Early Clinical Experience of Finerenone in People with Chronic Kidney Disease and Type 2 Diabetes in Japan-A Multi-Cohort Study from the FOUNTAIN (FinerenOne mUltidatabase NeTwork for Evidence generAtIoN) Platform.

Background: In the phase 3 clinical trials FIGARO-DKD and FIDELIO-DKD, finerenone reduced the risk of cardiovascular and kidney events among people with chronic kidney disease (CKD) and type 2 diabetes (T2D). Evidence regarding finerenone use in real-world settings is limited. Methods: A retrospective cohort study (NCT06278207) using two Japanese nationwide hospital-based databases provided by Medical Data Vision (MDV) and Real World Data Co., Ltd. (RWD Co., Kyoto Japan), converted to the OMOP common data model, was conducted. Persons with CKD and T2D initiating finerenone from 1 July 2021, to 30 August 2023, were included. Baseline characteristics were described. The occurrence of hyperkalemia after finerenone initiation was assessed. Results: 1029 new users of finerenone were included (967 from MDV and 62 from RWD Co.). Mean age was 69.5 and 72.4 years with 27.3% and 27.4% being female in the MDV and RWD Co. databases, respectively. Hypertension (92 and 95%), hyperlipidemia (59 and 71%), and congestive heart failure (60 and 66%) were commonly observed comorbidities. At baseline, 80% of persons were prescribed angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers. Sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists were prescribed in 72% and 30% of the study population, respectively. The incidence proportions of hyperkalemia were 2.16 and 2.70 per 100 persons in the MDV and RWD Co. databases, respectively. There were no hospitalizations associated with hyperkalemia observed in either of the two datasets. Conclusions: For the first time, we report the largest current evidence on the clinical use of finerenone in real-world settings early after the drug authorization in Japan. This early evidence from clinical practice suggests that finerenone is used across comorbidities and comedications.

Occipital condyle syndrome due to small-cell lung carcinoma: A case report.

Skull base metastases, including those from small-cell lung carcinoma (SCLC), can present with various syndromes depending on the site of involvement, such as orbital syndrome, parasellar syndrome, middle fossa syndrome, jugular foramen syndrome, and occipital condyle syndrome (OCS). One such example is OCS, which consists of unilateral occipital headache accompanied with ipsilateral hypoglossal palsy. This case report describes a 51-year-old man initially diagnosed with OCS, which led to the discovery of systemic bone metastases from SCLC. Magnetic resonance imaging showed lesions in the occipital condyle and hypoglossal canal, while positron emission tomography-computed tomography identified a lung mass and widespread metastases. SCLC is highly aggressive and metastatic, with the bone being a common site of spread. In this case, the OCS preceded the diagnosis of the underlying malignancy. Prompt diagnosis and treatment are crucial, as patients with OCS often have advanced disease. This case highlights the importance of considering SCLC as a potential etiology for OCS, given the propensity for bone metastases. Early recognition and evaluation of OCS is essential to initiate appropriate management.

Host preference explains the high endemism of ectomycorrhizal fungi in a dipterocarp rainforest.

Ectomycorrhizal (ECM) fungi are important tree symbionts within forests. The biogeography of ECM fungi remains to be investigated because it is challenging to observe and identify species. Because most ECM plant taxa have a Holarctic distribution, it is difficult to evaluate the extent to which host preference restricts the global distribution of ECM fungi. To address this issue, we aimed to assess whether host preference enhances the endemism of ECM fungi that inhabit dipterocarp rainforests. Highly similar sequences of 175 operational taxonomic units (OTUs) for ECM fungi that were obtained from Lambir Hill's National Park, Sarawak, Malaysia, were searched for in a nucleotide sequence database. Using a two-step binomial model, the probability of presence for the query OTUs and the registration rate of barcode sequences in each country were simultaneously estimated. The results revealed that the probability of presence in the respective countries increased with increasing species richness of Dipterocarpaceae and decreasing geographical distance from the study site (i.e. Lambir). Furthermore, most of the ECM fungi were shown to be endemic to Malaysia and neighbouring countries. These findings suggest that not only dispersal limitation but also host preference are responsible for the high endemism of ECM fungi in dipterocarp rainforests. Moreover, host preference likely determines the areas where ECM fungi potentially expand and dispersal limitation creates distance-decay patterns within suitable habitats. Although host preference has received less attention than dispersal limitation, our findings support that host preference has a profound influence on the global distribution of ECM fungi.

