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Abstract: In coronavirus disease 2019 (COVID-19), thrombus formation is related to the pathogen-esis of acute respiratory distress syndrome (ARDS) and the progression of clinical symptoms. Se-vere damage to vascular endothelial cells and the associated cytokine storm after SARS-CoV-2 in-fection cause thrombogenesis and contribute to the development of more severe and unique throm-boses compared to other infectious diseases. Thromboses occur more often in critically ill patients. In addition to pulmonary thromboembolism (PE) and deep vein thrombosis, acute myocardial in-farction, peripheral arterial thrombosis, and aortic thrombosis have also been reported. In PE, thrombi develop in both pulmonary arteries and alveolar capillaries. These, together with intra-alveolar fibrin deposition, interfere with effective gaseous exchange in the lungs and exacerbate the clinical symptoms of ARDS in patients with COVID-19. Pharmacological thromboprophylaxis is recommended for all hospitalized patients to prevent both thrombosis and aggravation of ARDS, and other organ failures. Although the pediatric population is mostly asymptomatic or develops mild disease after SARS-CoV-2 infection, a new inflammatory disorder affecting the cardiovascular system, multisystem inflammatory syndrome in children (MIS-C), has been reported. Similar to Kawasaki disease, acute myocarditis, coronary vasculitis, and aneurysms are typically seen in MIS-C, although these two are now considered distinct entities. A similar acute myocarditis is also ob-served in young male adults, in which a hyperinflammatory state after SARS-CoV-2 infection seems to be involved. Several side effects following vaccination against COVID-19 have been re-ported, including vaccine-induced immune thrombotic thrombocytopenia and acute myocarditis. Although these could be serious and life-threatening, the cases are very rare, thus, the benefits of immunization still outweigh the risks.

In older adults, arm circumference and arm muscle circumference are common nutritional assessment tools. Bioelectrical impedance analysis devices can automatically measure arm circumference and arm muscle circumference. However, the interchangeability of the measurements made by bioelectrical impedance analysis with the actual manual measurements has not been clarified. This study examined the interchangeability of these two measurements and their relationship with sarcopenia.The interchangeability between bioelectrical impedance analysis and manual arm circumference and arm muscle circumference measurements was calculated using Bland-Altman analysis in 112 older adults certified to require long-term care in the Japanese system. Furthermore, multivariate analysis was used to investigate the association between arm circumference and arm muscle circumference obtained using the bioelectrical impedance analysis method and sarcopenia.The bioelectrical impedance analysis and manual methods were interchangeable, with a percentage error of15% (arm circumference 13.54% and arm muscle circumference 13.54%) for the upper arm anthropometric measurement. In multivariate analysis, decreased arm muscle circumference was significantly associated with sarcopenia risk.Values obtained using the bioelectrical impedance analysis method were interchangeable with the values obtained using manual measurement. This shows that upper arm anthropometric measurement using bioelectrical impedance analysis might be useful as a nutritional assessment tool for older adults requiring long-term care. Geriatr Gerontol Int 2022; 22: 938-942.

The dorsal parietal visual system plays an important role in self-motion perception and spatial cognition. It also strongly responds to visual inputs from the lower visual field. Postural control is modified in a process called sensory reweighting based on the reliability of available sensory sources. The question of whether visual stimuli presented to either the lower or upper visual field affect postural control and sensory reweighting has not been resolved.Do visual stimuli presented to the lower and upper visual fields affect postural control and sensory reweighting?Twenty-nine healthy young adults participated in the study. Four conditions (full visual field, upper visual field, lower visual field, and no optic flow condition) were simulated in a VR environment using a head-mounted display. The optic flow stimuli used were swarms of small white spheres originating from the central point of the visual field, moving radially towards the periphery, and expanding across the scene. Participants were instructed to stand quietly for 50 s under each visual condition. Using force plate signals, we measured the center of pressure (COP) signal in the horizontal plane and calculated its 95 % ellipse area, root mean square (RMS) deviations, the mean velocity, and power spectral density (PSD).Optic flow in the full and lower visual fields produced significantly smaller 95 % ellipse area and RMS of COP in the anterior-posterior direction compared to optic flow in the upper visual field. Furthermore, the PSD of the lower frequency band (0-0.3 Hz) was decreased and that of higher frequency bands (0.3-1 Hz and 1-3 Hz) was increased for the lower compared to the upper visual field.Visual feedback affects static postural control more when presented in the lower visual field compared to the upper visual field.

Polymorphous adenocarcinoma is a common intraoral minor salivary gland carcinoma in Western countries but is extremely rare in Japan. The current study aimed to characterize the clinicopathological features and status of molecular alterations of polymorphous adenocarcinoma-associated genes, such as PRKD1/2/3, ARID1A, and DDX3X, in a large cohort of Japanese patients with polymorphous adenocarcinoma.We examined the cases of 36 Japanese patients with salivary gland polymorphous adenocarcinoma and 26 cases involving histopathological mimics. To detect gene splits, fluorescence in situ hybridization was carried out for polymorphous adenocarcinoma-associated genes. Additionally, we applied a SNaPshot multiplex assay to identify PRKD1 hotspot mutations.This study revealed the indolent clinical course of polymorphous adenocarcinoma with a high 10-year overall survival rate (92.9%), accompanied by occasional local recurrences and cervical lymph node metastasis (23.3%). Twenty cases (55.6%) of polymorphous adenocarcinoma (but none of the mimics) exhibited alterations in at least one polymorphous adenocarcinoma-associated gene. Rearrangement of polymorphous adenocarcinoma-associated genes and PRKD1 E710D were identified in 17 (47.2%) and 4 (11.1%) cases, respectively; one case showed coexisting PRKD3 split and PRKD1 E710D. In the multivariate analysis, high clinical stage (p = 0.0005), the presence of prominent nucleoli (p = 0.0003), and ARID1A split positivity (p = 0.004) were independent risk factors for disease-free survival.Japanese patients with polymorphous adenocarcinoma showed clinicopathological features similar to those reported in Western countries. This study disclosed that polymorphous adenocarcinoma-associated genetic alterations were common and specific findings in polymorphous adenocarcinomas. The diagnostic role and possible prognostic significance of polymorphous adenocarcinoma-associated genetic alterations in polymorphous adenocarcinomas were suggested.

Effective amelioration of type II diabetes requires therapies that increase both glucose uptake activity per cell and skeletal muscle mass. Myristic acid (14:0) increases diacylglycerol kinase (DGK) δ protein levels and enhances glucose uptake in myotubes in a DGKδ-dependent manner. However, it is still unclear whether myristic acid treatment affects skeletal muscle mass. In this study, we found that myristic acid treatment increased the protein level of β-tubulin, which constitutes microtubules and is closely related to muscle mass, in C2C12 myotubes but not in the proliferation stage in C2C12 myoblasts. However, lauric (12:0), palmitic (16:0) and oleic (18:1) acids failed to affect DGKδ and β-tubulin protein levels in C2C12 myotubes. Moreover, knockdown of DGKδ by siRNA significantly inhibited the increased protein level of β-tubulin in the presence of myristic acid, suggesting that the increase in β-tubulin protein by myristic acid depends on DGKδ. These results indicate that myristic acid selectively affects β-tubulin protein levels in C2C12 myotubes via DGKδ, suggesting that this fatty acid improves skeletal muscle mass in addition to increasing glucose uptake activity per cell.

