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Many circulating proteins are associated with risk of ESKD, but their source and the biological pathways/disease processes they represent are unclear. Using OLINK proteomics platform, concentrations of 455 proteins were measured in plasma specimens obtained at baseline from 399 individuals with diabetes. Elevated concentrations of 46 circulating proteins were associated (P < 1 × 10-5) with development of ESKD (n = 143) during 7-15 years of follow-up. Twenty of these proteins enriched apoptosis/TNF receptor signaling pathways. A subset of 20 proteins (5-7 proteins), summarized as an apoptosis score, together with clinical variables accurately predicted risk of ESKD. Expression of genes encoding the 46 proteins in peripheral WBCs showed no difference between cells from individuals who did or did not develop ESKD. In contrast, plasma concentration of many of the 46 proteins differed by this outcome. In single-nucleus RNA-Seq analysis of kidney biopsies, the majority of genes encoding for the 20 apoptosis/TNF receptor proteins were overexpressed in injured versus healthy proximal tubule cells. Expression of these 20 genes also correlated with the overall index of apoptosis in these cells. Elevated levels of circulating proteins flagging apoptotic processes/TNF receptor signaling pathways - and likely originating from kidney cells, including injured/apoptotic proximal tubular cells - preceded the development of ESKD.

Background: Atrial fibrillation (AF) is a prevalent multifactorial arrhythmia associated with specific single-nucleotide polymorphisms (SNPs). Pulmonary vein (PV) isolation is an established treatment for AF; however, recurrence risk remains caused by AF triggers beyond the PVs. Understanding the embryological origins of these triggers could improve treatment outcomes., Objectives: This study aimed to investigate the association between embryologically categorized AF triggers, clinical and genetic backgrounds, and postablation prognosis., Methods: In cohort 1, comprising 3,067 patients with AF undergoing PV isolation, the clinical characteristics and outcomes were analyzed. Among them, 815 patients underwent genetic analysis using AF-associated SNPs (cohort 2). Patients were delineated based on the developmental origin of the AF triggers: common PV, sinus venosus (SV), and primitive atrium (PA)., Results: SV-origin extra-PV AF triggers occurred in 20.3% (n = 622) of patients, whereas PA-origin triggers occurred in 11.9% (n = 365) of patients in cohort 1. Multivariate analysis of cohort 2 revealed that female sex, lower body mass index, absence of hypertension, rs2634073 near PITX2, and rs6584555 in NEURL1 were associated with SV-AF, whereas nonparoxysmal AF and rs2634073 near PITX2 were predictors of PA-AF. The PA group had a significantly higher arrhythmia recurrence rate after repeated procedures than the common PV (HR: 1.75; 95% CI: 1.34-2.29; P < 0.001) and SV-AF (HR: 1.31; 95% CI: 1.19-1.45; P < 0.001) groups with more de novo AF triggers. However, the incidence of adverse events did not differ significantly among the 3 groups., Conclusions: SV-derived AF triggers may have hereditary factors with a favorable postablation prognosis, whereas PA-derived triggers are linked to AF persistence and poor ablation response. Variants near PITX2 may play a pivotal role in extra-PV triggers., Competing Interests: Funding Support and Author Disclosures This research received financial support from the Tailor-made Medical Treatment Program (grant number 1K157), Grant-in-Aid (Grant No. 26293052) bestowed by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, and the Practical Research Project for Life-Style Related Diseases Including Cardiovascular Diseases and Diabetes Mellitus, courtesy of the Japan Agency for Medical and Development (AMED) under Project Code 15656344. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with migraine are typically advised to avoid passive smoking because it may aggravate headaches and other health conditions. However, there is insufficient high-quality evidence on the association between passive smoking and migraine, which warrants further investigation using animal models. Therefore, using a mouse model, we examined the effect of passive smoking on susceptibility to cortical spreading depolarization (CSD), the biological basis of migraine with aura., Findings: Fifty C57BL/6 mice (25 males and 25 females) were exposed for one hour to cigarette smoke or room air. Subsequently, potassium chloride (KCl) was administered under isoflurane anesthesia to induce CSD, and the CSD threshold, frequency of induction, and propagation velocity were determined. The threshold to induce CSD (median [interquartile range (IQR)]) was significantly lower in female mice (adjusted p = 0.01) in the smoking group (0.05 [0.05, 0.088]) than in the sham group (0.125 [0.1, 0.15]); however, there was no significant difference in the male mice (adjusted p = 0.77). CSD frequency or propagation velocity did not differ significantly between the two groups for either sex., Conclusions: Female mice in the smoking group showed lower CSD threshold compared to the sham group, suggesting a potential sex-specific difference in the effect of smoking on the pathogenesis of CSD and migraine with aura. This finding may contribute to the understanding of migraine pathophysiology in association with passive smoking and sex difference., (© 2024. The Author(s).)

Objective: To investigate whether robotic surgery (RS) decreases the risk of circumferential resection margin (CRM) positivity compared with conventional laparoscopic surgery (LS) in patients with rectal cancer (RC) undergoing mesorectal excision (ME)., Background: Although it is well known that CRM positivity affects postoperative outcomes in patients with RC undergoing ME, few studies have investigated whether RS is superior to conventional LS for the risk of CRM positivity., Methods: We performed a comprehensive electronic search of the literature up to December 2022 to identify studies that compared the risk of CRM positivity between patients with RC undergoing robotic and conventional laparoscopic surgery. A meta-analysis was performed using random-effects models to calculate risk ratios (RRs) and 95 % confidence intervals (CIs), and heterogeneity was analyzed using I 2 statistics., Results: Eighteen studies, consisting of 4 randomized controlled trials (RCTs) and 14 propensity score matching (PSM) studies, involved a total of 9203 patients with RC who underwent ME were included in this meta-analysis. The results demonstrated that RS decreased the overall risk of CRM positivity (RR, 0.82; 95 % CI, 0.73-0.92; P = 0.001; I 2  = 0 %) compared with conventional LS. Results of a meta-analysis of the 4 selected RCTs also showed that RS decreased the risk of CRM positivity (RR, 0.62; 95 % CI, 0.43-0.91; P = 0.01; I 2  = 0 %) compared with conventional LS., Conclusions: This meta-analysis revealed that RS is associated with a decreased risk of CRM positivity compared with conventional LS in patients with RC undergoing ME., Competing Interests: Declaration of competing interest The authors have no personal conflicts of interest. The authors have no relevant financial disclosures., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose of Review: Headache disorders are highly prevalent worldwide. Rapidly advancing capabilities in artificial intelligence (AI) have expanded headache-related research with the potential to solve unmet needs in the headache field. We provide an overview of AI in headache research in this article., Recent Findings: We briefly introduce machine learning models and commonly used evaluation metrics. We then review studies that have utilized AI in the field to advance diagnostic accuracy and classification, predict treatment responses, gather insights from various data sources, and forecast migraine attacks. Furthermore, given the emergence of ChatGPT, a type of large language model (LLM), and the popularity it has gained, we also discuss how LLMs could be used to advance the field. Finally, we discuss the potential pitfalls, bias, and future directions of employing AI in headache medicine. Many recent studies on headache medicine incorporated machine learning, generative AI and LLMs. A comprehensive understanding of potential pitfalls and biases is crucial to using these novel techniques with minimum harm. When used appropriately, AI has the potential to revolutionize headache medicine., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: To detect early cognitive impairment in community-dwelling older adults, this study explored the viability of artificial intelligence (AI)-assisted linear acceleration and angular velocity analysis during walking., Methods: This cross-sectional study included 879 participants without dementia (female, 60.6%; mean age, 73.5 years) from the 2011 Comprehensive Gerontology Survey. Sensors attached to the pelvis and left ankle recorded the triaxial linear acceleration and angular velocity while the participants walked at a comfortable speed. Cognitive impairment was determined using Mini-Mental State Examination scores. Deep learning models were used to discern the linear acceleration and angular velocity data of 12,302 walking strides., Results: The models' average sensitivity, specificity, and area under the curve were 0.961, 0.643, and 0.833, respectively, across 30 testing datasets., Discussion: AI-enabled gait analysis can be used to detect signs of cognitive impairment. Integrating this AI model into smartphones may help detect dementia early, facilitating better prevention., Highlights: Artificial intelligence (AI)-enabled gait analysis can be used to detect the early signs of cognitive decline.This AI model was constructed using data from a community-dwelling cohort.AI-assisted linear acceleration and angular velocity analysis during gait was used.The model may help in early detection of dementia., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The approval of splice-switching oligonucleotides with phosphorodiamidate morpholino oligomers (PMOs) for treating Duchenne muscular dystrophy (DMD) has advanced the field of oligonucleotide therapy. Despite this progress, PMOs encounter challenges such as poor tissue uptake, particularly in the heart, diaphragm, and central nervous system (CNS), thereby affecting patient's prognosis and quality of life. To address these limitations, we have developed a PMOs-based heteroduplex oligonucleotide (HDO) technology. This innovation involves a lipid-ligand-conjugated complementary strand hybridized with PMOs, significantly enhancing delivery to key tissues in mdx mice, normalizing motor functions, muscle pathology, and serum creatine kinase by restoring internal deleted dystrophin expression. Additionally, PMOs-based HDOs normalized cardiac and CNS abnormalities without adverse effects. Our technology increases serum albumin binding to PMOs and improves blood retention and cellular uptake. Here we show that PMOs-based HDOs address the limitations in oligonucleotide therapy for DMD and offer a promising approach for diseases amenable to exon-skipping therapy., (© 2024. The Author(s).)