Usefulness of an ultrathin endoscope in esophageal endoscopic submucosal dissection.

Background and study aims Endoscopic submucosal dissection (ESD) is sometimes challenging because of stenosis and scarring. We examined the use of an ultrathin endoscope for esophageal ESD, which is difficult using conventional endoscopes. Patients and methods A designated transparent hood and ESD knife for ultrathin endoscopes have been developed and clinically introduced. Esophageal ESD was performed on 303 lesions in 220 patients in our hospital from February 2021 to February 2023. Of them, an ultrathin endoscope was used on 26 lesions in 23 cases. The safety and utility of an ultrathin endoscope in esophageal ESD were retrospectively verified. Results All 26 lesions were resected en bloc, and serious complications such as perforation, massive bleeding, or pneumonia, were not observed. Lesions were found on the anal side of the stenosis and over the scarring in 38.6% (10/26) and 50% (13/26) of participants, respectively. Moreover, 46.2% of participants (12/26) had lesions on the cervical esophagus. The total procedure time was 64.1 ± 37.7 minutes, but the average time from oral incision to pocket creation was 121.2 ± 109.9 seconds. Conclusions Ultrathin endoscopes may be useful for difficult esophageal ESD.

Impact of sex, age at onset, and anti-cN1A antibodies on sporadic inclusion body myositis.

BACKGROUND: Inclusion body myositis (IBM) is a progressive myopathy occurring in patients over 45 years of age, with heterogeneous and variable clinical features. This study aimed to determine the influence of autoantibodies, gender, and age of onset on the clinical features of IBM. METHODS: Medical records and muscle histology findings of 570 participants with suspected IBM were reviewed. Various characteristics of patients who met the 2011 ENMC IBM diagnostic criteria were compared based on the presence of anti-cytosolic 5'-nucleotidase 1 A (cN1A) autoantibodies, gender, age of onset, and disease duration. RESULTS: Of the 353 patients who met the criteria, 41.6% were female. The mean age at onset was 64.6 ± 9.3 years, and the mean duration from onset to diagnosis was 5.7 ± 4.7 years. 196 of the 353 patients (55.5%) were positive for anti-cN1A autoantibodies and 157 were negative. Logistic regression showed that patients with anti-cN1A autoantibodies had a higher frequency of finger flexion weakness. Multiple regression showed that patients with later age of onset had shorter disease duration, lower BMI, and lower serum CK levels. Male patients had a higher frequency of onset with finger weakness and female patients had a lower BMI. CONCLUSION: Autoantibodies, gender, age of onset, and disease duration may influence the clinical presentation of IBM, highlighting the need for a precision medicine approach that considers these factors along with the underlying mechanisms of the disease.

Cross-site reproducibility of human cortical organoids reveals consistent cell type composition and architecture.

While guided human cortical organoid (hCO) protocols reproducibly generate cortical cell types at one site, variability in hCO phenotypes across sites using a harmonized protocol has not yet been evaluated. To determine the cross-site reproducibility of hCO differentiation, three independent research groups assayed hCOs in multiple differentiation replicates from one induced pluripotent stem cell (iPSC) line using a harmonized miniaturized spinning bioreactor protocol across 3 months. hCOs were mostly cortical progenitor and neuronal cell types in reproducible proportions that were consistently organized in cortical wall-like buds. Cross-site differences were detected in hCO size and expression of metabolism and cellular stress genes. Variability in hCO phenotypes correlated with stem cell gene expression prior to differentiation and technical factors associated with seeding, suggesting iPSC quality and treatment are important for differentiation outcomes. Cross-site reproducibility of hCO cell type proportions and organization encourages future prospective meta-analytic studies modeling neurodevelopmental disorders in hCOs.

