Research integrity in Instructions for Authors in Japanese medical journals using ICMJE Recommendations: A descriptive literature study.

BACKGROUND: The International Committee of Medical Journal Editors (ICMJE) has published Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. These provide a global standard for writing and editing medical articles, including research integrity. However, no study has examined the research integrity-related content of Japanese medical journals' Instructions for Authors. We therefore compared research integrity content in ICMJE member journals with those in the English- and Japanese-language journals of the Japanese Association of Medical Sciences (JAMS). MATERIALS AND METHODS: This was a descriptive literature study. We obtained Instructions for Authors from English- and Japanese-language journals listed on the JAMS website and the ICMJE member journals listed on the ICMJE website as of September 1, 2021. We compared the presence of 20 topics (19 in the ICMJE Recommendations plus compliance with ICMJE) in the Instructions for Authors, and analyzed the content of the conflict of interest disclosure. RESULTS: We evaluated 12 ICMJE member journals, and 82 English-language and 99 Japanese-language subcommittee journals. The median number of topics covered was 10.5 for ICMJE member journals, 10 for English-language journals, and three for Japanese-language journals. Compliance with ICMJE was mentioned by 10 (83%) ICMJE member journals, 75 (91%) English-language journals, and 29 (29%) Japanese-language journals. The ICMJE Conflicts of Interest Disclosure Form was requested by seven (64%) ICMJE member journals, 15 (18%) English-language journals, and one (1%) Japanese-language journal. CONCLUSIONS: Although the topics in the JAMS English-language journals resembled those in the ICMJE member journals, the median value of ICMJE-related topic inclusion was approximately one-third lower in JAMS Japanese-language journals than in ICMJE member journals. It is hoped that Japanese-language journals whose conflict of interest disclosure policies differ from ICMJE standards will adopt international standards to deter misconduct and ensure publication quality.

Laparoscopic Gastrectomy Using External Oblique Intercostal Block Versus Wound Infiltration: A Trial Protocol.

OBJECTIVE: A novel external oblique intercostal block (EOIB) might have analgesic effects on T6-10 and be indicated for laparoscopic gastrectomy. However, EOIB effects on postoperative pain are unknown. We aim to generate evidence to support such EOIB application. We will compare the efficacy of EOIB and wound infiltration (WI) in a single-center, single-blind, randomized controlled trial. METHODS: We will assess plasma concentrations of levobupivacaine after EOIB, its pharmacokinetics, and the pinprick test in patients randomly assigned to receive EOIB or WI before laparoscopic or robot-assisted gastric distal or total gastrectomy. The EOIB and WI will start after general anesthesia induction with 20 and 40 mL of 0.25% levobupivacaine per side, respectively, before skin closure. The outcomes will be numeric rating scale (NRS) scores at 12 h postoperatively (primary) and postoperative NRS scores at 2, 24, and 48 h; fentanyl application; QoR-15 scores on postoperative days 1, 2, and 7; and World Health Organization Disability Assessment Schedule 2.0 scores at 3 months (secondary). CONCLUSIONS: We hope that our study will provide evidence to support EOIB application in laparoscopic surgery. Plasma concentrations will help determine levobupivacaine pharmacokinetics, which if similar to conventional nerve blocks, will indicate EOIB's safety.

A robust system of hybridogenesis that increases genetic variability and promotes evolutionary succession in greenlings (Teleostei: Hexagrammidae, genus Hexagrammos): Regeneration of a new hemiclonal lineage.

Unisexual hybrids that reproduce either clonally or hemiclonally are considered to be evolutionarily short-lived as they lack the ability to reduce deleterious mutations and increase genetic diversity. In the greenling (Teleostei: Hexagrammidae, genus Hexagrammos), unisexual hybrids that produce haploid eggs containing only the H. octogrammus (maternal species) genome generate hemiclonal offspring by fertilization with haploid sperm of H. agrammus (paternal species). When hemiclonal hybrids are backcrossed to a male of the maternal species, the offspring (BC-Hoc) are phenotypically similar to the maternal species and produce recombinant gametes through conventional meiosis. BC-Hoc (recombinant generation) individuals referred to as carriers harbor the genetic factor for hybridogenesis, thereby facilitating the production of new hemiclonal lineages through hybridization. Previous studies based on field research have suggested that the carriers produced by two-way backcrossing (mating pattern in which hemiclonal hybrids are backcrossed with both parental species) may overcome the evolutionary dead end imposed by the lack of recombination. The present study verified this hypothesis by regenerating a newly hemiclonal lineage through artificial hybridization. To clarify the genetic mode of hybrids produced by crosses between BC-Hoc and Hag, mature eggs were obtained from 16 individuals and fertilized with either Hag or Hoc sperm. Hybridogenesis was confirmed in one of the 16 individuals. Based on the low occurrence rate, these findings suggest that hemiclonal lineages can be regenerated, and that the hemiclonal factors are likely distributed across multiple genes on different chromosomes. The findings provide important evidence for the retention of a robust system for increasing genetic variability and maintaining evolutionary succession in unisexual hybrids that reproduce hemiclonally.