As atrial fibrillation (AF) progresses from initial paroxysmal episodes to the persistent phase, maintaining sinus rhythm for an extended period through pharmacotherapy and catheter ablation becomes difficult. A major cause of the deteriorated treatment outcome is the atrial structural and electrophysiological heterogeneity, which AF itself can exacerbate. This heterogeneity exists or manifests in various dimensions, including anatomically segmental structural features, the distribution of histological fibrosis and the autonomic nervous system, sarcolemmal ion channels, and electrophysiological properties. All these types of heterogeneity are closely related to the development of AF. Recognizing the heterogeneity provides a valuable approach to comprehending the underlying mechanisms in the complex excitatory patterns of AF and the determining factors that govern the seemingly chaotic propagation. Furthermore, substrate modification based on heterogeneity is a potential therapeutic strategy. This review aims to consolidate the current knowledge on structural and electrophysiological atrial heterogeneity and its relation to the pathogenesis of AF, drawing insights from clinical studies, animal and cell experiments, molecular basis, and computer-based approaches, to advance our understanding of the pathophysiology and management of AF.

Background: The term 'precision medicine' encompasses strategies to optimize diagnosis and outcome prediction and to tailor treatment for individual patients, in consideration of their unique characteristics. The greater availability of multifaceted datasets and strategies to model such data have made precision medicine increasingly possible in recent years. Precision medicine is especially needed in the migraine field since the response to migraine treatments is not universal amongst all individuals with migraine., Objective: To provide a narrative review describing contributions to achieving precision medicine for migraine treatment., Methods: A search of PubMed for English language articles of human participants published from 2005 to January 2024 was conducted to identify articles that reported research contributing to precision medicine for migraine treatment. The published literature was categorized and summarized according to the type of data that were included: clinical phenotypes, genomics, proteomics, physiologic measures, and brain imaging., Results: Published studies have investigated characteristics associated with acute and preventive treatment responses, such as nonsteroidal anti-inflammatory drugs, triptans, onabotulinumtoxinA, and anti-calcitonin gene-related peptide monoclonal antibodies, in patients with episodic or chronic migraine. There is evidence that clinical, genetic, epigenetic, proteomic, physiologic, and brain imaging features might associate with migraine treatment outcomes, although inconsistencies for such findings clearly exist., Conclusions: The published literature suggests that there are clinical and biological features which associate with, and might be useful for predicting, migraine treatment responses. To achieve precision medicine for migraine treatment, further research is needed that validates and expands on existing findings and tests the accuracy and value of migraine treatment prediction models in clinical settings., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.I., F.C., A.D., H.G., A.J. and K.K.: None. W.L.: Was involved as a site investigator of a multicenter trial sponsored by Eli Lilly and Co., WhanIn Pharm Co. Ltd., and Handok-Teva. He has received lecture honoraria from Abbott and SK chemical in the past 36 months. Y.C.L. and T.M.: None H.K.P.: Lecture honorarium from AbbVie, Allergan, Amgen, Boryung Pharmaceutical Co., Ltd, Chong Kun Dang Pharmaceutical Corp, Dong-A ST, Jeil Pharmaceutical Co, Ltd, Pfizer, SAMJIN Pharm, SK Chemicals, TEVA-HANDOK, Takeda Pharmaceuticals Korea Co, Ltd, and YuYu. B.P., T.H.U., N.V. and A.Z.: None. P.P.R.: has received honoraria as a consultant and speaker for: AbbVie, Amgen, Biohaven, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer and Teva. Her research group has received research grants from Novartis, Teva, AbbVie, EraNET Neuron, RIS3CAT FEDER, AGAUR, ISCIII; has received funding for clinical trials from Alder, Amgen, Biohaven, Electrocore, Eli Lilly, Lundbeck, Novartis, Teva. She is the Honorary Secretary of the International Headache Society. She is the founder of www.midolordecabeza.org. P.P.R. does not own stocks from any pharmaceutical company. T.J.S.: Consulting income from AbbVie, Allergan, Amgen, Axsome, Biodelivery Science, Biohaven, Click Therapeutics, Collegium, Eli Lilly, Ipsen, Linpharma, Lundbeck, Novartis, Satsuma, Scilex, Theranica, and Tonix. Royalties from Up To Date. Stock options in Aural Analytics and Nocira. Research funding from American Heart Association, Amgen, Henry Jackson Foundation, National Headache Foundation, National Institutes of Health, Patient Centered Outcomes Research Institute, Pfizer, Spark Neuro, and United States Department of Defense.

