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Background: Catheter ablation (CA) for premature ventricular contractions (PVCs) restores cardiac and renal functions in patients with reduced left ventricular ejection fraction (LVEF); however, its effects on preserved EF remain unelucidated., Methods: The study cohort comprised 246 patients with a PVC burden of >10% on Holter electrocardiography. Using propensity matching, we compared the changes in B-type natriuretic peptide (BNP) levels and estimated glomerular filtration rate (eGFR) in patients who underwent CA or did not., Results: Postoperative BNP levels were decreased significantly in the CA group, regardless of the degree of LVEF, whereas there was no change in those of the non-CA group. Among patients who underwent CA, BNP levels decreased from 44.1 to 33.0 pg/mL in those with LVEF ≥50% ( p  = .002) and from 141.0 to 87.9 pg/mL in those with LVEF <50% ( p  < .001). Regarding eGFR, postoperative eGFR was significantly improved in the CA group of patients with LVEF ≥50% (from 71.4 to 74.7 mL/min/1.73 m 2 , p  = .006), whereas it decreased in the non-CA group. A similar trend was observed in the group with a reduced LVEF. Adjusted for propensity score matching, there was a significant decrease in the BNP level and recovery of eGFR after CA in patients with LVEF >50%., Conclusions: This study showed that CA for frequent PVCs decreases BNP levels and increases eGFR even in patients with preserved LVEF., Competing Interests: Authors declare that there no conflicts of interest for this article., (© 2024 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

In the present study, we tried to clarify when and how pupal commitment (PT) better to use PC occurs and what is involved in the PT of Bombyx mori. To clarify this, we examined the responsiveness of a wing disc to ecdysone, referring to metamorphosis-related BR-C, development-related Myc and Wnt, and chromatin remodeling-related genes at around the predicted PT stage of the Bombyx wing disc. Wing disc responsiveness to juvenile hormone (JH) and ecdysone was examined using Methoprene and 20-hydroxyecdysone (20E) in vitro. The body weight of B. mori increased after the last larval ecdysis, peaked at Day 5 of the fifth larval instar (D5L5), and then decreased. The responsiveness of the wing disc to JH decreased after the last larval ecdysis up to D3L5. Bmbr-c (the Broad Complex of B. mori) showed enhanced expression in D4L5 wing discs with 20E treatment. Some chromatin remodeler and histone modifier genes (Bmsnr1, Bmutx, and Bmtip60) showed upregulation after being cultured with 20E in D4L5 wing discs. A low concentration of 20E is suggested to induce responsiveness to 20E in D4L5 wing discs. Bmbr-c, Bmsnr1, Bmutx, and Bmtip60 were upregulated after being cultured with a low concentration of 20E in D4L5 wing discs. The expression of Bmmyc and Bmwnt1 did not show a change after being cultured with or without 20E in D4L5 wing discs, while enhanced expression was observed with 20E in D5L5 wing discs. From the present results, we concluded that PT of the wing disc of B. mori occurred beginning on D4L5 with the secretion of low concentrations of ecdysteroids. Bmsnr1, Bmutx, Bmtip60, and BR-C are also involved., (© 2024 Wiley Periodicals LLC.)

Vitrification is a valuable technology that enables semipermanent preservation and long-distance or international transportation of genetically modified and native animals. In laboratory mice, vitrification maintains and transports embryos, and many institutions and companies sell vitrified embryos. In contrast, despite numerous papers reporting on vitrification in livestock over the past decade, practical implementation has yet to be achieved. However, with advances in genome editing technology, it is anticipated that the number of genetically modified domestic animals will increase, leading to a rise in demand for vitrification of oocytes and embryos. Here, we provide an objective overview of recent advancements in vitrification technology for livestock, drawing a comparison with the current developments in laboratory animals. Additionally, we explore the future prospects for vitrification in livestock, focusing on its potential benefits and drawbacks., (© 2024 Japanese Society of Animal Science.)

