of carcinomas, no established methods have been confirmed to elucidate their morphological features., Methods: Three-dimensional structure of esophageal carcinomas was assessed using transparency-enhancing technology. Endoscopically resected esophageal squamous cell carcinoma was fluorescently stained, optically cleared using a transparency-enhancing reagent called LUCID, and visualized using laser scanning microscopy. The resulting microscope images were converted to virtual HE images for observation using ImageJ software., Results: Microscopic observation and image editing enabled three-dimensional image reconstruction and conversion to virtual HE images. The structure of abnormal blood vessels in esophageal carcinoma recognized by endoscopy could be observed in the 3 dimensions. Squamous cell carcinoma and normal squamous epithelium could be distinguished in the virtual HE images., Conclusions: The results suggested that transparency-enhancing technology and virtual HE images may be feasible for clinical application and represent a novel histopathological method for evaluating endoscopically resected specimens., (© 2024. The Author(s).)

Rationale: Enteral nutrition is beneficial for stroke patients with oral intake difficulties. However, it is time consuming and may interfere with routine medical care. Therefore, there is a clinical benefit if enteral nutrition can be safely administered in a short time. Although our retrospective study showed the safety of rapid administration, it remains unclear whether rapid administration of enteral nutrition is as safe as conventional administration., Aim: The randomized study of Enteral Nutrition with Rapid versus conventional administration in acute stroke patients (Rapid EN trial) aims to clarify the safety of rapid feeding of enteral nutrition compared with conventional feeding., Methods and Design: This is an investigator-initiated, multicenter, prospective, randomized, open-label, blinded end-point clinical trial. Eligible criteria include acute stroke patients who have difficulty with oral intake defined as severe altered consciousness (Japan Coma Scale 10-300) or modified water swallowing test <4. The target enrollment is 700 patients, with 350 patients receiving rapid enteral nutrition at a rate of 100 mL in 5 min (Rapid EN group) and 350 patients receiving conventional enteral nutrition at a rate of 100 mL in 30 min (Conventional EN group)., Study Outcome: The primary outcome is the incidence of one or more complications of vomiting or diarrhea or pneumonia within 7 days would be non-inferior in the rapid EN group compared to the conventional EN group. Secondary outcomes were total time spent on enteral nutrition within 7 days from enteral nutrition, the incidence of vomiting, diarrhea and pneumonia within 3 or 7 days, and the rate of favorable clinical outcome., Discussion: Since no previous reports have focused on the speed of administration, we felt it was necessary to prove the safety of rapid administration. If this study shows positive results, it will not only benefit patients, but also reduce the burden of medical care. We believe this study is novel and will be useful in clinical practice., Clinical Trial Registration: https://rctportal.niph.go.jp/s/detail/um?trial&#95;id=UMIN000046610 Identifier UMIN000046610., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Suzuki, Onodera, Sugiyama, Okubo, Kimura, Kaku, Seki, Fujita, Nomura, Takagiwa, Katafuchi, Nakamura, Kanamaru, Oda, Kimura, Sonoda, Kakita, Otsuka and Kimura.)

Anamorelin (ANAM) is a novel ghrelin receptor agonist for the treatment of cancer cachexia. In clinical trials of ANAM, glucose metabolism disorders as adverse effects were relatively frequent, however, when and how they occur remains unclear. Moreover, the safety in patients with pancreatic cancer and/or diabetes has not been clarified because most previous studies focused on patients with non-small cell lung cancer and had excluded patients with poorly controlled diabetes. Herein, a 66-year-old man with advanced pancreatic cancer and diabetes was administered ANAM, and acute hyperglycemia was developed and could be monitored by the self-monitoring of blood glucose (SMBG). Increasing the insulin dose failed to control hyperglycemia adequately, but the hyperglycemia ameliorated quickly after ANAM discontinuation. The continuous glucose monitoring (CGM) revealed that the sensor glucose levels had remained in the high range throughout the day during ANAM administration despite using 1.5 times more insulin. Our report is one of the few that describe the details of ANAM-induced hyperglycemia and provides important information for the safe and effective use of ANAM.

Competing Interests: Conflict of interest statement. None declared.