Background: Understanding background factors is beneficial for interpreting general movements (GMs). This study examines the factors involved in preterm-writhing GMs by comparing twins and singletons., Method: The subjects were 107 infants cared for at Oita University. The cohort consisted of very-low-birth-weight infants, including twins with a birth weight < 2000 g. The median gestational age (GA) was 29 weeks 1 day. The subjects consisted of 75 singletons, 32 twins (16 pairs), 20 monochorionic twins (M-twins), and 12 dichorionic twins (D-twins). GMs were scored according to the GMs optimality score (GMOS) and integrated into 6 items: the quality, neck-trunk and space, amplitude-speed, rotation, onset-offset and cramped, and tremulous score at 32-34 weeks, 35-36 weeks, and 37-42 weeks' GA. A hierarchical cluster analysis was performed using integrated GMOS, and the characteristics of clusters were examined according to clinical backgrounds., Results: Three clusters were identified. Cluster 1 was characterized by good-quality GMs, cluster 2 by a poor repertoire but optimal space and rotatory components, and cluster 3 by overall poor-quality GMs, respectively. The mean GMOSs were 36.6, 31.8 and 24.3 in clusters 1, 2, and 3, respectively. There were no marked differences in proportions within clusters with respect to sex and twins. Small-for-gestational age (SGA) was significantly more frequent in cluster 3 at 32-34 weeks' GA than in other clusters. Perinatal brain injury had a significantly lower proportion in cluster 1 and a higher proportion in cluster 3 at 35-36 weeks' GA and 37-42 weeks' GA. M-twin pairs tended to belong to the same clusters at 35-36 weeks' GA., Conclusion: Preterm writhing GMs are associated with SGA and perinatal brain injury. Cluster matching in M-twins suggests that certain genetic factors may substantially influence GMs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective In randomized clinical trials and real-world studies, calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs), including erenumab, have demonstrated efficacy for migraine prevention. However, there have been no real-world studies focusing on erenumab in East Asia that investigated its efficacy on migraine-associated symptoms and patient-reported satisfaction levels. Methods This single-center, observational, retrospective, real-world study examined patients who received at least three doses of erenumab at Keio University Hospital, Tokyo, Japan, between December 2021 and March 2023 as their first CGRP mAb treatment in a real-world setting. The patients were administered 70 mg of erenumab monthly. We assessed changes in monthly migraine days (MMDs), responder rates, migraine-associated symptoms including photophobia, phonophobia, nausea/vomiting, and patient-reported satisfaction levels. In addition, injection site reactions and other adverse events were recorded to investigate safety. Results Nineteen patients were considered eligible for the analysis. At 3 months, erenumab decreased MMDs by 6.6 (95% confidence interval, 2.3-10.8; p<0.01). The 50% responder rate was 42%. A total of 83% (n=15), 56% (n=10), and 71% (n=10) of patients reported either improvement in or disappearance of photophobia, phonophobia, and nausea/vomiting, respectively, and 44% (n=8) and 28% (n=5) answered "very satisfied" and "somewhat satisfied", respectively, with erenumab treatment, leaving only 28% (n=5) as "unsatisfied". Injection site reactions (n=6, 32%) and constipation (n=4, 21%) were frequent adverse events. Conclusion In a real-world setting in Japan, erenumab proved to be effective in not only reducing migraine and headache frequency but also improving migraine-associated symptoms and satisfying the majority of patients.

Aim: The Japanese Society for Respiratory Care and Rehabilitation, Japanese Association on Sarcopenia and Frailty, Japanese Society of Respiratory Physical Therapy, and Japanese Association of Rehabilitation Nutrition proposed the definition and diagnosis of respiratory sarcopenia using low respiratory muscle strength and appendicular skeletal muscle mass (ASM; ASM/height 2 ) instead of respiratory muscle mass; however, these parameters have not been validated. This study aimed to confirm the validity of the respiratory sarcopenia definition proposed by these four professional organizations., Methods: Participants of our cohort study in 2015 of 468 community-dwelling older people who were evaluated for sarcopenia and underwent spirometry were included in this analysis. We determined two respiratory sarcopenia models based on low skeletal muscle mass and respiratory muscle strength. Low skeletal muscle mass was defined by low ASM/height 2 , and low respiratory muscle strength was defined by peak expiratory flow rate (PEFR) or percentage of predicted PEFR (%PEFR). Survival status was assessed 5 years after baseline assessment (in 2020). To evaluate the validity of the cut-off values for PEFR and %PEFR, we determined different respiratory sarcopenia models by sequentially varying the cut-off values for each parameter, including ASM/height 2 , from high to low. We subsequently calculated the hazard ratio (HR) for mortality for each respiratory sarcopenia model using the Cox proportional hazards model. Additionally, we plotted the HR for each combination of cut-off values for ASM/height 2 and PEFR or %PEFR on a three-dimensional chart to observe the relationship between the different cut-off values and HR., Results: A total of 31 people died during the 5-year observation period. With ASM/height 2 cut-off values of approximately 7.0 kg/m 2 for men and 5.7 kg/m 2 for women and %PEFR cut-off values of 66-75%, respiratory sarcopenia was associated with mortality risk (HR, 2.36-3.27, point estimation range)., Conclusions: The definition of respiratory sarcopenia by the four professional organizations is related to future health outcomes, and this definition is valid. Geriatr Gerontol Int 2024; ••: ••-••., (© 2024 Japan Geriatrics Society.)

The predictive abilities of computer-based screening devices for early cognitive decline (CD) in older adults have rarely been longitudinally examined. Therefore, this study examined the ability of CogEvo, a short-duration, computer-based cognitive screening device requiring little professional involvement, to predict CD among community-dwelling older adults. We determined whether 119 individuals aged ≥ 65 years living in Japanese rural communities who scored ≥ 24 on the Mini-Mental State Examination (MMSE) at baseline developed CD by annually administering the MMSE to them. CD was defined as an MMSE score of ≤23. At baseline, the overall CogEvo judgment grade, with lower grades indicating better cognitive function, was calculated from the results of various cognitive tasks. Over 2 years, 10 participants developed CD. Participants with grades of 4 had a higher percentage of CD cases than those with grades of ≤3 ( p < 0.01). This relationship remained significant after controlling for possible confounders, including the MMSE score at baseline. The sensitivity and specificity of the CogEvo grade cutoff of 4 were 50.0% and 93.6%, respectively. In conclusion, CogEvo may be an efficient tool for identifying individuals at a high risk for dementia. The possibility of missing CD cases should be considered when using CogEvo for screening.

Introduction: Social isolation is associated with increased mortality risk. On the other hand, some older adults prefer to be alone. Additionally, predictors of isolation are mostly unchanged across interventions. Therefore, knowledge of how to prevent negative health outcomes in isolation would be beneficial. One of the factors that reduces the risk of mortality is regular exercise. However, to date, no studies to our knowledge have examined whether regular exercise reduces mortality among socially isolated individuals. This study aimed to determine the effects of the combination of social isolation and regular exercise on mortality among community-dwelling older adults., Methods: This prospective cohort study was part of the larger Otassha Study of community-dwelling older adults living in Itabashi Ward, Tokyo, Japan. In October 2012, 835 individuals (males = 350, females = 485; mean age 73.1 years) completed a comprehensive baseline health survey. Individuals were considered socially isolated if their frequency of interactions with others averaged less than once per week. Regular exercise was defined as exercise performed at least twice a week. The participants were assigned to one of the following four groups: (1) not isolated with regular exercise, (2) not isolated without regular exercise, (3) isolated with regular exercise, and (4) isolated without regular exercise. All-cause mortality information was obtained from the ward office database. Follow-ups were conducted until 1 November 2020. A Cox proportional regression analysis was performed., Results: A final analysis was performed on a complete dataset of 735 participants (males = 303, females = 432; mean age 72.9 years). A total of 132 (18.0%), 426 (58.0%), 27 (3.7%), and 150 (20.4%) participants were assigned to groups 1, 2, 3, and 4, respectively. The mortality rates in groups 1, 2, 3, and 4 were 6.1%, 9.2%, 7.4%, and 19.3%, respectively. Compared with group 1, isolated individuals who did not perform regular exercise had a significantly higher mortality rate [adjusted hazard ratio (aHR), 2.48; 95% confidence interval (CI), 1.12-5.52]. However, no significant association was noted in isolated individuals who performed regular exercise (aHR, 1.25; 95% CI, 0.26-5.91)., Conclusion: Regular exercise was associated with a decrease in mortality risk, regardless of social isolation status. Thus, our results indicate that encouraging isolated older adults to exercise regularly may reduce their negative health outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ejiri, Kawai, Imamura, Fujiwara, Ihara, Hirano and Obuchi.)

