Search

Abstract The seasonality and epidemiology of viral acute respiratory infections (ARIs) have changed since the coronavirus disease 2019 pandemic. However, molecular-based ARI surveillance has not been conducted in Japan. We developed a regional surveillance program to define the local epidemiology of ARIs. Between December 2023 and March 2024, 2,992 upper respiratory samples collected from patients suspected of having ARIs at five facilities in Kyoto City, Japan, were tested for SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) using RT‒PCR. Samples negative for these viruses were randomly selected for testing with the FilmArray Respiratory Panel, and the detection rates of other viruses were estimated. SARS-CoV-2, influenza virus, and RSV were detected in 598 (20.3%), 165 (5.6%), and 40 (1.4%) of the 2,949 samples with valid RT‒PCR results, respectively. The most prevalent viruses in the

Chronic Fatigue Syndrome (CFS) is a complex disorder characterized by prolonged, unexplained fatigue and challenging diagnosis. We report the case of a 35-year-old Japanese woman with CFS who had experienced chronic fatigue since the age of 11 years. Despite treatment with modafinil, methylphenidate, levocarnitine, and ubiquinone, the symptoms persisted. Introduction of oral 5-aminolevulinic acid with sodium ferrous citrate (5-ALA/SFC) led to significant improvements in daily activities, mobility, and psychosocial functioning. Genetic analysis revealed a novel heterozygous frameshift deletion in ADCK1 (p.Asn280fs), a gene related to mitochondrial function, which was confirmed using cDNA sequencing. ADCK1 deficiency has been associated with developmental disabilities, mitochondrial dysfunction, increased reactive oxygen species levels, and apoptosis in Drosophila and muscle cells. This case supports the hypothesis that ADCK1 mutations contribute to mitochondrial dysfunction and CFS pathogenesis. The patient’s significant clinical improvement with 5-ALA/SFC and ubiquinone suggests their potential for addressing mitochondrial dysfunction. Further functional and familial analyses are required to confirm the role of this heterozygous ADCK1 mutation in CFS. This case highlights the importance of considering mitochondrial dysfunction in CFS, and the potential therapeutic benefits of 5-ALA/SFC and ubiquinone.

Abstract Growth-associated protein 43 (GAP43) is a membrane-associated phosphoprotein predominantly expressed in the nervous systems, and controls axonal growth, branching, and pathfinding. While the association between GAP43 and human neurological disorders have been reported, the underlying mechanisms remain largely unknown. We performed whole exome sequencing on a patient with intellectual disability (ID), neurodevelopmental disorders, short stature, and skeletal abnormalities such as left–right difference in legs and digital deformities, and identified a heterozygous missense variation in the GAP43 gene [NM_001130064.2: c.436G > A/p.(E146K)]. The variant GAP43 protein was unstable in primary cultured cortical neurons and hippocampal neurons in vitro. In utero electroporation of the variant protein also confirmed its instability in vivo, suggesting that the variant led to a condition similar with haploinsufficiency in the patient. Silencing of GAP43 via in utero electroporation of RNAi vectors demonstrated that loss of GAP43 suppressed axon elongation into the contralateral hemisphere and impaired the dendritic arbor formation as shown by decreased dendritic branch points and shortened total dendritic lengths. Collectively, these findings confirmed the critical roles of GAP43 in brain development and the pathological basis of GAP43-associated diseases. Our study will contribute to a better understanding of how dysregulation of GAP43 leads to human diseases.

Mariko Siyue Koh,1,2 Sean Shao Wei Lam,3– 6 Xiaomeng Xu,7 Jun Tian Wu,3,4,8 Priyan Ratnasingham,7 Ricco Marsel,7 Marcus Eng Hock Ong,3,9 David Bruce Matchar,2,10,11 Ngiap Chuan Tan,2,12 Chian Min Loo1,2 1Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore, Singapore; 2Duke-NUS Medical School, National University of Singapore, Singapore, Singapore; 3Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore; 4Health Services Research Centre, SingHealth, Singapore, Singapore; 5Health Services Research Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore; 6Lee Kong Chian School of Business, Singapore Management University, Singapore, Singapore; 7Medical, GSK, Singapore, Singapore; 8NUS Yong Loo Lin School of Medicine, Singapore, Singapore; 9Department of Emergency Medicine, Singapore General Hospital, Singapore, Singapore; 10Department of Internal Medicine (General Internal Medicine), Duke University Medical School, Durham, NC, USA; 11Department of Internal Medicine, Singapore General Hospital, Singapore, Singapore; 12SingHealth Polyclinics, SingHealth, Singapore, SingaporeCorrespondence: Mariko Siyue Koh, Department of Respiratory and Critical Care Medicine, Singapore General Hospital, 20 College Road, Academia Level 3, Singapore, 169856, Singapore, Tel +65 65767862, Fax +65 62275247, Email mariko.koh.s.y@singhealth.com.sgPurpose: Patients with asthma in Singapore often have complex patient journeys, with diagnosis and management across various primary and speciality care settings. Real-world population health data is needed to identify care gaps and inform policies.Patients and Methods: This retrospective, longitudinal cohort study assessed real-world data from adults (aged ≥ 18 years) with asthma in the SingHealth Chronic Obstructive Pulmonary Disease and Asthma Data Mart, an integrated database of electronic medical records of patients who attended primary and/or speciality care clinics in the SingHealth Regional Health System 01/01/2015– 12/31/2020. Patients were indexed by first asthma diagnosis and categorized into cohorts of index year. Patient characteristics, asthma management and outcomes were described during baseline (1-year pre-index) and follow-up periods (1-year post-index).Results: Overall, 21,215 patients were included across 4 cohorts: 2016, N=12,947; 2017, N=3419; 2018, N=2816; 2019, N=2033. Most common baseline asthma medication changed from inhaled corticosteroids (ICS) alone in the 2016 cohort (32.8% [n=4252]) to ICS/long-acting β2-agonist in the 2019 cohort (33.3% [n=677]). Asthma symptom control (mean [SD] Asthma Control Test scores) improved from 2016 to 2019 during baseline (18.38 [4.93] vs 19.87 [4.56]; p< 0.001) and follow-up (18.34 [4.23] vs 21.07 [3.51]; p< 0.001). Mean (standard deviation [SD]) number of exacerbations per patient during follow-up decreased from 2016 to 2019 (1.91 [3.11] vs 0.89 [2.07]; p< 0.001). Mean (SD) number of emergency department visits per patient during follow-up decreased from 0.21 (0.75) in 2016 to 0.17– 0.18 (0.60– 0.65; p< 0.001) between 2017 and 2019.Conclusion: Health status at first asthma diagnosis improved for each succeeding cohort from 2016 to 2019, along with improvements in patient management and outcomes. This reflects greater awareness of the condition and improved use of medication and referrals in recent years, suggesting policy changes and their implementation, including promotion of disease awareness and adoption of guideline recommendations, may improve asthma outcomes in Singapore.Plain Language Summary: In Singapore, up to 4 in 100 people are living with asthma. People with asthma can experience frequent symptoms and attacks that affect day-to-day activities, create emotional stress and reduce quality of life. Asthma has a financial impact on patients and the economy, as it can lead to missed work and reduced productivity. In Singapore, managing asthma can be complex, with patients often seeing both primary care physicians and specialists from diagnosis to treatment. This study assessed trends in the care that patients with asthma in Singapore received and their outcomes over a 4-year period. Patients’ medical records from primary and specialist care were collected for 1 year before and after their asthma diagnosis to determine whether treatment changed over time, whether symptoms improved and whether use of healthcare services changed.Between 2016 and 2019, patients with asthma had fewer, less severe asthma attacks, and fewer emergency department visits over time. The treatment types also changed; in 2019 versus 2016, more patients received combination inhalers of corticosteroids with a long-acting beta 2 (β2) agonist, or other add-on treatments, which improve patients’ asthma, including symptoms. This indicates that there was an increasing trend for physicians following new guidelines for recommended asthma care and these changes in practice ensured combination inhalers were made available to patients by the government, leading to improvement in asthma outcomes.This study shows that asthma management in Singapore improved over the 4-year period, potentially through healthcare professionals taking on board improved treatment guideline recommendations and policy changes.Keywords: asthma, asthma control, exacerbations, real world, Singapore, health outcomes