The United States Senate passed the "FDA Modernization Act 2.0." on September 29, 2022. Although the effectiveness of this Bill, which aims to eliminate the mandatory use of laboratory animals in new drug development, is limited, it represents a significant trend that will change the shape of drug applications in the United States and other countries. However, pharmaceutical companies have not taken major steps towards the complete elimination of animal testing from the standpoint of product safety, where they prioritize patient safety. Nonetheless, society is becoming increasingly opposed to animal testing, and efforts will be made to use fewer animals and conduct fewer animal tests as a natural and reasonable response. These changes eventually alter the shape of new drug applications. Based on the assumption that fewer animal tests will be conducted or fewer animals will be used in testing, this study explored bioinformatics and new technologies as alternatives to compensate for reduced information and provide a picture of how future new drug applications may look. The authors also discuss the directions that pharmaceutical companies and nonclinical contract research organizations should adopt to promote the replacement, reduction, and refinement of animals used in research, teaching, testing, and exhibitions., Competing Interests: The authors declare no conflicts of interest., (©2024 The Japanese Society of Toxicologic Pathology.)

False windows can display a variety of outdoor scenery in rooms without real windows. We aimed to assess the effects of three different hospital beds on the change in the frontal assessment battery scores in patients aged ≥ 20-year-old admitted in our neurological ward. We included 24 patients on the window side, 12 patients on the aisle side with a false window, and 12 patients on the aisle side without a false window. There were no statistical differences in the change of cognitive function among the three hospital beds. Only the length of hospital stay was a significant associated factor.

Ocular motility has been linked to Sports Concussion Assessment Tool 5 scores. However, the link between ocular motility changes and assessment result changes remains unclear. Hence, we investigated that potential link in patients with sports-related concussions. We retrospectively included participants aged≥18 years who were diagnosed with a sports-related concussion. They underwent smooth pursuit eye movement assessment for allocation to the good improvement (rate of fundamental frequency≥15%) or minor improvement (<15%) groups. Sports Concussion Assessment Tool 5 scores were determined at baseline and two weeks later, and score changes were compared between the groups. Thirteen men (mean±standard deviation age: 20.6±5.0 years) were included: eight (19.0±4.5 years) in the good improvement group and five (20.6±5.7 years) in the minor improvement group. Symptom number (median=2.0 vs. 0.0), symptom severity (median=22.0 vs. 3.0), single-leg stance (median=4.0 vs. 0.5), tandem stance (median=1.0 vs. 0.0), and total errors (median=5.0 vs. 0.5) were worse (all p<0.05) in the minor improvement group. Smooth pursuit eye movement improvements measured using eye-tracking technology was linked to symptom recovery in patients with sports-related concussions. Therefore, ocular motility may be an objective indicator of sports-related concussions. Future studies with more patients are needed to confirm these findings., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: The increased availability of content of uncertain integrity obtained through the internet is a major concern. To date, however, there has been no comprehensive scrutiny of the fitness-for-purpose of web-based content on diet and nutrition., Objective: This cross-sectional study aims to describe diet- and nutrition-related web-based content written in Japanese, identified via a systematic extraction strategy using Google Trends and Google Search., Methods: We first identified keywords relevant for extracting web-based content (eg, blogs) on diet and nutrition written in Japanese using Google Trends. This process included identification of 638 seed terms, identification of approximately 1500 pairs of related queries (top) and search terms, the top 10% of which were extracted to identify 160 relevant pairs of related queries (top) and search terms, and identification of 107 keywords for search. We then extracted relevant web-based content using Google Search., Results: The content (N=1703) examined here was extracted following a search based on 107 keywords. The most common themes included food and beverages (390/1703, 22.9%), weight management (366/1703, 21.49%), health benefits (261/1703, 15.33%), and healthy eating (235/1703, 13.8%). The main disseminators were information technology companies and mass media (474/1703, 27.83%), food manufacturers (246/1703, 14.45%), other (236/1703, 13.86%), and medical institutions (214/1703, 12.57%). Less than half of the content (790/1703, 46.39%) clearly indicated the involvement of editors or writers. More than half of the content (983/1703, 57.72%) was accompanied by one or more types of advertisement. The proportion of content with any type of citation reference was 40.05% (682/1703). The themes and disseminators of content were significantly associated with the involvement of editors or writers, accompaniment with advertisement, and citation of reference. In particular, content focusing on weight management was more likely to clearly indicate the involvement of editors or writers (212/366, 57.9%) and to be accompanied by advertisement (273/366, 74.6%), but less likely to have references cited (128/366, 35%). Content from medical institutions was less likely to have citation references (62/214, 29%)., Conclusions: This study highlights concerns regarding the authorship, conflicts of interest (advertising), and the scientific credibility of web-based diet- and nutrition-related information written in Japanese. Nutrition professionals and experts should take these findings seriously because exposure to nutritional information that lacks context or seems contradictory can lead to confusion and backlash among consumers. However, more research is needed to draw firm conclusions about the accuracy and quality of web-based diet- and nutrition-related content and whether similar results can be obtained in other major mass media or social media outlets and even other languages., (©Kentaro Murakami, Nana Shinozaki, Nana Kimoto, Hiroko Onodera, Fumi Oono, Tracy A McCaffrey, M Barbara E Livingstone, Tsuyoshi Okuhara, Mai Matsumoto, Ryoko Katagiri, Erika Ota, Tsuyoshi Chiba, Yuki Nishida, Satoshi Sasaki. Originally published in JMIR Formative Research (https://formative.jmir.org), 16.11.2023.)

