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Background There is limited evidence regarding the relationship between Diabetes mellitus (DM) in middle age and mild cognitive impairment after a follow-up. Therefore, we investigated the relationship between fasting blood glucose (FBG) levels in middle age and cognitive function (assessed using the Japanese version of the Montreal Cognitive Assessment (MoCA-J) in later life, following over 15 years of follow-up in the Aichi Workers' Cohort Study in Japan. Methods Participants were 253 former local government employees aged 60-79 years in 2018 who participated in a baseline survey conducted in 2002. Using baseline FBG levels and self-reported history, participants were classified into the normal, impaired fasting glucose (IFG) and, and DM groups. Total MoCA-J score ranges from 0 to 30, and cognitive impairment was defined as MoCA-J score ≤25 in this study. A general linear model was used to estimate the mean MoCA-J scores in the FBG groups, adjusted for age, sex, educational year, smoking status, alcohol consumption, physical activity, body mass index, systolic blood pressure, total cholesterol, and estimated glomerular filtration rate. Results The mean MoCA-J score in the total population was 25.0, and the prevalence of MoCA-J score ≤25 was 49.0%. Multivariable-adjusted total MoCA-J scores were 25.2, 24.8, and 23.4 in the normal, IFG, and DM groups, respectively. The odds ratio of MoCA-J score ≤25 in the DM group was 3.29. Conclusions FBG level in middle age was negatively associated with total MoCA-J scores assessed later in life, independent of confounding variables.

An 84-year-old woman visited our hospital for dyspnea due to right pleural effusion, with lymphocytic dominance and a high adenosine deaminase (ADA) level, that had been noted 1 month earlier. She was suspected of having tuberculosis pleurisy; however, anti-tuberculosis treatment yielded no improvements. She was diagnosed with pleural effusion due to primary Sjögren's syndrome (SjS) based on her dry eyes and mouth, positivity for anti-Sjögren's-syndrome-related antigen A/B, and histopathologic findings of a lip biopsy and thoracoscopic pleural biopsy. Her symptoms improved after starting steroid therapy. Cases of pleural effusion due to SjS with a high ADA level may be misdiagnosed as tuberculosis pleurisy.

Background Tolvaptan is the first effective drug treatment for autosomal dominant polycystic kidney disease (ADPKD) patients, but few long-term observations of the effects of tolvaptan have been reported. Methods In this single center, retrospective cohort study, we investigated nine patients who participated in a phase 3 trial of tolvaptan for ADPKD patients at our hospital between 2008 and 2014. Six of the patients discontinued tolvaptan at the end of the clinical trial and were defined as the discontinuation group, and three continued to take it; these were defined as the continuation group. The observation period was 3 years before and after the end of the tolvaptan trial, and we compared the following data in each group: serum creatinine, estimated glomerular filtration rate (eGFR), total kidney volume, serum sodium concentration, and urine specific gravity. Results eGFR was significantly improved after the end of the trial in the continuation group (P = 0.0446), but there was no significant change in the regression line before and after the end of the trial in the discontinuation group. The increases in mean total kidney volume rates over the 3 years before and after the trial were 0.01 %/year vs. 0.067 %/year in the discontinuation group (P = 0.0247). On the other hand, serum sodium concentration and urine specific gravity showed no change during the observation period. Conclusion This study suggested that long-term administration of tolvaptan may improve renal function and inhibit total kidney volume growth.

A 58-year-old Japanese man was brought to the emergency room due to disturbance of consciousness. He regained consciousness on the day of admission and started taking hospital meals, but he needed intravenous glucose administration for eight days. The total amount of glucose administration was 4,464 g. It took over three weeks for exogenous insulin to be almost undetectable. While degludec binds to albumin and exerts glucose-lowering effects for a long time, the above-mentioned period of three weeks was consistent with the half-life of albumin. Hypoglycemia induced by massive dose of insulin degludec is persistent and prominent.