Background: The European Society for Clinical Nutrition and Metabolism recommends nutrition screening using the Mini Nutritional Assessment Short-Form (MNA-SF) in older adult patients preoperatively. However, the association of nutrition condition with postoperative complications is poorly documented. We aimed to identify preoperative nutrition status using the MNA-SF and to determine whether preoperative nutrition status affects postoperative outcomes., Methods: Inpatients aged ≥55 years who underwent elective abdominal surgery under general anesthesia between April 1, 2016, and December 28, 2018, were included. We assessed nutrition status using the MNA-SF before surgery. Multiple logistic regression including the MNA-SF score was applied to determine associated factors with our primary outcome, postoperative complications defined as Clavien-Dindo classification ≥3a. Secondary outcomes including length of hospital stay and unplanned readmission were compared between normal, at risk, and malnourished patients., Results: The data of 1248 patients with a mean age of 69 years were analyzed. The prevalence of at risk and malnutrition was 33.0% (412 of 1248) and 6.9% (87 of 1248), respectively. Overall, 12.4% (155 of 1248) had major postoperative complications, and the MNA-SF score was a significant predictor (odds ratio: 0.92, 95% CI: 0.86-0.99) after adjusting for confounders. Patients at risk of malnutrition and those with malnutrition had a longer hospital length of postoperative stay than normal patients (P = 0.001); however, there was no statistical significance in unplanned readmission rate between the three groups (P = 0.14)., Conclusion: Preoperative nutrition disorder was common, and it affected postoperative adverse outcomes. The MNA-SF score was associated with major postoperative complications., (© 2022 American Society for Parenteral and Enteral Nutrition.)

Objective: Cutaneous ulcerative skin lesions in a complex of invasive Gulf of Mexico lionfish (Red Lionfish Pterois volitans, Devil Firefish P. miles, and the hybrid Red Lionfish × Devil Firefish) became epizootic beginning in mid-August 2017. Herein, we provide the first pathological descriptions of these lesions and summarize our analyses to elucidate the etiology of the disease., Methods: We examined ulcerated and normal fish through gross pathology and histopathology, bacterial sampling, and unbiased metagenomic next-generation sequencing. We tracked prevalence of the disease, and we used biological health indicators (condition factor, splenosomatic and hepatosomatic index) to evaluate impacts to health, while considering sex and age as potential risk factors., Result: Typical ulcerative lesions were deep, exposing skeletal muscle, and were bordered by pale or reddened areas often with some degree of scale loss. Only incidental parasites were found in our examinations. Most fish (86%; n = 50) exhibited wound healing grossly and histologically, confirmed by the presence of granulation tissues. A primary bacterial pathogen was not evident through bacterial culture or histopathology. Metagenomic next-generation sequencing did not reveal a viral pathogen (DNA or RNA) but did provide information about the microbiome of some ulcerated specimens. Compared with clinically healthy fish, ulcerated fish had a significantly lower condition factor and a higher splenosomatic index. Disease prevalence at monitored sites through July 2021 indicated that ulcerated fish were still present but at substantially lower prevalence than observed in 2017., Conclusion: Although some common findings in a number of specimens suggest a potential role for opportunistic bacteria, collectively our suite of diagnostics and analyses did not reveal an intralesional infectious agent, and we must consider the possibility that there was no communicable pathogen., (© 2023 The Authors. Journal of Aquatic Animal Health published by Wiley Periodicals LLC on behalf of American Fisheries Society.)

Genetic mosaicism is considered one of the main limitations of the electroporation method used to transfer CRISPR-Cas9/guide RNA (gRNA) into porcine zygotes. We hypothesized that fertilization of oocytes with sperm from gene-deficient boars, in combination with electroporation (EP) to target the same region of the gene in subsequent zygotes, would increase the gene modification efficiency. As myostatin (MSTN) and α1,3-galactosyltransferase (GGTA1) have beneficial effects on agricultural production and xenotransplantation, respectively, we used these two genes to test our hypothesis. Spermatozoa from gene-knockout boars were used for oocyte fertilization in combination with EP to transfer gRNAs targeting the same gene region to zygotes. No significant differences in the rates of cleavage and blastocyst formation as well as in the mutation rates of blastocysts were observed between the wild-type and gene-deficient spermatozoa groups, irrespective of the targeted gene. In conclusion, the combination of fertilization with gene-deficient spermatozoa and gene editing of the same targeted gene region using EP had no beneficial effects on embryo genetic modification, indicating that EP alone is a sufficient tool for genome modification., (© 2023 Japanese Society of Animal Science.)