Background: The clinical benefits of faster recanalization in acute large vessel occlusion are well recognized, but the optimal procedure time remains uncertain. The aim of this study was to identify patient characteristics that necessitate puncture-to-recanalization (P-R) time within 30 min to achieve favorable outcome., Methods: We evaluated the patients from a prospective, multicenter, observational registry of acute ischemic stroke patients. The study included patients who underwent endovascular therapy for ICA or MCA M1 occlusion and achieved successful recanalization. Patients were categorized into subgroups based on pre-treatment characteristics and the frequency of favorable outcomes was compared between P-R time < 30 min and ≥ 30 min. Interaction terms were incorporated into the models to assess the correlation between each patient characteristic and P-R time., Results: A total of 1053 patients were included in the study. Univariate analysis within each subgroup revealed a significant association between P-R < 30 min and favorable outcomes in patients with DWI ASPECTS ≤6, age > 85 and NIHSS ≥16. In the multivariable analysis, NIHSS, age, time from symptom recognition to puncture, and DWI ASPECTS were significant independent predictors of favorable outcomes. Notably, only DWI ASPECTS exhibited interaction terms with P-R < 30 min. The multivariable analysis indicated that P-R < 30 min was an independent predictor for favorable outcome in DWI ASPECTS ≤6 group, whereas not in DWI ≥7., Conclusions: P-R time < 30 min is predictive of favorable outcomes; however, the effect depends on DWI ASPECTS. Target P-R time < 30 min is appropriate for patients with DWI ASPECTS ≤6., Competing Interests: Declaration of Competing Interest The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. T.U. reports consulting fees from Kaneka Medix. Dr. Y.H. reports consulting fees from Bayer Pharmaceutical and Nippon Boehringer Ingelheim. Dr. M.T. reports consulting and lecture fees from Johnson and Johnson and Stryker., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: For patients who undergo endovascular treatment for acute ischemic stroke, the total time for treatment may increase during off-duty hours leading to worse outcomes. The present study compared endovascular treatment outcomes for on-duty and off-duty hours and examined factors that could be responsible for the prolonged treatment of patients in a multicenter registry., Methods: The study group comprised 1571 patients listed in the multicenter stroke registry (K-NET) who had undergone endovascular treatment between January 2018 and June 2020. The modified Rankin Scale (mRS), evaluated at 90 days after stroke onset, was utilized as the primary outcome. Patients were divided into on-duty and off-duty patients based on admission time. Multivariate logistic regression analysis was used to identify the independent factors that increased the time from admission to puncture during the off-duty period., Results: The mean mRS score at 90 days after stroke onset was 2.9, similar in both on-duty and off-duty patients, with no significant difference ( p  = 0.77); however, significant differences were observed in time from door-to-puncture (74.7 vs. 88.8, p  < 0.01). Additionally, the mRS score at 90 days worsened significantly for door-to-puncture time >60 min in the off-duty period. Multivariate logistic regression analysis revealed that a low National Institute of Health Stroke Scale (NIHSS) score, high pre-mRS score, posterior circulation, and diabetes were independent indicators of door-to-puncture time >60 min during the off-duty period., Conclusion: Door-to-puncture time >60 min during off-duty hours was associated with poor outcomes related to low NIHSS, high pre-mRS, posterior circulation, and diabetes., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Ueda reports consulting fees from Kaneka Medix. Dr. Hasegawa reports consulting fees from Bayer Pharmaceutical and Nippon Boehringer Ingelheim. Dr. Takeuchi reports consulting and lecture fees from Johnson, Johnson, and Stryker. Dr. Tsumoto reports on consulting and lecture fees from Stryker and Terumo.

