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Mucopolysaccharidosis III (MPSIII, Sanfilippo syndrome) is a devastating lysosomal storage disease that primarily affects the central nervous system. MPSIIIA is caused by loss-of-function mutations in the gene coding for sulfamidase (N-sulfoglucosamine sulfohydrolase/SGSH) resulting in SGSH enzyme deficiency, a buildup of heparin sulfate and subsequent neurodegeneration. There is currently no cure or disease modifying treatment for MPSIIIA. A mouse model for MPSIIIA was characterized in 1999 and later backcrossed onto the C57BL/6 background. In the present study, a novel immune deficient MPSIIIA mouse model (MPSIIIA-TKO) was created by backcrossing the immune competent, C57BL/6 MPSIIIA mouse to an immune deficient mouse model lacking Rag2, CD47 and Il2rg genes. The resulting mouse model has undetectable SGSH activity, exhibits histological changes consistent with MPSIIIA and lacks T cells, B cells and NK cells. This new mouse model has the potential to be extremely useful in testing human cellular therapies in an animal model as it retains the MPSIIIA disease phenotype while tolerating xenotransplantation.

Abstract In 67Ga-citrate scintigraphy (Ga-S), visual assessment is used by evaluating renal-uptake comparison with liver and spine and is simple and objective. We adopted the standardized uptake value (SUV) for 67Ga-citrate and proposed two quantitative indices, active nephritis volume (ANV) and total nephritis uptake (TNU). This study clarified the utility of new Ga-S-based quantitative indices in nephritis management. Before SUV measurement, the Becquerel calibration factor of 67Ga-citrate was obtained using a phantom experiment. Seventy patients who underwent SPECT/CT imaging were studied. SUV, ANV, and TNU were calculated using a quantitative analysis software for bone SPECT. SUVmean, ANV, and TNU were analyzed using the (1) threshold method (set 40%) and constant-value method for (2) vertebral SUVmax, and (3) vertebral SUVmean. ROC analysis was used to evaluate SUV, ANV, and TNU diagnostic abilities to distinguish nephritis presence and absence as well as interstitial nephritis (IN) and non-IN. The area under the curve (AUC) for nephritis presence or absence had a good value (0.80) for SUVmean (1), ANV (3), and TNU (3). The AUC for differentiation between IN and non-IN groups had a good value (0.80) for SUVmean (1). Thus, the new Ga-S-based quantitative indices were useful to evaluate nephritis and distinguish IN and non-IN.

Abstract Background Atezolizumab, one of the immune checkpoint inhibitors, has been approved as an adjuvant treatment following resection and platinum‐based chemotherapy in patients with stage II–IIIA non‐small cell lung cancer with 1% or more programmed death ligand‐1 (PD‐L1) expression. The Food and Drug Administration (FDA) has approved SP263 as a companion diagnostic assay for adjuvant treatment with atezolizumab; however, in clinical practice, the 22C3 assay is most commonly used for advanced non‐small cell lung cancer. Therefore, our study aimed to compare two PD‐L1 assays, SP263 and 22C3, to evaluate whether 22C3 could replace SP263 when deciding whether to administer adjuvant atezolizumab. Methods We retrospectively and prospectively analyzed 98 patients who underwent surgical resection at Kanagawa Cancer Center (Japan). An immunohistochemistry assay was performed for all the cases with both SP263 and 22C3. We statistically analyzed the concordance of PD‐L1 expression between SP263 and 22C3 assays. Results The concordance between the two assays using Cohen's kappa was κ = 0.670 (95% CI: 0.522–0.818) at the 1% cutoff and κ = 0.796 (95% CI: 0.639–0.954) at the 50% cutoff. The Spearman correlation coefficient of 0.874 (p

Abstract Lysyl oxidase-like 2 (LOXL2) mediates the crosslinking of extracellular collagen, reflecting qualitative changes in liver fibrosis. This study aimed to validate the utility of serum LOXL2 levels as a predictive biomarker for the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection who achieved a sustained virological response (SVR). This retrospective study included 137 patients with chronic HCV infection without history of HCC development and who achieved SVR via direct-acting antiviral therapy. Median LOXL2 levels decreased significantly after SVR achievement (pre-Tx, 2.33 ng/mL; post-Tx, 1.31 ng/mL, p