Background Obstructive sleep apnea, characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), is a risk factor for Alzheimer’s disease (AD) progression. Recent epidemiological studies point to CIH as the best predictor of developing cognitive decline and AD in older adults with obstructive sleep apnea. However, the precise underlying mechanisms remain unknown. This study was undertaken to evaluate the effect of CIH on pathological human tau seeding, propagation, and accumulation; cognition; synaptic plasticity; neuronal network excitability; and gene expression profiles in a P301S human mutant tau mouse model of AD and related tauopathies. Methods We exposed 4- to 4.5-month-old male P301S and wild-type mice to an 8-week CIH protocol (6-min cycle: 21% O2 to 8% O2 to 21% O2, 80 cycles per 8 hours during daytime) and assessed its effect on tau pathology and various AD-related phenotypic and molecular signatures. Age- and sex-matched P301S and wild-type mice were reared in normoxia (21% O2) as experimental controls. Results CIH significantly enhanced pathological human tau seeding and spread across connected brain circuitry in P301S mice; it also increased phosphorylated tau load. CIH also exacerbated memory and synaptic plasticity deficits in P301S mice. However, CIH had no effect on seizure susceptibility and network hyperexcitability in these mice. Finally, CIH exacerbated AD-related pathogenic molecular signaling in P301S mice. Conclusions CIH-induced increase in pathologic human tau seeding and spread and exacerbation of other AD-related impairments provide new insights into the role of CIH and obstructive sleep apnea in AD pathogenesis.

A 48-year-old woman with extensive clarithromycin-resistant Mycobacterium avium complex pulmonary disease (MAC-PD) was successfully treated by left lower lobectomy and lingulectomy following combination treatment of intravenous/inhaled amikacin plus bronchial occlusion by Endobronchial Watanabe Spigots (EWSs). A left pneumonectomy was initially indicated for removing all the lesions, but the procedure would have been barely tolerated by the patient. However, her preoperative combination treatment sufficiently reduced the lesions requiring resection to allow surgical preservation of the left upper division. This novel approach might be promising for patients with Mycobacterium avium complex lung disease whose pulmonary reserve will not allow an extensive parenchymal resection.

[Background and Aims] Multiple developments of squamous dysplasia and squamous cell carcinoma (SCC) in the upper aerodigestive tract have been explained by field cancerization phenomenon and were associated with alcohol and cigarette use. Second primary SCC development after curative treatment impairs patients’ quality of life and survival; however, how these consumption and cessation affect field cancerization is still unknown. [Methods] This is a multicenter cohort study including 331 patients with superficial esophageal SCC (ESCC) treated endoscopically and pooled data from 1022 healthy subjects for comparison. Physiological condition in the background esophageal mucosa was classified into 3 groups based on the number of Lugol-voiding lesions (LVLs) per endoscopic view: grade A, 0; grade B, 1–9; or grade C, ≥10 LVLs. Lifestyle surveys were conducted using a self-administered questionnaire. Patients were counseled on the need for alcohol and smoking cessation by physicians and were endoscopically surveyed every 6 months. [Results] LVL grades were positively associated with alcohol drinking intensity, flushing reactions, smoking, and high-temperature food and were negatively associated with eating green and yellow vegetables and fruit. Second primary ESCC and head/neck SCC were significantly more prevalent in the grade C LVL (cumulative 5-y incidences 47.1%, 95% confidence interval [CI] = 38.0–57.2 and 13.3%, 95% CI = 8.1–21.5, respectively). Alcohol and smoking cessation significantly reduced the development of second primary ESCC (adjusted hazard ratios 0.47, 95% = CI 0.26–0.85 and 0.49, 95% CI = 0.26–0.91, respectively). [Conclusion] Alcohol drinking, smoking, flushing reaction, and high-temperature food were closely associated with field cancerization, and cessation of alcohol and smoking significantly reduced the risk of development of second primary cancer. UMIN Clinical Trials Registry ID:UMIN000001676.

© 2020, The Author(s), under exclusive licence to Springer Nature Limited.Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Here, we report a case of allogeneic islet transplantation in Japan. A 48-year-old man received intraportal islet transplantation (5,945 islet equivalent/kg), and stabilization of blood glucose levels and suppression of hypoglycemia were achieved. In this case, we used our original assessment method to detect the responses of the recipient's T cells to islet autoantigens over time to monitor cellular autoimmunity. Other markers could not predict graft dysfunction in advance, but our method detected the activation of islet antigen-specific CD8+ T cell responses before the deterioration of pancreatic beta cell function, indicating the possibility of the non-invasive detection of pancreatic beta cell damage due to recurrent autoimmunity.