Salivary gland intraductal papillary mucinous neoplasm (SG IPMN) is a recently proposed entity characterized by a papillary-cystic proliferation of mucin-producing cells. Because of overlapping histologic features and a clonal AKT1 p.E17K variant, SG IPMN has been presumed to be a precursor or a low-grade subtype of mucinous adenocarcinoma. NKX3.1 is a tumor suppressor gene located on chromosome 8p and is a known immunohistochemical marker of prostate epithelium and mucinous acinar cells of the intraoral salivary glands.We retrieved 12 SG IPMN cases, and performed histologic and genetic analysis. Given the association of SG IPMN with mucinous acinar cells, we also investigated the performance of NKX3.1 as a marker of this tumor entity.Diffuse and strong NKX3.1 expression was observed in all SG IPMN cases (12/12, 100%) as well as in normal mucinous acinar cells. In contrast, mucoepidermoid carcinoma and pancreatic IPMN cases as well as normal serous acinar cells were negative for NKX3.1. Genetically, 11 of 12 cases (92%) harbored an AKT1 p.E17K variant. A novel PTEN frameshift deletion (p.G36Dfs*18) was detected in the other single case. At least one of the histologic features implying malignant tumors, such as severe cellular atypia, brisk mitotic activity, high Ki-67 proliferating index, lymphovascular invasion, and lymph node metastasis, was detected in 6 SG IPMN cases (50%).The findings suggest that SG IPMN is a low-grade subtype of mucinous adenocarcinoma which may be derived from mucinous acinar cells of the minor salivary gland.

The Hsa adhesin of Streptococcus gordonii strain DL1 was previously identified as a hemagglutinin that binds specifically to sialoglycoconjugates. We recently found that among oral streptococcal species, S. gordonii strains most frequently express Hsa homologs on the bacterial cell surface. However, the effect of amino acid sequence diversity of nonrepetitive region 2 (NR2), a putative binding site of Hsa, on antigenicity and hemagglutinating (HA) properties is unclear due to difficulties in DNA sequencing the NR2 coding region. The aim of this study was to elucidate the similarity of the low NR2 antigenicity Hsa homolog of strain NDU1118 to that of strain DL1 and the association of the homolog with HA properties of the strain.The hsa homolog of NDU1118 was sequenced using a long-read next-generation sequencer, and the Hsa homolog was assessed by alignment analysis of the deduced amino acid sequences. The hsa mutant of NDU1118 was generated by insertion of the erythromycin resistance gene. The HA properties of the wild type and the hsa mutant were assessed with human erythrocytes.The NR2 amino acid sequence of the NDU1118 Hsa homolog was almost identical to that of the S. gordonii M99 Hsa homolog, also known as GspB, and less similar to that of DL1 Hsa. The hsa mutation of NDU1118 induced reduction of HA activity in untreated erythrocytes, but surprisingly increased lactose-inhibitable HA activity in neuraminidase-treated erythrocytes.The results suggest the existence of an adhesin other than the Hsa homolog on the cell surface of NDU1118.

Background: Depression and anxiety-related disorders are common among adolescents. Research attention to early adolescence and low-income ethnically diverse populations is limited. Aim: To conduct screening for depression and anxiety at an early age with attention to gender and socioenvironmental context within a low-income setting. Method: Mixed methods included the PHQ-9A and GAD-10 screening instruments and ethnographic interviews. Results: 75 ethnically diverse middle school students were included. Mean years age was 11.2 (0.74). Females had higher PHQ-9A sum scores than males ( p = .002, Mann-Whitney test) and higher GAD-10 sum scores than males ( p = .016, Mann-Whitney test). After controlling for multiple comparisons, girls had higher mean responses on three PHQ-9A items ( p Conclusion: Specific attention to early adolescence is needed to identify emergence of subsyndromal conditions which may benefit from therapeutic attention to reduce symptom severity, identify sociocultural, structural, and gender-specific stressors, and to enhance educational engagement.

Although it is well known that women have higher risk of frailty, mechanisms are not clear. Reproductive history may be related to the sex difference in frailty.A total of 1249 community-dwelling women aged ≥60 in England were examined for associations between age at menopause and risk of developing frailty. Frailty defined by the frailty phenotype was measured at baseline and 4 years later. Age at menopause was used as a continuous variable and categorical groups: premature/early (10-45 years), normal (46-55 years), and late (56 years or older). Men with comparable conditions from the same cohort were also used as a comparison.Earlier age at menopause was significantly associated with higher risk of incident frailty. One year later menopause age was associated with a 3% decrease in incident frailty risk (Odds ratio [OR] = 0.97, 95%CI = 0.95-1.00, p = 0.02). Women with premature or early menopause had a significantly higher risk of developing frailty compared with those with normal menopause (OR = 1.90, 95%CI = 1.28-2.81, p = 0.001), while those with late menopause did not. In a supplementary analysis with older men, older women with premature or early menopause were more likely to develop frailty compared with older men (OR = 2.29, 95%CI = 151-3.48, p 0.001), however, there was no significant difference between women with normal or late menopause.Earlier menopause was significantly associated with higher risk of developing frailty. Our findings suggest that menopause or its related factors, such as decline in estrogen after menopause, potentially play an important role in the sex difference in frailty.

OBJECTIVES: Immediately before the state of emergency was declared, there was an outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among special training participants with severe physical stress. For promoting the optimization of infection prevention measures by identifying acts and situations with high risk of infection, we conducted a survey and analysis to understand the detailed process of infection spread in these cases. METHODS: A structured interview was conducted for the special training participants on their health status, changes in symptoms, training methods, and behavior history in their private lives. Additionally, a patrol of the training facility was carried out to understand the training environment, and antibody tests were conducted on the close contacts for more accurately grasping the spread of infection, by identifying subclinical infected persons. RESULTS: Within 10 days of COVID-19 onset in the first patient, 15 of the 19 original training participants developed symptoms, and 14 patients tested positive for RT-PCR. PCR tests were also performed on four patients who did not develop the disease - two were positive and negative, each. The two negatives turned positive on a later antibody test, suggesting that there was an asymptomatic infection. In addition, all five patients who participated in the training for only a day developed symptoms and tested positive for PCR in a few days. Of the 64 people who underwent testing for antibodies as close contacts, all but one who was living together with a patient were negative on antibody testing. CONCLUSIONS: The onset of COVID-19 occurred after the start of practice-based training continuously; therefore, the practice-based training was thought to be the main cause of the transmission. We speculate that the main factors behind the rapid spread of infection are as follows: during practice-based training, increased ventilation made it difficult to wear a mask; repeated loud vocalizations at close range; and the training pair was not fixed. Physical training without shouting and desk work, however, did not possess the risk of COVID-19, and avoiding certain situations at high risk of respiratory infections may have significantly reduced SARS-CoV-2 transmission. If personnel become infected with SARS-CoV-2, emergency measures should be devised by identifying patients and close contacts and facilitating the investigation of their behavioral history. Furthermore, evaluating and improving the effectiveness of infection control measures is necessary by ascertaining potentially infected persons by performing PCR tests, antigen tests, antibody tests, etc. in combination.