Comprehensive genomic profiling from C-CAT database unveiled over 80% presence of oncogenic drivers in anaplastic thyroid carcinoma including BRAF, RAS family, NF1, and FGFR1.

OBJECTIVE: Anaplastic thyroid carcinoma (ATC) is considered a very aggressive carcinoma and has been difficult to treat with therapeutic strategies. This study examines the landscape of genomic alteration in ATC, including the BRAF V600E mutation, and its clinical implications. DESIGN, PATIENTS AND MESUREMENT: A retrospective observational study was conducted using collected at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan, utilizing comprehensive genomic profiling data from 102 ATC cases. Additionally, AACR-GENIE data from 267 cases were analysed for validation. Statistical methods, including the conditional Kendall tau statistic and χ2 tests, were employed for survival analysis and gene mutation comparisons. RESULTS: Among 102 ATCs, BRAF, RAS, and other driver mutations were found in 83 cases (81.2%). The prevalence of BRAF V600E mutations was as high as 60%. Co-mutation analysis identified different genomic profiles in the BRAF, RAS, and wild-type groups. Despite the diverse molecular backgrounds, no significant differences in clinical variables and overall survival were observed. The analysis considering left-side amputation suggested that RAS mutations had a poorer prognosis. In the BRAF/RAS wild-type group, FGFR1 and NF1 were identified as driver mutations, with an accumulation of copy number variations and less TERT promoter mutations. This molecular subgrouping was also supported by the AACR-GENIE data. CONCLUSIONS: Comprehensive genomic analysis of ATC in Japan revealed distinct molecular subgroups, highlighting the importance of BRAF V600E mutations, particularly V600E, as potential therapeutic targets and suggest the relevance of tailor-made therapeutic strategies based on genomic profiling.

Lowering pH optimum of activity of SshEstI, a slightly alkaliphilic archaeal esterase of the hormone-sensitive lipase family.

SshEstI, a carboxylesterase from the thermoacidophilic archaeon Saccharolobus shibatae, is a member of the hormone-sensitive lipase family that displays slightly alkaliphilic activity with an optimum activity at pH 8.0. In this study, three distinct strategies were explored to confer acidophilic properties to SshEstI. The first strategy involved engineering the oxyanion hole by replacing Gly81 with serine or aspartic acid. The G81S mutant showed optimum activity at pH 7.0, whereas the aspartic acid mutant (G81D) rendered the enzyme slightly acidophilic with optimum activity observed at pH 6.0; however, kcat and kcat/Km values were reduced by these substitutions. The second strategy involved examining the effects of surfactant additives on the pH-activity profiles of SshEstI. The results showed that cetyltrimethylammonium bromide (CTAB) enhanced wild-type enzyme (WT) activity at acidic pH values. In the presence of 0.1 mM CTAB, G81S and G81D were acidophilic enzymes with optimum activity at pH 6.0 and 4.0, respectively, although their enzyme activities were low. The third strategy involved engineering the active site to resemble that of kumamolisin-As (kuma-As), an acidophilic peptidase of the sedolisin family. The catalytic triad of kuma-As was exchanged into SshEstI using site-directed mutagenesis. X-ray crystallographic analysis of the mutants (H274D and H274E) revealed that the potential hydrogen donor-acceptor distances around the active site of WT were fully maintained in these mutants. However, these mutants were inactive at pH 4-8.

Time Course of Left Ventricular Strain Assessment via Cardiovascular Magnetic Resonance Myocardial Feature Tracking in Takotsubo Syndrome.