Background/Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) was recently proposed as an alternative disease concept to nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prognosis of patients with biopsy-confirmed MASLD using data from a multicenter study. Methods This was a sub-analysis of the Clinical Outcome Nonalcoholic Fatty Liver Disease (CLIONE) study that included 1,398 patients with NAFLD. Liver biopsy specimens were pathologically diagnosed and histologically scored using the NASH Clinical Research Network system, the FLIP algorithm, and the SAF score. Patients who met at least one cardiometabolic criterion were diagnosed with MASLD. Results Approximately 99% of cases (n=1,381) were classified as MASLD. Patients with no cardiometabolic risk (n=17) had a significantly lower BMI than patients with MASLD (20.9 kg/m2 vs. 28.0 kg/m2, P

Abstract Partial anomalous pulmonary venous return (PAPVR) is a rare congenital malformation where the pulmonary vein partially refluxes into the venous system. Here, we present the first robotic‐assisted right S3 segmentectomy in a 70‐year‐old male with early‐stage lung cancer and PAPVR in the right upper pulmonary vein. The patient, with suspected primary lung cancer (11 mm diameter, pure solid appearance in right S3 segment), exhibited clinical stage T1bN0M0 stage IA2. Preoperative computed tomography revealed severe lung emphysema, and right V1–3 returned directly to the superior vena cava. However, no signs of right‐sided heart failure were observed, and echocardiogram was normal with a pulmonary‐to‐systemic blood flow ratio of 1.4. Successful robot‐assisted right S3 segmentectomy with hilar nodal dissection was performed, and the patient was discharged on the sixth postoperative day without complications. One year postoperatively, there has been no recurrence of lung cancer or respiratory/right‐sided heart failure symptoms.

Background Phase angle, which is associated with cellular health, has attracted attention as a noninvasive and objective method for nutritional assessment. However, the association between malnutrition and phase angle in older inpatients with hip fractures has not been reported. Therefore, this study investigated this association in older inpatients (aged ≥65 years) with hip fractures and determined the cutoff phase angle for determining malnutrition. Methods This cross-sectional study retrospectively analyzed the data of 96 inpatients with hip fractures who were hospitalized in rehabilitation units after surgery (male, 29.4%; mean age, 82.4±6.2 years). Nutritional status was assessed using the Geriatric Nutritional Risk Index (GNRI), with malnutrition defined as a GNRI ≥98. Bioelectrical impedance analysis was used to measure phase angles. Results The phase angle was associated with malnutrition (B=−1.173; odds ratio=0.310; 95% confidence interval 0.58–0.83; p=0.015). The area under the receiver operating characteristic curve was 0.71. The cutoff phase angle for malnutrition was 3.96° (sensitivity=0.85, specificity=0.63). Conclusion Phase angle could be an indicator of malnutrition in older inpatients with hip fractures. Our findings will help formulate rehabilitation strategies for these patients.

A multidisciplinary Japan–UK Network identified cross-cultural and cross-national lessons for research aimed at improving the design of homes for people living with dementia. Previous research has suggested that improved, multidimensionally sustainable design may improve quality of life for people living with dementia and meet societal challenges of increasing populations of people with the condition. Adopting a social citizenship perspective, the paper argues that people living with dementia are considered equal citizens with rights to enjoy the life they choose. On this basis, research on home design must be underpinned by understanding the concept of home. The definition of good outcomes should be led by people living with dementia. Conceptualisation of costs of design innovations is complex and will involve judgements from a societal perspective. Methodologically, an ethnographic approach is desirable, underpinned by co-production. These points are suggested to inform further research. In conclusion, the paper confirms the value of cross-cultural insights.