The present study investigated the relationship between the type of residential area and each factor of the International Classification of Functioning, Disability and Health (ICF) framework among elderly subjects receiving home-visit rehabilitation.This was a cross-sectional study conducted at two institutions. A total 84 participants (46 men and 38 women, age: 79.1±7.8 years old) who were receiving home-visit rehabilitation in urban and rural areas were examined. The parameters measured included the modified Gait Efficacy Scale (mGES), grip strength, 30-seconds chair stand test (CS-30), Functional Independence Measure (FIM), Life-Space Assessment (LSA), Frenchay Activities Index (FAI), Ikigai-9, and Home and Community Environment (HACE), which is based on the ICF concepts of health status, physical structure, physical and mental functions, activities, participation, personal factors, and environmental factors respectively; these points were evaluated by physical or occupational therapists. The health status was based on the diagnosis obtained from the clinical record.Receiving home-visit rehabilitation in a rural area was significantly associated with the LSA (odds ratio [OR]=1.075, p=0.028), optimistic and positive feelings for life (OR=0.698, p=0.040), and community mobility scores (OR=5.755, p=0.001).Environmental factors, activities, and personal factors differed depending on the region where the elderly subject received home-visit rehabilitation. Thus, intervention methods concerning home-visit rehabilitation may need to be adjusted according to the region where the patient lives.

The two patterns of pathogenesis for pancreatic colloid carcinoma are reported; (1) progression from ordinary ductal adenocarcinoma, a subtype of invasive pancreatic ductal carcinoma, and (2) progression from papillary adenocarcinoma derived from intraductal papillary mucinous neoplasm (IPMN) or mucinous cystic neoplasm (MCN). Whether these two conditions are the same disease remains controversial. Case Report 1. An 81-year-old woman was evaluated for an increased carbohydrate antigen 19-9 (CA19-9) value (130 U/mL) detected at 4-year follow-up after distal pancreatectomy for IPMN. Based on the image findings, a local recurrence of IPMN was diagnosed, and the patient underwent a remnant total pancreatectomy. Histopathologic findings showed marked mucus production from the tumor, also noteworthy because mucous nodule formation occurs in more than 80% of tumor. Fibrosis around the mucous cavity was noted, and a low papillary lesion was found in part of the cyst wall, which was contiguous to a flat, basal area; its nucleus was enlarged and heterogeneous in size, which is considered to be a component of intraductal papillary mucinous (IPMC). Therefore, the patient was diagnosed with pancreatic colloid carcinoma derived from IPMN. Case report 2 a 71-year-old man was evaluated for jaundice. Based on the image findings, a diagnosis of pancreatic head cancer was made, and a substomach preserving pancreaticoduodenectomy was performed. Histologically, marked mucus production and floating cuboidal masses of atypical cells without mucinous nodules were seen. Mucinous nodule formation is observed in more than 80% of tumor, but there was no IPMN component, which led to the diagnosis of pancreatic colloid carcinoma. In conclusion, there might be two types of colloid carcinoma of the pancreas, and further study is needed to determine whether these diseases are truly the same or not.

Aims/hypothesis Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons. Methods The effect of the GLP-1R agonists dulaglutide and exenatide was examined in Wfs1 knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome, and humanised mice. Results Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons. Conclusions/interpretation Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome. Graphical abstract

Streptococcus gordonii, one of the early colonizers of oral biofilms, is involved in the development of dental caries, periodontal disease, and infective endocarditis. The Hsa adhesin of S. gordonii DL1 has the ability to bind strongly to the terminal sialic acid groups of host glycoproteins via the binding region, NR2, which is important for the pathogenicity of S. gordonii DL1. Low similarity with the NR2 of Hsa homologs among other streptococcal species has been reported. However, the reports have been limited to certain strains. This study attempted to assess frequency of the expression on the bacterial cell surface and to analyze the diversity of Hsa homologs among different wild strains of oral streptococci. We isolated 186 wild-type strains of oral streptococci from healthy volunteers and analyzed their hemagglutinating activity on human erythrocytes and their Hsa homologs and NR2 homologous regions by dot immunoblotting using anti-Hsa and anti-NR2 antisera, respectively. We found 30 strains reacted with anti-NR2 antiserum (NR2-positive) and determined the sequence of the NR2 regions. Many strains with high hemagglutinating activity were also NR2-positive, suggesting that the NR2 region may be associated with hemagglutinating activity. Among the NR2-positive strains, four different amino acid sequence patterns were observed, demonstrating diversity in the NR2 region. Notably, S. gordonii strains frequently possessed Hsa homologs and NR2-like antigens compared to other streptococci. It is speculated that the possessing frequency of Hsa homologs and the amino acid sequence of NR2 region may vary among streptococcal species. This article is protected by copyright. All rights reserved.

This study investigated the impact of polymorphisms of metabolic enzymes on plasma concentrations of cilostazol and its metabolites, and the influence of the plasma concentrations and polymorphisms on the cardiovascular side effects in 30 patients with cerebral infarction. Plasma concentrations of cilostazol and its active metabolites, and CYP3A5*3 and CYP2C19*2 and *3 genotypes were determined. The median plasma concentration/dose ratio of OPC-13213, an active metabolite by CYP3A5 and CYP2C19, was slightly higher and the median plasma concentration rate of cilostazol to OPC-13015, another active metabolite by CYP3A4, was significantly lower in CYP3A5*1 carriers than in *1 non-carriers (p = 0.082 and p = 0.002, respectively). The CYP2C19 genotype did not affect the pharmacokinetics of cilostazol. A correlation was observed between changes in pulse rate from the baseline and plasma concentrations of cilostazol (R = 0.539, p = 0.002), OPC-13015 (R = 0.396, p = 0.030) and OPC-13213 (R = 0.383, p = 0.037). A multiple regression model, consisting of factors of the plasma concentration of OPC-13015, levels of blood urea nitrogen, and pulse rate at the start of the therapy explained 55.5% of the interindividual variability of the changes in pulse rate. These results suggest that plasma concentrations of cilostazol and its metabolites are affected by CYP3A5 genotypes, and plasma concentration of OPC-13015, blood urea nitrogen, and pulse rate at the start of therapy may be predictive markers of cardiovascular side effects of cilostazol in patients with cerebral infarction.