The transfection efficiency of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas ribonucleoprotein complexes was compared using three nonviral vector transfection reagents: nonliposomal polymeric (TransIT-X2), lipid nanoparticle delivery (CRISPRMAX), and peptide (ProteoCarry) systems. Porcine zona pellucida-free zygotes and embryos were incubated for 5 h with CRISPR-associated protein 9 (Cas9), guide RNA (gRNA) targeting GGTA1, and one of the reagents. In Experiment 1, optimization of Cas9 protein to gRNA molar ratios of 1:2, 2:2, and 4:2, along with single or double doses of reagents, was performed on zygotes at 10 h post-in vitro fertilization. In Experiment 2, optimization of timing was performed at 10 or 29 h post-in vitro fertilization, using optimal molar ratios and reagent doses. Blastocyst formation, mutation rates, and mutation efficiency were measured in each experiment. For each reagent, a 4:2 Cas9:gRNA molar ratio and addition of a double reagent dose exhibited a higher mutation rate; however, blastocyst rate tended to decrease compared with that of control. Moreover, the optimal transfection time varied depending on the reagent, and the proportions of blastocysts carrying mutations were <34%. In conclusion, the above three transfectants allowed gene editing of porcine zygotes and embryos; however, this newly established chemistry-based technology needs further improvement, especially regarding editing efficiency and embryo development., (© 2023 Japanese Society of Animal Science.)

Background: Micra leadless pacemaker is secured to the myocardium by engagement of at least 2/4 tines confirmed with pull and hold test. However, the pull and hold test is sometimes difficult to assess. This study was performed to evaluate whether the angle of the tines before the pull and hold test predicts engagement of the tines in Micra leadless pacemaker implantation., Methods: We retrospectively enrolled 93 consecutive patients (52.7% male, age 82.4 ± 9.4 years), who received Micra implantation from September 2017 to June 2020 at our institution. After deployment and before the pull and hold test, the angle of the visible tines to the body of the pacemaker was measured using the RAO view of the fluoroscopy image. The engagement of the tines was then confirmed with the pull and hold test., Results: A total of 326 tines were analyzed. The angle of the engaged tines was significantly lower than the non-engaged tines (9.2 degrees [4.0-14.0] vs. 16.6 degrees [14.2-18.8], p  < .0001). All tines with angles <10 degrees were engaged. In higher angles, engagement could not be predicted., Conclusion: A low angle of the tines before the pull and hold test can predict engagement of the tines in Micra leadless pacemaker implantation. The tines which are already open after deployment may be presumed that they are engaged., Competing Interests: Masahiko Goya received a lecture fee from Johnson and Johnson, Daiichi‐Sankyo, Bayer, and Japan Lifeline and a research grant from Japan Lifeline. The other authors have no conflict of interest to disclose. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors., (© 2022 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Objective: To determine senescence-associated changes in the gingival tissues of aged mice and gingival fibroblast cultures., Materials and Methods: The production of senescence-associated β-galactosidase (SA-β-gal) and mRNA expression of p16, p21, interleukin (IL)-1β, and tumor necrosis factor α (TNF-α) were evaluated in gingival tissues, gingival fibroblasts of 10- and 20-month-old C57BL/6NCrl mice, and multiple-passaged and hydrogen peroxide-stimulated human gingival fibroblasts (HGFs). Changes in molecular expression in HGF cultures due to senescent cell elimination by the senolytic drug ABT-263 (Navitoclax) were analyzed., Results: Compared to 10-week-old mice, the 20-month-old mice had higher numbers of M1 macrophages. The proportion of cells expressing SA-β-gal were also higher in 20- month-old mice than in 10-week-old-mice. Gingival fibroblasts in 20-month-old mice expressed less collagen 1a1, collagen 4a1, and collagen 4a2 mRNA than those in 10-week-old mice. Compared to control cells, H2O2 treated HGF cells expressed higher levels of SA-β-gal and p16, p21, IL-1β, and TNF-α. Furthermore, ABT-263 suppressed HGF cell expression of cytokines after senescence induction., Conclusions: Senescence-associated changes were observed in the gingival tissues of aged mice and HGF cultures. In addition, the potential of senolytic drugs to modify aging-related changes in the gingiva was shown., (© 2022 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