Background: It has been reported that patients with acute myocardial infarction (AMI) transferred to low-volume primary percutaneous coronary intervention (PCI) hospitals (<115/year) in low population density areas experience higher in-hospital mortality rates. This study compared in-hospital outcomes of patients admitted to high-volume primary PCI hospitals (≥115/year) with those for other regional general hospitals., Methods and results: Retrospective analysis was conducted on data obtained from 2,453 patients with AMI admitted to hospitals in Iwate Prefecture (2014-2018). Multivariate analysis revealed that the in-hospital mortality rate of AMI among patients in regional general hospitals was significantly higher than among patients in high-volume hospitals. However, no significant difference in mortality rate was observed among patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI. Although no significant difference was found in the in-hospital mortality rate of patients with Killip class I STEMI, significantly lower in-hospital mortality rates were observed in patients admitted in high-volume hospitals for Killip classes II, III, and IV., Conclusions: Although in-hospital outcomes for patients with STEMI undergoing primary PCI were similar, patients with heart failure or cardiogenic shock exhibited better in-hospital outcomes in high-volume primary PCI hospitals than those in regional general hospitals.

Herein, we investigated possible practical issues for the smooth implementation of the revised Japanese Guidelines for Non-clinical Studies of Vaccines for the Prevention of Infectious Diseases, which were raised in response to public comments on the proposed guideline revision and a gap analysis of the World Health Organization and European Medicines Agency guidelines. We identified main issues such as the non-clinical safety studies of adjuvants and evaluation of local cumulative tolerance in toxicity studies. The revised Japanese Pharmaceuticals and Medical Devices Agency (PMDA)/Ministry of Health, Labour and Welfare (MHLW) guidelines require non-clinical safety studies for vaccines containing new adjuvants, but additional safety pharmacology studies or safety studies in two animal species may be required if non-clinical safety studies raise any concerns (i.e., systemic distribution). Adjuvant biodistribution studies may aid in understanding vaccine characteristics. The evaluation of local cumulative tolerance in non-clinical studies, which was the focus of the Japanese review, can be omitted by including a warning in the package insert to avoid injection to the same site. The study's findings will be reflected in a Q&A to be released by the Japanese MHLW. We hope that this study will contribute to the global and harmonized development of vaccines., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: /Objectives: This study aimed to evaluate the usefulness of three-dimensional (3D) immunohistochemistry for the Ki67 index of small tissue specimens of pancreatic neuroendocrine tumor (PanNET)., Methods: Clinicopathological materials from 17 patients with PanNET who underwent surgical resection at Jichi Medical University Hospital were analyzed. We compared the Ki67 index of endoscopic ultrasonography-fine-needle aspiration biopsy (EUS-FNAB) specimens, surgical specimens, and small tissue specimens hollowed from paraffin blocks of surgical specimens that were substituted for EUS-FNAB specimens ("sub-FNAB"). The sub-FNAB specimens were optically cleared using LUCID (IlLUmination of Cleared organs to IDentify target molecules) and analyzed using 3D immunohistochemistry., Results: The median Ki67 index in FNAB, sub-FNAB, and surgical specimens with conventional immunohistochemistry were 1.2% (0.7-5.0), 2.0% (0.5-14.6), and 5.4% (1.0-19.4), respectively. The median Ki67 index in sub-FNAB specimens with tissue clearing was calculated separately using the total number of cells on multiple images ("multiple slice"), with the image of the fewest positive cells ("coldspot"), and with the image of most positive cells ("hotspot"), which were 2.7% (0.2-8.2), 0.8% (0-4.8), and 5.5% (2.3-12.4), respectively. PanNET grade evaluated for the hotspot of the surgical specimens was significantly more consistent with those of the hotspot than multiple images of sub-FNAB specimens (16/17 vs. 10/17, p = 0.015). Hotspot evaluation using 3D immunohistochemistry of the sub-FNAB specimens showed agreement with the assessment of the surgical specimens (Kappa coefficient: 0.82)., Conclusions: Tissue clearing and 3D immunohistochemistry for the Ki67 index can potentially improve the preoperative evaluation of EUS-FNAB specimens of PanNET in routine clinical practice., Competing Interests: Declaration of competing interest None., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: This study assessed the efficacy and safety of thrombectomy for acute ischaemic stroke in a population with pre-stroke modified Rankin scale (mRS) scores of 2-3 using real-world data., Methods: Our sample set included 2313 consecutive patients enrolled in the Kanagawa Registry of Intravenous and Endovascular Treatment of Acute Ischemic Stroke registry between January 2018 and June 2020 in 40 stroke centres in Kanagawa Prefecture, Japan. Patients treated with intravenous tissue plasminogen activator (t-PA), thrombectomy, or both were included. Patients with pre-stroke mRS scores of 4-5 and those treated only with intra-arterial thrombolysis were excluded. The primary outcome of this study was an mRS score of 0-3 at 90 days after onset to assess the efficacy of thrombectomy for pre-stroke disabled individuals. We performed multivariate logistic regression analyses to investigate independent factors for a 90-day mRS score of 0-3. We also performed nearest-neighbour within-calliper matching between thrombectomy and t-PA only., Results: After excluding patients meeting the exclusion criteria, we analysed data of 2136 consecutive patients, of which 315 (14.7%) had pre-stroke disabilities (mRS score 2-3). A 90-day mRS score of 0-3 was achieved by 33.3% of patients with pre-stroke mRS scores of 2-3. According to multivariate analysis, the National Institutes of Health Stroke Scale (NIHSS) score was an independent factor. Furthermore, after propensity-score matching, thrombectomy showed considerable superiority for achieving a 90-day mRS score of 0-3., Conclusion: Intravenous t-PA and especially thrombectomy were safe and effective for the population with pre-stroke disabilities, particularly for patients with low NIHSS scores.