24(S)-Hydroxycholesterol (24S-OHC) and 25-hydroxycholesterol (25-OHC) are produced by cholesterol 24-hydroxylase and cholesterol 25-hydroxylase, respectively. The purpose of the present study was to determine the type of cell death induced by these oxysterols in neuronal cells, hepatic cells, and keratinocytes, and to elucidate the inhibitory effect of vitamin E homologues on various types of cell death. In human neuronal cells (SH-SY5Y cells), 24S-OHC and 25-OHC caused a cell death that was independent of caspase activation. We reported previously that the esterification of 24S-OHC by acyl-CoA:cholesterol acyltransferase 1 (ACAT1) and the resulting formation of a lipid droplet (LD)-like structure are responsible for the 24S-OHC-induced neuronal cell death. Here, we found that 25-OHC also induced ACAT1-mediated 25-OHC esterification and LD formation in neuronal cells. 25-OHC-induced cell death was inhibited by α-tocopherol (α-Toc) but not by α-tocotrienol (α-Toc3), as observed for 24S-OHC-induced cell death in SH-SY5Y cells. In human hepatic cells (HepG2 cells), these oxysterols caused a cell death that was caspase- and oxysterol-esterification-independent. This cell death was suppressed by both α-Toc and α-Toc3, suggesting the involvement of free-radical-mediated lipid peroxidation in the cell death induced by these oxysterols in hepatic cells. In human keratinocytes (HaCaT cells), these oxysterols caused a caspase-dependent but oxysterol-esterification-independent cell death that was inhibited by α-Toc but not by α-Toc3. These results suggest that α-Toc and α-Toc3 act as radical-scavenging antioxidants against oxysterol-induced cell death in the same way in hepatic cells, whereas their behavior is different in inhibition of cell death in neuronal cells and keratinocytes. Collectively, these results demonstrated that 24S-OHC and 25-OHC induced the same type of cell death in each of the cell types examined, and that α-Toc and α-Toc3 exerted different effects, depending on the type of cell death.

AIM The present study investigated the rejuvenation of physical function in terms of walking speed and grip strength. Specifically, it examined the rejuvenation of physical functions in community-dwelling older individuals between 2006 and 2019. The study is novel, because it analyzes this by focusing on gait balance. METHODS Data were collected from 339 participants (52 men, 287 women) in 2006, and 382 participants (83 men, 299 women) in 2019. They were categorized according to age: early-stage and late-stage groups for men, and early-stage, late-stage and latest-stage groups for women. These groups were analyzed by participants' walking speed, grip strength, Timed Up and Go test, Functional Reach test and One-Leg Standing test. The results were compared based on two factors: time (2006 to 2019) and age group. RESULTS The scores for the Timed Up and Go and One-Leg Standing tests were better in 2019 than in 2006 for all age groups in both older men and women. However, improvement in walking speed was observed only in women. Additionally, the decline in physical function with age was slower for walking speed among men, and Functional Reach and One-Leg Standing tests among women. CONCLUSIONS The changes over this 13-year period showed that the physical function of community-dwelling older individuals was rejuvenated in terms of improved standing and walking balance. These rejuvenations will aid in preventing falls among community-dwelling older individuals. Geriatr Gerontol Int 2021; 21: 975-980.

Background The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a risk-stratification reporting system that was introduced in 2018. The objective of this multi-institutional study was to evaluate the utility of the MSRSGC in Japan. Methods In total, 1608 fine-needle aspiration samples with matching histologic diagnoses were retrieved from 12 large institutions in Japan. The diagnostic categories of the MSRSGC were assigned prospectively or retrospectively, and the results were compared with the histologic diagnoses. Results The cases were classified as follows: nondiagnostic, 18.1%; non-neoplastic, 4.1%; atypia of undetermined significance, 11.5%; neoplasm-benign, 43.7%; salivary gland neoplasm of uncertain malignant potential, 9.6%; suspicious for malignancy, 3.6%; and malignant, 9.4%. The risk of neoplasm and the risk of malignancy in each MSRSGC category were as follows: nondiagnostic, 72.9% and 13.4%, respectively; non-neoplastic, 15.2% and 9.1%, respectively; atypia of undetermined significance, 77.9% and 24.9%, respectively; neoplasm-benign, 99% and 1.8%, respectively; salivary gland neoplasm of uncertain malignant potential, 94.8% and 37%, respectively; suspicious for malignancy, 100% and 89.7%, respectively; and malignant, 100% and 99.3%, respectively. The accuracy of the MSRSGC for diagnosing neoplasms was 97.8%, and its accuracy for diagnosing malignancy was 97.3%. Institutions that used Romanowsky-stained preparations had lower nondiagnostic rates and lower risks of neoplasm and malignancy in the non-neoplastic category. Conclusions The MSRSGC is useful for risk stratification and quality control. Widespread use of the MSRSGC would improve the accuracy of salivary gland cytology and lead to better patient care in Japan.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, the precise mechanisms leading to HTLV-1 chronic infection and the onset of the diseases have remained unclear, and effective vaccines for inhibiting the infection and the progression of pathogenesis have therefore not been developed. The use of a nonhuman primate (NHP) model is thought to be important for revealing the mechanisms of the progressive status and for the development of prevention procedures. In this study, we developed a cynomolgus macaque (CM) model of HTLV-1 infection by direct intravenous inoculation of HTLV-1-producing cells derived from ATL patients. The cell line used for infection, ATL-040, was selected as the most infectious one in our cell line library. CMs inoculated intravenously with 1 × 10

During the treatment of cardiogenic shock, various continuous infusion drugs are used simultaneously. However, administration from the same route may result in stability changes due to mixing of drugs. In addition, stability tests after mixing more than three types of drugs have hardly been conducted. In this study, noradrenaline, milrinone, dobutamine hydrochloride, and landiolol hydrochloride were used to evaluate the chemical stability of the mixture. Chemical stability was evaluated by measuring the change in each drug concentration over time and calculating the content. The concentration of each drug was measured using an optimized gradient elution method by HPLC. In a four-drug mixed sample, noradrenaline, milrinone, dobutamine hydrochloride, and landiolol hydrochloride had retention times of 2.1 min, 5.2 min, 9.3 min, and 11.9 min, respectively. The concentration immediately after mixing each drug was almost the same as the theoretical concentration at the time of mixing each drug. Furthermore, noradrenaline, milrinone, and dobutamine hydrochloride concentrations were maintained up to 99% in each drug mixture until 24 h after mixing all the samples. However, the content of landiolol hydrochloride was 90% or less 24 h after mixing, except for two types of mixed solutions with dobutamine hydrochloride. This result suggested that landiolol hydrochloride was being degraded owing to acidic conditions. The results of this study suggest that noradrenaline, milrinone, and dobutamine hydrochloride can be administered from one route, while it is recommended that landiolol hydrochloride be administered from another route.

In this prospective longitudinal cohort study, we explored the characteristics of older people with lower respiratory muscle strength, according to sarcopenia severity, over the course of 1 year. The maximum expiratory pressure (MEP), grip strength, walking speed, and skeletal muscle mass index of 58 participants (28 men, 30 women; mean age, 76.9 ± 7.7 years) were measured at baseline and at the 1-year follow-up. Participants were classified into a decreased MEP group (n = 29; MEP decreased by ≥10% after 1 year) and a non-decreased MEP group (n = 29; MEP decreased by

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672CT, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672CT, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell-derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672CT variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672CT, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672CT, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.