Abstract Mutations in proline‐rich transmembrane protein 2 (PRRT2) cause paroxysmal kinesigenic dyskinesia (PKD). Recently, we reported that a Prrt2 mutation exacerbated L‐dopa‐induced motor deficits in mice, suggesting that the basal ganglia might contribute to PKD pathology. Here, we demonstrated that the Prrt2 mutation enhanced depolarization stimuli‐induced extracellular dopamine levels in the mouse striatum, which were attenuated by repeated stimulation. L‐dopa administration maintained high dopamine levels in Prrt2‐KI mice even during repetitive stimuli but did not affect dopamine levels in wild‐type mice. Thus, the enhanced and prolonged responsiveness of dopamine release in nigrostriatal dopaminergic neurons to sequential excitation may be partially implicated in Prrt2‐related dyskinesia.

Abstract Targeting the drug tolerant persister (DTP) state in cancer cells should prevent further development of resistance mechanisms. This study explored combination therapies to inhibit alectinib-induced DTP cell formation from anaplastic lymphoma kinase–positive non-small cell lung cancer (ALK + NSCLC) patient–derived cells. After drug-screening 3114 compounds, pan-HER inhibitors (ErbB pathway) and tankyrase1/2 inhibitors (Wnt/β-catenin signaling) emerged as top candidates to inhibit alectinib-induced DTP cells growth. We confirmed knockdown of both TNKS1/2 in DTP cells recovered the sensitivity to alectinib. Further, our study suggested knockdown of TNKS1/2 increased stability of Axin1/2, which induced β-catenin degradation and decreased its nuclear translocation, thereby suppressing transcription of antiapoptotic and proliferation-related genes (survivin, c-MYC). Targeting both pathways with alectinib+pan-HER inhibitor and alectinib+TNKS1/2 inhibitor suppressed alectinib-induced DTP cells, and the triple combination almost completely prevented the appearance of DTP cells. In conclusion, combination with ALK-TKI, pan-HER and TNKS1/2 inhibitors has the potential to prevent the emergence of DTP in ALK + NSCLC.

Abstract Background Extracorporeal membrane oxygenation (ECMO) might be required as a treatment option in patients with critical pulmonary embolism (PE). However, the clinical features and outcomes of the use of ECMO for critical acute PE are still limited. The present study aimed to clarify the clinical characteristics, management strategies and outcomes of patients with acute PE requiring ECMO in the current era using data from a large-scale observational database. Methods We analyzed the data of the COMMAND VTE Registry-2: a physician-initiated, multicenter, retrospective cohort study enrolling consecutive patients with acute symptomatic venous thromboembolism (VTE). Among 2035 patients with acute symptomatic PE, there were 76 patients (3.7%) requiring ECMO. Results Overall, the mean age was 58.4 years, and 34 patients (44.7%) were men. Cardiac arrest or circulatory collapse at diagnosis was reported in 67 patients (88.2%). The 30-day incidence of all-cause death was 30.3%, which were all PE-related deaths. The 30-day incidence of major bleeding was 54.0%, and the vast majority of bleedings were procedure site-related bleeding events and surgery-related bleeding (22.4%). The 30-day incidence of all-cause death was 6.3% in 16 patients with surgical intervention, 43.8% in 16 patients with catheter intervention, 25.0% in 16 patients with thrombolytic therapy, and 39.3% in 28 patients with anticoagulation only. Conclusions The current large real-world VTE registry in Japan revealed clinical features and outcomes of critical acute PE requiring ECMO in the current era, which suggested several unmet needs for future clinical trials.

Abstract Background Repeated inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently approved in Japan as a treatment for autoimmune pulmonary alveolar proteinosis. However, the detailed physiological and pathological effects of repeated inhalation in the long term, especially at increasing doses, remain unclear. Methods In this chronic safety study, we administered 24 cynomolgus monkeys (Macaca fascicularis) aged 2–3 years with aerosolized sargramostim (a yeast-derived recombinant human GM-CSF [rhGM-CSF]) biweekly for 26 weeks across four dosing groups (0, 5, 100, and 500 µg/kg/day). We measured the serum GM-CSF antibody (GM-Ab) concentration by an ELISA and assessed the neutralizing capacity of GM-Ab using the GM-CSF-dependent cell line TF-1. We subjected lung tissue samples taken from all monkeys at 27 weeks to histopathological assessment using a sargramostim-specific monoclonal antibody to detect localization of residual sargramostim. Results All the animals maintained good body condition and showed steady weight gain throughout the study. The pathological analyses of the lung revealed the formation of induced bronchus-associated lymphoid tissue (iBALT) in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day. There was a relationship between the number or size of BALT and sargramostim dose or the serum GM-Ab levels. Immunohistochemical analyses revealed GM-Ab–producing cells in the follicular region of iBALT, with residual sargramostim in the follicles. Leucocyte counts were inversely correlated with GM-Ab levels in the high-dose groups. Additionally, serum GM-Ab from the treated animals significantly suppressed the alveolar macrophage proliferation activity of both Cynomolgus recombinant and rhGM-CSF in vitro. Conclusion Long-term repeated inhalation of sargramostim led to iBALT formation in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day, with the extent of iBALT formation increasing in a dose-dependent manner. Inhaled sargramostim was localized to the follicular region of iBALT nodules, which may induce the production of GM-Ab.

Abstract Introduction To diagnose sinusoidal obstruction syndrome/veno‐occlusive disease (SOS/VOD), transabdominal ultrasonography is usually used to detect hemodynamic changes, but we tried to detect the changes using four‐dimensional computed tomography (4D‐CT). A 42‐year‐old Japanese woman was diagnosed with late‐onset SOS/VOD with transabdominal ultrasonography and was also assessed using 4D‐CT. Method We analyzed the portal vein (PV) contrast effect every 1.5 seconds and plotted the values of the contrast effect. With this graph, we analyzed three hemodynamic parameters. Result We found that these parameters correlated with the patient's status and indicated stasis due to sinusoid constriction. Conclusion 4D‐CT may become a helpful tool to diagnose and follow up with SOS/VOD.