Association Between Early Mobilization and Functional Outcomes in Patients with Aneurysmal Subarachnoid Hemorrhage: A Multicenter Retrospective Propensity Score-Matched Study.

BACKGROUND: Early mobilization has been shown to promote functional recovery and prevent complications in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the efficacy of early mobilization in patients with aSAH remains unclear. This study aimed to investigate the association between early mobilization and functional outcomes in patients with aSAH. METHODS: This multicenter retrospective study was conducted in Japan and included patients with aSAH who received physical therapy with or without occupational therapy from April 2014 to March 2019. The primary outcome was the modified Rankin Scale (mRS) score, with a favorable functional outcome defined as an mRS score of 0-2 and an unfavorable outcome with an mRS score of 3-5. Patients initiating walking training within 14 days of aSAH onset were classified into the early mobilization group, whereas those initiating training after 14 days were classified into the delayed mobilization group. Propensity score matching analysis was performed to assess the association between early mobilization and favorable outcomes. RESULTS: A total of 718 patients were screened, and 450 eligible patients were identified. Before matching, 229 patients (50.9%) were in the early mobilization group and 221 (49.1%) were in the delayed mobilization group. After matching, each group consisted of 122 patients, and the early mobilization group exhibited a higher proportion of favorable outcomes than did the delayed mobilization group (81.1% vs. 52.5%, risk difference 28.7%, 95% confidence interval 17.4-39.9, p < 0.001). CONCLUSIONS: This multicenter retrospective study suggests that initiating walking training within 14 days of aSAH onset is associated with favorable outcomes.

ATP2B1 gene polymorphisms associated with resistant hypertension in the Japanese population.

Single-nucleotide polymorphisms (SNP) of ATP2B1 gene are associated with essential hypertension but their association with resistant hypertension (RHT) remains unexplored. The authors examined the relationship between ATP2B1 SNPs and RHT by genotyping 12 SNPs in ATP2B1 gene of 1124 Japanese individuals with lifestyle-related diseases. Patients with RHT had inadequate blood pressure (BP) control using three antihypertensive drugs or used ≥4 antihypertensive drugs. Patients with controlled hypertension had BP controlled using ≤3 antihypertensive drugs. The association between each SNP and RHT was analyzed by logistic regression. The final cohort had 888 (79.0%) and 43 (3.8%) patients with controlled hypertension and RHT, respectively. Compared with patients homozygous for the minor allele of each SNP in ATP2B1, a significantly higher number of patients carrying the major allele at 10 SNPs exhibited RHT (most significant at rs1401982: 5.8% vs. 0.8%, p = .014; least significant at rs11105378: 5.7% vs. 0.9%, p = .035; most nonsignificant at rs12817819: 5.1% vs. 10%, p = .413). After multivariate adjustment for age, sex, systolic BP, and other confounders, the association remained significant for rs2681472 and rs1401982 (OR: 7.60, p < .05 and OR: 7.62, p = .049, respectively). Additionally, rs2681472 and rs1401982 were in linkage disequilibrium with rs11105378. This study identified two ATP2B1 SNPs associated with RHT in the Japanese population. rs1401982 was most closely associated with RHT, and major allele carriers of rs1401982 required significantly more antihypertensive medications. Analysis of ATP2B1 SNPs in patients with hypertension can help in early prediction of RHT and identification of high-risk patients who are more likely to require more antihypertensive medications.

The clinical trial of alternative relugolix administration for uterine leiomyoma prior to surgically treatment: a study protocol for Non-Adverse Relugolix Administration (NARA) trial.