Objectives Although systemic chemotherapy for pancreatic ductal adenocarcinoma (PDAC) has made progress, ensuring long-term survival remains difficult. There are several reports on the usefulness of neutrophil-to-lymphocyte ratio (NLR) in predicting the prognosis of PDAC, but few reports in systemic chemotherapy. We hereby investigated the usefulness of NLR in systemic chemotherapy for PDAC.Materials and methods A retrospective study was conducted on patients with advanced PDAC treated with first-line systemic chemotherapy. Cox regression hazards models were performed to analyze the association between baseline patient characteristics and the initial treatment response, and overall survival (OS).Results A total of 60 patients with PDAC were enrolled. At baseline, there were significant differences in NLR and carbohydrate antigen 19-9 (CA19-9), as well as the selection rate of combination chemotherapy, between patients with partial response or stable disease and those with progressive disease. Univariate and multivariate analysis showed that NLR < 3.10, combination chemotherapy, and CA19-9

Abstract Background Segmentectomy is considered a less invasive procedure than lobectomy for patients with non‐small cell lung cancer (NSCLC); however, little is known about the physiological mechanism underlying the lower invasiveness of segmentectomy. This study is aimed to compare the differences in the long‐term changes in the psoas muscle mass after segmentectomy and lobectomy in patients with NSCLC. Methods Overall 315 recurrence‐free patients who underwent segmentectomy (n = 93) or lobectomy (n = 222) for clinical stage 0‐I NSCLC between January 2016 and December 2018 and underwent computed tomography during the entire period of 6 months ≤ postoperative year (POY) 0.5

Chronic obstructive pulmonary disease (COPD) and periodontal disease are chronic inflammatory conditions that significantly affect an individual’s overall health and well-being. Generally, the prevalence of periodontitis is higher in patients with COPD than those without COPD, which may partly be attributed to common risk factors in COPD, such as smoking, respiratory infections, and inflammation. In particular, periodontitis may exacerbate the progression of COPD and further deteriorate the respiratory system by promoting inflammatory responses and bacterial infections. Immunocytes, including neutrophils, and microorganisms such as Fusobacterium nucleatum originating from oral biofilms are believed to be crucial factors influencing to COPD. Furthermore, the potential benefits of treating periodontal disease in COPD outcomes have been investigated. Although the relationship between COPD and periodontal disease has been preliminarily studied, there is currently a lack of large-scale clinical studies to validate this association. In addition to clinical examinations, investigating biomarkers and microbiology may contribute to explore the underlying mechanisms involved in the management of these conditions. This review aims to contribute to a better understanding of the clinical and basic research aspects of COPD and periodontitis, allowing for potential therapeutic approaches and interdisciplinary management strategies.

Abstract Background The recurrence site that influences post-recurrence survival (PRS) in patients with non-small cell lung cancer (NSCLC) undergoing surgery and the preoperative predictors of recurrence remain unclear. Methods Cohorts 1 and 2 had 4520 (who underwent complete resection for p-stage 0-IIIA NSCLC) and 727 (who experienced recurrence after surgery) patients, respectively. The initial sites of recurrence were the lungs (309 cases), thoracic lymph nodes (225 cases), pleura (112 cases), bone (110 cases), central nervous system (86 cases), adrenal gland (25 cases), abdomen (60 cases), cervical and axillary lymph nodes (38 cases), chest wall (13 cases), skin (5 cases), and eye and tongue (3 cases). For cohort 2 analysis, the initial recurrence site that resulted in poor PRS was analyzed by multivariable analysis using a Cox proportional hazard model. For cohort 1 analysis, the preoperative predictors of recurrence patterns with poor PRS were analyzed by multivariable analysis using a logistic regression model. Results In cohort 2 analysis, recurrence in the central nervous system (hazard ratio [HR], 1.70; p

Multiaxial creep investigations at high temperatures are required to guarantee the integrity of structural materials such as boiler pipes for power generation and turbine blades for aviation and industrial applications. The multiaxial creep testing method using a cruciform specimen has several advantages, and the authors successfully downsized the specimen. The authors also developed a technique for the in situ observation of the specimen in an electric furnace and the non-contact displacement measurement in the development of a biaxial tensile creep testing machine for the miniature cruciform specimen. By observing the specimen at a target mark during the creep testing through an observation window installed at the bottom of the furnace, it was possible to visualize the specimen surface variations and obtain the axial strain from the locus of the target marks. The Mises-type equivalent strain was calculated from the axial strains obtained in the equi-biaxial tensile multiaxial creep testing and was compared with the strains obtained in the uniaxial creep testing. The Mises-type equivalent strain can be expressed using a unified method up to approximately 5% of the initial strain in the test, even in the multiaxial stress state.