Aim: The aim of this study is to examine the long-term impact of early menarche with adult depression, and to assess whether this association was explained by childhood traumatic experience and socioeconomic condition in early adulthood., Methods: The data were derived from World Mental Health Survey Japan Second, a cross-sectional survey conducted among Japanese community residents between 2013 and 2015. We used the data of female respondents aged 20-75 years ( N  = 1171). Hazard ratio (HR) of the onset of major depression up to 40 years was calculated for an early-menarche group and a non-early-menarche group, respectively. Kaplan-Meier curve and log-rank statistics were used to examine the difference in failure. Cox proportional hazard models were administered for the association of major depression with early-menarche and early-life psychosocial factors., Results: Risk for major depressive disorders were three to four times higher in an early-menarche group, and the differences in survival functions were significant ( p  < 0.001). HR of early menarche was 2.79 (95% CI = 1.29-6.02), and was slightly changed when childhood traumatic experience and socioeconomic conditions in young adulthood were added in the model (HR = 2.88, 95% CI = 1.30-6.38; HR = 3.19, 95% CI = 1.41-7.21)., Conclusion: Early menarche was significantly associated with increased risk for depression by the age of 40 years. Childhood trauma and socioeconomic hardship in early adulthood did not account for the association. Both physical and psychosocial risk factors in early life need to be addressed for preventing women's depression., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Background: The self-care deficit nursing theory (SCDNT) advocated by Dorothea E. Orem is widely known and used in nursing practice worldwide. However, its broader philosophical and sociological context is often ignored., Design: The theoretical analysis of Orem's SCDNT reported in this article focuses on four aspects of the theory: its essential structure/core values, affirmation of nursing as a practical science, philosophical foundations, and the sociological context surrounding its development., Results: By interpreting the SCDNT from a philosophical and sociological viewpoint, it can be concluded that Orem established human-to-human nursing as a science premised on the existence of human beings as the central value of the theory. Moreover, Orem emphasized that the human-to-human relationship necessarily precedes the nurse-patient interface., Conclusion: The new interpretation and evaluation perspectives presented in this report may further the understanding of Orem's SCDNT. Moreover, they highlight the multifaceted aspects of nursing practice and role of person-to-person relationships as the basis of the SCDNT., (© 2022 Wiley Periodicals LLC.)

We aimed to develop a simple method for the short-term preservation of in vitro-produced porcine zygotes at 25°C for up to 2 days. Firstly, we evaluated the efficiency of three storage solutions to preserve porcine zygotes at 25°C for 24 h. Two of these were commercially available defined media for cell storage (Cell-W and Cell-S), and the third was fetal bovine serum (FBS). Thereafter, we examined the effects of storing the zygotes in the Cell-W solution for 24-72 h at 25°C. The Cell-W solution was the most efficient for 24 h storage of porcine zygotes at 25°C, with no apparent effects on blastocyst quality. However, short-term storage of porcine zygotes for 24 h reduced the blastocyst formation rate compared with the fresh control group. As storage duration increased from 24 to 48 or 72 h, blastocyst formation rates were significantly decreased from 11.3% to 4.4% and 0%, respectively. In conclusion, during zygote storage, the developmental competence to the blastocyst stage decreased with time. Storage of zygotes in chemically defined media did not affect blastocyst quality, but the storage in 100% serum had an adverse effect on developing embryos causing apoptosis., (© 2022 Japanese Society of Animal Science.)