BACKGROUND: Uterine leiomyomas are common for reproductive-aged women and affect women's quality of life due to heavy menstrual bleeding or dysmenorrhea. Leiomyomas grow according to estradiol exposure and decrease after post-menopause. In case serious symptoms are caused by leiomyomas, pharmacotherapy or surgical treatment is proposed. Prior to surgical treatment, pharmacotherapies aimed at the reduction of leiomyoma and uterine volume or improvement of anemia are introduced to conduct minimum invasive surgery (i.e., to reduce blood loss or surgical duration). Recently, relugolix (40 mg orally once daily) as a gonadotropin-releasing hormone (GnRH) receptor antagonist has proved its sufficient efficacy in suppressing estradiol levels without the transient estradiol flare-up compared with GnRH agonist. However, long-term administration should not be permitted liable to for climacteric disorder or osteoporosis, and evidence is lacking on the actual efficacy and extent of adverse effects of the every-other-day dosing regimen. This trial aimed to prove non-inferiority in volume reduction effect on leiomyoma and safety (i.e., reduction of adverse effects) by every-other-day administration after 2 months of everyday administration compared to daily administration throughout the duration. METHODS: A minimization adaptive randomized control trial (RCT) will be conducted. Patients (over 20 years old) harboring leiomyoma who will be undergoing surgical treatment will be invited to participate. Patients who are enrolled in the intervention group will receive every-other-day administration for 16 weeks after 8 weeks of daily administration. Patients who are enrolled in the control group will receive daily throughout the 24 weeks. The primary outcome is the leiomyoma volume reduction, and the secondary endpoints are the reduction of uterine volume, the occurrence of the climacteric disorder, genital bleeding days, change rate of serum hormone or bone turnover markers, and bone mineral density after 24 weeks compared to before administration. DISCUSSION: This study aims to prove both the non-inferiority in leiomyoma volume reduction and superiority in adverse effects occurrence reduction, which will provide a novel method to escape adverse effects while maintaining the effect of leiomyoma reduction. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs051230078. Registered on 26 July 2023.

Runx1 is upregulated by STAT3 and promotes proliferation of neonatal rat cardiomyocytes.

Though it is well known that mammalian cardiomyocytes exit cell cycle soon after birth, the mechanisms that regulate proliferation remain to be fully elucidated. Recent studies reported that cardiomyocytes undergo dedifferentiation before proliferation, indicating the importance of dedifferentiation in cardiomyocyte proliferation. Since Runx1 is expressed in dedifferentiated cardiomyocytes, Runx1 is widely used as a dedifferentiation marker of cardiomyocytes; however, little is known about the role of Runx1 in the proliferation of cardiomyocytes. The purpose of this study was to clarify the functional significance of Runx1 in cardiomyocyte proliferation. qRT-PCR analysis and immunoblot analysis demonstrated that Runx1 expression was upregulated in neonatal rat cardiomyocytes when cultured in the presence of FBS. Similarly, STAT3 was activated in the presence of FBS. Interestingly, knockdown of STAT3 significantly decreased Runx1 expression, indicating Runx1 is regulated by STAT3. We next investigated the effect of Runx1 on proliferation. Immunofluorescence microscopic analysis using an anti-Ki-67 antibody revealed that knockdown of Runx1 decreased the ratio of proliferating cardiomyocytes. Conversely, Runx1 overexpression using adenovirus vector induced cardiomyocyte proliferation in the absence of FBS. Finally, RNA-sequencing analysis revealed that Runx1 overexpression induced upregulation of cardiac fetal genes and downregulation of genes associated with fatty acid oxidation. Collectively, Runx1 is regulated by STAT3 and induces cardiomyocyte proliferation by juvenilizing cardiomyocytes.

Acute Fatty Liver of Pregnancy Complicated With Mild Encephalitis/Encephalopathy With a Reversible Splenial Lesion: A Case Report.