The coronavirus (COVID-19) pandemic significantly affected the physical and mental functions in older adults, resulting in “corona-frailty”. This 2-year prospective study characterized changes in quantitative measures and corona-frailty among a cohort of community-dwelling older women. Changes were evaluated using face-to-face interactions with 39 Japanese women (mean age: 76.1 ± 5.9) in 2019 (pre-pandemic baseline) and 2021 (follow-up during the pandemic). Quantitative measurements of handgrip strength, walking speed, calf circumference, body composition, and background factors were evaluated. Body weight and trunk muscle mass significantly decreased at follow-up. Multiple regression analysis, using change in trunk muscle mass as the dependent variable and background factors as independent variables, identified that decrease in trunk muscle mass was associated with “being robust at baseline” and answering “Yes” to the question of “Do you go out less frequently compared with last year”? The 2-year trunk muscle mass change for each baseline frailty stage showed a significant decrease only in the robust group (−8.0%). The decrease in trunk muscle mass might be related to pandemic-induced lifestyle restraint, suggesting that robust older adults who are healthy and active should take measures that focus on trunk muscles to avoid “corona-frailty”.

Isogenic induced pluripotent stem cell (iPSC) lines are currently mostly created by homology directed repair evoked by a double-strand break (DSB) generated by CRISPR-Cas9. However, this process is in general lengthy and inefficient. This problem can be overcome, specifically for correction or insertion of transition mutations, by using base editing (BE). BE does not require DSB formation, hence avoiding creation of genomic off-target breaks and insertions and deletions, and as it is highly efficient, it also does not require integration of selection cassettes in the genome to enrich for edited cells. BE has been successfully used in many cell types as well as in some in vivo settings to correct or insert mutations, but very few studies have reported generation of isogenic iPSC lines using BE. Here, we describe a simple and fast workflow to generate isogenic iPSCs efficiently with a compound heterozygous or a homozygous Wolfram syndrome 1 (WFS1) mutation using adenine BE, without the need to include a genomic selection cassette and without off-target modifications. We demonstrated that correctly base-edited clones can be generated by screening only five cell clones in less than a month, provided that the mutation is positioned in a correct place with regards to the protospacer adjacent motif sequence and no putative bystander bases exist.

Background Copy number variants (CNVs) linked to genes involved in nervous system development or function are often associated with neuropsychiatric disease. While CNVs involving deletions generally cause severe and highly penetrant patient phenotypes, CNVs leading to duplications tend instead to exhibit widely variable and less penetrant phenotypic expressivity among affected individuals. CNVs located on chromosome 15q13.3 affecting the alpha-7 nicotinic acetylcholine receptor subunit (CHRNA7) gene contribute to multiple neuropsychiatric disorders with highly variable penetrance. However, the basis of such differential penetrance remains uncharacterized. Here, we generated induced pluripotent stem cell (iPSC) models from first-degree relatives with a 15q13.3 duplication and analyzed their cellular phenotypes to uncover a basis for the dissimilar phenotypic expressivity. Results The first-degree relatives studied included a boy with autism and emotional dysregulation (the affected proband-AP) and his clinically unaffected mother (UM), with comparison to unrelated control models lacking this duplication. Potential contributors to neuropsychiatric impairment were modeled in iPSC-derived cortical excitatory and inhibitory neurons. The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or unrelated controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress. Both the neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also dysregulated in the AP, including reduced expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and Wnt, axonal guidance, and GABA receptor signaling. The UM model instead exhibited upregulated expression of genes in many of these same pathways, suggesting that molecular compensation could have contributed to the lack of neurodevelopmental phenotypes in this model. However, both AP- and UM-derived neurons exhibited shared alterations of neuronal function, including increased action potential firing and elevated cholinergic activity, consistent with increased homomeric CHRNA7 channel activity. Conclusions These data define both diagnosis-associated cellular phenotypes and shared functional anomalies related to CHRNA7 duplication that may contribute to variable phenotypic penetrance in individuals with 15q13.3 duplication. The capacity for pharmacological agents to rescue some neurodevelopmental anomalies associated with diagnosis suggests avenues for intervention for carriers of this duplication and other CNVs that cause related disorders.

Aim Advanced glycation end-products (AGEs) are a known factor that accelerates vascular complications. AGEs (e.g. pentosidine or N-e-carboxy-methyl-lysine [CML]) have been particularly investigated in patients with diabetes or chronic kidney disease and have been associated not only with arteriosclerosis, but also with novel vascular events. On the contrary, the correlation of vascular events with AGEs has not been sufficiently investigated in groups excluding those with diabetes or chronic kidney disease. The present study aimed to evaluate the impact of AGEs on the history of vascular events in postmenopausal women excluding those with diabetes or renal insufficiency. Methods Japanese postmenopausal women were registered to the study after obtaining informed consent. Patients with critical illness, including diabetes mellitus and renal insufficiency, were excluded from the study. Participants were asked about their medical histories during the registration for the Nagano Cohort Study. Non-fasting serum and urine samples were collected to measure biochemical markers, including urinary pentosidine and serum CML levels. Results Among 357 postmenopausal women, 32 had a history of vascular events. After adjusting age and other variables known to be associated with the presence of vascular event history, positive correlations between AGEs and vascular event history were observed (standardized odds ratio of log[pentosidine] 1.38, 95% CI 0.96-2.00, P = 0.086; standardized odds ratio of log[CML] 1.73, 95% CI 1.10-2.74, P = 0.019). Discussion The present results showed a significant association between serum CML and the presence of vascular event history, suggesting that serum CML might play a role in vascular events. Geriatr Gerontol Int ••; ••: ••-•• Geriatr Gerontol Int 2021; ••: ••-••.

Acidification of intracellular vesicles, such as endosomes and lysosomes, is a key pathway for regulating the function of internal proteins. Most conventional methods of measuring pH are not satisfactory for quantifying the pH inside these vesicles. Here, we investigated the molecular requirements for a fluorescence probe to measure the intravesicular acidic pH in living cells by means of fluorescence lifetime imaging microscopy (FLIM). The developed probe

The brain-specific cholesterol metabolite 24(S)-hydroxycholesterol (24S-OHC) has been shown to cause neuronal cell death when subjected to esterification by acyl-CoA:cholesterol acyltransferase 1 (ACAT1). Accumulating 24S-OHC esters in the endoplasmic reticulum (ER) provoked ER membrane disruption and an integrated stress response (ISR), a signaling pathway that regulates adaptation to various stresses. We have previously reported that α-tocopherol (α-Toc) but not α-tocotrienol (α-Toc3), among vitamin E homologs, suppressed 24S-OHC-induced cell death without affecting ACAT1 activity in human neuroblastoma SH-SY5Y cells. However, the precise mechanisms underlying the inhibitory activity of α-Toc have yet to be elucidated. In the present study, we aimed to investigate the effects of α-Toc on the 24S-OHC-induced cell death machinery. We showed that α-Toc, but not α Toc3, suppressed 24S-OHC-induced ISR and downstream eukaryotic translation initiator factor 2α (eIF2α) phosphorylation. We also found that α-Toc inhibited stress granule formation and robust downregulation of nascent protein synthesis, which were induced by 24S-OHC treatment. Furthermore, disruption of ER membrane integrity was suppressed by α-Toc, but not by α-Toc3. Our findings suggest that the inhibitory effects of α-Toc on 24S-OHC-induced cell death may be attributed to its protective function against ER membrane disruption.