Abstract Aims In recent years, there has been remarkable development in machine learning (ML) models, showing a trend towards high prediction performance. ML models with high prediction performance often become structurally complex and are frequently perceived as black boxes, hindering intuitive interpretation of the prediction results. We aimed to develop ML models with high prediction performance, interpretability, and superior risk stratification to predict in‐hospital mortality and worsening heart failure (WHF) in patients with acute heart failure (AHF). Methods and results Based on the Kyoto Congestive Heart Failure registry, which enrolled 4056 patients with AHF, we developed prediction models for in‐hospital mortality and WHF using information obtained on the first day of admission (demographics, physical examination, blood test results, etc.). After excluding 16 patients who died on the first or second day of admission, the original dataset (n = 4040) was split 4:1 into training (n = 3232) and test datasets (n = 808). Based on the training dataset, we developed three types of prediction models: (i) the classification and regression trees (CART) model; (ii) the random forest (RF) model; and (iii) the extreme gradient boosting (XGBoost) model. The performance of each model was evaluated using the test dataset, based on metrics including sensitivity, specificity, area under the receiver operating characteristic curve (AUC), Brier score, and calibration slope. For the complex structure of the XGBoost model, we performed SHapley Additive exPlanations (SHAP) analysis, classifying patients into interpretable clusters. In the original dataset, the proportion of females was 44.8% (1809/4040), and the average age was 77.9 ± 12.0. The in‐hospital mortality rate was 6.3% (255/4040) and the WHF rate was 22.3% (900/4040) in the total study population. In the in‐hospital mortality prediction, the AUC for the XGBoost model was 0.816 [95% confidence interval (CI): 0.815–0.818], surpassing the AUC values for the CART model (0.683, 95% CI: 0.680–0.685) and the RF model (0.755, 95% CI: 0.753–0.757). Similarly, in the WHF prediction, the AUC for the XGBoost model was 0.766 (95% CI: 0.765–0.768), outperforming the AUC values for the CART model (0.688, 95% CI: 0.686–0.689) and the RF model (0.713, 95% CI: 0.711–0.714). In the XGBoost model, interpretable clusters were formed, and the rates of in‐hospital mortality and WHF were similar among each cluster in both the training and test datasets. Conclusions The XGBoost models with SHAP analysis provide high prediction performance, interpretability, and reproducible risk stratification for in‐hospital mortality and WHF for patients with AHF.

Abstract The eyes play a special role in human communications. Previous psychological studies have reported reflexive attention orienting in response to another individual’s eyes during live interactions. Although robots are expected to collaborate with humans in various social situations, it remains unclear whether robot eyes have the potential to trigger attention orienting similarly to human eyes, specifically based on mental attribution. We investigated this issue in a series of experiments using a live gaze-cueing paradigm with an android. In Experiment 1, the non-predictive cue was the eyes and head of an android placed in front of human participants. Light-emitting diodes in the periphery served as target signals. The reaction times (RTs) required to localize the valid cued targets were faster than those for invalid cued targets for both types of cues. In Experiment 2, the gaze direction of the android eyes changed before the peripheral target lights appeared with or without barriers that made the targets non-visible, such that the android did not attend to them. The RTs were faster for validly cued targets only when there were no barriers. In Experiment 3, the targets were changed from lights to sounds, which the android could attend to even in the presence of barriers. The RTs to the target sounds were faster with valid cues, irrespective of the presence of barriers. These results suggest that android eyes may automatically induce attention orienting in humans based on mental state attribution.

Tham T Le,1 David B Price,2– 4 Clement Erhard,5 Bill Cook,6 Anna Quinton,7 Rohit Katial,8 George C Christoff,9 Luis Perez-de-Llano,10 Alan Altraja,11,12 Celine Bergeron,13 Arnaud Bourdin,14 Mariko Siyue Koh,15,16 Lauri Lehtimäki,17,18 Bassam Mahboub,19 Nikolaos G Papadopoulos,20,21 Paul Pfeffer,22,23 Chin Kook Rhee,24 Victoria Carter,2,3 Neil Martin,25,26 Trung N Tran1 On behalf of the EVEREST Study Working Group1BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 2Observational and Pragmatic Research Institute, Singapore; 3Optimum Patient Care Global, Cambridge, UK; 4Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 5BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK; 6Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 7BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; 8Global Medical Respiratory, BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 9Faculty of Public Health, Medical University Sofia, Sofia, Bulgaria; 10Department of Respiratory Medicine, University Hospital Lucus Augusti, Lugo, Spain; 11Department of Pulmonology, University of Tartu, Tartu, Estonia; 12Lung Clinic, Tartu University Hospital, Tartu, Estonia; 13Centre for Lung Health, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada; 14PhyMedExp, University of Montpellier, CNRS, INSERM, University Hospital of Montpellier, Montpellier, France; 15Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore; 16Duke-NUS Medical School, Singapore; 17Allergy Centre, Tampere University Hospital, Tampere, Finland; 18Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; 19Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates; 20Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK; 21Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece; 22Department of Respiratory Medicine, Barts Health NHS Trust, London, UK; 23Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 24Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, South Korea; 25Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK; 26University of Leicester, Leicester, UKCorrespondence: Trung N Tran, BioPharmaceuticals Medical, Respiratory and Immunology, AstraZeneca, Gaithersburg, MD, USA, Email trung.tran1@astrazeneca.comIntroduction: Patients with severe asthma may be prescribed biologic therapies to improve disease control. The EVEREST study aimed to characterize the global disease burden of patients with severe asthma without access to biologics and those who have access but do not receive biologics, as well as the remaining unmet need despite use of these therapies.Methods: This was a historical cohort study of patients with severe asthma (aged ≥ 18 years) in the International Severe Asthma Registry receiving Global Initiative for Asthma (GINA) 2018 step 5 treatment, or with uncontrolled disease at GINA step 4. Prospective data on patient clinical characteristics, healthcare resource utilization, and medication use over a 12-month period between December 2017 and May 2022 were assessed for the following five groups: biologics accessible (omalizumab, mepolizumab, reslizumab, benralizumab, or dupilumab); biologics inaccessible; biologics accessible but not received; biologics accessible and received; and biologic recipients whose asthma remained suboptimally controlled.Results: Overall, 9587 patients from 21 countries were included. Among patients in the biologics accessible (n=5073), biologics inaccessible (n=3041), and biologics accessible but not received (n=382) groups, 41.4%, 18.7%, and 49.6% experienced at least two exacerbations, 11.5%, 10.5%, and 6.2% required at least one hospitalization, 47.9%, 54.6%, and 71.2% had uncontrolled asthma, and 23.9%, 8.6%, and 11.0% received long-term oral corticosteroids (LTOCS), respectively. Following biologic therapy, among patients who received biologics overall (n=2666) and among those whose asthma remained suboptimally controlled (n=1780), 19.1% and 23.0% experienced at least two exacerbations, 2.7% and 2.9% required at least one hospitalization, and 16.7% and 22.0% received LTOCS, respectively.Conclusion: There is a substantial disease burden in both patients without access to biologics and those with access who do not receive these therapies, although specific outcomes may vary between these groups. There also remains a high unmet need among biologic recipients, many of whom have a suboptimal response to treatment.Keywords: biologic, disease burden, healthcare resource utilization, severe asthma