Acute fatty liver of pregnancy (AFLP) is a rare complication of pregnancy that may result in fulminant hepatic failure. A 28-year-old woman, at 36 weeks of gestation, presented to a maternal-fetal outpatient clinic with fever and headache. She was prescribed analgesics and was planned for follow-up. Two days later, she was taken back for evaluation by her husband to the previous physician again because of the subacute onset of impaired consciousness. Blood tests showed a marked elevation of liver enzymes and C-reactive protein (CRP), and the patient was transported to a tertiary hospital. A clinical diagnosis of AFLP or hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome was made, and an emergency cesarean section was performed. Unconsciousness was prolonged due to mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) for three days. A liver biopsy was performed on postoperative day 11. Liver biopsy results showed large and small droplet fatty deposits, and the diagnosis of AFLP was confirmed. Thereafter, the elevated liver enzymes resolved spontaneously solely by supportive care. The patient presented with symptoms of impaired consciousness due to mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), which led to a visit to a tertiary hospital and early intervention for AFLP. This case suggested that there may be similarities between the two pathologies of AFLP and MERS.

Influence on the accuracy in ChatGPT: Differences in the amount of information per medical field.

OBJECTIVES: Although ChatGPT was not developed for medical use, there is growing interest in its use in medical fields. Understanding its capabilities and precautions for its use in the medical field is an urgent matter. We hypothesized that differences in the amounts of information published in different medical fields would be proportionate to the amounts of training ChatGPT receives in those fields, and hence its accuracy in providing answers. STUDY DESIGN: A non-clinical experimental study. METHODS: We administered the Japanese National Medical Examination to GPT-3.5 and GPT-4 to examine the rates of accuracy and consistency in their responses. We counted the total number of documents in the Web of Science Core Collection per medical field and assessed the relationship with ChatGPT's accuracy. We also performed multivariate-adjusted models to investigate the risk factors for incorrect answers. RESULTS: For GPT-4, we confirmed an accuracy rate of 81.0 % and a consistency rate of 88.8 % on the exam; both showed improvement compared to those for GPT-3.5. A positive correlation was observed between the accuracy rate and consistency rate (R = 0.51, P < 0.001). The number of documents per medical field was significantly correlated with the accuracy rate in that medical field (R = 0.44, P < 0.05), with relatively few publications being an independent risk factor for incorrect answers. CONCLUSIONS: Checking consistency may help identify incorrect answers when using ChatGPT. Users should be aware that the accuracy of the answers by ChatGPT may decrease when it is asked about topics with limited published information, such as new drugs and diseases.

Cardioprotective effect of Interleukin-11 against warm ischemia-reperfusion injury in a rat heart donor model.

Shortage of donor organs for heart transplantation is a worldwide problem. Donation after circulatory death (DCD) has been proposed to expand the donor pool. However, in contrast to the donation after brain death that undergoes immediate cold preservation, warm ischemia and subsequent reperfusion injury are inevitable in DCD. It has been reported that interleukin-11 (IL-11) mitigates ischemia-reperfusion injury in rodent models of myocardial infarction and donation after brain death heart transplantation. We hypothesized that IL-11 also offers benefit to warm ischemia in an experimental model of cardiac transplantation that resembles DCD. The hearts of naïve male Sprague Dawley rats (n = 15/group) were procured, subjected to 25-min warm ischemia, and reperfused for 60 min using Langendorff apparatus. IL-11 or saline was administered intravenously before the procurement, added to maintenance buffer, and infused via perfusion during reperfusion. IL-11 group exhibited significantly better cardiac function post-reperfusion. Severely damaged mitochondria was found in the electron microscopic analysis of control hearts whereas the mitochondrial structure was better preserved in the IL-11 treated hearts. Immunoblot analysis using neonatal rat cardiomyocytes revealed increased signal transducer and activator of transcription 3 (STAT3) phosphorylation at Ser727 after IL-11 treatment, suggesting its role in mitochondrial protection. Consistent with expected activation of mitochondrial respiration by mitochondrial STAT3, immunohistochemical staining demonstrated a higher mitochondrial cytochrome c oxidase subunit 2 expression. In summary, IL-11 protects the heart from warm ischemia reperfusion injury by alleviating mitochondrial injury and could be a viable therapeutic option for DCD heart transplantation.

Internet-Based Inquiries From Users With the Intention to Overdose With Over-the-Counter Drugs: Qualitative Analysis of Yahoo! Chiebukuro.