The Kihon Checklist (KCL) is used to assess frailty in daily life. We aimed to identify KCL items associated with the development of frailty and recovery to robust status during the COVID-19 pandemic.We conducted a 1-year prospective cohort study of community-dwelling adults aged 70 and 75 years in Otawara City, Tochigi Prefecture, Japan. Information regarding age, sex, presence of disease and KCL items was collected in May 2020 (baseline) and June 2021 (follow-up) using a mailed questionnaire. Changes in frailty status as determined by the KCL at baseline and follow-up were evaluated. To clarify factors related to changes in the frailty status, we conducted two sets of binomial logistic regression analyses with the presence/absence of development of frailty and presence/absence of recovery to robust status at follow-up as the dependent variables and the KCL items as the independent variables.The analysis included 716 participants who provided complete responses to both questionnaires. The KCL Items 6, 10, 20, 23 and 24 were related to the development of frailty, and the KCL Items 6, 15, 21 and 23 were associated with the recovery to robust status.The baseline KCL items regarding physical function and associated mental aspects were related to both development of frailty and recovery to robust status during the COVID-19 pandemic. Cognitive and depressive declines were associated with the development of frailty, while good oral environment and sense of fulfillment in life were associated with the recovery to robust status. Geriatr Gerontol Int 2022; 22: 745-752.

Several studies have established the advantage of using anthropometric measurements as indicators of sarcopenia. Nevertheless, no study has explored the association between sarcopenia and neck circumference. In this cross-sectional study, we examined the data of 90 older adults requiring long-term care to evaluate this association and establish cut-off points for individuals at risk of sarcopenia as defined by the Asian Working Group for Sarcopenia (AWGS) 2019. A significant association was found between sarcopenia and neck circumference using binomial logistic regression and receiver operating characteristic analyses. The optimal cut-off value for neck circumference associated with increased risk for sarcopenia among older adults was 32.8 cm for females and 38.0 cm for males. Given the potential of declining neck circumference as an anthropometric marker of sarcopenia, it has clinical applications in screening for sarcopenia in older adults requiring long-term care.

The number of elderly patients requiring dialysis is continuously increasing. In Japan, many patients undergo hemodialysis; however, it has been associated with huge stress-mainly on the cardiovascular system-and requires frequent hospital visits. Conversely, peritoneal dialysis is much less invasive with a much lower frequency of hospital visits than that of hemodialysis; therefore, it is suitable for elderly patients. In addition, peritoneal dialysis, which originally had a high affinity for home care, has become more useful for elderly patients with renal failure thanks to the recent introduction of a cloud-based remote monitoring system at home. We performed percutaneous placement of a peritoneal dialysis catheter to reduce physical invasiveness and initiate peritoneal dialysis. The Barthel Index before hospitalization was 0 but increased to 65 at discharge. Further technology advancements in peritoneal dialysis are expected in the future. The cloud-based remote monitoring system is also expected to maintain or increase activities of daily living and the quality of life in elderly patients with renal failure with decreased activities of daily living.

Three pathological grading systems advocated by Perzin/Szanto, Spiro, and van Weert are currently used for adenoid cystic carcinoma (AdCC). In these systems, the amount or presence of the solid tumor component in AdCC specimens is an important index. However, the “solid tumor component” has not been well defined. Salivary AdCC cases (N = 195) were collected after a central pathology review. We introduced a novel criterion for solid tumor component, minAmax (minor axis maximum). The largest solid tumor nest in each AdCC case was histologically screened, the maximum oval fitting the solid nest was estimated, and the length of the minor axis of the oval (minAmax) was measured. The prognostic cutoff for the minAmax was determined using training and validation cohorts. All cases were evaluated for the four grading systems, and their prognostic impact and interobserver variability were examined. The cutoff value for the minAmax was set at 0.20 mm. Multivariate prognostic analyses showed the minAmax and van Weert systems to be independent prognostic tools for overall, disease‐free, and distant metastasis‐free survival while the Perzin/Szanto and Spiro systems were selected for overall survival but not for disease‐free or distant metastasis‐free survival. The highest hazard ratio for overall survival (11.9) was obtained with the minAmax system. The reproducibility of the minAmax system (kappa coefficient of 0.81) was scored as very good while those of the other three systems were scored as moderate. In conclusion, the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary AdCC., The amount or presence of the solid tumor component is an important index for histopathological grading of adenoid cystic carcinoma. However, the “solid tumor component” has not been well defined. We introduced a novel objective criterion for solid tumor component, minAmax (minor axis maximum), and showed that the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary adenoid cystic carcinoma.

The purpose of this study was to examine differences in texture features between olfactory neuroblastoma (ONB) and sinonasal squamous cell carcinoma (SCC) on contrast-enhanced CT (CECT) images, and to evaluate the predictive accuracy of texture analysis compared to radiologists’ interpretations. Forty-three patients with pathologically-diagnosed primary nasal and paranasal tumor (17 ONB and 26 SCC) were included. We extracted 42 texture features from tumor regions on CECT images obtained before treatment. In univariate analysis, each texture features were compared, with adjustment for multiple comparisons. In multivariate analysis, the elastic net was used to select useful texture features and to construct a texture-based prediction model with leave-one-out cross-validation. The prediction accuracy was compared with two radiologists’ visual interpretations. In univariate analysis, significant differences were observed for 28 of 42 texture features between ONB and SCC, with areas under the receiver operating characteristic curve between 0.68 and 0.91 (median: 0.80). In multivariate analysis, the elastic net model selected 18 texture features that contributed to differentiation. It tended to show slightly higher predictive accuracy than radiologists’ interpretations (86% and 74%, respectively; P = 0.096). In conclusion, several texture features contributed to differentiation of ONB from SCC, and the texture-based prediction model was considered useful.

Although romidepsin as monotherapy appears to be useful for treating T-cell lymphoma, combined chemotherapy with other therapeutic agents is required for improvement of the treatment outcome. To establish safer and more effective regimens, systematic screening was conducted to identify suitable drugs to be used in combination with romidepsin for T-cell malignancies, and the underlying molecular mechanisms were examined. The most effective agent was tamoxifen. The combination of romidepsin and tamoxifen had a significant synergistic effect in inducing apoptosis. The growth-inhibitory effects of the combined treatment were reversed by α-tocopherol. FOXO1 expression was greatly upregulated in MOLT-4 cells treated with romidepsin plus tamoxifen. Knockdown of FOXO1 expression by siRNA significantly reduced the cell death induced by romidepsin plus tamoxifen. The combination of romidepsin and tamoxifen might be considered for the treatment of T-cell lymphoma patients.