Baharudin Abdullah,1 Kar Chai Koh,2 Mohazmi Mohamed,3 Vincent Eng Soon Tan,4 Nurashikin Mohammad,5 Zamberi Sekawi,6 Petrick Periyasamy,7 Anitha Ramadas,8 Martin Duerden9 1School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia; 2Kepong Baru Polyclinic, Kuala Lumpur, Malaysia; 3Department of Primary Care Medicine, Universiti Malaya Medical Centre, Kuala Lumpur, Malaysia; 4KPJ Klang Specialist Centre, Klang, Selangor, Malaysia; 5KPJ Ampang Puteri Specialist Hospital, Selangor, Malaysia; 6Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; 7Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia; 8Department of Pharmacy, Hospital Kuala Lumpur, Ministry of Health, Kuala Lumpur, Malaysia; 9Centre for Medical Education, Cardiff University, Cardiff, UKCorrespondence: Baharudin Abdullah, Department of Otorhinolaryngology – Head and Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, 16150, Malaysia, Tel +6097676416, Email profbaha@gmail.comIntroduction: Using antibiotics in the treatment of acute sore throats has been linked with antimicrobial resistance (AMR) and needs to be addressed. The consensus sought to improve diagnostic accuracy, decrease unwarranted antibiotic prescriptions and enhance patient outcomes.Methods: A multidisciplinary panel of nine experts reviewed published literature and discussed current practices in managing sore throat. Ten evidence-based statements on sore throat and AMR, diagnostic accuracy and antibiotic prescribing, and symptomatic therapy were developed. A modified Delphi exercise was then carried out. A consensus was reached if at least 70% of the group agreed with the statement.Results: All 10 statements for managing acute sore throat achieved consensus. The major concern of AMR caused by improper antibiotic prescribing, particularly in cases of viral sore throat, was recognized. This underscores the need for improved diagnostic tools, such as the McIsaac score, to reduce needless antibiotic prescriptions. To improve patient satisfaction, effective pain management using non-antibiotic alternatives such as paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), and flurbiprofen throat lozenges was recommended. Pain and inflammation can be adequately managed with low-dose NSAIDs. The potential benefits of topical NSAIDs were acknowledged for their milder safety profile than oral formulations.Conclusion: A consensus was achieved on the use of a clinical diagnostic tool, prudent use of antibiotics, and symptomatic therapy in acute sore throat management. The McIsaac score and point-of-care testing (POCT) for the presence of group A beta-hemolytic Streptococcus (GABHS) can aid in the decision-making process for antibiotic use, reducing needless prescriptions. The mainstay of therapy is symptomatic treatment, which includes the use of NSAIDs.Keywords: antibiotic, antimicrobial resistance, diagnosis, sore throat, symptomatic treatment

Seafood by-products from various organisms like fish, shellfish, squids, and bivalves are often thrown away as waste, even though they could be utilized in creating new types of valuable foods. Up to 75% of the entire organism consists of industrial processing wastes, which can lead to a loss of profit and ecological sustainability if natural resources are not recycled efficiently. Various types of fish parts and byproducts, such as heads, viscera, skin, bones, scales, exoskeletons, pens, ink, and clam shells, can be categorized as valuable waste based on their weight percentages, which vary depending on the species and taxonomy. This review paper delves into the extraction and valorization strategies of seafood by-products, with a focus on transforming waste into valuable resources. Marine by-products can provide bioactive substances such as collagen, peptides, polyunsaturated fatty acids, antioxidants, chitin, and catalysts for biodiesel production. This review highlights the utilization of innovative techniques like microwave- and ultrasound-assisted extraction as well as supercritical fluid extraction and subcritical water extraction to extract bioactive compounds from seafood waste efficiently. This section also discusses the optimization of extraction processes to enhance efficiency and yield. Furthermore, the paper explores the potential applications of seafood by-products across various industries, emphasizing sustainable resource utilization and the creation of high-value products to be applied in our current circular economy.

Abstract Background We aim to determine the multiethnic patterns of the prevalence and associated factors of poor muscle health and its associated components in older Chinese, Malays, and Indian Asian adults. Methods We included 2199 participants (mean age ± SD: 72.9 ± 8.3 years; 54.3% female) from the baseline assessment of the Population Health and Eye Disease Profile in Elderly Singaporeans (PIONEER; 2017–2022) cohort study. Poor muscle health was defined as the presence of either low muscle mass (DEXA), or low muscle strength (handgrip strength), or low physical performance (gait speed). Its components include poor muscle function (low muscle strength and/or low physical performance without low muscle mass), pre‐sarcopenia (low muscle mass only), and any sarcopenia (low muscle mass with low muscle strength and/or low physical performance). Sociodemographic, clinical, and lifestyle factors were assessed using biochemistry, clinical tests, and validated questionnaires. Regression models were utilized to evaluate the independent risk factors of poor muscle health and its components. Results The national census‐adjusted prevalence of poor muscle health (88%) was similar across the three ethnic groups. However, Chinese individuals had higher prevalence of pre‐sarcopenia and any sarcopenia, and a lower prevalence of poor muscle function compared with Indians or Malays. We observed ethnic differences in modifiable risk factors (low physical activity, diabetes, osteoporosis, and obesity) of poor muscle health and its components. Although obesity was protective of pre‐sarcopenia (RRR = 0.19, 95% CI: 0.11, 0.36) and any sarcopenia (RRR = 0.29, 95% CI: 0.18, 0.47) in the overall population and across ethnic groups, it was associated with 1.7 times (95% CI: 1.07, 2.67) the likelihood of poor muscle function in the entire population. Conclusions Almost 90% of community dwelling Singaporean aged ≥60 years have poor muscle health across the three ethnic groups with ethnic disparities in modifiable risk factors, highlighting an urgent need for community‐wide targeted interventions to promote muscle health.

Abstract Information about the concordance between dynamic emotional experiences and objective signals is practically useful. Previous studies have shown that valence dynamics can be estimated by recording electrical activity from the muscles in the brows and cheeks. However, whether facial actions based on video data and analyzed without electrodes can be used for sensing emotion dynamics remains unknown. We investigated this issue by recording video of participants’ faces and obtaining dynamic valence and arousal ratings while they observed emotional films. Action units (AUs) 04 (i.e., brow lowering) and 12 (i.e., lip-corner pulling), detected through an automated analysis of the video data, were negatively and positively correlated with dynamic ratings of subjective valence, respectively. Several other AUs were also correlated with dynamic valence or arousal ratings. Random forest regression modeling, interpreted using the SHapley Additive exPlanation tool, revealed non-linear associations between the AUs and dynamic ratings of valence or arousal. These results suggest that an automated analysis of facial expression video data can be used to estimate dynamic emotional states, which could be applied in various fields including mental health diagnosis, security monitoring, and education.