Background: Knee osteoarthritis negatively affects the gait of patients, especially that of elderly people. However, the assessment of wearable sensors in knee osteoarthritis patients has been under-researched. During clinical assessments, patients may change their gait patterns under the placebo effect, whereas wearable sensors can be used in any environment., Methods: Sixty patients with knee osteoarthritis and 20 control subjects were included in the study. Wearing shoes with an IMU sensor embedded in the insoles, the participants were required to walk along a walkway. The sensor data were collected during the gait. To discriminate between healthy and knee osteoarthritis patients and to classify different subgroups of knee osteoarthritis patients (patients scheduled for surgery vs. patients not scheduled for surgery; bilateral knee osteoarthritis diagnosis vs. unilateral knee osteoarthritis diagnosis), we used a machine learning approach called the support vector machine. A total of 88 features were extracted and used for classification., Findings: The patients vs. healthy participants were classified with 71% accuracy, 85% sensitivity, and 56% specificity. The "patients scheduled for surgery" vs. "patients not scheduled for surgery" were classified with 83% accuracy, 83% sensitivity, and 81% specificity. The bilateral knee osteoarthritis diagnosis vs. unilateral knee osteoarthritis diagnosis was classified with 81% accuracy, 75% sensitivity, and 79% specificity., Interpretation: Gait analysis using wearable sensors and machine learning can discriminate between healthy and knee osteoarthritis patients and classify different subgroups with reasonable accuracy, sensitivity, and specificity. The proposed approach requires no complex gait factors and is not limited to controlled laboratory settings., Competing Interests: Declaration of competing interest K. Fukushi, C. Huang, K. Ihara, Y. Nozaki, K. Nakahara are employees of the NEC Corporation., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended treatment for adults with chronic kidney disease (CKD), but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk-benefit profile in a post-hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial., Methods: The EMPA-KIDNEY trial randomized 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20<45 mL/min/1.73m2, or ≥45<90 mL/min/1.73m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed for two years (median). Additional characteristics analysed in subgroups were multimorbidity, polypharmacy and health-related quality of life (HRQoL) at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable., Results: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility and diabetes; then eGFR and other comorbidities. Empagliflozin was generally well-tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82); and all-cause hospitalization by 14% (HR 0.86, 95% CI 0.78-0.95); with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy or HRQoL. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms., Conclusions: These findings support the use of SGLT2 inhibitors in CKD, irrespective of frailty, multimorbidity or polypharmacy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Background: Maintaining higher-level functional capacity is important for independent living in older age. The aging trajectory of the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) has three patterns; however, the subscale patterns are unclear., Aims: This study aimed to clarify the aging trajectory patterns of the TMIG-IC subscales among community-dwelling older Japanese., Methods: Participants were 3,169 community-dwelling older Japanese who participated in the 2012-2022 mail survey of the Otassha study. The aging trajectory patterns of the TMIG-IC total and subscale scores for those aged 65-90 years were identified using group-based trajectory modeling. Further, the combination frequency of the subscale trajectory patterns was determined., Results: Three patterns were identified: early-onset decreasing, late-onset decreasing, and high-stable., Discussion: The instrumental activities of daily living (IADL) trajectory was maintained until approximately 80 years of age; however, chronic disease prevailed the most in the early-onset decreasing pattern. The early-onset decreasing pattern of intellectual activity (IA) was present in 25% of participants, showing impaired IA from 65 years of age. The late-onset decreasing pattern of social roles (SR) was present in 30% of participants, showing a sharp decline compared to other subscales. For many people, the patterns of decrease in SR and IA overlapped., Conclusions: To maintain higher-level functional capacity, interventions that include disease management and prevention of decline in IADL and increase the awareness of the social support provided throughout old age and interventions for people with an early decline in IA should be implemented., (© 2024. The Author(s).)

DNA-binding transcription factors (TFs) play a central role in transcriptional regulation mechanisms, mainly through their specific binding to target sites on the genome and regulation of the expression of downstream genes. Therefore, a comprehensive analysis of the function of these TFs will lead to the understanding of various biological mechanisms. However, the functions of TFs in vivo are diverse and complicated, and the identified binding sites on the genome are not necessarily involved in the regulation of downstream gene expression. In this study, we investigated whether DNA structural information around the binding site of TFs can be used to predict the involvement of the binding site in the regulation of the expression of genes located downstream of the binding site. Specifically, we calculated the structural parameters based on the DNA shape around the DNA binding motif located upstream of the gene whose expression is directly regulated by one TF AoXlnR from Aspergillus oryzae , and showed that the presence or absence of expression regulation can be predicted from the sequence information with high accuracy ([Formula: see text]-1.0) by machine learning incorporating these parameters.

ADH5/ALDH2 deficiency is a rare inherited syndrome characterized by short stature, microcephaly, delayed mental development, and hematopoietic dysfunction and has recently been proposed as a disease paradigm. Acute and severe presentations include aplastic anemia, myelodysplastic syndrome, or leukemia, requiring bone marrow transplantation during childhood. Conversely, non-hematological manifestations may exhibit a prolonged and nonspecific clinical trajectory, with growth failure and developmental delay, most of which are often overlooked, particularly in patients with milder symptoms. Here, we describe the clinical course of a girl with a wide spectrum of clinical presentations, including nonspecific hematopoietic disorders, growth retardation, mild developmental delay, amblyopia, hemophagocytic lymphohistiocytosis, and verruca vulgaris, culminating in a genetic diagnosis of AMeD syndrome at 12 years of age. We also summarized the clinical manifestations of previously reported cases of AMeD syndrome. Cumulatively, 13 females and 5 males have been documented, with a cardinal triad of symptoms, aplastic anemia, short stature, and intellectual disability. Additional characteristic observations included pigmentary deposition in approximately half of the cases and skeletal difficulties in one-quarter. We propose that early diagnosis of patients who exhibit relatively mild phenotypes of skin or skeletal lesions is important for managing and improving the quality of life of patients with AMeD syndrome., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose of Review: Posttraumatic headache (PTH), a headache that develops within 7 days of a causative injury, is one of the most common secondary headaches, mostly attributed to mild traumatic brain injury (mTBI). Because presence of preinjury headache is a risk factor for developing PTH and PTH symptoms often resemble migraine or tension-type headache, the association between PTH and primary headaches has attracted attention from clinicians and scientists., Recent Findings: Recent studies on epidemiological aspects, headache features, risk factors, imaging characteristics, and response to treatment, suggest overlapping features and distinct objective findings in PTH compared to migraine., Summary: We argue that PTH is distinct from migraine. Therefore, PTH epidemiology, pathophysiology, diagnosis, treatment, and prognosis should continue to be investigated separately from migraine., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Biallelic pathogenic variants of LARS1 cause infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute hepatic failure with steatosis in infants. LARS functions as a protein associated with mTORC1 and plays a crucial role in amino acid-triggered mTORC1 activation and regulation of autophagy. A previous study demonstrated that larsb-knockout zebrafish exhibit conditions resembling ILFS. However, a comprehensive analysis of larsb-knockout zebrafish has not yet been performed because of early mortality., Methods: We generated a long-term viable zebrafish model carrying a LARS1 variant identified in an ILFS1 patient (larsb-I451F zebrafish) and analyzed the pathogenesis of the affected liver of ILFS1., Results: Hepatic dysfunction is most prominent in ILFS1 patients during infancy; correspondingly, the larsb-I451F zebrafish manifested hepatic anomalies during developmental stages. The larsb-I451F zebrafish demonstrates augmented lipid accumulation within the liver during autophagy activation. Inhibition of DGAT1, which converts fatty acids to triacylglycerols, improved lipid droplets in the liver of larsb-I451F zebrafish. Notably, treatment with an autophagy inhibitor ameliorated hepatic lipid accumulation in this model., Conclusions: Our findings suggested that enhanced autophagy caused by biallelic LARS1 variants contributes to ILFS1-associated hepatic dysfunction. Furthermore, the larsb-I451F zebrafish model, which has a prolonged survival rate compared with the larsb-knockout model, highlights its potential utility as a tool for investigating the pathophysiology of ILFS1-associated liver dysfunction., (© 2024. The Author(s).)