Sialadenoma papilliferum (SP) is a rare benign tumor of the salivary glands, and only three unequivocal cases of SP arising in the bronchus have been reported. We herein describe the histomorphologic and molecular features of four bronchial SP cases and discuss the differential diagnosis of this entity and the relationship with its clinicopathological mimics, in particular, glandular papilloma and mixed squamous cell and glandular papilloma (GP/MP). We encountered 2 male and 2 female patients with bronchial SP (mean 66.8 years old). All four tumors arose in the central bronchus and were characterized by a combination of surface exophytic endobronchial papillary proliferation and a submucosal multicystic component with complex architecture. The neoplastic epithelium consisted predominantly of non-ciliated stratified columnar cells with ciliated, squamous, and mucinous cells present focally. While 2 tumors (50%) harbored a BRAF V600E mutation by molecular and immunohistochemical analysis, similar to GP/MP, no KRAS, HRAS, AKT1 or PIK3CA mutations were detected in any of the cases. Two patients were treated with limited resection, while two patients underwent lobectomy based on the diagnosis of adenocarcinoma or possible squamous cell carcinoma in situ in the preoperative biopsy. All survived without recurrence or metastasis for 23 to 122 months after treatment. SP can develop in the central bronchus as the bronchial counterpart of the salivary gland tumor and should be considered in the differential diagnosis of endobronchial tumors. In addition, some histological resemblance and frequent BRAF V600E mutation raise the possibility of SP and GP/MP being on the same disease spectrum.

The aim of this study was to examine whether lymphatic invasion in papillary thyroid carcinoma (PTC) occurs when tumour-associated macrophages (TAMs) injure lymphatic vessels together with cancer cells. While there was no difference in the lymphatic vessel density in PTC and follicular thyroid carcinoma (FTC), the number of TAMs around the lymphatic vessels was increased in PTC compared to that in FTC. In particular, TAMs were observed together with cancer cells in lymphatic invasive lesions, and the number of M2 cells inside and outside the lymphatic vessels showed a significant correlation. MMP-2 mRNA was expressed in nonneoplastic stromal cells as well as cancer cells, and double immunofluorescence staining confirmed M2 positivity. Consequently, this study reveals that M2 TAMs around lymphatic vessels within the tumour border of PTC may be associated with the lymphatic invasion of cancer cells. This study represents a step forward in elucidating the mechanism of lymphatic invasion.

Background: There is limited evidence regarding associations between fruit and vegetable consumption and incident frailty risk among older people. Objectives: The objective of this study was to conduct a systematic review and meta-analysis regarding the association between fruit and vegetable consumption and incident frailty risk among older adults. Methods: A systematic search of the literature was conducted according to the PRISMA guidelines using PubMed in January 2021 for studies that prospectively examined risk of incident frailty in relation to fruit and vegetable consumption in older adults aged 60 and older. Methodological quality and heterogeneity were assessed. Odds ratios (OR) were pooled using random-effects or fixed-effects meta-analysis, depending on the presence of heterogeneity. Results: Among three studies included in this review, data of four cohorts were provided by two studies and used in meta-analysis. The highest fruit and vegetable consumption was significantly associated with lower risk of incident frailty compared with the lowest consumption (pooled OR=0.38, 95%CI=0.24-0.59, p=

A vast body of evidence implicates increased oxidative stress and extracellular glutamate accumulation in the pathomechanism of sporadic amyotrophic lateral sclerosis (ALS). Cystine/glutamate antiporter (xCT) carries extracellular cystine uptake and intracellular glutamate release (cystine/glutamate exchange) in the presence of oxidative stress. The aim of the present study was to determine the involvement of xCT in ALS. Immunohistochemical observations in the spinal cord sections demonstrated that xCT was mainly expressed in astrocytes, with staining more intense in 12 sporadic ALS patients as compared to 12 age-matched control individuals. Western blot and densitometric analyses of the spinal cord samples revealed that the relative value of xCT/s-actin optical density ratio was significantly higher in the ALS group as compared to the control group. Next, we conducted cell culture experiments using a human astrocytoma-derived cell line (1321N1) and a mouse motor neuron/neuroblastoma hybrid cell line (NSC34). In 1321N1 cells, the normalized xCT expression levels in cell lysates were significantly increased by H2 O2 treatment. Glutamate concentrations in 1321 N1 cell culture-conditioned media were significantly elevated by H2 O2 treatment, and the H2 O2 -driven elevations were completely canceled by the xCT inhibitor erastin pretreatment. In motor neuron-differentiated NSC34 cells (NSC34d cells), both the normalized xCT expression levels in the cell lysates and glutamate concentrations in the cell-conditioned media were constant with or without H2 O2 treatment. The present results provide in vivo and in vitro evidence that astrocytes upregulate xCT expression to release glutamate in response to increased oxidative stress associated with ALS, contributing to extracellular glutamate accumulation.

Breast-conserving surgery has become the preferred treatment method for breast cancer. Surgical margin assessment is performed during surgery, as it can reduce local recurrence in the preserved breast. Development of reliable and lower-cost ex vivo cancer detection methods would offer several benefits for patient care. Here, a practical and quantitative evaluation method for the ex vivo fluorescent diagnosis of breast lesions was developed and confirmed through a three-step clinical study. Gamma-glutamyl-hydroxymethyl rhodamine green (gGlu-HMRG) has been reported to generate fluorescence in breast lesions. Using this probe, we constructed a reliable and reproducible procedure for the quantitative evaluation of fluorescence levels. We evaluated the reliability of the method by considering reproducibility, temperature sensitivity, and the effects of other clinicopathological factors. The results suggest that the fluorescence increase of gGlu-HMRG is a good indicator of the malignancy of breast lesions. However, the distributions overlapped. A 5 min reaction with this probe could be used to distinguish at least part of the normal breast tissue. This method did not affect the final pathological examination. In summary, our results indicate that the methods developed in this study may serve as a feasible intraoperative negative-margin assessment tool during breast-conserving surgery.

As evidence-based interventions (EBIs) become more widely disseminated, fidelity of implementation (FOI) often wanes. This study explores the association between FOI and malleable variables within classrooms that could be targeted to optimize resources without compromising FOI as school-based EBIs are disseminated across real-world settings. We utilized process evaluation data from a national dissemination project of the Botvin LifeSkills Training (LST) middle school program, a universal prevention intervention shown to reduce substance use. The sample included 1,626 teachers in 371 schools across 14 states. Hierarchical linear models examined the relationship between observational measures of implementation factors and three domains of fidelity (e.g., adherence, student responsiveness, and quality of delivery). Findings suggest that curriculum modifications, student misbehavior, and shortage of time to implement the LST middle school program were factors most associated with lower FOI. Class size, access to program materials, and whether LST was delivered in a traditional classroom setting that is well-suited for instruction (versus in a less structured environment such as the school cafeteria) are less predictive. In scale-up of classroom-based universal interventions targeting behavioral health outcomes, our findings indicate that carefully vetting modifications, supporting classroom management strategies, and ensuring sufficient class time for implementation of highly interactive EBIs such as LST are important considerations. Since changes to EBIs are inevitable, efforts are needed to guide facilitators in making adjustments that improve program fit without compromising the essential intervention activities deemed necessary to produce desired outcomes.