Aim: The PREDICT tool is used to estimate survival in breast cancer patients according to the types of treatment given. This study aimed to assess the accuracy of the PREDICT tool and identify the prognostic factors for survival in patients with breast cancer.Material and Methods: A retrospective study was performed based on data collected from the Hospital Sultanah Nur Zahirah, Terengganu, Malaysia. All female patients diagnosed with stage I to IV breast cancer were identified from the year 2011 to 2017.Results: Based on data from 355 eligible patients, the predicted and observed 5-year overall survival rates were 75.8% and 75.2%, respectively. The model performed fairly well, with the area under the curve (AUC) of 0.747 (95% confidence interval (CI): 0.69-0.81) in the predicted 5-year overall survival. Among the 585 patients diagnosed with stage I to IV breast cancer, stage at the presentation (stage III hazard ratio (HR): 5.80, 95% CI: 1.69-19.94, p=0.005, stage IV HR: 10.61, 95% CI: 3.09-36.49, p

Hypecoum erectum L., a widespread species in northern Eurasia, is a valuable medicinal plant, but its chloroplast genome has not previously been reported. We determined its complete chloroplast genome using a high-throughput sequencing technique. Its total length was 169,241 bp, consisting of a large single-copy region of 93,301 bp and a small single-copy region of 17,316 bp, separated by a pair of inverted repeat regions of 29,312 bp. A total of 140 genes were annotated, including 91 protein coding genes, 41 tRNA genes, and eight rRNA genes. The phylogenetic analysis shows that H. erectum and H. zhukanum of the subfamily Hypecoideae are monophyletic with the highest support.

Elevated Fulminant Index (FI), [plasma glucose (PG)/glycosylated hemoglobin A1c (HbA1c)], was reportedly a sensitive index to differentiate fulminant type 1 diabetes (FT1D) from non-fulminant T1D (nFT1D). Aim of this study was to describe a better, but simpler index of FT1D. 49 and 52 patients with FT1D and nFT1D, respectively, were registered, and the discriminating ability of the rounded, normalized ratio, [PG (mmol/L) – 5.0]/[HbA1c (%) – 5.0], and the original ratio, [PG (mmol/L)]/[HbA1c (%)], was compared. Normalizing the ratio significantly raised its accuracy: area under the curve for receiver operating curve, AUROC (95%CI), 0.927 (0.858–0.964) and 0.851 (0.763–0.910), respectively, with and without the normalization (p < 0.01). Rounding of the figure into [PG (mmol/L) – 5.0]/[HbA1c (%) – 5.0] did not significantly sacrifice the discriminating ability of the index. Namely, the optimal cut point of rounded and normalized GAR, 10.0, showed 89.8% sensitivity. In conclusion, rounded, normalized (rn) GAR ≥10 (the rounded optimal cut-off) could be used for the snap diagnosis of FT1D.

C26H21BrN2O4, triclinic, P1̄ (no. 2), a = 9.061(3) Å, b = 11.640(3) Å, c = 12.751(3) Å, α = 65.985(7)°, β = 87.683(8)°, γ = 72.332(12)°, V = 1165.1(5) Å3, Z = 2, R gt(F) = 0.0351, wR ref(F 2) = 0.0873, T = 296(2) K.

Purpose: To compare the usefulness of microperimetry and static automated perimetry in patients with retinitis pigmentosa (RP), using macular anatomical metrics as a reference. Design: Prospective observational study. Participants: Forty-eight eyes of 48 patients with RP in Kyushu University Hospital who underwent microperimetry-3 (MP-3) and Humphrey Field Analyzer (HFA) 10-2 testing ≥3 times during ≥2 years were included. Methods: Macular anatomy (ellipsoid zone [EZ] length) was assessed by OCT, and macular function was assessed by MP-3 (mean retinal sensitivity at radii 2°, 4°, and 8°) and HFA10-2 program (mean retinal sensitivity at radii 2°, 4°, and 8°). Correlations between functional and anatomical parameters were analyzed cross sectionally at baseline and longitudinally by comparing the rate of progression. Main Outcome Measures: Correlation coefficients between anatomical and functional metrics. Results: The mean age at baseline was 50.1 ± 12.3 years, and the mean follow-up period was 2.8 ± 0.7 years. At baseline, EZ length was significantly correlated with MP-3 mean retinal sensitivity at radii 2°, 4°, and 8° (Spearman’s ρ = 0.65, 0.84, 0.89; all P

AIM: To develop a statistical model to diagnose influenza in international travelers using data on symptoms and the number of influenza cases in each country. BACKGROUND: The importation of infectious diseases has increased dramatically in recent years. Diagnosis of infectious diseases is traditionally based on symptoms and blood and biochemical tests. Although it is known that cases of influenza are common throughout the year in tropical and subtropical regions, and that cases are also common among travelers from these regions, the number of infected cases in each country has not been fully utilized for diagnosis. METHODS: This study included cases registered in the Japan Registry for Infectious Diseases from Abroad (https://jrida-jprecor.ncgm.go.jp/en/j-rida/index.html) with influenza test results and information on travel destination and duration. Multivariate logistic regression was used for the diagnostic model, and the explanatory variables were symptoms and the infection probability score calculated from information on the number of cases in each country and the incubation period. RESULTS: Analysis showed significant differences in sore throat (p

Objectives: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study.Methods: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma.Results: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n = 8; essential thrombocythemia, n = 14; and primary myelofibrosis, n = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed (n = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy.Conclusion: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

Lysosome-associated membrane protein-2 (LAMP2) deficiency causes the human Danon disease and represents a lysosomal dysfunction because of its pivotal role in regulating autophagy and lysosome biogenesis. LAMP2-deficient mice exhibit a spectrum of phenotypes, including cardioskeletal myopathy, mental retardation, and retinopathy, similar to those observed in patients with Danon disease. Its pathology is thought to involve altered energy metabolism and lipid dysregulation; however, the lipidomic profiles of LAMP2-deficient animals have not been investigated. In this study, we investigated lipid alterations in LAMP2 KO mice tissues, including those of the liver, plasma, and retina, using liquid chromatography-mass spectrometry. Our results revealed significantly increased free fatty acid (FFA) levels and decreased in triglyceride (TG) levels in LAMP2 KO liver tissues at three and six months. Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species significantly decreased in LAMP2 KO mice livers at six months. Similarly, plasma TG and PC/PE levels decreased in LAMP2 KO mice. In contrast, plasma FFA levels were significantly lower in LAMP2 KO mice. Retina FFA levels were elevated in LAMP2 KO mice, accompanied by a partial decrease in PC/PE at six months. In summary, FFA levels increased in several tissues but not in the LAMP2 KO mice plasma, suggesting the potential consumption of FFA as an energy source in the peripheral tissues. The depletion of TG and PC/PE accelerated with age, suggesting an underlying age-dependent energy crisis condition. Our findings underscore the dysregulated distribution of fatty acids in LAMP2-deficient animals and provide new mechanistic insights into the pathology of Danon disease.

In the study of PAM (McKibben-type pneumatic artificial muscle)-driven bipedal robots, it is essential to investigate whether the intrinsic properties of the PAM contribute to achieving stable robot motion. Furthermore, it is crucial to determine if this contribution can be achieved through the interaction between the robot’s mechanical structure and the PAM. In previous research, a PAM-driven bipedal musculoskeletal robot was designed based on the principles of the spring-loaded inverted pendulum (SLIP) model. The robot features low leg inertia and concentrated mass near the hip joint. However, it is important to note that for this robot, only the design principles were based on the SLIP model, and no specialized controller was specifically designed based on the model. To address this issue, based on the characteristics of the developed robot, a PAM controller designed also based on the SLIP model is developed in this study. This model-based controller regulates ankle flexion PAM to adjust the direction of the ground reaction force during robot walking motion. The results indicate that the proposed controller effectively directs the leg ground reaction force towards the center of mass during walking.