Noroviruses are major causative agents of acute nonbacterial gastroenteritis in humans. There are neither antiviral therapeutic agents nor vaccines for noroviruses at this time. To evaluate the potential usefulness of two previously isolated human monoclonal antibody fragments, CV-1A1 and CV-2F5, we first conducted a single-particle analysis to determine the cryo-electron microscopy structure of virus-like particles (VLPs) from the genogroup I genotype 4 (GI.4) Chiba strain uniformly coated with CV-1A1 fragments. The results revealed that the GI.4-specific CV-1A1 antibody bound to the P2 subdomain, in which amino acids are less conserved and variable. Interestingly, a part of the CV-1A1 intrudes into the histo-blood group antigen-binding site, suggesting that this antibody might exert neutralizing activity. Next, we determined the crystal structure of the protruding (P) domain of the capsid protein in the complex form with the CV-2F5 antibody fragment. Consistent with the cross-reactivity, the CV-2F5 bound to the P1 subdomain, which is rich in amino acids conserved among the GI strains, and moreover induced a disruption of Chiba VLPs. These results suggest that the broadly reactive CV-2F5 antibody can be used as both a universal detection reagent and an antiviral drug for GI noroviruses., Importance: We conducted the structural analyses of the VP1 protein from the GI.4 Chiba norovirus to identify the binding sites of the previously isolated human monoclonal antibodies CV-1A1 and CV-2F5. The cryo-electron microscopy of the Chiba virus-like particles (VLPs) complexed with the Fv-clasp forms of GI.4-specific CV-1A1 revealed that this antibody binds to the highly variable P2 subdomain, suggesting that this antibody may have neutralizing ability against the GI.4 strains. X-ray crystallography revealed that the CV-2F5 antibody bound to the P1 subdomain, which is rich in conserved amino acids. This result is consistent with the ability of the CV-2F5 antibody to react with a wide variety of GI norovirus strains. It is also found that the CV-2F5 antibody caused a disruption of VLPs. Our findings, together with previous reports on the structures of VP1 proteins and VLPs, are expected to open a path for the structure-based development of antivirals and vaccines against norovirus disease., Competing Interests: The authors declare no conflict of interest.

Objectives: To investigate the trajectories of social networks and interactions among older Japanese individuals during the COVID-19 pandemic., Study Design: We used data from a cohort of community-dwelling older individuals from the Otassha study's 2019-2022 survey. Participants comprised 606 older individuals who participated in the 2019 survey and were followed up at least once., Main Outcome Measures: Social networks were assessed using the Lubben Social Network Scale-6 (LSNS-6), whereas social interactions were assessed by the frequency of face-to-face or non-face-to-face contact with non-resident family members and friends. Trajectories of the LSNS-6 and face-to-face and non-face-to-face interactions were identified using group-based semiparametric mixture modeling. The trajectories of change in the LSNS-6 from 2019 were also identified. The factors associated with the changes in trajectory patterns were examined using logistic regression analysis., Results: Three LSNS-6 trajectories were identified, with slightly decreasing patterns over time. Specifically, face-to-face interactions tended to decrease over time, whereas non-face-to-face interactions exhibited almost no change. The reduction in LSNS-6 in the decreased pattern failed to recover to its pre-pandemic level. The group of participants with the decreased pattern had a significantly higher proportion of people participating in group activities [odds ratio (95 % confidence interval): 2.27 (1.12-4.59)] and performing calisthenics twice a week than the group with the maintained pattern [2.08 (1.18-3.68)]., Conclusions: During the three years of the pandemic, no changes were observed in the social networks of community-dwelling older Japanese individuals., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Epilepsy, a recurrent neurological disorder involving abnormal neurotransmitter kinetics in the brain, has emerged as a global health concern. The mechanism of epileptic seizures is thought to involve a relative imbalance between excitatory and inhibitory neurotransmitters. Despite the recent advances in clinical and basic research on the pathogenesis of epilepsy, the complex relationship between the neurotransmitter changes and behavior with and without antiepileptic drugs (AEDs) during seizures remains unclear. To investigate the effects of AEDs such as levetiracetam (LEV), carbamazepine (CBZ), and fenfluramine (FFR) on key neurotransmitters in the pentylenetetrazol (PTZ)-induced seizures in adult zebrafish, we examined the changes in glutamic acid, gamma-aminobutyric acid (GABA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), choline, acetylcholine, norepinephrine, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and adenosine. In this study, we observed that 5-HT and DA levels in the brain increased immediately after PTZ-induced seizures. Behavioral tests clearly showed that all of these AEDs suppressed the PTZ-induced seizures. Upon treatment of PTZ-induced seizures with these AEDs, CBZ decreased the glutamic acid and FFR increased the GABA levels; however, no neurotransmitter changes were observed in the brain after LEV administration. Thus, we demonstrated a series of neurotransmitter changes linked to behavioral changes during PTZ-induced epileptic seizures when LEV, CBZ, or FFR were administered. These findings will lead to a more detailed understanding of the pathogenesis of epilepsy associated with behavioral and neurotransmitter changes under AED treatment., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The ACTA2 gene encodes actin α2, a major smooth muscle protein in vascular smooth muscle cells. Missense variants in the ACTA2 gene can cause inherited thoracic aortic diseases with characteristic symptoms, such as dysfunction of smooth muscle cells in the lungs, brain vessels, intestines, pupils, bladder, or heart. We identified a heterozygous missense variant of Gly148Arg (G148R) in a patient with a thoracic aortic aneurysm, dissection, and left ventricular non-compaction. We used zebrafish as an in vivo model to investigate whether or not the variants might cause functional or histopathological abnormalities in the heart. Following the fertilization of one-cell stage embryos, we injected in vitro synthesized ACTA2 mRNA of wild-type, novel variant G148R, or the previously known pathogenic variant Arg179His (R179H). The embryos were maintained and raised for 72 h post-fertilization for a heart analysis. Shortening fractions of heart were significantly reduced in both pathogenic variants. A histopathological evaluation showed that the myocardial wall of ACTA2 pathogenic variants was thinner than that of the wild type, and the total cell number within the myocardium was markedly decreased in all zebrafish with pathogenic variants mRNAs. Proliferating cell numbers were also significantly decreased in the endothelial and myocardial regions of zebrafish with ACTA2 variants compared to the wild type. These results demonstrate the effects of ACTA2 G148R and R179H on the development of left ventricle non-compaction and cardiac morphological abnormalities. Our study highlights the previously unknown significance of the ACTA2 gene in several aspects of cardiovascular development., (© 2024. The Author(s).)

Purpose: To evaluate the feasibility of breath-hold (BH) high-resolution (HR) T1-weighted gradient echo hepatobiliary phase (HBP) imaging using compressed sensing (CS) in gadoxetic acid-enhanced liver MRI in comparison with standard HBP imaging using parallel imaging (PI)., Methods: The study included 122 patients with liver tumors with hypointensity in the HBP who underwent both HR HBP imaging with CS and standard HBP imaging with PI. Two radiologists evaluated the liver edge sharpness, hepatic vessel conspicuity, bile duct conspicuity, image noise, and overall image quality, as well as the lesion conspicuity on HR and standard HBP imaging and the contrast-enhanced (CE) MR cholangiography (MRC) image quality reconstructed from HBP images. As a quantitative analysis, the SNR of the liver and the liver to lesion signal intensity ratio (LLSIR) were also determined., Results: The liver edge sharpness, hepatic vessel conspicuity, bile duct conspicuity, and overall image quality as well as the lesion conspicuity and the LLSIR on HR HBP imaging with CS were significantly higher than those on standard HBP imaging (all of P < 0.001). The image quality of CE-MRC reconstructed from HR HBP imaging with CS was also significantly higher than that from standard HBP imaging (P < 0.001). Conversely, the SNR of liver in standard HBP was significantly higher than that in HR HBP with CS (P < 0.001)., Conclusion: BH HR HBP imaging with CS provided an improved overall image quality, lesion conspicuity, and CE-MRC visualization when compared with standard HBP imaging without extending the acquisition time.