Background: In recent decades, the use of near-infrared light and fluorescence-guidance during open and laparoscopic surgery has exponentially expanded across various clinical settings. However, tremendous variability exists in how it is performed. Objective: In this first published survey of international experts on fluorescence-guided surgery, we sought to identify areas of consensus and nonconsensus across 4 areas of practice: fundamentals; patient selection/preparation; technical aspects; and effectiveness and safety. Methods: A Delphi survey was conducted among 19 international experts in fluorescence-guided surgery attending a 1-day consensus meeting in Frankfurt, Germany on September 8(th), 2019. Using mobile phones, experts were asked to anonymously vote over 2 rounds of voting, with 70% and 80% set as a priori thresholds for consensus and vote robustness, respectively. Results: Experts from 5 continents reached consensus on 41 of 44 statements, including strong consensus that near-infrared fluorescence-guided surgery is both effective and safe across a broad variety of clinical settings, including the localization of critical anatomical structures like vessels, detection of tumors and sentinel nodes, assessment of tissue perfusion and anastomotic leaks, delineation of segmented organs, and localization of parathyroid glands. Although the minimum and maximum safe effective dose of ICG were felt to be 1 to 2 mg and >10 mg, respectively, there was strong consensus that determining the optimum dose, concentration, route and timing of ICG administration should be an ongoing research focus. Conclusions: Although fluorescence imaging was almost unanimously perceived to be both effective and safe across a broad range of clinical settings, considerable further research remains necessary to optimize its use.

We report a patient with inoperable hilar cholangiocarcinoma due to invasion at the umbilical portion who survived more than 4 years after right portal vein embolization and administration of S-1(50 mg/day). A 64-year-old male patient was immediately hospitalized for liver dysfunction and a high level of HbA1c. The disease was diagnosed as hilar cholangiocarcinoma mainly extending along the right hepatic duct. We made a request for operation to Nagoya University. He received right portal vein embolization in order to grow the residual liver but was deemed inoperable because of invasion at the umbilical portion. He refused chemotherapy but accepted administration of S-1(50 mg/day). Approximately 3 months after starting S-1, his ALP level normalized and about 9 months later stenting tube was lost. Subsequently, he returned to his job. Approximately 2 years and 2 months later, administration of S-1 was interrupted due to a harmful side effect. After approximately 13 months without S-1, the levels of CA19-9 and ALP again became elevated and administration of S-1 was restarted. He was temporarily hospitalized for abdominal pain and fever, but quickly recovered. Although CA19-9 and ALP levels re-normalized, he died after returning home. We emphasize the possibility of maintaining long-term health by minimal- dose S-1 therapy for inoperable hilar cholangiocarcinoma.

In recent years, the assessment of and support for the safety of driving for people with higher brain dysfunction to allow them to resume car driving have become issues to be addressed in Japan. It is difficult to determine whether or not people with higher brain dysfunction may safely resume car driving; in addition, methods of supporting this resumption have not been established. To support people with higher brain dysfunction and allow them to live at home in areas where public means of transportation may be insufficient, initiatives promoting the resumption of car driving are necessary in healthcare sectors, including day rehabilitation facilities. We provided support to a patient with an attention disorder due to left thalamic infarction, with the aim of achieving sufficient independence to drive a car, in a day rehabilitation facility. We herein report this case from the perspective of a speech-language-hearing therapist. The patient was a right-handed man in his 60s who had higher brain dysfunction with attention disorder as the main symptom. No marked motor paralysis of the extremities was observed. Use of a day rehabilitation service was started approximately two months after the onset of symptoms. Rehabilitation and support aimed at the resumption of car driving were provided approximately one month after the start of the day rehabilitation service use. To determine whether or not the patient was fit to drive a car, higher brain function tests for the intellectual function, attention function, and frontal function, as well as a theoretical evaluation based on the Stroke Drivers' Screening Assessment Japanese Version (J-SDSA) and monitoring of daily behaviors were performed. In addition, after the patient was given permission from an attending physician to drive a car on the condition that the patient did not drive fast and the patient's wife always accompanied him while driving, a safety assessment was also performed. As a result, approximately 10 months later, the J-SDSA theoretical evaluation score showed a passing grade, in contrast to the failing grade he had previously earned. Furthermore, errors in performing household activities due to a decreased attention function became unremarkable with respect to daily behaviors; therefore, we determined, together with the attending physician, that the patient now had sufficient independence to drive a car. In our day rehabilitation facility, the number of requests for advice on car driving from people with higher brain dysfunction living in the community had been increasing. Multisectoral assessments, training, and instruction should be continued in collaboration with attending physicians, other facilities located within the community, and driving schools in order to support people with higher brain dysfunction and help them once again be able to drive a car.

Background Oral health is a key factor of overall health and closely associated with well-being and quality of life. Mastication is one the most important oral functions and may deteriorate with aging. Evidence on association between masticatory dysfunction and frailty in the literature is scarce and not coherent. Methods A search strategy was developed to conduct a systematic review of the literature in PubMed, CINAHL, and AMED in accordance with the PRISMA 2020 guidelines. We searched for studies published in 2000 or later that examined associations between self-reported masticatory dysfunction and frailty risk. The reference lists of the relevant articles were reviewed for additional studies. We calculated pooled odds ratios (OR) of association between self-reported masticatory dysfunction and the risk of frailty by fixed-effects meta-analysis. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess risk of bias. Publication bias was assessed by visually inspecting a funnel plot. Results A total of 285 studies were identified by the literature search. Among 5 studies selected for this review, 4 cross-sectional studies including a total of 7425 individuals were used for meta-analysis. The pooled results by a fixed-effects model showed that there was a significant association between self-reported masticatory dysfunction and frailty risk (pooled OR = 1.83, 95%CI = 1.55–2.18, p Conclusions This systematic review and meta-analysis highlighted pooled cross-sectional evidence that community-dwelling older people who report masticatory dysfunction are significantly more likely to be frail than those who do not. The limitations of this study are: inclusion of only cross-sectional studies, no gold standard to measure masticatory functions, self-reported information on masticatory function, and the limited number of included studies. More longitudinal studies are warranted for further understanding of the causal pathways and elucidate underlying mechanisms. Registration: PROSPERO CRD42021277173

Herein, we report an extremely rare case of intraductal tubulopapillary carcinoma (ITPC) that was detected due to the pancreatic duct dilatation newly appeared on CT after surgery for gallbladder cancer associated with pancreaticobiliary maljunction. Present case: a 77-year-old female. Extended cholecystectomy, extra-bile duct resection, and hepaticojejunostomy was performed and resected specimen showed that this gallbladder tumor was papillary adenocarcinoma, pT2(ss), pN0, pDM0, pHM0, pEM0. Thereafter, the follow-up CT scan 2 years after surgery detected the dilatation of main pancreatic duct (MPD) and the elevation of carcinoembryonic antigen (CEA) level was pointed out (4.9 to 5.9 ng/ml). Moreover, pancreatic juice cytology revealed adenocarcinoma cells. Thus, distal pancreatectomy was performed based on the diagnosis of pancreatic adenocarcinoma associated with pancreaticobiliary maljunction (PBM). Histologically, proliferation of highly columnar atypical cells in the dilated main pancreatic duct with marked papillary and irregular tubular structures is seen. No mucus production is observed. Based on immunohistochemistry, Mucin (MUC) 1, 2 and 5AC were focal weak positive, negative and negative, respectively. Taken together of these findings, we could diagnose this tumor with ITPC without invasive component. The patient is alive without any recurrence for 36 months after a second surgery. In conclusion, it is essential to be fully aware that PBM is a disease in which there is still a possibility that pancreatic or biliary tract cancer may occur in the future, and that careful routine follow-up for a long period after diversion surgery may lead to early detection of complicated cancers.