Background: Endovascular treatment (EVT) for acute large vessel occlusion has proven to be effective in randomized controlled trials. We conducted a prospective cohort study to evaluate the real-world efficacy of EVT in a metropolitan area with a large number of comprehensive stroke centers and to compare it with the results of other registries and randomized controlled trials (RCTs)., Methods: We analyzed the Kanagawa Intravenous and Endovascular Treatment of Acute Ischemic Stroke registry, a prospective, multicenter observational study of patients treated by EVT and/or intravenous tissue-type plasminogen activator (tPA). Of the 2488 patients enrolled from January 2018 to June 2020, 1764 patients treated with EVT were included. The primary outcome was a good outcome, which was defined as a modified Rankin Scale (mRS) of 0-2 at 90 days. Secondary analysis included predicting a good outcome using multivariate logistic regression analysis., Results: The median age was 77 years, and the median National Institute of Health Stroke Scale (NIHSS) score was 18. Pretreatment mRS score 0-2 was 87%, and direct transport was 92%. The rate of occlusion in anterior circulation was 90.3%. Successful recanalization was observed in 88.7%. The median time from onset to recanalization was 193 min. Good outcomes at 90 days were 43.3% in anterior circulation and 41.9% in posterior circulation. Overall mortality was 12.6%. Significant predictors for a good outcome were as follows: age, male, direct transfer, NIHSS score, Alberta Stroke Program Early Computed Tomography Score, intravenous tPA, and successful recanalization., Conclusion: EVT in routine clinical use in a metropolitan area showed comparable good outcomes and lower mortality compared to previous studies, despite the high proportion of patients with older age, pretreatment mRS score of >2, posterior circulation occlusion, and higher NIHSS. Those results may have been associated with more direct transport and faster onset-to-recanalization times.