BACKGROUND: Public concern with regard to over-the-counter (OTC) drug abuse is growing rapidly across countries. OTC drug abuse has serious effects on the mind and body, such as poisoning symptoms, and often requires specialized treatments. In contrast, there is concern about people who potentially abuse OTC drugs whose symptoms are not serious enough to consult medical institutions or drug addiction rehabilitation centers yet are at high risk of becoming drug dependent in the future. OBJECTIVE: Consumer-generated media (CGM), which allows users to disseminate information, is being used by people who abuse (and those who are trying to abuse) OTC drugs to obtain information about OTC drug abuse. This study aims to analyze the content of CGM to explore the questions of people who potentially abuse OTC drugs. METHODS: The subject of this research was Yahoo! Chiebukuro, the largest question and answer website in Japan. A search was performed using the names of drugs commonly used in OTC drug abuse and the keywords overdose and OD, and the number of questions posted on the content of OTC drug abuse was counted. Furthermore, a thematic analysis was conducted by extracting text data on the most abused antitussive and expectorant drug, BRON. RESULTS: The number of questions about the content of overdose medications containing the keyword BRON has increased sharply as compared with other product names. Furthermore, 467 items of question data that met the eligibility criteria were obtained from 528 items of text data on BRON; 26 codes, 6 categories, and 3 themes were generated from the 578 questions contained in these items. Questions were asked about the effects they would gain from abusing OTC drugs and the information they needed to obtain the effects they sought, as well as about the effects of abuse on their bodies. Moreover, there were questions on how to stop abusing and what is needed when seeking help from a health care provider if they become dependent. It has become clear that people who abuse OTC drugs have difficulty in consulting face-to-face with others, and CGM is used as a means to obtain the necessary information anonymously. CONCLUSIONS: On CGM, people who abused or tried to abuse OTC drugs were asking questions about their abuse expectations and anxieties. In addition, when they became dependent, they sought advice to quit their abuse. CGM was used to exchange information about OTC drug abuse, and many questions on anxieties and hesitations were posted. This study suggests that it is necessary to produce and disseminate information on OTC drug abuse, considering the situation of those who abuse or are willing to abuse OTC drugs. Support from pharmacies and drugstores would also be essential to reduce opportunities for OTC drug abuse.

Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding.

Hydroxycarboxylic acid receptors (HCA) are expressed in various tissues and immune cells. HCA2 and its agonist are thus important targets for treating inflammatory and metabolic disorders. Only limited information is available, however, on the active-state binding of HCAs with agonists. Here, we present cryo-EM structures of human HCA2-Gi and HCA3-Gi signaling complexes binding with multiple compounds bound. Agonists were revealed to form a salt bridge with arginine, which is conserved in the HCA family, to activate these receptors. Extracellular regions of the receptors form a lid-like structure that covers the ligand-binding pocket. Although transmembrane (TM) 6 in HCAs undergoes dynamic conformational changes, ligands do not directly interact with amino acids in TM6, suggesting that indirect signaling induces a slight shift in TM6 to activate Gi proteins. Structural analyses of agonist-bound HCA2 and HCA3 together with mutagenesis and molecular dynamics simulation provide molecular insights into HCA ligand recognition and activation mechanisms.

Study of assessment of knowledge and understanding for coping with sick days among patients with diabetes in community pharmacy: a cluster randomized controlled trial (SAKURA trial).

BACKGROUND: Awareness regarding coping with sick days among patients with diabetes is limited. Thus, we evaluated the effectiveness of sick-day education by community pharmacists among patients with type 2 diabetes (T2D) using sick-day educational materials (sick-day cards). METHODS: A cluster randomized controlled trial was conducted. Pharmacists in the intervention group educated patients with T2D on coping with sick days (adjusting medication dosage and seeking medical advice) using sick-day cards compared with the usual counseling. Differences in questionnaire scores ("Anxiety", "Intention", "Attitude", and "Knowledge" about sick days) before and after the intervention were compared between the groups. RESULTS: Overall, 318 patients with T2D (intervention, 119; control, 199) participated in this study, and 270 (intervention, 92; control, 178) patients were examined. There were no significant differences in "Anxiety", "Intention", or "Attitude" scores between the two groups, but "Knowledge" scores improved in the intervention group. For all intervention groups (92/92), a physician reviewed and approved medication and adjustment doses for sick days on the cards. CONCLUSIONS: According to patients' responses, sick-day education using teaching materials improved patient knowledge. This may help patients and their caregivers cope with sick days appropriately through medication dose adjustment and fluid intake. Research registration number: UMIN000043161 (February 1, 2021), https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr.cgifunction=brows&action=brows&recptno=R000048124&type=summary&language=J.