ABSTRACT Ventricular assist device (VAD) infections are frequent causes of hospital readmission. The risk factors and optimal preventive strategies for such, including chronic suppressive antibiotics (CSA), remain uncertain. We performed a single-center, retrospective, observational cohort study assessing continuous flow VAD recipients who underwent implantation between 2008 and 2018 in Japan. From primary VAD infection (VADI), we followed the patients for recurrent infection, defined as relapsing VAD-specific (e.g., localized infections) or VAD-related (e.g., bacteremia) infections requiring hospital readmission. CSA was defined as the use of oral antimicrobial agents continued beyond initial antibiotic use until transplantation, VAD withdrawal, VADI recurrence, or death. Survival analysis was performed to identify risk factors for recurrent infection accounting for competing risks (e.g., deaths and transplants). Among 163 eligible patients, 76 patients had VADIs. The main causative organism in primary VADI was Staphylococcus aureus (63%, 48/76). Among them, 41 had recurrent infections, whereas 35 had none during the follow-up period (median, 335 days). Thirty-six patients received CSA for a median of 478 days. Although CSA was associated with a decreased risk of recurrent infection [adjusted sub-distribution hazard ratio (SHR), 0.40; 95% confidence interval (CI), 0.18–0.89; P = 0.03], this protective effect was observed only after primary VAD-specific infection (SHR, 0.28; 95% CI, 0.12–0.64; P < 0.01) but not after VAD-related infection. Surgical procedures during primary VADI were associated with an increased risk (SHR, 2.00; 95% CI, 1.10–3.66; P = 0.02). One patient had an adverse drug reaction. CSA may be an effective approach to limit relapsing VADIs following a primary VAD-specific infection with minimal adverse events.IMPORTANCEVentricular assist device infections (VADIs) are a significant complication leading to hospital readmissions. However, the risk factors and optimal preventive strategies for VADI remain unclear. This study investigated the effectiveness of chronic suppressive antibiotic therapy in patients with VADI. We found that the use of chronic suppressive antibiotic therapy was associated with a reduction in the risk of VADI recurrence with few adverse reactions. Our findings suggest the potential benefit of chronic suppressive antibiotics in preventing infections in selected cases. Our findings are relevant for the management of patients with ventricular assist devices awaiting heart transplantation, providing valuable insights for clinical practice.

Background The impact of high‐risk coronary artery plaques identified using optical coherence tomography on late luminal narrowing and clinical events remains poorly understood. Methods and Results This multicenter prospective study included 176 patients who underwent percutaneous coronary intervention and serial optical coherence tomography at baseline and 1‐year follow‐up to investigate nontarget regions with angiographically intermediate stenosis. At 1 year after percutaneous coronary intervention, the coronary artery lumen area decreased significantly from 6.06 (95% CI, 5.60–6.53) mm2 to 5.88 (95% CI, 5.41–6.35) mm2 (difference, −0.18; 95% CI, −0.22 to −0.14 mm2; P

Abstract We investigated the association of retinopathy with the risk of dementia in a general older Japanese population. A total of 1709 population-based residents aged 60 years or older without dementia were followed prospectively for 10 years (2007–2017). They underwent color fundus photography in 2007. Retinopathy was graded according to the Modified Airlie House Classification. Main outcome was the Incidence of dementia. A Cox proportional hazards model was used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) for the risk of dementia by the presence of retinopathy. During the follow-up period, 374 participants developed all-cause dementia. The cumulative incidence of dementia was significantly higher in those with retinopathy than those without (p

Premature ventricular contraction (PVC) is usually eliminated in the earliest activation site based on the conventional electrode of ablation catheter. However, the large size electrode may contain far-field potential. The QDOT MICRO ablation catheter has three micro electrodes with 0.33 mm electrode length, in addition to the conventional electrode with 3.5 mm electrode length. The micro electrodes can reflect only near-field potential.A 78-year-old with symptomatic frequent PVCs underwent catheter ablation. PVC-1 showed good pace-mapping in distal great cardiac vein (GCV). The local bipolar electrograms in the conventional electrode of ablation catheter preceded the PVC-QRS onset by 32 ms in distal GCV and 13 ms in left coronary cusp (LCC), but those in the micro electrodes preceded only by 13 ms both in distal GCV and LCC. PVC-1 was eliminated by radiofrequency (RF) application, not in distal GCV, but in LCC. PVC-2 showed good pace-mapping in LCC. The local bipolar electrograms in both the conventional electrode and the micro electrodes of ablation catheter preceded the PVC-QRS onset by 32 ms in LCC. PVC-2 was eliminated by RF application in LCC.Comparing the local electrograms of micro electrodes and the conventional electrodes may be important for identifying depth of the origin of PVCs.

Influenza causes significant healthcare burden globally1 with highest risks in children and the elderly. In children, multiple studies have identified risk factors for severe influenza such as young age (

Abstract Background Lipoprotein glomerulopathy (LPG) is a apolipoprotein E (ApoE)-related glomerular disease and has been associated with type III hyperlipidemia. Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1–27 years of disease onset. However, few studies have highlighted the clinical course of cardiovascular diseases (CVDs) in patients with LPG. Herein, we report the first case of LPG in which the CVD risk was assessed using arterial stiffness. Case presentation A 32-year-old Japanese man was referred to our hospital due to persistent proteinuria. Kidney biopsy showed markedly dilated capillary lumens containing pale-stained thrombi, which stained positively with Oil Red O. Electron microscopy revealed the presence of thrombi in the capillary lumen with low electron density and vacuoles of various sizes in part of the thrombi. Toluidine blue and Sudan IV stains were used to stain the thin sections of Epon-embedded tissue samples for electron microscopy. Sudan IV-positive droplets were observed in the capillary lumens, vascular walls, and cytoplasm of tubular cells. Increased serum ApoE concentration was observed. Liquid chromatography-tandem mass spectrometry of laser-microdissected glomeruli from paraffin sections revealed an increase in ApoE. Direct deoxyribonucleic acid sequencing of ApoE revealed a heterozygous ApoE Sendai mutation (Arg145Pro). The patient was finally diagnosed with LPG with heterozygosity for ApoE-Sendai mutation (Arg145Pro). Notably, at the time of diagnosis, he had markedly increased arterial stiffness for his age. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV), which was equivalent to that of a 56-year-old man. After three months of treatment with fenofibrate and losartan, a significant reduction in proteinuria was achieved along with an improvement in baPWV. Furthermore, these effects were maintained despite the lack of decrease in serum ApoE levels. Conclusion Herein, we report the case of a patient with LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved proteinuria and arterial stiffness. To the best of our knowledge, this is the first case report of LPG in which CVD risk was assessed using arterial stiffness.