Background: Although takotsubo syndrome (TTS) is characterized by transient systolic dysfunction of the left ventricle (LV), the time course and mechanism of LV function recovery remain elusive. The aim of this study is to evaluate cardiac functional recovery in TTS via serial cardiac magnetic resonance feature tracking (CMR-FT). Methods: In this Japanese multicenter registry, patients with newly diagnosed TTS were prospectively enrolled. In patients who underwent serial cardiovascular magnetic resonance (CMR) imaging at 1 month and 1 year after the onset, CMR-FT was performed to determine the global circumferential strain (GCS), global radial strain (GRS) and global longitudinal strain (GLS). We compared LV ejection fraction, GCS, GRS and GLS at 1 month and 1 year after the onset of TTS. Results: Eighteen patients underwent CMR imaging in one month and one year after the onset in the present study. LV ejection fraction had already normalized at 1 month after the onset, with no significant difference between 1 month and 1 year (55.8 ± 9.2% vs. 58.9 ± 7.3%, p = 0.09). CMR-FT demonstrated significant improvement in GCS from 1 month to 1 year (-16.7 ± 3.4% vs. -18.5 ± 3.2%, p < 0.01), while there was no significant difference in GRS and GLS between 1 month and year (GRS: 59.6 ± 24.2% vs. 59.4 ± 17.3%, p = 0.95, GLS: -12.8 ± 5.9% vs. -13.8 ± 4.9%, p = 0.42). Conclusions: Serial CMR-FT analysis revealed delayed improvement of GCS compared to GRS and GLS despite of rapid recovery of LV ejection fraction. CMR-FT can detect subtle impairment of LV systolic function during the recovery process in patients with TTS.

Clinicopathological Features of Early Gastric Cancer Complicated by Autoimmune Gastritis.

INTRODUCTION: In the post-Helicobacter pylori era, autoimmune gastritis (AIG) is attracting increasing attention as an origin of gastric cancer. Here, we performed clinicopathological examination of gastric cancer complicating AIG treated in our hospital. METHODS: Eighty-six early gastric cancer lesions complicating AIG in 50 patients were treated by endoscopic submucosal dissection (ESD) at our hospital in 2008-2022. Their clinicopathological characteristics were compared with those of a control group comprising 2,978 early gastric cancer lesions (excluding lesions in the remnant stomach after surgery) in 2,278 patients treated by ESD during the same period. RESULTS: Mean age was significantly higher in the AIG group than in the control group (74.7 years vs. 70.9 years; p < 0.01). In the respective groups, the occurrence rate of synchronous/metachronous lesions was 38.0% and 20.4% (p < 0.01), the ratio of longitudinal cancer locations (upper/middle/lower third [U/M/L]) was 27/32/27 and 518/993/1,467 (p < 0.01), the ratio of circumferential cancer locations (lesser curvature/greater curvature/anterior wall/posterior wall) was 25/31/12/18 and 1,259/587/475/657 (p < 0.01), the ratio of major macroscopic types (I/IIa/IIb/IIc) was 13/38/5/30 and 65/881/220/1,812 (p < 0.01). The rates of multiple gastric cancer and cancers in the U region, at the greater curvature, and of protruding types were significantly higher in the AIG group. CONCLUSION: The occurrence rate of multiple gastric cancer was significantly higher in gastric cancer complicating AIG (approximately 40%), and compared with the control group, the proportions of cancers at the U region, at the greater curvature, and of protruding types were significantly higher.

Electrocardiogram Electrode Positioning on the Back During Echocardiography: An Exploratory Cross-Sectional Study.