Background: Although several recent meta-analyses have investigated the clinical influence of the addition of lateral lymph node dissection (LLND) on oncologic outcomes in patients with mid-low rectal cancer (RC) undergoing mesorectal excision (ME), most studies included in such meta-analyses were retrospectively designed. Therefore, this study aimed to explore the clinical influence of prophylactic LLND on oncologic outcomes in patients with mid-low RC undergoing ME., Methods: A comprehensive electronic search of the literature up to July 2022 was performed to identify studies that compared oncologic outcomes between patients with mid-low RC undergoing ME who underwent LLND and patients with mid-low RC undergoing ME who did not undergo LLND. A meta-analysis was performed using fixed-effects models and the generic inverse variance method to calculate hazard ratios (HRs) and 95% CIs, and heterogeneity was analyzed using I 2 statistics., Results: A total of 6 studies, consisting of 3 randomized and 3 propensity score matching studies, were included in this meta-analysis. The results of the meta-analysis of 2 randomized studies demonstrated no significant effect of prophylactic LLND on improving oncologic outcomes concerning overall survival (OS) (HR, 1.22; 95% CI, 0.89-1.69; I 2 = 0%; P = .22) and relapse-free survival (RFS) (HR, 1.03; 95% CI, 0.81-1.31; I 2 = 28%; P = .83)., Conclusion: The results of this meta-analysis revealed no significant influence of prophylactic LLND on oncologic outcomes-OS and RFS-in patients with mid-low RC who underwent ME., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Peritoneal lymphomatosis (PL) is a rare lymphoma-associated condition defined as the dissemination of lymphoma cells in the peritoneum. An 82-year-old man presented with abdominal pain, heartburn, and high fever. Radiological findings, including positron emission tomography-computed tomography (PET-CT), and gastrointestinal fiberscopy, showed diffuse thickening of the peritoneum, omentum, and mesentery; however, no lymphadenopathy, hepatosplenomegaly, or gastrointestinal lesions were observed. Under suspicion of peritonitis carcinomatosa of unknown origin, exploratory laparoscopy was performed that revealed multiple white nodules and masses on the surfaces of the peritoneum, mesentery, and intestinal serosa. The histopathological and cytogenetic findings of the peritoneum revealed high-grade B-cell lymphoma, not otherwise specified, and a gain of MYC by fluorescence in-situ hybridization. The patient was treated with two cycles of R-CHOP therapy, followed by six cycles of dose-adjusted EPOCH-R therapy, and a complete metabolic response was confirmed by PET-CT. Since there are no specific radiological findings to confirm the diagnosis of PL, a histopathological diagnosis is usually required. Most PL exhibit an aggressive lymphoma phenotype and can be cured by appropriate chemotherapy. Therefore, early diagnosis and treatment are desirable.

The association between the gut microbiota and muscle strength has garnered attention in the context of mitigating muscle decline. However, many study subjects have been individuals with existing illnesses or the elderly only. This study aims to elucidate the association between the gut microbiota and muscle strength indicators using grip strength/BMI in a large-scale study of community residents. The mean age of men ( n = 442) and women ( n = 588) was 50.5 (15.3) and 51.2 (15.9) years, respectively. The muscle strength indicator used was grip/BMI. The association between total read count and genus-level gut microbiota and muscle strength was analyzed. The mean grip/BMI was 1.8 (0.3) for men and 1.2 (0.2) for women. The genus of the gut microbiota that showed an association in both sexes was Eggerthella (men: β = 0.18, CI: 0.04-0.31, p = 0.009; women: β = 0.07, CI: 0.00-0.12, p = 0.028). Blautia , Eggerthella and Faecalibacterium were found to be significantly associated with grip/BMI in both the multiple regression analysis and Spearman's correlation analysis after the multiple comparison adjustment. These results suggest that an increase in Blautia and Eggerthella , coupled with a decrease in Faecalibacterium , may contribute to muscle strengthening or the suppression of muscle weakness.

The motility of Vibrio species plays a pivotal role in their survival and adaptation to diverse environments and is intricately associated with pathogenicity in both humans and aquatic animals. Numerous mutant strains of Vibrio alginolyticus have been generated using UV or EMS mutagenesis to probe flagellar motility using molecular genetic approaches. Identifying these mutations promises to yield valuable insights into motility at the protein structural physiology level. In this study, we determined the complete genomic structure of 4 reference specimens of laboratory V . alginolyticus strains: a precursor strain, V . alginolyticus 138-2, two strains showing defects in the lateral flagellum (VIO5 and YM4), and one strain showing defects in the polar flagellum (YM19). Subsequently, we meticulously ascertained the specific mutation sites within the 18 motility-deficient strains related to the polar flagellum (they fall into three categories: flagellar-deficient, multi-flagellar, and chemotaxis-deficient strains) by whole genome sequencing and mapping to the complete genome of parental strains VIO5 or YM4. The mutant strains had an average of 20.6 (±12.7) mutations, most of which were randomly distributed throughout the genome. However, at least two or more different mutations in six flagellar-related genes were detected in 18 mutants specifically selected as chemotaxis-deficient mutants. Genomic analysis using a large number of mutant strains is a very effective tool to comprehensively identify genes associated with specific phenotypes using forward genetics., Competing Interests: The authors declare that they have no competing interests., (© 2024 Uesaka et al.)

Introduction: Social isolation has been recognized as a contributing factor to negative health outcomes. Although living alone is associated with health-related outcomes, existing findings are inconsistent. It is not the act of living alone that may predict poor health, but rather social isolation that can lead to increased mortality risk. This study investigated the combined associations of social isolation and living alone with mortality among community-dwelling older adults., Methods: We included older adults from Itabashi ward, Tokyo, who participated in comprehensive health checkups. Participants were categorized into four groups based on their social isolation status and living alone. The primary outcome was all-cause mortality, analyzed using Cox proportional hazards models., Results: Of the 1,106 participants (mean age 73, 42% male), 4.5% experienced both social isolation and living alone. This combination was associated with a worse prognosis regarding all-cause mortality (hazard ratio (HR): 2.08 [95% confidence interval (CI), 1.08-4. 00]). Those who were socially isolated but not living alone also showed a trend towards higher mortality risk (HR: 1.41 [95% CI, 0.90-2.20]). Contrastingly, those who were not socially isolated and lived alone did not show an increased mortality risk (HR: 0.81 [95% CI, 0.44-1.49])., Discussion and Conclusion: Living alone is not inherently associated with a poor prognosis in older adults; however, social isolation was associated with a higher mortality risk. Healthcare providers should focus on enhancing social interactions and support for older adults because of their effects on health rather than solely addressing living arrangements to prevent adverse health events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Imamura, Kawai, Ejiri, Sasai, Hirano, Fujiwara, Ihara and Obuchi.)

Background: Anti-calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) have greatly changed migraine treatment options. In Japan, although CGRPmAb guidelines (≥ 4 monthly migraine days (MMDs) and ≥ 1 previous preventive failure) are well-acknowledged, the actual use of CGRPmAbs and the circumstances of the related headache care are unknown., Methods: We conducted an online survey of Japanese Headache Society members, inquiring about the physicians' experience with CGRPmAbs and how they make decisions related to their use., Results: Of the 397 respondents, 320 had prescribed CGRPmAbs. The threshold number of previous preventive failures for recommending a CGRPmAb was two for the majority of the respondents (n = 170, 54.5%), followed by one (n = 64, 20.5%). The MMD threshold was ≥ 4 for 71 respondents (22.8%), ≥ 6 for 68 (21.8%), ≥ 8 for 76 (24.4%), and ≥ 10 for 81 (26.0%). The respondents tended to assess treatment efficacy after 3 months (episodic migraine: n = 217, 69.6%, chronic migraine: n = 188, 60.3%). The cost of CGRPmAbs was described by many respondents in two questions: (i) any request for a CGRPmAb (27.7%), and (ii) the most frequently reported reason for responders to discontinue CGRPmAbs (24.4%)., Conclusions: Most of the respondents recommended CGRPmAbs to patients with ≥ 2 preventive failures, followed by ≥ 1. The MMD threshold ranged mostly from ≥ 4 to ≥ 10. The concern for costs was raised as a major limiting factor for prescribing CGRPmAbs., (© 2024. The Author(s).)