Video-based learning can improve the understanding of pharmacists’ contributions during the COVID-19 pandemic: A cross-sectional survey of pharmacy students in Japan

Backgound: It has been challenging to conduct university education in face-to-face and large group settings during the COVID-19 pandemic. Accordingly, there is a pressing need for online educational videos. Objective: To create educational videos to highlight community pharmacists’ efforts during the COVID-19 pandemic in Japan and investigate pharmacy students’ awareness of community pharmacists’ efforts. Methods: To assess the importance of five educational videos, we conducted a cross-sectional survey. In July 2020, first-year pharmacy students (n = 120) were invited to watch these educational videos, which dealt with infection control measures for COVID-19 in pharmacies and the questions received from patients on COVID-19. Subsequently, the students were asked to respond to a questionnaire to assess the impact of the videos on them. Results: Seventy percent of the students revealed that after watching the videos, they, for the first time, realized the contributions of community pharmacists toward healthcare during the COVID-19 pandemic. Many of the students reported that their image of the pharmacist profession changed to “a familiar medical professional who is close to patients.” Furthermore, 102 of the participants (85%) were satisfied with the videos and more than 60% said they gave them confidence for their future studies. Conclusions: Creating these five educational videos provided the first-year pharmacy students with an improved understanding of the role played by pharmacists in public health. Through the videos, the role of pharmacists during the COVID-19 pandemic was particularly highlighted. This helped students feel closer to pharmacists, whose role is rarely reported in the media. Moreover, their future goal of becoming a pharmacist was concretized. (AU)

Possible Relationship between the Deteriorated Accuracy of Intermittent-Scanning Continuous Glucose Monitoring Device and the Contact Dermatitis: Post-hoc analysis of the ISCHIA Study.

OBJECTIVE: We previously reported the mean average relative difference (MARD) of the sensor glucose (SG) of the first-generation FreeStyle Libre with the original algorithm, an intermittent scanning continuous glucose monitoring (isCGM) device, was 15.6% in the Effect of Intermittent-Scanning Continuous Glucose Monitoring to Glycemic Control Including Hypoglycemia and Quality of Life of Patients with Type 1 Diabetes Mellitus Study (ISCHIA Study). In the present study, we aimed to further analyze its accuracy in detail by conducting a post-hoc analysis of the study. METHODS: The ISCHIA Study was a multicenter, randomized, cross-over trial to assess the efficacy of isCGM. The SG levels of isCGM and the measured capillary blood glucose (BG) levels of 91 participants were used for the analysis. RESULTS: Bland-Altman analysis showed bias of -13.0 mg/dl when the SG levels were compared to the BG levels, however no proportional bias was observed (r = 0.085). MARD of the participants without and with contact dermatitis were 15.0 ± 6.0% and 27.4 ± 21.4% (P = 0.001), respectively. CONCLUSION: There was negative bias in the SG levels of isCGM compared to the BG levels. There is a possibility that the complication of the contact dermatitis during isCGM use may be related with deteriorated accuracy of the SG levels.

Structural analysis of the water channel AQP2 by single-particle cryo-EM.

Water channels, which are small membrane proteins almost entirely buried in lipid membranes, are challenging research targets for single-particle cryo-electron microscopy (cryo-EM), a powerful technique routinely used to determine the structures of membrane proteins. Because the single-particle method enables structural analysis of a whole protein with flexible parts that interfere with crystallization, we have focused our efforts on analyzing water channel structures. Here, utilizing this system, we analyzed the structure of full-length aquaporin-2 (AQP2), a primary regulator of vasopressin-dependent reabsorption of water at the renal collecting ducts. The 2.9 Å resolution map revealed a cytoplasmic extension of the cryo-EM density that was presumed to be the highly flexible C-terminus at which the localization of AQP2 is regulated in the renal collecting duct cells. We also observed a continuous density along the common water pathway inside the channel pore and lipid-like molecules at the membrane interface. Observations of these constructions in the AQP2 structure analyzed without any fiducial markers (e.g., a rigidly bound antibody) indicate that single-particle cryo-EM will be useful for investigating water channels in native states as well as in complexes with chemical compounds.