Background: Left atrial volume index (LAVI) of >34 mL/m 2 is the cutoff value for identifying an enlarged left atrium. The definition of left atrial (LA) reverse remodeling after atrial fibrillation (AF) ablation is undetermined. We hypothesized that patients with LA dilatation who achieve normal LA volume (LAVI<34 mL/m 2 ) after AF ablation have better long-term outcomes than those who do not. Furthermore, we investigated whether patients with a normal LA volume can also achieve normal LA function with AF ablation., Methods: We enrolled 140 AF patients with baseline LAVI of ≥34 mL/m 2 , without AF recurrence for 1 year after the initial AF ablation. We acquired conventional and speckle-tracking echocardiographic parameters within 24 hour and at 1 year after the procedure. To define the normal range of LA function, age- and sex-matched controls without a history of AF were also enrolled., Results: After restoration of sinus rhythm, LA structural and functional parameters significantly improved, and 75 patients (54%) had normal LA volume. During a median follow-up of 44 (31-61) months, 32 patients (23%) experienced a late recurrence of AF (AF recurrence >1 year). Patients who achieved normal LA volume after AF ablation had fewer late recurrences than those who did not ( P  < .01). However, LA abnormalities, especially LA dysfunction, persisted in AF patients even when the LA volume was normalized compared with controls., Conclusion: Patients who achieved normal LA volume had better long-term outcomes of AF ablation than those who did not; however, LA abnormalities persisted even after successful ablation of AF., Competing Interests: The authors have no conflicts to disclose. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors., (© 2021 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Objective: This study aimed to investigate risk factors predictive of local recurrence and/or lymph node metastasis after transoral resection of early hypopharyngeal cancer., Methods: Forty-nine consecutive patients who underwent transoral videolaryngoscopic surgery (TOVS) as an initial treatment for hypopharyngeal cancer were evaluated. On univariate and multivariate analysis, local recurrence rates were assessed respectively using log-rank test and cox regression analysis according to the following parameters: subsite, pT, mucosal margin, lymphatic invasion, vessel invasion, tumor thickness (> 4 mm vs ≤4 mm), history of esophageal cancer, and multiple Lugol-voiding lesions (LVLs) in the esophagus. Categorical variables were evaluated for their associations with lymph node metastasis using chi-squared test or Fisher's exact test., Result: The subsites of primary lesions were piriform sinus in 24 patients, posterior wall in 15 patients, and postcricoid in 10 patients. Thirty patients had esophageal cancer. Local recurrence occurred in 14 patients. Three patients had lymph node metastasis at the time of diagnosis and four patients developed lymph node metastasis after the initial treatment, resulting a total of seven patients having lymph node metastasis. While mucosal margin and LVLs showed significant associations with local recurrence on univariate analysis, only LVLs remained as a significant risk factor on multivariate analysis ( P  = .0395; hazard ratio = 8.897; 95% confidence interval, 1.113-71.15). Most cases of local recurrence were satisfactorily controlled by repeated TOVS. While multivariate analysis could not be performed due to the small number of the patients with lymph node metastases, venous invasion ( P  = .0166) and tumor thickness ( P  = .0092) were significantly associated with lymph node metastasis on univariate analysis., Conclusions: Local recurrence was more frequent in patients with LVLs, but most of them were salvaged by repeated TOVS. Patients with venous invasion and/or tumor thickness greater than 4 mm should be followed up with special attention to lymph node metastasis.Level of Evidence: 3., Competing Interests: The authors declare no conflicts of interest., (© 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC. on behalf of The Triological Society.)

Clozapine (CLZ) is a key drug in treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) of CLZ and its metabolites, N-desmethylclozapine and clozapine N-oxide, is required to monitor and manage the risks of side effects. Although quantification methods for TDM have been developed for CLZ and its metabolites, they were not sufficiently accurate for the quantification of CLZ owing to the upper limits of the calibration curves. An analytical method using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry was developed and validated for the simultaneous measurement of CLZ and its metabolites in human plasma. To expand the concentration range of the calibration curves, we used a linear range shift technique using in-source collision-induced dissociation (CID). Using our approach, the linearity and quantitative range were improved compared to those reported by previous studies, and were sufficient for TDM in clinical practice. The intra- and inter-assay accuracy was 84.6%-114.8%, and the intra- and inter-assay precisions were ≤9.1% and ≤9.9%, respectively. Moreover, all samples from patients with treatment-resistant schizophrenia were successfully quantified. Therefore, our novel analytical method using in-source CID had the appropriate performance to measure the plasma concentrations of CLZ and its metabolites for TDM in clinical practice., (© 2021 John Wiley & Sons, Ltd.)