Social isolation among older adults affects their physical and mental health. Ego-resilience is associated with flexible adaptation to various environments and acceptable behaviors. However, its association with social isolation among older people is unclear. Therefore, a health survey was conducted with 510 adults aged 65 years or older to assess social isolation, its associated factors, and ego resilience. The results showed that the social isolation group had a lower median ego-resiliency scale score (42.0) compared to the non-social isolation group (38.0). The social isolation group were mostly males without spouses, took time to move, had more depressive moods, and poorer subjective health status. The non-social isolated group had faster maximum walking speed. Low ego-resilience was newly identified as a factor associated with social isolation among older people, as were being male, having no spouse, and depressive symptoms. Mediation analysis revealed that ego-resilience affected social isolation and was partially mediated by depressive symptoms., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2024 The Author(s).)

V-ATPase is an ATP hydrolysis-driven proton pump involved in the acidification of intracellular organelles and systemic acid-base homeostasis through H + secretion in the renal collecting ducts. V-ATPase dysfunction is associated with hereditary distal renal tubular acidosis (dRTA). ATP6V1B1 encodes the B1 subunit of V-ATPase that is integral to ATP hydrolysis and subsequent H + transport. Patients with pathogenic ATP6V1B1 mutations often exhibit an early onset of sensorineural hearing loss. However, the mechanisms underlying this association remain unclear. We employed morpholino oligonucleotide-mediated knockdown and CRISPR/Cas9 gene editing to generate Atp6v1ba-deficient (atp6v1ba -/- ) zebrafish as an ortholog model for ATP6V1B1. The atp6v1ba -/- zebrafish exhibited systemic acidosis and significantly smaller otoliths compared to wild-type siblings. Moreover, deficiency in Atp6v1ba led to degeneration of inner ear hair cells, with ultrastructural changes indicative of autophagy. Our findings indicate a critical role of ATP6V1B1 in regulating lysosomal pH and autophagy in hair cells, and the results provide insights into the pathophysiology of sensorineural hearing loss in dRTA. Furthermore, this study demonstrates that the atp6v1ba -/- zebrafish model is a valuable tool for further investigation into disease mechanisms and potential therapies for acidosis-related hearing impairment., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest regarding the contents of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The burden and disability associated with headaches are conceptualized and measured differently at patients' and populations' levels. At the patients' level, through patient-reported outcome measures (PROMs); at population level, through disability weights (DW) and years lived with a disability (YLDs) developed by the Global Burden of Disease Study (GBD). DW are 0-1 coefficients that address health loss and have been defined through lay descriptions. With this literature review, we aimed to provide a comprehensive analysis of disability in headache disorders, and to present a coefficient referring to patients' disability which might inform future GBD definitions of DW for headache disorders., Methods: We searched SCOPUS and PubMed for papers published between 2015 and 2023 addressing disability in headache disorders. The selected manuscript included a reference to headache frequency and at least one PROM. A meta-analytic approach was carried out to address relevant differences for the most commonly used PROMs (by headache type, tertiles of medication intake, tertiles of females' percentage in the sample, and age). We developed a 0-1 coefficient based on the MIDAS, on the HIT-6, and on MIDAS + HIT-6 which was intended to promote future DW iterations by the GBD consortium., Results: A total of 366 studies, 596 sub-samples, and more than 133,000 single patients were available, mostly referred to cases with migraine. Almost all PROMs showed the ability to differentiate disability severity across conditions and tertiles of medication intake. The indexes we developed can be used to inform future iterations of DW, in particular considering their ability to differentiate across age and tertiles of medication intake., Conclusions: Our review provides reference values for the most commonly used PROMS and a data-driven coefficient whose main added value is its ability to differentiate across tertiles of age and medication intake which underlie on one side the increased burden due to aging (it is likely connected to the increased impact of common comorbidities), and by the other side the increased burden due to medication consumption, which can be considered as a proxy for headache severity. Both elements should be considered when describing disability of headache disorders at population levels., (© 2024. The Author(s).)

Background: Ureaplasma spp. is an endemic microorganism that causes placental chorioamnionitis or preterm delivery in pregnant women, and the occurrence of bronchopulmonary dysplasia or intraventricular hemorrhaging in preterm infants after birth, although the pathogenicity of Ureaplasma remains controversial. The association between Ureaplasma exposure and the symptoms or outcomes of infected mothers or their infants born at term remains poorly understood. We investigated the clinical characteristics of preterm and term infants with or without Ureaplasma in their gastric fluid., Methods: Gastric fluid samples were collected from 47 newborns in the neonatal intensive-care unit immediately after birth and tested using multiplex polymerase chain reaction (PCR) assays targeting Ureaplasma spp., Ureaplasma parvum, and Ureaplasma urealyticum. The clinical findings and outcomes of the neonates and their mothers were retrospectively evaluated., Results: Ureaplasma spp. were detected in 9/47 samples (19%) by multiplex PCR assays. In all cases, the subspecies was U. parvum. The Ureaplasma-positive group had a significantly higher incidence of chorioamnionitis in utero than the Ureaplasma-negative group. Regarding preterm infants, the IgM levels in the Ureaplasma-positive group were significantly higher than in the Ureaplasma-negative group. In contrast, in term infants, the rates of a non-reassuring fetal status, a maternal fever, and maternal leukocyte counts and maternal C-reactive protein levels within five days before delivery in the Ureaplasma-positive group were significantly higher than those in the Ureaplasma-negative group. All three extremely-low-birth-weight infants with Ureaplasma developed bronchopulmonary dysplasia. The length of hospitalization in the Ureaplasma-positive group was almost same as that in the Ureaplasma-negative group for term infants., Conclusion: Mothers or their fetuses with exposure to Ureaplasma expressed characteristic clinical features during pregnancy and after birth., (Copyright © 2023 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Aim: To clarify the relationship between early infantile spontaneous movement of very-low-birth-weight infants (VLBWIs) and sensory characteristics in childhood., Study Design: Prospective cohort study. We investigated the association between the Motor Optimality Score-Revised (MOS-R), a detailed assessment of general movements (GMs) at the corrected age of 9-17 weeks and the Infant/Toddler Sensory Profile Japanese version (ITSP-J) at the corrected age of 3 years. A multiple regression analysis was performed to examine the correlation of ITSP-J and MOS-R with patient clinical background factors., Subjects: Fifty-three VLBWIs (median gestational age: 28 weeks, 6 days; median birth weight: 997 g) who were managed at the NICU of Oita University from September 2013 to June 2019., Results: A multiple regression analysis revealed that the ITSP-J subscale in the sensory section of visual score was significantly correlated with the age-adequate movement repertoire subscore of MOS-R, and in the sensory section of vestibular score was correlated with the fidgety subscore of MOS-R. For both visual and vestibular section scores, intraventricular hemorrhage (IVH) showed an independent association with the MOS-R subscore., Conclusion: Spontaneous movement characteristics in early infancy were associated with sensory characteristics in early childhood., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