Purpose: Little evidence is available regarding bradypnea measured using continuous monitoring following cesarean section. We aimed to evaluate the rate of cumulative bradypnea time (total bradypnea time/total monitoring time) and its related factors in these parturients., Methods: This prospective observational study included women undergoing cesarean section under single-shot spinal anesthesia of 0.1 mg morphine. The Berlin Questionnaire was used to screen for sleep apnea syndrome preoperatively. Respiratory rate and oxygen saturation (SpO 2 ) were monitored continuously using an adhesive acoustic respiration sensor and pulse oximeter, respectively, at least 6 h after cesarean section. Bradypnea was defined as a respiratory rate < 8 breaths/min lasting at least 25 s (sustained bradypnea) or at least 15 s (immediate bradypnea). Hypoxemia was defined as SpO 2  < 92% lasting at least 25 s (sustained hypoxemia) or at least 15 s (immediate hypoxemia). Multiple regression analysis was applied to assess factors related to the rate of cumulative sustained bradypnea., Results: Of 159 patients, the Berlin Questionnaire was positive in 16.3%, and 77 (48.4%) experienced sustained bradypnea. The median rate of cumulative sustained bradypnea time was 0.70% (interquartile range 0.35-1.45%) without any related factors. The incidence of immediate bradypnea and sustained and immediate hypoxemia were 58.5%, 24.5%, and 37.7%, respectively. However, none of the factors were significant., Conclusion: After cesarean section was performed with 0.1 mg intrathecal morphine, respiratory depression events were commonly observed. However, the rate of cumulative bradypnea time was very low and there were no related factors., (© 2023. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Escherichia coli has multiple pathways to release nonproductive ribosome complexes stalled at the 3' end of nonstop mRNA: tmRNA (SsrA RNA)-mediated trans-translation and stop codon-independent termination by ArfA/RF2 or ArfB (YaeJ). The arfA mRNA lacks a stop codon and its expression is repressed by trans-translation. Therefore, ArfA is considered to complement the ribosome rescue activity of trans-translation, but the physiological situations in which ArfA is expressed have not been elucidated. Here, we found that the excision of CP4-57 prophage adjacent to E. coli ssrA leads to the inactivation of tmRNA and switches the primary rescue pathway from trans-translation to ArfA/RF2. This "rescue-switching" rearranges not only the proteome landscape in E. coli but also the phenotype such as motility. Furthermore, among the proteins with significantly increased abundance in the ArfA + cells, we found ZntR, whose mRNA is transcribed together as the upstream part of nonstop arfA mRNA. Repression of ZntR and reconstituted model genes depends on the translation of the downstream nonstop ORFs that trigger the trans-translation-coupled exonucleolytic degradation by polynucleotide phosphorylase (PNPase). Namely, our studies provide a novel example of trans-translation-dependent regulation and re-define the physiological roles of prophage excision., (© 2022 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

The development of vaccines against infectious diseases requires a different approach from that of therapeutics, because vaccines are inoculated into healthy individuals and have a preventive effect by activating the immunity of the inoculated human. In Japan, "The Guideline for Clinical Trials of Vaccines for the Prevention of Infectious Diseases" was published in 2010 before changes occurred in the vaccine development environment in Japan, such as the introductions of foreign vaccines and simultaneous global development. This study aimed to identify current challenges in vaccine development through a questionnaire-based survey of pharmaceutical companies in Japan and by comparing the domestic and international guidelines and surveying review reports of 35 vaccines approved in Japan between April 2010 and December 2020. Identified challenges included the requirement for protective efficacy trials, efficacy evaluation of combination vaccines, development of multiregional and foreign clinical trials, and immunization of older adults and immunocompromised patients. We propose that new vaccines against infectious diseases should be evaluated for the protective efficacy, preferably through multiregional clinical trials. Additionally, differences in the incidence of infectious diseases or in epidemic virus strains between regions may affect the trials, when multiregional clinical trials are conducted, but immunogenicity-based studies can be conducted if a correlation between protective efficacy and immunogenicity has been established. We suggest that licensed combination vaccines can be used as comparators when an antigen is added to a licensed combination vaccine. We also proposed that the efficacy of a vaccine in non-major subjects, such as older adults or immunocompromised patients could be evaluated by comparing immunogenicity in major subjects with the confirmed protective effects of the vaccine. It is expected that these revisions will lead to the rapid advancement of vaccine development, which should contribute to the improvement of public health., 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. Conflict of Interest Takashi Nakano receives honorarium from Daiichi Sankyo Co., ltd., Sanofi Co., ltd., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., and Denka Co., ltd., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To investigate the relationship between body weight loss and activities of daily living (ADL) 3 months after stroke onset., Materials and Methods: This retrospective cohort study included 81 patients at a rehabilitation hospital after receiving acute treatment at our hospital (mean age 70.7 years). Patients were divided into two groups, namely independent and non-independent, based on their ADL 3 months after stroke. Receiver operating characteristic (ROC) curves were constructed with the ADL independence possibility as the objective variable and body weight change rate (%) at 3 months as the explanatory variable. Patients were classified using the weight change rate calculated from the ROC curve and the NIHSS cut-off values, and the ADL independence percentage was compared., Results: The ADL-independent group had significantly lesser body weight loss than the non-independent group (median rate of body weight change: -2.7% vs. -7.2%; p<0.001). The area under the ROC curve was 0.76. The cut-off value was -5.6% for the body weight change rate. When participants with NIHSS ≤ 8 points were selected, the ADL-independent participants' proportion was significantly higher in the body weight loss ≤ -5.6% group than in the > -5.6% group (56.0% vs. 15.4%, p=0.016). However, there was no significant difference in the ADL-independent participants' proportion when those with NIHSS >8 points were selected (p=0.19)., Conclusions: Our findings indicate that weight loss after stroke onset is associated with non-independent ADL at 3 months. Weight maintenance from the onset is important for ADL independence, especially in patients with mild to moderate stroke., 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 © 2022 Elsevier Inc. All rights reserved.)