Introduction: Women who have undergone radical trachelectomy as a fertility-sparing treatment for early-stage cervical cancer may be at higher risk for retained tissues after early-term miscarriage due to cervical cerclage or cervical necrosis. Dilatation and curettage or aspiration may present additional risks in these women. The aim of this study was to assess the efficacy of expectant management for early pregnancy miscarriage after radical trachelectomy., Material and Methods: Keio University Hospital records were reviewed for women who conceived after abdominal radical trachelectomy and received perinatal care between 1 April 2012 and 31 March 2020. A total of 62 women (76 pregnancies) were identified, and 13 of these women experienced miscarriage before 12 gestational weeks. The management and outcome of these cases were reviewed in detail., Results: The median maternal age at miscarriage was 39 years (range 31-42 years) and the median duration from abdominal radical trachelectomy to conception was 2.60 years (range 0.49-7.30 years). Cervical necrosis before conception occurred in one case (8%). One patient requested treatment with aspiration and the remaining 12 cases were managed with observation for a median of 23 days (range 7-50 days). There were no cases of endometritis or cases requiring dilatation and curettage for residue tissue. Further, no cases developed laceration of the residual cervix and no loss of cerclage sutures after discharge was noted., Conclusions: Expectant management seems to be safe and appropriate for first trimester miscarriage after abdominal radical trachelectomy., (© 2021 Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Published by John Wiley & Sons Ltd.)

Previous studies indicate that musical instrument training may improve the cognitive function of older adults. However, little is known about the neural origins of training-related improvement in cognitive function. Here, we assessed the effects of instrumental training program on cognitive functions and neural efficiency in musically naïve older adults (61-85 years old). Participants were assigned to either the intervention group, which received a 4-month instrumental training program using keyboard harmonica, or a control group without any alternative training. Cognitive measurements and functional magnetic resonance imaging during visual working memory (VWM) task were administered before and after the intervention in both groups. Behavioral data revealed that the intervention group significantly improved memory performance on the test that measures verbal recall compared to the control group. Neuroimaging data revealed that brain activation in the right supplementary motor area, left precuneus, and bilateral posterior cingulate gyrus (PCgG) during the VWM task decreased after instrumental training only in the intervention group. Task-related functional connectivity (FC) analysis revealed that the intervention group showed decreased FC between the right PCgG and left middle temporal gyrus, and between the left putamen and right superior temporal gyrus (lPu-rSTG) during a VWM task after the intervention. Furthermore, a greater improvement in memory performance in the intervention group was associated with a larger reduction in lPu-rSTG FC, which might be interpreted as improved neural efficiency. Our results indicate that the musical instrument training program may contribute to improvements in verbal memory and neural efficiency in novice older adults., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: Cortical microinfarcts (CMIs) are frequently found in the brains of patients with advanced cerebral amyloid angiopathy (CAA) at autopsy. The small vessel disease (SVD) score for CAA (i.e., the CAA-SVD score) has been proposed to evaluate the severity of CAA-associated vasculopathic changes by a combination of magnetic resonance imaging (MRI) markers. The aim of this study was to examine the association between total CAA-SVD score and features of CMIs on in vivo 3-Tesla MRI., Methods: Eighty patients with probable CAA were retrospectively analyzed. Lobar cerebral microbleeds, cortical superficial siderosis, enlargement of perivascular space in the centrum semiovale and white matter hyperintensity were collectively assessed, and the total CAA-SVD score was calculated. The presence of CMI was also examined., Results: Of the 80 patients, 13 (16.25%) had CMIs. CMIs were detected more frequently in the parietal and occipital lobes. A positive correlation was found between total CAA-SVD score and prevalence of CMI (ρ = 0.943; p = 0.005). Total CAA-SVD score was significantly higher in patients with CMIs than in those without (p = 0.009). In a multivariable logistic regression analysis, the presence of CMIs was significantly associated with total CAA-SVD score (odds ratio 2.318 [95% confidence interval 1.228-4.376]; p = 0.01, per each additional point)., Conclusions: The presence of CMIs with a high CAA-SVD score could be an indicator of more severe amyloid-associated vasculopathic changes in patients with probable CAA., (© 2020 European Academy of Neurology.)

Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14-based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B-based "double-negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high-dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double-negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development., (© 2020 Amgen, Inc.; Pfizer, Inc.; Takeda Inc.; Bayer; Novartis; Merck; Bristol-Myers Squibb; and Janssen. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

In mice, the conditional knockout strategy using the Cre-loxP system is useful for various types of research. The Cre mouse line with progesterone receptor promoter (Pgr Cre ) has been widely used to produce specific uterine gene-deficient mice, but in the Cre line, endogenous Pgr gene is replaced by Cre recombinase gene, which makes the breeding of homozygous mice (Pgr Cre/Cre ) difficult because they are infertile. Yang et al. (2013, https://10.1016/j.cell.2013.04.017) reported the generation of another Pgr iresCre mouse line that still has endogenous Pgr gene, and they inserted Cre recombinase downstream of the Pgr gene via an internal ribosome entry site (IRES). It is possible that this new Pgr iresCre line would be useful for uterine research as the mice can be bred as homozygotes (Pgr iresCre/iresCre ). Herein, we confirmed the Pgr iresCre mice effectively directed recombination in the female reproductive tract and was capable of genetic alteration in the endometrium that enables the studies of its uterine function. Our findings demonstrate that the new Pgr iresCre mouse line is also useful for the generation of uterine-specific knockout mice. The findings using Pgr iresCre mouse will contribute to the understanding of reproductive systems and diseases in humans and domestic animals., (© 2021 The Authors. Animal Science Journal published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Animal Science.)

The delivery of cancer care has never changed as rapidly and dramatically as we have seen with the coronavirus disease 2019 (COVID-19) pandemic. During the early phase of the pandemic, recommendations for the management of oncology patients issued by various professional societies and government agencies did not recognize the significant regional differences in the impact of the pandemic. California initially experienced lower than expected numbers of cases, and the health care system did not experience the same degree of the burden that had been the case in other parts of the country. In light of promising trends in COVID-19 infections and mortality in California, by late April 2020, discussions were initiated for a phased recovery of full-scale cancer services. However, by July 2020, a surge of cases was reported across the nation, including in California. In this review, the authors share the response and recovery planning experience of the University of California (UC) Cancer Consortium in an effort to provide guidance to oncology practices. The UC Cancer Consortium was established in 2017 to bring together 5 UC Comprehensive Cancer Centers: UC Davis Comprehensive Cancer Center, UC Los Angeles Jonsson Comprehensive Cancer Center, UC Irvine Chao Family Comprehensive Cancer Center, UC San Diego Moores Cancer Center, and the UC San Francisco Helen Diller Family Comprehensive Cancer Center. The interventions implemented in each of these cancer centers are highlighted, with a focus on opportunities for a redesign in care delivery models. The authors propose that their experiences gained during this pandemic will enhance pre-pandemic cancer care delivery., (© 2020 American Cancer Society.)

This study aimed to investigate the efficiency of KRAS gene editing via CRISPR/Cas9 delivery by electroporation and analyzed the effects of the non-homologous end-joining pathway inhibitor Scr7 and single-stranded oligodeoxynucleotide (ssODN) homology arm length on introducing a point mutation in KRAS. Various concentrations (0-2 µM) of Scr7 were evaluated; all concentrations of Scr7 including 0 µM resulted in the generation of blastocysts with a point mutation and the wild-type sequence or indels. No significant differences in the blastocyst formation rates of electroporated zygotes were observed among ssODN homology arm lengths, irrespective of the gRNA (gRNA1 and gRNA2). The proportion of blastocysts carrying a point mutation with or without the wild-type sequence and indels was significantly higher in the ssODN20 group (i.e., the group with a ssODN homology arm of 20 bp) than in the ssODN60 group (gRNA1: 25.7% vs. 5.4% and gRNA2: 45.5% vs. 5.9%, p < .05). In conclusion, the CRISPR/Cas9 delivery with ssODN via electroporation is feasible for the generation of point mutations in porcine embryos. Further studies are required to improve the efficiency and accuracy of the homology-directed repair., (© 2021 Japanese Society of Animal Science.)

One male and three female captive proboscis monkeys (Nasalis larvatus) were used as test animals to compare fecal nutrients after being fed seasonal foliage. Foliage and fecal samples were collected during three seasons (spring, summer, and winter). We analyzed crude ash (CA), ether extract (EE), crude protein (CP), neutral detergent fiber (NDF), acid detergent fiber (ADF), and acid detergent lignin (ADL). In addition to the above components, for the fecal samples, we examined total fecal nitrogen (TFN), nitrogen in fecal NDF (NDF-N), metabolic fecal nitrogen (MFN), and particle size distribution (MPS). Seasonal differences in foliage components were observed, with NDF and ADF being lowest in spring (p < 0.05). Fecal NDF and ADF also tended to be lowest in spring. Further, the distribution of fecal particle size indicated that MPS tended to increase in winter. The mean fecal NDF content (47.4%) for all three seasons measured in this study was as much as 1.3 times lower than previously reported values in free-ranging specimens. These data provide useful information that can be used to find some suitable food items for the endangered highly folivorous monkeys in captivity., (© 2021 Japanese Society of Animal Science.)