To understand the lifespan of higher organisms, including humans, it is important to understand lifespan at the cellular level as a prerequisite. So, fission yeast is a good model organism for the study of lifespan. To identify the novel factors involved in longevity, we are conducting a large-scale screening of long-lived mutant strains that extend chronological lifespan (cell survival in the stationary phase) using fission yeast. One of the newly acquired long-lived mutant strains (No.98 mutant) was selected for analysis and found that the long-lived phenotype was due to a missense mutation (92Phe → Ile) in the plb1 + gene. plb1 + gene in fission yeast is a nonessential gene encoding a homolog of phospholipase B, but its functions under normal growth conditions, as well as phospholipase B activity, remain unresolved. Our analysis of the No.98 mutant revealed that the plb1 mutation reduces the integrity of the cellular membrane and cell wall and activates Sty1 via phosphorylation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Exposure to environmental heavy metals is associated with telomere length (TL) alteration. Available information regarding the effect of prenatal exposure to environmental pollutants on newborn TL is controversial. The aim of this study is to systematically review and conduct a meta-analysis of the existing epidemiological studies on the associations between prenatal metal exposure and newborn TL. A comprehensive literature search was performed using the online databases of PubMed, Web of Science, and ScienceDirect from their inception to December 1, 2023. Thirteen eligible studies were included from the overall initial identification of 3559 records. The effect size was expressed as standardized beta coefficients with 95% confidence intervals (CIs) by the restricted maximum-likelihood approach with a weighted random-effects model. Prenatal exposure to environmental heavy metals was associated with a shorter newborn TL (standardized beta = -0.04; 95% CI: -0.08, 0.00; p = 0.05). Subgroup analysis showed that prenatal exposure to cadmium was significantly, negatively associated with TL in newborns (standardized beta = -0.05; 95% CI: -0.10, -0.01; p = 0.021). Heavy metal exposure during the third trimester was significantly associated with a shorter TL in newborns (standardized beta = -0.05; 95% CI: -0.11, -0.01; p = 0.045). No significant association was found between the newborn's sex and exposure sample type. This study provides evidence for the negative effect of prenatal exposure to heavy metals on newborn TL. In particular, cadmium exposure and exposure during the third trimester of pregnancy are critical factors associated with heavy metal-induced TL shortening., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Stoma outlet obstruction (SOO) occurs with an incidence of approximately 40% after proctocolectomy for Ulcerative colitis (UC) with diverting ileostomy. This study aimed to identify the risk factors for SOO after proctocolectomy with diverting ileostomy for patients with UC., Methods: We reviewed the data of 68 patients with UC who underwent proctocolectomy and diverting ileostomy between April 2006 and September 2021. These cases were analyzed on the basis of clinicopathological and anatomical factors. SOO was defined as small bowel obstruction displaying symptoms of intestinal obstruction, such as abdominal distention, abdominal pain, insertion of a tube through the stoma., Results: The study included 38 (56%) men and 30 (44%) women with a median age of 42 years (range, 21-80). SOO categorized as at least Clavien-Dindo grade II occurred in 11 (16%) patients. Six patients required earlier stoma closure than scheduled. Compared with patients without SOO, patients with SOO had a significantly higher total steroid dose from the onset of UC to surgery (p = 0.02), a small amount of intraabdominal fat (p = 0.04), and a higher rate of laparoscopic surgery (p < 0.01)., Conclusions: A high preoperative steroid dose, a small amount of intraabdominal fat and laparoscopic surgery were identified as risk factors for SOO. Early detection and treatment for SOO are important for patients at risk., Competing Interests: Conflicts of Interest There are no conflicts of interest., (Copyright © 2024 The Japan Society of Coloproctology.)

Background: Sacubitril/valsartan (SacVal) has been shown to improve the prognosis of heart failure; however, whether SacVal reduces the occurrence of atrial fibrillation (AF) in heart failure has not yet been elucidated. In this study, we aimed to determine whether SacVal is effective in reducing the occurrence of AF in heart failure and identify the underlying mechanism of its electrophysiological effect in mice., Methods: Adult male mice underwent transverse aortic constriction, followed by SacVal, valsartan, or vehicle treatment for two weeks. Electrophysiological study (EPS) and optical mapping were performed to assess the susceptibility to AF and the atrial conduction properties, and fibrosis was investigated using heart tissue and isolated cardiac fibroblasts (CFs)., Results: EPS analysis revealed that AF was significantly less inducible in SacVal-treated mice than in vehicle-treated mice. Optical mapping of the atrium showed that SacVal-treated and valsartan-treated mice restored the prolonged action potential duration (APD); however, only SacVal-treated mice showed the restoration of decreased conduction velocity (CV) compared to vehicle-treated mice. In addition, the electrophysiological distribution analysis demonstrated that heterogeneous electrophysiological properties were rate-dependent and increased heterogeneity was closely related to the susceptibility to AF. SacVal attenuated the increased heterogeneity of CV at short pacing cycle length in atria, whereas Val could not. Histological and molecular evaluation showed that SacVal exerted the anti-fibrotic effect on the atria. An in vitro study of CFs treated with natriuretic peptides and LBQ657, the metabolite and active form of sacubitril, revealed that C-type natriuretic peptide (CNP) combined with LBQ657 had an additional anti-fibrotic effect on CFs., Conclusions: Our results demonstrated that SacVal can improve the conduction disturbance and heterogeneity through the attenuation of fibrosis in murine atria and reduce the susceptibility of AF in heart failure with pressure overload, which might be attributed to the enhanced function of CNP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Iwamiya, Ihara, Furukawa and Sasano.)

The progressive ratio (PR) lever-press task serves as a benchmark for assessing goal-oriented motivation. However, a well-recognized limitation of the PR task is that only a single data point, known as the breakpoint, is obtained from an entire session as a barometer of motivation. Because the breakpoint is defined as the final ratio of responses achieved in a PR session, variations in choice behavior during the PR task cannot be captured. We addressed this limitation by constructing four reinforcement learning models: a simple Q-learning model, an asymmetric model with two learning rates, a perseverance model with choice traces, and a perseverance model without learning. These models incorporated three behavioral choices: reinforced and non-reinforced lever presses and void magazine nosepokes, because we noticed that male mice performed frequent magazine nosepokes during PR tasks. The best model was the perseverance model, which predicted a gradual reduction in amplitudes of reward prediction errors (RPEs) upon void magazine nosepokes. We confirmed the prediction experimentally with fiber photometry of extracellular dopamine (DA) dynamics in the ventral striatum of male mice using a fluorescent protein (genetically encoded GPCR activation-based DA sensor: GRAB DA2m ). We verified application of the model by acute intraperitoneal injection of low-dose methamphetamine (METH) before a PR task, which increased the frequency of magazine nosepokes during the PR session without changing the breakpoint. The perseverance model captured behavioral modulation as a result of increased initial action values, which are customarily set to zero and disregarded in reinforcement learning analysis. Our findings suggest that the perseverance model reveals the effects of psychoactive drugs on choice behaviors during PR tasks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ihara, Shikano, Kato, Yagishita, Tanaka and Takata.)

Noonan syndrome is a congenital disorder characterized by distinctive facial appearance, congenital heart defects, short stature, and skeletal dysplasia. Although boys with Noonan syndrome frequently exhibit cryptorchidism, a mild form of 46,XY disorders of sex development (DSD), they barely manifest more severe genital abnormalities. Here, we report a boy with ambiguous genitalia, short stature, and non-specific dysmorphic features. He had no cardiac abnormalities or skeletal dysplasia. His score in the Noonan syndrome diagnostic criteria (36 of 157 points, 23%) was lower than the cutoff for diagnosis (50%). Whole-exome sequencing identified a de novo heterozygous variant (c.922A>G: p.Asn308Asp) in PTPN11 and a maternally inherited hemizygous variant (c.1439C>T: p.Pro480Leu) in FLNA . The PTPN11 variant was a known causative mutation for Noonan syndrome. FLNA is a causative gene for neurodevelopmental and skeletal abnormalities and has also been implicated in 46,XY DSD. The p.Pro480Leu variant of FLNA was assessed as deleterious by in silico analyses. These results provide evidence that whole-exome sequencing is a powerful tool for diagnosing patients with atypical disease manifestations. Furthermore, our data suggest a possible role of digenic mutations as phenotypic modifiers of Noonan syndrome., Competing Interests: The authors declare no conflicts of interest., (2024©The Japanese Society for Pediatric Endocrinology.)