Background/Objectives: During the COVID-19 pandemic, children in Japan were restricted from sports and outdoor activities. Regular physical activity is essential for healthy growth and development in children, with recommendations advocating for activities such as strength training. However, the long-term effects of the restrictions have not been fully investigated. This study aimed to evaluate the effectiveness of an “exercise class”, specifically a dance program, designed to improve motor function in elementary school children affected by the coronavirus disease 2019 (COVID-19) pandemic, which may have compromised their motor function. Methods: The dance program was developed by a sports science teacher, a professional dancer, and a physical therapist, and it was evaluated in a community-based participatory study. Trained dance instructors conducted one-hour dance sessions in a medical center, held once a week for two months from June to August 2023. A physical therapist and dance instructors led the elementary school children. Outcome measures included grip strength, lower extremity muscle strength, back muscle strength, dynamic balance function during movement, physical activity time, and body fat percentages. Descriptive statistics were used for analysis. Results: Twenty-four children aged 6–9 years participated in the exercise class over a two-month period. Improvement was observed in grip strength, lower extremity muscle strength, and dynamic balance function during movement. However, physical activity time, body fat percentages, and back muscle strength did not change. Conclusions: The results indicated a significant improvement in motor skills. Dance is an inexpensive program that elementary school children can enjoy while improving their motor skills.

Abstract Mucopolysaccharidosis III (MPSIII, Sanfilippo syndrome) is a devastating lysosomal storage disease that primarily affects the central nervous system. MPSIIIA is caused by loss-of-function mutations in the gene coding for sulfamidase (N-sulfoglucosamine sulfohydrolase/SGSH) resulting in SGSH enzyme deficiency, a buildup of heparin sulfate and subsequent neurodegeneration. There is currently no cure or disease modifying treatment for MPSIIIA. A mouse model for MPSIIIA was characterized in 1999 and later backcrossed onto the C57BL/6 background. In the present study, a novel immune deficient MPSIIIA mouse model (MPSIIIA-TKO) was created by backcrossing the immune competent, C57BL/6 MPSIIIA mouse to an immune deficient mouse model lacking Rag2, CD47 and Il2rg genes. The resulting mouse model has undetectable SGSH activity, exhibits histological changes consistent with MPSIIIA and lacks T cells, B cells and NK cells. This new mouse model has the potential to be extremely useful in testing human cellular therapies in an animal model as it retains the MPSIIIA disease phenotype while tolerating xenotransplantation.

Abstract Associative learning is crucial for adapting to environmental changes. Interactions among neuronal populations involving the dorso-medial prefrontal cortex (dmPFC) are proposed to regulate associative learning, but how these neuronal populations store and process information about the association remains unclear. Here we developed a pipeline for longitudinal two-photon imaging and computational dissection of neural population activities in male mouse dmPFC during fear-conditioning procedures, enabling us to detect learning-dependent changes in the dmPFC network topology. Using regularized regression methods and graphical modeling, we found that fear conditioning drove dmPFC reorganization to generate a neuronal ensemble encoding conditioned responses (CR) characterized by enhanced internal coactivity, functional connectivity, and association with conditioned stimuli (CS). Importantly, neurons strongly responding to unconditioned stimuli during conditioning subsequently became hubs of this novel associative network for the CS-to-CR transformation. Altogether, we demonstrate learning-dependent dynamic modulation of population coding structured on the activity-dependent formation of the hub network within the dmPFC.

Abstract The value of one’s own reward is affected by the reward of others, serving as a source for envy. However, it is not known which neural circuits mediate such socially subjective value modulation. Here, we chemogenetically dissected the circuit from the medial prefrontal cortex (MPFC) to the lateral hypothalamus (LH) while male macaques were presented with visual stimuli that concurrently signaled the prospects of one’s own and others’ rewards. We found that functional disconnection between the MPFC and LH rendered animals significantly less susceptible to others’ but not one’s own reward prospects. In parallel with this behavioral change, inter-areal coordination, as indexed by coherence and Granger causality, decreased primarily in the delta and theta bands. These findings demonstrate that the MPFC-to-LH circuit plays a crucial role in carrying information about upcoming other-rewards for subjective reward valuation in social contexts.