Elevated phosphorus (P) loading from the watersheds draining into Lake Erie, particularly from agricultural (53%) and urban (43%) sources, is identified as one of the main drivers of the severe eutrophication. In this study, we present a comprehensive evaluation of 11 process-based models to characterize the water cycle as well as nutrient fate and transport within a watershed context, and to find a robust and replicable way to optimize the modelling strategy for the Lake Erie watershed. Our primary objective is to review the conceptual/technical strengths and weaknesses of the individual models for reproducing surface runoff, groundwater, sediment transport, nutrient cycling, and channel routing, and to collectively guide the management of the Lake Erie Basin. Our analysis suggested that the available models either opted for simpler approximations of the multifaceted, nonlinear dynamics of nutrient fate and transport, and instead placed more emphasis on the advanced representation of the water cycle or, introduced a greater degree of biogeochemical complexity but simplified their strategies to recreate the roles of critical hydrological processes. Notwithstanding its overparameterization problem, the MIKE SHE model provides the most comprehensive 3D representation of the interplay between surface and subsurface hydrological processes with a fully dynamic description, whereby we can recreate the solute transport that infiltrates from the surface to the unsaturated soil layer and subsequently percolates into the saturated layer. Likewise, the physically based submodels designed to represent the sediment detachment and erosion/removal processes (DWSM, HBV-INCA, HSPF, HYPE, and MIKE SHE), offer a distinct alternative to USLE-type empirical strategies. The ability to explicitly simulate the daily plant growth (SWAT and APEX) coupled with a dynamic representation of soil P processes can be critical when evaluating the long-term watershed responses to various agricultural management strategies. Drawing parallels with the (sub)surface and sediment erosion processes, a more complicated physically based approach, e.g., the dynamic wave model provided by MIKE SHE (coupled with MIKE URBAN or MIKE HYDRO) and SWMM may be more appropriate for realistically simulating the pressurized flow and backwater effects of water routing in both open channels and closed pipes. While our propositions seem to favor the consideration of complex models that may lack the commensurate knowledge to properly characterize the underlying processes, we contend this issue can be counterbalanced by the joint consideration of simpler empirical models under an ensemble framework, which can both constrain the plausible values of individual processes and validate macroscale patterns. Finally, our study discusses critical facets of the watershed modelling work in Lake Erie, such as the role of legacy P, the challenges in reproducing spring-freshet or event-flow conditions, and the dynamic characterization of water/nutrient cycles under the nonstationarity of a changing climate.

Introduction Programmed death-ligand 1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti–programmed cell death protein-1 (PD-1)/PD-L1 therapy in patients with advanced NSCLC. Immune-related tumor microenvironment (TME) is classified into four different types based on the tumor-infiltrating lymphocyte (TIL) status and PD-L1 expression. Methods We retrospectively reviewed patients with advanced NSCLC treated with anti–PD-1/PD-L1 therapy between 2015 and 2019. We investigated the association between the efficacy of anti–PD-1/PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, the density of CD8-positive TILs assessed by immunohistochemistry, and mutational profiles by next-generation sequencing. Results Overall, 228 patients were included in the analysis. The patients were classified into the following four groups: type I: PD-L1High (tumor proportion score ≥ 50%)/TILHigh (≥85/mm2; n = 73); type II: PD-L1Low (tumor proportion score Conclusions Differential types of TME, including PD-L1 expression and TIL status, could accurately predict the efficacy of anti–PD-1/PD-L1 therapy.