Impact of prior bevacizumab therapy on the incidence of ramucirumab-induced proteinuria in colorectal cancer: a multi-institutional cohort study.

BACKGROUND: The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC). METHODS: mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups. RESULTS: We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01). CONCLUSION: Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

Prevention of Contrast-Induced Nephropathy After Emergency Percutaneous Coronary Intervention With a Single Bolus Administration of High-Concentrate Sodium Bicarbonate　- Rationale and Design of a Single-Arm Study Compared With Historical Controls.

Background: Contrast-induced nephropathy (CIN) is clinically important because of its poor prognosis. The incidence of CIN is higher in emergency than elective percutaneous coronary intervention (PCI) because there is no established method to prevent CIN. The aim of this study is to evaluate whether bolus administration of a concentrated solution of sodium bicarbonate can prevent CIN in patients undergoing emergency PCI. Methods and Results: This multicenter prospective single-arm trial with historical controls will include patients who are aged ≥20 years and will undergo cardiac catheterization for suspected acute myocardial infarction (AMI). Patients will receive an intravenous bolus administration of concentrated sodium bicarbonate solution (7% or 8.4%, 20 mEq) and will be observed for 72±12 h. Data for the control group, comprising all patients who underwent PCI for AMI between January 1, 2020 and December 31, 2020 across participating hospitals, will be extracted. The primary endpoint is the incidence of CIN, defined as an increase in serum creatinine of >0.5 mg/dL or >25% from baseline within 48±12 h. We will evaluate the endpoints in the prospective group and compare them with those in the historical control group. Conclusions: This study will evaluate whether a single bolus administration of concentrated sodium bicarbonate can prevent CIN after emergency PCI.

A novel method for predicting the unbound valproic acid concentration.

In this study, we constructed a prediction formula for unbound valproic acid (VPA) concentration that was more accurate and widely applicable than previously reported formulae. A total of 136 datasets from 75 patients were analyzed retrospectively. The median of free fraction of VPA was 0.16 (interquartile range: 0.07; range: 0.07-0.45). The parameter that combined total VPA concentration (CtVPA) and serum albumin (SA), (CtVPA [µM] - 2 × SA [µM]), was significantly related to the free fraction of VPA (r = 0.76, p < 0.001). We constructed a combined parameter-based prediction formula for unbound VPA concentration. Analysis using external datasets from patients without severe renal failure showed that the prediction errors of the unbound VPA concentration were lower than those of previously reported formulae. Although the previous formulae showed large prediction errors, especially in the specific range of CtVPA values, the constructed formula showed a weak trend with CtVPA or SA. The formula based on (CtVPA [µM] - 2 × SA [µM]) had high prediction accuracy and wide applicability in predicting the unbound VPA concentration in patients without severe renal failure.

Loss of peroxisomal NAD kinase 3 (NADK3) affects photorespiration metabolism in Arabidopsis.

Nicotinamide adenine dinucleotides (NAD+ and NADP+) are electron mediators involved in various metabolic pathways. NADP(H) are produced by NAD kinase (NADK) through the phosphorylation of NAD(H). The Arabidopsis NADK3 (AtNADK3) is reported to preferentially phosphorylate NADH to NADPH and is localized in the peroxisome. To elucidate the biological function of AtNADK3 in Arabidopsis, we compared metabolites of nadk1, nadk2 and nadk3 Arabidopsis T-DNA inserted mutants. Metabolome analysis revealed that glycine and serine, which are intermediate metabolites of photorespiration, both increased in the nadk3 mutants. Plants grown for 6 weeks under short-day conditions showed increased NAD(H), indicating a decrease in the phosphorylation ratio in the NAD(P)(H) equilibrium. Furthermore, high CO2 (0.15%) treatment induced a decrease in glycine and serine in nadk3 mutants. The nadk3 showed a significant decrease in post-illumination CO2 burst, suggesting that the photorespiratory flux was disrupted in the nadk3 mutant. In addition, an increase in CO2 compensation points and a decrease in CO2 assimilation rate were observed in the nadk3 mutants. These results indicate that the lack of AtNADK3 causes a disruption in the intracellular metabolism, such as in amino acid synthesis and photorespiration.