Background: Studies evaluating long-term trends of intravenous immunoglobulin (IVIG) titers against microorganisms such as bacteria and fungi have not been conducted. We herein evaluated long-term trends of titers of IVIG lots manufactured from 1998 to 2018, derived from donors in Japan, against microorganisms affecting patients with primary or secondary immunodeficiency diseases., Study Design and Methods: Titers against four strains of Pseudomonas aeruginosa, three strains of Staphylococcus aureus, four strains of Haemophilus influenzae, two strains of Klebsiella pneumoniae, one strain of Streptococcus pneumoniae, Enterococcus faecium, Bordetella pertussis, Serratia marcescens, and Candida albicans, were tested immediately after lot release in a commercial clinical testing facility in 1998. The long-term (whole period) and short-term (first and second half of the period) trends of titers were evaluated using regression analysis., Results: The IVIG lots indicated meaningful titers against all microorganisms that were stable in the short term. The long-term trends could be categorized into stable, slightly decreasing, or decreasing trends, except for the metallo-β-lactamase-producing K. pneumoniae, which indicated a slight increase. Notably, three strains of P. aeruginosa showed remarkable decreasing long-term trends in the titer., Discussion: Some titers indicate decreasing trends against microorganisms over the long-term, however, is not clear whether the phenomenon diminishes the performance of IVIG. The titers of the IVIG lots could provide helpful information to optimize replacement therapy, such as considering trough values based on the titers in the patient plasma. Therefore, continuous monitoring of IVIG titers against microorganisms is important to understand titer fluctuation and epidemiological background., (© 2022 AABB.)

Although scatter correction improves SPECT image contrast and thus image quality, the effects of quantitation accuracy under various conditions remain unclear. The present study aimed to empirically define the conditions for the optimal scatter correction of quantitative bone SPECT/CT images. Scatter correction was performed by applying dual and triple energy windows (DEW and TEW) with different sub-energy window widths, and effective scatter source estimation (ESSE) to CT-based scatter correction. Scattered radiation was corrected on images acquired using a triple line source (TLSP) phantom and an uniform cylinder phantom. The TLSP consisted of a line source containing 74.0 MBq of 99mTc in the middle, and a background component containing air, water or a K2HPO4 solution with a density equivalent to that of bone. The sum of all pixels in air, water and the K2HPO4 solution was measured on SPECT images. Scatter fraction (SF) and normalized mean square error (NMSE) based on counts from the air background as a reference were then calculated to assess quantitative errors due to scatter correction. The uniform cylinder phantom contained the same K2HPO4 solution and 222.0 MBq of 99mTc. The coefficient of variation (CV) was calculated from the count profile of this phantom to assess the uniformity of SPECT images across scatter correction under various conditions. Both SF and NMSE in SPECT images of phantoms containing water in the background were lower at a TEW sub-window of 3% (TEW3%), than in other scatter corrections, whereas those in K2HPO4 were lower at a DEW sub-window of 20% (DEW20%). Larger DEW and smaller TEW sub-energy windows allowed more effective correction. The CV of the uniform cylinder phantom, DEW20%, was inferior to all other tested scatter corrections. The quantitative accuracy of bone SPECT images substantially differed according to the method of scatter correction. The optimal scatter correction for quantitative bone SPECT was DEW20% (k = 1), but at the cost of slightly decreased image uniformity., Competing Interests: The authors have declared that no competing interests exist.