Cabozantinib, a multiple tyrosine kinase inhibitor targeting AXL, vascular endothelial growth factor receptor (VEGFR), and MET, is used clinically to treat certain cancers, including hepatocellular carcinoma. This study aimed to assess the impact of cabozantinib on liver fibrosis and hepatocarcinogenesis in a rat model of metabolic dysfunction-associated steatohepatitis (MASH). MASH-based liver fibrosis and hepatocarcinogenesis were induced in rats by feeding them a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for eight and 16 weeks, respectively. Cabozantinib (1 or 2 mg/kg, daily) was administered concurrently with the diet in the fibrosis model and after eight weeks in the carcinogenesis model. Treatment with cabozantinib significantly attenuated hepatic inflammation and fibrosis without affecting hepatocyte steatosis and ballooning in CDAHFD-fed rats. Cabozantinib-treated rats exhibited a marked reduction in α-smooth muscle actin+ activated hepatic stellate cell (HSC) expansion, CD68+ macrophage infiltration, and CD34+ pathological angiogenesis, along with reduced hepatic AXL, VEGF, and VEGFR2 expression. Consistently, cabozantinib downregulated the hepatic expression of profibrogenic markers (Acta2, Col1a1, Tgfb1), inflammatory cytokines (Tnfa, Il1b, Il6), and proangiogenic markers (Vegfa, Vwf, Ang2). In a cell-based assay of human activated HSCs, cabozantinib inhibited Akt activation induced by GAS6, a ligand of AXL, leading to reduced cell proliferation and profibrogenic activity. Cabozantinib also suppressed lipopolysaccharide-induced proinflammatory responses in human macrophages, VEGFA-induced collagen expression and proliferation in activated HSCs, and VEGFA-stimulated proliferation in vascular endothelial cells. Meanwhile, administration of cabozantinib did not affect Ki67+ hepatocyte proliferation or serum albumin levels, indicating no negative impact on regenerative capacity. Treatment with cabozantinib also reduced the placental glutathione transferase+ preneoplastic lesions in CDAHFD-fed rats. In conclusion, cabozantinib shows promise as a novel option for preventing MASH progression.

Background The simplified Pulmonary Embolism Severity Index (sPESI) score could help identify low‐risk patients with pulmonary embolism for home treatment. However, the application of the sPESI score and selection for home treatment have not been fully evaluated in the direct oral anticoagulants era. Methods and Results The COMMAND VTE (Contemporary Management and Outcomes in Patients With Venous Thromboembolism) Registry‐2 is a multicenter registry enrolling consecutive patients with acute symptomatic venous thromboembolism. The current study population consists of 2496 patients with hemodynamically stable pulmonary embolism (2100 patients [84%] treated with direct oral anticoagulants), who were divided into 2 groups: sPESI scores of 0 and ≥1. We investigated the 30‐day mortality, home treatment prevalence, and factors predisposing to home treatment using the Kaplan‐Meier method and logistic regression model. Patients with an sPESI score of 0 accounted for 612 (25%) patients, and only 17% among 532 patients with out‐of‐hospital pulmonary embolism were treated at home. The cumulative 30‐day mortality was lower in patients with an sPESI score of 0 than the score of ≥1 (0% and 4.8%, log‐rank P

IntroductionIn Japan, the importance of medical checkups for pet dogs is increasing. In this study, we retrospectively explored the effects of age on plasma biomarkers in healthy small dogs that underwent medical checkups.MethodsBased on the modified American Animal Hospital Association Canine Life Stage Guidelines, 52 healthy small dogs were divided into 3 groups according to their life stage: young adult (1–4 years old), mature adult (5–11 years old), senior (12–15 years old). None of the dogs were obese. Plasma was collected from animals that underwent medical checkups at Muromi Animal Hospital (Fukuoka, Japan). Plasma glucose, triglyceride (TG), total protein, blood urea nitrogen (BUN), creatinine, total cholesterol, and albumin concentrations; alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase (ALP) activities; c-reactive protein (CRP), non-esterified fatty acid, malondialdehyde (MDA), serum amyloid A (SAA), insulin, and adiponectin (ADN) concentrations; glutathione peroxidase (GPx), superoxide dismutase (SOD), malate dehydrogenase (MDH), and lactate dehydrogenase (LDH) activities; and M/L ratio (MDH/LDH) were examined. Changes in the abovementioned plasma biomarker levels were compared between canines in different life stages.ResultsPlasma ADN concentrations and GPx, SOD, and MDH activities significantly decreased with age, whereas plasma ALP, BUN, TG, and MDA concentrations gradually increased. Plasma SAA levels measured by the latex agglutination method in 51 of the 52 small dogs that underwent medical checkups were below the detection limit.ConclusionPlasma ADN concentrations, GPx, SOD activity, and BUN levels may be important biomarkers for clarifying the effect of age in healthy dogs that undergo medical checkups. However, plasma SAA values obtained by the latex agglutination method were not considered an age-related inflammation marker for healthy dogs.

Introduction Caregivers of patients with end-stage kidney disease (ESKD) face significant challenges that contribute to caregiver burden, negatively impacting their psychosocial well-being. Virtual-reality (VR)-guided mindfulness interventions have shown promise in reducing stress, anxiety and depression in various populations.Methods and analysis This pilot study aims to evaluate the efficacy and feasibility of a VR-guided mindfulness intervention for ESKD caregivers. A single-centre, single-blind, parallel-group pilot randomised controlled trial will be conducted. Thirty ESKD caregivers will be randomly allocated to either the VR-guided mindfulness intervention group or the sham VR control group. The intervention group will receive a 6 week home-based VR-guided mindfulness programme, while the control group will view relaxing nature videos without mindfulness content. Participants will be assessed at baseline, post-intervention (6 weeks) and follow-up (12 weeks) using validated questionnaires for caregiver burden (Zarit Burden Interview (ZBI)), stress, anxiety, depression (Depression Anxiety Stress Scale-21 (DASS-21)), quality of life (36-Item Short Form Health Survey (SF-36)) and mindfulness (Five Facet Mindfulness Questionnaire (FFMQ)). Feasibility outcomes include accrual rates, retention, adherence, questionnaire completion and side effect rates. Semi-structured interviews will explore participants’ experiences with the intervention.Ethics and dissemination The study has been approved by the NHG Domain Specific Review Board (Reference: 2024–3940-APP1). The results of this pilot study will be reported in peer-reviewed open-access journals and shared with participants and stakeholders.Trial registration NCT06479200.

Abstract Background Despite its low sensitivity (approximately 30%), squamous cell carcinoma (SCC) antigen is commonly utilized as a serum tumor marker for oral SCC (OSCC) in clinical settings. The objective of this research was to identify novel biomarkers for OSCC. Methods Initially, we performed microarray analysis to evaluate the gene expression signatures of primary OSCC and normal oral mucosal tissues. Our findings showed the C‐X‐C motif chemokine ligand 13 (CXCL13) to be a promising novel biomarker as it was consistently overexpressed in primary OSCC tissues, a conclusion corroborated by polymerase chain reaction results. Subsequently, we measured serum CXCL13 levels in 125 patients with OSCC using a sandwich enzyme‐linked immunosorbent assay and compared the results with those of 29 healthy individuals. Results Remarkably, the levels of serum CXCL13 were consistently elevated in patients with OSCC, and the high expression of serum CXCL13 was notably associated with tumor size and neck lymph node metastasis. Patients with advanced OSCC with high‐serum CXCL13 levels exhibited poor prognosis regarding both overall and disease‐free survival. Finally, spatial transcriptome analysis revealed CXCL13 and CD8 expressions within tumor area clusters but not in adjacent normal areas, suggesting specific overexpression of CXCL13 in primary OSCC tissues. Conclusion These findings imply that serum CXCL13 holds diagnostic and prognostic value, showing promise as a novel biomarker for OSCC.