BACKGROUND: ECG interpretation is sometimes difficult due to baseline fluctuations and electrode detachments when placed on the subjects' front side, leading to misinterpretation of the rhythms and phases of the cardiac cycle. We aimed to compare the differences in the wave amplitudes and respiratory variations between conventional ECG electrode positioning on the front side of patients and an alternative position on the backs of patients. METHODS: Echocardiography was performed in 85 patients lying in the left lateral position. We attached the red electrode to the right clavicle, the yellow to the left clavicle, and the green to the left lateral abdomen on the front side of the patients; on the back, we attached the electrode to the right clavicle, the right upper posterior iliac spine, and the left upper posterior iliac spine. RESULTS: The ECG monitor amplitudes were greater on the front side compared to the back side, but the BF-breath values were smaller on the back side (6.0 pixels) compared to the front side (10.5 pixels, p<0.05). The P wave amplitude divided by the BF-breath on the back side was greater than that seen on the front side (2.8 vs. 1.8, p<0.05), whereas the QRS amplitude divided by the BF-breath was 15.0 and 16.3, respectively (p=ns). CONCLUSION: As an alternative to front-side ECG monitoring, electrodes placed on the back can help avoid misinterpretation of the ECG rhythms and the phases of the cardiac cycle due to respiration during echocardiography.

Structural insights into catalytic promiscuity of chalcone synthase from Glycine max (L.) Merr.: Coenzyme A-induced alteration of product specificity.

Catalytic promiscuity of enzymes plays a pivotal role in driving the evolution of plant specialized metabolism. Chalcone synthase (CHS) catalyzes the production of 2',4,4',6'-tetrahydroxychalcone (THC), a common precursor of plant flavonoids, from p-coumaroyl-coenzyme A (-CoA) and three malonyl-CoA molecules. CHS has promiscuous product specificity, producing a significant amount of p-coumaroyltriacetic lactone (CTAL) in vitro. However, mechanistic aspects of this CHS promiscuity remain to be clarified. Here, we show that the product specificity of soybean CHS (GmCHS1) is altered by CoA, a reaction product, which selectively inhibits THC production (IC50, 67 µM) and enhances CTAL production. We determined the structure of a ternary GmCHS1/CoA/naringenin complex, in which CoA is bound to the CoA-binding tunnel via interactions with Lys55, Arg58, and Lys268. Replacement of these residues by alanine resulted in an enhanced THC/CTAL production ratio, suggesting the role of these residues in the CoA-mediated alteration of product specificity. In the ternary complex, a mobile loop ("the K-loop"), which contains Lys268, was in a "closed conformation" placing over the CoA-binding tunnel, whereas in the apo and binary complex structures, the K-loop was in an "open conformation" and remote from the tunnel. We propose that the production of THC involves a transition of the K-loop conformation between the open and closed states, whereas synthesis of CTAL is independent of it. In the presence of CoA, an enzyme conformer with the closed K-loop conformation becomes increasingly dominant, hampering the transition of K-loop conformations to result in decreased THC production and increased CTAL production.

Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders.

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

Traction Devices May Not Affect the Vertical Margin Distance in the Endoscopic Submucosal Dissection of Rectal Neuroendocrine Tumors.

Introduction The usefulness of traction devices (TDs) in endoscopic submucosal dissection (ESD) for rectal neuroendocrine tumors (NETs) has not been reported. The aim of this study was to investigate the impact of using a TD on the vertical margin (VM) distance in the ESD of rectal NETs. Methods In this single-center, retrospective study, we included patients with rectal NETs who were treated with ESD during 2013-2023. They were divided into TD and non-TD groups. One pathologist remeasured the VM distance (primary outcome) and the depth of submucosal invasion (SM depth). Secondary outcomes were margins, resection time, delayed bleeding, and perforation. First, we performed propensity score matching (PSM) to assess the usefulness of TD for VM distance. Then, we used multiple regression analysis to identify factors affecting the VM distance. Results The TD and non-TD groups comprised 24 and 117 lesions, respectively. Patients in the TD group were significantly younger than those in the non-TD group (P = 0.003). In the TD and non-TD groups, the VM distance was 150 µm and 100 µm, respectively (P = 0.70). Only resection time significantly differed between groups, shorter in the TD group (P = 0.005). Twenty-two cases in each group were matched after PSM, yielding no significant differences in VM distance. The use of a TD was not an independent predictor of VM distance (P = 0.65), but age (P < 0.001) and SM depth (P = 0.003) were. Conclusion Using a TD does not seem to affect the VM distance in ESD for rectal NETs.