Long-term high-fidelity electroencephalogram (EEG) recordings are critical for clinical and brain science applications. Conductive liquid-like or solid-like wet interface materials have been conventionally used as reliable interfaces for EEG recording. However, because of their simplex liquid or solid phase, electrodes with them as interfaces confront inadequate dynamic adaptability to hairy scalp, which makes it challenging to maintain stable and efficient contact of electrodes with scalp for long-term EEG recording. Here, we develop an on-skin paintable conductive biogel that shows temperature-controlled reversible fluid-gel transition to address the abovementioned limitation. This phase transition endows the biogel with unique on-skin paintability and in situ gelatinization, establishing conformal contact and dynamic compliance of electrodes with hairy scalp. The biogel is demonstrated as an efficient interface for long-term high-quality EEG recording over several days and for the high-performance capture and classification of evoked potentials. The paintable biogel offers a biocompatible and long-term reliable interface for EEG-based systems.

Background: The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have published guidelines on the use of cancer treatments in young people of reproductive potential. However, no such guideline is available in Japan. Therefore, this project aimed to gather relevant data and draft a respective guidance paper., Methods: From April 2019 to March 2021, the Study Group for Providing Information on the Proper Use of Pharmaceuticals in Patients with Reproductive Potential at the Japan Agency for Medical Research and Development gathered opinions from experts in reproductive medicine, toxicology, and drug safety measures. The group considered these opinions, the FDA and EMA guidelines, and relevant Japanese guidelines and prepared a guidance paper, which they sent to 19 related organizations for comment., Results: By November 2020, the draft guidance paper was completed and sent to the related organizations, 17 of which provided a total of 156 comments. The study group finalized the guidance paper in March 2021., Conclusions: The "Guidance on the Need for Contraception Related to Use of Pharmaceuticals" (The report of the Study Group for Providing Information on the Proper Use of Pharmaceuticals in Patients with Reproductive Potential, Research on Regulatory Science of Pharmaceuticals and Medical Devices, Japan Agency for Medical Research and Development: JP20mk0101139) is expected to help Japanese healthcare professionals provide fertility-related care and advice to adolescents, and young adults with cancer and their families., (© 2022. The Author(s).)

The efficacy and safety of vaccines for the prevention of infectious diseases are mostly evaluated based on the induction of an immune response against antigens, and do not necessarily depend on the dose administered. Therefore, there are some specific aspects that need to be considered in the development of vaccines and have been described in "The Guidelines for the non-clinical studies of vaccines for the prevention of infectious disease" in Japan. Recent changes in the vaccine development field, such as the introduction of vaccines developed overseas in Japan and vaccine development on a global scale have increased the need for revision of these guidelines. In this study, we identified the current challenges in the development of vaccines through comparison of Japanese and international guidelines. We conducted a questionnaire-based survey of pharmaceutical industries in Japan, and found issues related to non-clinical studies, such as the necessity of safety pharmacology studies and repeated-dose toxicity studies for each route of administration. We examined international guidelines on these issues as well as review reports by regulatory authorities, and determined that the results of repeated-dose toxicity studies can be used to decide whether safety pharmacology studies are required, and that studies to evaluate toxicity due to systemic effects may not be necessary for both intramuscular and subcutaneous administration. We propose revision of the guidelines for the non-clinical studies of vaccines in Japan taking international harmonizaion into account. We expected that the revised guidelines will promote smooth and rational vaccine development., 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: [Takashi Nakano receives honorarium from Daiichi Sankyo Co., Ltd., Sanofi Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., and Denka Co., Ltd.]., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to examine the effects of protein intake on physical performance in critically ill adult patients admitted to the intensive care unit (ICU)., Methods: This was a retrospective cohort study of adult patients mechanically ventilated over 48 h in the ICU who were classified into two groups based on the amount of protein intake: >1.0 g/kg/d (high-protein group) or <1.0 g/kg/d (low-protein group). After adjustment for possible confounding factors with propensity score matching, we compared muscle strength at the time of ICU discharge and the rate of recovery to independent walking between the two groups., Results: One-to-one propensity score matching created 20 pairs. The high-protein group had significantly higher muscle strength than the low-protein group at the time of discharge from the ICU. In addition, the rate of recovery to independent walking before hospital discharge was higher in the high-protein group than the low-protein group (16 of 20 patients [80%] vs. 8 of 20 patients [40%]; P = 0.032)., Conclusions: Our findings indicate that a sufficient amount of protein intake may lead to a higher rate of recovery to independent walking before discharge from the hospital in critically ill patients admitted to the ICU. This finding is likely related to preserved muscle strength at the time of ICU discharge., (Copyright © 2021 Elsevier Inc. All rights reserved.)