Hepatitis E virus (HEV) is a pathogen that causes hepatitis. There are few reports of HEV seroprevalence among people with human immunodeficiency virus (PWH) in Japan. This study aimed to determine the HEV seroprevalence among PWH at our hospital. Anti-HEV IgG was tested for using enzyme immunoassays and immunoblot assays. Clinical information was obtained from medical records and additional patient questionnaires. Sixty-eight PWH were included in this study. Four patients (5.9 %) showed HEV IgG seropositivity with both methods, while one patient (1.5 %) was seropositive using only the immunoblot assay, and three patients (4.4 %) were seropositive using only the enzyme immunoassay. There was a significant difference in age between anti-HEV IgG-seropositive and -negative individuals (median, 57.5 and 48.0 years, respectively; p = 0.012). There were no significant differences in the other clinical characteristics. Our results revealed that age is a risk factor for HEV infection among PWH.

Background There have been limited data on the changes in clinical outcomes after the introduction of direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) in real clinical practice. We evaluated the changes in management strategies and long‐term outcomes from the warfarin era to the DOAC era. Methods and Results We compared the 2 series of multicenter COMMAND VTE (Contemporary Management and Outcomes in Patients With Venous Thromboembolism) registries in Japan enrolling consecutive patients with acute symptomatic VTE: Registry 1: 3027 patients in the warfarin era (2010–2014) and Registry 2: 5197 patients in the DOAC era (2015–2020). The prevalence of DOAC use increased more in Registry 2 than in the Registry 1 (Registry 1: 2.6% versus Registry 2: 79%, P

Background The effects of aspirin‐free strategy on bleeding and cardiovascular events in patients undergoing percutaneous coronary intervention with oral anticoagulation (OAC) have not been fully elucidated. Methods and Results We conducted the prespecified subgroup analysis based on the use of OAC, including vitamin K antagonist and direct oral anticoagulants, within 7 days before percutaneous coronary intervention in the STOPDAPT‐3 (Short and Optimal Duration of Dual Antiplatelet Therapy‐3) trial, which randomly compared prasugrel monotherapy (2984 patients) to dual antiplatelet therapy (DAPT) with prasugrel and aspirin (2982 patients) in patients with acute coronary syndrome or high bleeding risk. The coprimary end points were major bleeding events (Bleeding Academic Research Consortium types 3 or 5) and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke) at 1 month. Among 5966 study patients, there were 530 patients (8.9%) with OAC (no aspirin: N=248, and DAPT: N=282) and 5436 patients (91.1%) without OAC (no aspirin: N=2736, and DAPT: N=2700). Regardless of the use of OAC, the effects of no aspirin compared with DAPT were not significant for the bleeding end point (OAC: 4.45% and 4.27%, hazard ratio [HR], 1.04 [95% CI, 0.46–2.35]; no‐OAC: 4.47% and 4.75%, HR, 0.94 [95% CI, 0.73–1.20]; P for interaction=0.82), and for the cardiovascular end point (OAC: 4.84% and 3.20%, HR, 1.53 [95% CI, 0.64–3.62]; no‐OAC: 4.06% and 3.74%, HR, 1.09 [95% CI 0.83–1.42]; P for interaction =0.46). Conclusions The no‐aspirin strategy compared with the DAPT strategy failed to reduce major bleeding events irrespective of the use of OAC. There was a numerical excess risk of the no‐aspirin strategy relative to the DAPT strategy for cardiovascular events in patients with OAC.

Meihui Li,1,2 Haiyan Zheng,3 Jae Chul Koh,4 Ghee Young Choe,5,6 Eun Joo Choi,1,2 Francis Sahngun Nahm,1,2 Pyung Bok Lee1,2 1Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, Korea; 2Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; 3Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Department of Anesthesiology and Pain Medicine, Korea University College of Medicine, Seoul, Korea; 5Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea; 6Department of Pathology, Seoul National University College of Medicine, Seoul, KoreaCorrespondence: Pyung Bok Lee, Email painfree@snu.ac.krObjective: To create a deep learning (DL) model that can accurately detect and classify three distinct types of rat dorsal root ganglion neurons: normal, segmental chromatolysis, and central chromatolysis. The DL model has the potential to improve the efficiency and precision of neuron classification in research related to spinal injuries and diseases.Methods: H&E slide images were divided into an internal training set (80%) and a test set (20%). The training dataset was labeled by two pathologists using pre-defined grades. Using this dataset, a two-component DL model was developed with the first component being a convolutional neural network (CNN) that was trained to detect the region of interest (ROI) and the second component being another CNN used for classification.Results: A total of 240 lumbar dorsal root ganglion (DRG) pathology slide images from rats were analyzed. The internal testing results showed an accuracy of 93.13%, and the external dataset testing demonstrated an accuracy of 93.44%.Conclusion: The DL model demonstrated a level of agreement comparable to that of pathologists in detecting and classifying normal and segmental chromatolysis neurons, although its agreement was slightly lower for central chromatolysis neurons. Significance: DL in improving the accuracy and efficiency of pathological analysis suggests that it may have a role in enhancing medical decision-making.Keywords: deep learning, dorsal root ganglion, chromatolysis, automated detection and spinal stenosis

Abstract It has been postulated that being breastfed in infancy affects not only health status in childhood but also disease risk in adulthood. To investigate the association of being breastfed with the risks of adult colorectal cancer and benign tumor, we conducted a case–control study including 1190 colorectal cancer and 1585 benign tumor cases and 5301 controls, admitted to a single hospital in Miyagi Prefecture, Japan, between 1997 and 2013. History of having been breastfed was assessed using a self-administered questionnaire, and odds ratios (ORs) were estimated using unconditional logistic regression. There was no association between being breastfed and colorectal cancer risk (breastfed versus formula-only fed, OR = 1.21; 95% CI 0.87–1.67). There was also no association with the risk of benign tumor (OR = 1.04). On the other hand, analyses stratified by sex and birth year found heterogeneous associations. Women born after 1950 who had been breastfed tended to have increased risks of colorectal cancer (OR = 1.58) and benign tumor (OR = 1.51) relative to those who had been formula-only fed, although not statistically significant. In men born after 1950, being breastfed was associated with a significantly decreased risk of benign tumor (OR = 0.57; 95% CI 0.33–0.98).

Subclavian artery aneurysms, occasionally related to connective tissue diseases, including Marfan syndrome, are rare and conventionally managed with surgery or endovascular treatment. However, in some cases, both interventions are challenging because of the inability to reach an aneurysm through a safe route or postoperative adhesion. This report describes the case of a 43-year-old patient with a left subclavian artery aneurysm and Marfan syndrome. In this case, the patient's 5 previous surgeries related to Marfan syndrome made surgery and endovascular treatment difficult. Therefore, an alternative was researched, and we decided to perform a method of percutaneous embolization with coils and N-butyl cyanoacrylate using the direct puncture technique, which succeeded in eliminating the blood flow in the left subclavian artery aneurysm. No severe complications were associated with the procedure. The patient was free from the risk of an aneurysm rupture post-treatment, and the left back pain improved. Follow-up computed tomography 2 years postsurgery revealed the aneurysm being under control without re-enlarging. Our method is considered an effective and safe therapeutic option for cases in which surgical approach and transarterial access routes are limited.