A 57-year-old woman was diagnosed with adrenocortical carcinoma. Following the adrenalectomy, she underwent adjuvant radiation and mitotane therapy; however, liver metastases were observed. Repeated radiofrequency ablation (RFA) was performed for liver metastases. In addition, a multidisciplinary approach combining systemic chemotherapy, radiotherapy, and surgery was used for lung and distant lymph node metastases that arose during the course of treatment. Notably, 49 months have passed since the adrenalectomy and 36 months since the recurrence of the liver metastases, and the patient remains on multidisciplinary therapy. Thus, RFA for liver metastasis of adrenocortical carcinoma may be an effective component of a multidisciplinary treatment.

Abstract Animals can expect rewards under equivocal situations. The lateral hypothalamus (LH) is thought to process motivational information by producing valence signals of reward and punishment. Despite rich studies using rodents and non-human primates, these signals have been assessed separately in appetitive and aversive contexts; therefore, it remains unclear what information the LH encodes in equivocal situations. To address this issue, macaque monkeys were conditioned under a bivalent context in which reward and punishment were probabilistically delivered, in addition to appetitive and aversive contexts. The monkeys increased approaching behavior similarly in the bivalent and appetitive contexts as the reward probability increased. They increased avoiding behavior under the bivalent and aversive contexts as the punishment probability increased, but the mean frequency was lower under the bivalent context than under the aversive context. The population activity correlated with these mean behaviors. Moreover, the LH produced fine prediction signals of reward expectation, uncertainty, and predictability consistently in the bivalent and appetitive contexts by recruiting context-independent and context-dependent subpopulations of neurons, while it less produced punishment signals in the aversive and bivalent contexts. Further, neural ensembles encoded context information and “rewarding-unrewarding” and “reward-punishment” valence. These signals may motivate individuals robustly in equivocal environments.

Abstract Background Once older persons become frail, the risk of falls, bone fractures, and other problems increases. Exercise intervention is a form of prevention that has a high degree of evidence. Objective We investigated the effectiveness of frailty prevention consisting of exercise intervention by community pharmacists at 11 pharmacies operated by Osaka Pharma Plan. Methods In total, 103 older persons between 70 and 79 years of age (53 males and 50 females) who were suffering from chronic conditions and who visited one of 11 pharmacies between January and March 2021 were enrolled. They were then randomly assigned to either the Intervention group (IG: 6 pharmacies, 61 patients) who were subjected to intervention by a pharmacist, or the Usual Care group (UG: 5 pharmacies, 42 patients) who were not subjected to intervention. At the beginning of the trial and 6 month after, their muscle mass, etc. were measured using a body composition meter, and their Five-Times Sit-To-Stand Test results were also measured. Patients in the IG were provided with information by way of leaflets during the time they were guided regarding taking their medication for a period of one to six months that encouraged exercising at home. Those in the UG were given the standard guidance related to taking their medication. Results The amount of change in muscle mass was 1.08 ± 7.83% (95%CI: -1.24-3.41) in IG and − 0.43 ± 2.73% (95%CI:-1.58-0.72) in UG, indicating that there was a trend toward an increase in IG. The percent change in the Five Times Sit-To-Stand Test times at + 6 M was − 0.002 ± 0.24% (95%CI: -0.09-0.05) in IG and − 0.04 ± 0.21% (95%CI:-0.13-0.07) in UG, but in cases in which the second measured time was faster than the first measured time, the results were 65.2% for IG and 29.2% for UG, indicating a significant difference (p = 0.00563). Conclusion Despite the fact that the amount of time community pharmacists can devote to providing guidance on taking medications is limited, it has been previously reported that providing information to patients causes a change in patient behavior. The results of the present study are highly significant as they suggest the possibility that this may hold true even when used to prevent frailty, based on the evidence obtained. Trial registration This trial was registered at UMIN-CRT on 1st of January, 2021. The registration number is UMIN000042571.