Background: Catheter ablation (CA) for atrial fibrillation (AF) is widely performed. However, the indication for CA in patients with asymptomatic persistent AF is still controversial., Methods: Among 259 consecutive patients who were hospitalized for initial CA of AF, a total of 45 patients who had asymptomatic persistent AF were retrospectively analyzed. Quality of life (QOL) before and 1 year after CA was evaluated, and changes in the cardiac function over 5 years after CA were also examined. QOL was assessed using the AF QOL questionnaire (AFQLQ) developed by the Japanese Heart Rhythm Society. In addition, cardiac function was assessed by measuring the plasma B-type natriuretic peptide (BNP) level, left ventricular ejection fraction (LVEF), left atrial diameter (LAD) with transthoracic echocardiogram, and left atrial (LA) volume with computed tomography (CT)., Results: The AFQLQ significantly improved after CA in terms of "symptom frequency" and "activity limits and mental anxiety." The plasma BNP level, LVEF, and LAD significantly improved in the first 3 months after the first CA, with no significant changes thereafter (from 149.0 pg/dL [95% confidence intervals {CI}, 114.5-183.5 pg/dL] to 49.8 pg/dL [95% CI, 26.5-70.1], P  < .0001; from 60.8% [95% CI, 58.1%-63.6%] to 65.0% [95% CI, 62.6-67.4], P  = .001; and from 41.3 mm [95% CI, 39.7-42.9] to 36.8 [95% CI, 34.5-39.1 mm], P  < .0001, respectively). LA volume revealed LA reverse remodeling after CA., Conclusion: Improvement in the QOL and cardiac function after CA of asymptomatic persistent AF was revealed. Asymptomatic persistent AF should be appropriately treated by CA., Competing Interests: Authors declare no conflict of interest for this article. The study protocol was approved on May 13, 2017 by a suitably constituted Ethics Committee of Tenri Hospital (no. 429), and it conforms to the provisions of the Declaration of Helsinki., (© 2020 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.)

Background: Electroencephalography (EEG) is required for the diagnosis of canine idiopathic epilepsy as a highest confidence level of diagnosis by the International Veterinary Epilepsy Task Force; however, EEG is seldom used and a standardised assessment method has not been reported., Methods: Interictal EEG was performed under medetomidine sedation in dogs with idiopathic epilepsy and in control dogs. Epileptiform discharge (ED) frequency was compared between dogs with more severe and less severe seizures during one month before EEG and control dogs., Results: All 10 dogs with more severe seizures had ED, as had 7 of 11 with less severe seizures. All epileptic dogs without ED had good long-term outcomes. ED frequency (number of ED per five minutes) was significantly higher in dogs with more severe (median, 4.5) than with less severe seizure (median, 0.46) and in the control dogs (median, 0.15). An ED frequency greater than 0.8 was considered to indicate epilepsy., Conclusion: Interictal EEG in a light sleep state under medetomidine sedation had a high detection rate of ED, and ED frequency had a positive correlation with the recent severity of epileptic seizures. This allows interictal EEG recordings to be used as a simplified and objective test that may help to diagnose epilepsy and to assess the recent severity of the disease in dogs., Competing Interests: Competing interests: None declared., (© British Veterinary Association 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

An artificial cell membrane that is composed of bilayer lipid membranes (BLMs) with transmembrane proteins incorporated within them represents a well-defined system for the analysis of membrane proteins, especially ion channel proteins that are major targets for drug design. Because the BLM system has a high compatibility with recently developed cell-free expression systems, it has attracted attention as a next-generation drug screening system. However, three issues associated with BLM systems, i. e., their instability, the need for non-volatile organic solvents and a low efficiency of ion channel incorporation, have limited their use as a drug screening platform. In this personal account, we discuss our recent approaches to address these issues based on microfabrication. We also discuss the potential for using the BLM system combined with cell-free expression systems as a drug screening system for future personalized medicine., (© 2020 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)