Cell-free translation system with artificial lipid-monolayer particles as a unique tool for characterizing lipid-monolayer binding proteins.

Methods for functional analysis of proteins specifically localizing to lipid monolayers such as rubber particles and lipid droplets are limited. We have succeeded in establishing a system in which artificially prepared lipid monolayer particles are added to a cell-free translation system to confirm the properties of proteins that specifically bind to lipid monolayers in a translation-coupled manner.

Severe induction of aberrant DNA methylation by nodular gastritis in adults.

BACKGROUND: Nodular gastritis (NG) is characterized by marked antral lymphoid follicle formation, and is a strong risk factor for diffuse-type gastric cancer in adults. However, it is unknown whether aberrant DNA methylation, which is induced by atrophic gastritis (AG) and is a risk for gastric cancer, is induced by NG. Here, we analyzed methylation induction by NG. METHODS: Gastric mucosal samples were obtained from non-cancerous antral tissues of 16 NG and 20 AG patients with gastric cancer and 5 NG and 6 AG patients without, all age- and gender-matched. Genome-wide methylation analysis and expression analysis were conducted by a BeadChip array and RNA-sequencing, respectively. RESULTS: Clustering analysis of non-cancerous antral tissues of NG and AG patients with gastric cancer was conducted using methylation levels of 585 promoter CpG islands (CGIs) of methylation-resistant genes, and a large fraction of NG samples formed a cluster with strong methylation induction. Promoter CGIs of CDH1 and DAPK1 tumor-suppressor genes were more methylated in NG than in AG. Notably, methylation levels of these genes were also higher in the antrum of NG patients without cancer. Genes related to lymphoid follicle formation, such as CXCL13/CXCR5 and CXCL12/CXCR4, had higher expression in NG, and genes involved in DNA demethylation TET2 and IDH1, had only half the expression in NG. CONCLUSIONS: Severe aberrant methylation, involving multiple tumor-suppressor genes, was induced in the gastric antrum and body of patients with NG, in accordance with their high gastric cancer risk.

The combination of hydrogen gas and hydrogen-rich solution does not protect against ischemic spinal cord injury in rabbits.

PURPOSE: This study aimed to determine whether the combination of H2 gas inhalation and administration of hydrogen-rich acetated Ringer's solution (HS) could protect against ischemic spinal cord injury in rabbits. METHODS: In Experiment 1, rabbits were randomly assigned to a 1.2% H2 gas group, HS group, 1.2% H2 gas + HS group (combination group), or control group (n = 6 per group). The H2 concentration of HS was 0.65 mM. H2 was inhaled for 60 min, starting 5 min before reperfusion. HS (20 mL/kg) was divided into six bolus injections at 10-min intervals, starting 5 min before reperfusion. Spinal cord ischemia was produced by occluding the abdominal aorta for 15 min. Neurologic and histopathologic evaluations were performed 7 days after reperfusion. In Experiment 2, H2 concentrations in spinal cord tissue according to the administration of 1.2% H2 gas or HS were compared by measuring the electric current through a platinum needle electrode (n = 2). In Experiment 3, rabbits were assigned to a 2% H2 gas group or control group (n = 6 per group). Spinal cord ischemia was produced and neurologic and histopathologic evaluations were performed as in Experiment 1. RESULTS: There were no significant differences among the groups in the neurologic and histopathologic outcomes in Experiments 1 and 3. Bolus administration of HS (10 mL) transiently increased the current to only 1/30th and 1/27th of the plateau current with 1.2% H2 gas inhalation in two animals. CONCLUSION: These results suggest that the combination of 1.2% H2 gas inhalation and administration of a hydrogen-rich solution does not protect against ischemic spinal cord injury and that the increase in H2 concentration in spinal cord tissue after administration of HS is very low compared to 1.2% H2 gas inhalation.