We aimed to investigate the impact of long corrective fusion to the ilium on the physical function in elderly patients with adult spinal deformity and its correlation with spinopelvic parameters and health-related quality of life outcomes.We included 60 female patients who underwent long corrective fusion from T9 or T10 to the pelvis for adult spinal deformities (mean age of 69.8 years, range 55-78 years). The radiographic parameters, health-related quality of life outcomes using the Scoliosis Research Society Outcome Instrument-22 and physical function assessments were reviewed preoperatively and at 1-year postoperatively.All spinopelvic parameters, except for thoracolumbar kyphosis, and all domains of the Scoliosis Research Society Outcome Instrument-22 significantly improved at 1-year postoperatively (p 0.0001). Physical function results, including those for one-leg standing time, timed up-and-go test, and 6-min walk tests, significantly improved at 1-year postoperatively (p 0.005). Based on forward stepwise multivariate logistic regression, the predicted timed up-and-go test and 6-min walk test outcomes at 1-year postoperatively were as follows: timed up-and-go test, 7.8 + 0.47 × preoperative timed up-and-go test - 0.21 × 1-year postoperative grasping power +0.015 × 1-year postoperative C1 sagittal vertical axis (R2 = 0.6209, p 0.0001); 6-min walk test, 309.2-9.1 × body mass index + 11.6 × 1-year postoperative grasping power + 3.3 × 1-year postoperative thoracolumbar kyphosis - 0.59 × 1-year postoperative C1 sagittal vertical axis (R2 = 0.4409, p 0.0001).Corrective long fusion surgery for adult spinal deformity in normalizing sagittal alignment improves trunk balance and gait performance. Postoperative physical function depends on the preoperative physical performance status and skeletal muscle status; thus, preoperative interventions for improved physical function are recommended.

Tyrosine kinase 2 (Tyk2) is a member of the Janus family of protein tyrosine kinases (Jaks). Tyk2 associates with interferon (IFN)-α, IFN-β, interleukin (IL)-6, IL-10, IL-12, and IL-23 receptors and mediates their downstream signaling pathways. Based on our data using Tyk2-deficient mice and cells, Tyk2 plays crucial roles in the differentiation, maintenance, and function of T helper 1 (Th1) and Th17 cells, and its dysregulation may promote autoimmune and/or inflammatory diseases. IFN-α-induced growth inhibition of B lymphocyte progenitors is dependent on Tyk2-mediated signals to regulate death-associated protein (Daxx) nuclear localization and Daxx-promyelocytic leukemia protein interactions. Tyk2-deficient mice show impaired constitutive production of type I IFNs by macrophages under steady-state conditions. When heat-killed Cutibacterium acnes is injected intraperitoneally, Tyk2-deficient mice show less granuloma formation through enhanced prostaglandin E2 and protein kinase A activities, leading to high IL-10 production by macrophages. Thus, Tyk2 is widely involved in the immune and inflammatory response at multiple events; therefore, Tyk2 is likely to be a suitable target for treating patients with autoimmune and/or chronic inflammatory diseases. Clinical trials of Tyk2 inhibitors have shown higher response rates and improved tolerability in the treatment of patients with psoriasis and inflammatory bowel diseases. Taken together, Tyk2 inhibition has great potential for clinical application in the management of a variety of diseases.

BACKGROUND/AIM Programmed death-ligand 1 (PD-L1) expression on tumor cells is a predictive biomarker of programmed cell death 1 (PD-1) blockade therapy. This study sought to clarify predictors of the efficacy of nivolumab in non-small cell lung cancer (NSCLC) patients with PD-L1 expression-negative tumors. PATIENTS AND METHODS We retrospectively reviewed the records of advanced NSCLC patients between January 2016 and April 2019, and investigated the predictive marker of nivolumab including the status of CD8+ tumor infiltrating lymphocytes (TILs). RESULTS A total of 70 NSCLC patients were included. Overall response rate (ORR) and progression-free survival (PFS) were better in patients with a heavy smoking history (smoking index: SI≥600) than in those without (SI

Objective: Recent advances in high-precision mammography and ultrasound screening have led to an increase in the detection of early lesions (ductal carcinoma in situ and small cancers) appearing as microcalcified lesions or microcystic images, and there needs to be an improvement in the accuracy of breast fine-needle aspiration biopsy (FNAB) assessing these lesions. The objective of this study was to investigate whether fractal analysis of Kirsch edge images for the tissue fragment inner structure (FKT) is useful in breast FNAB. FKT measures tissue fragment chromasia of hyperchromatic crowded tissue fragments (HCG), tissue fragment shape unevenness, and tissue fragment inner structure complexity. Study Design Materials: Nineteen epithelial tissue fragments of fibroadenoma (FA) from 7 patients and 52 tissue fragments of invasive breast carcinoma of no special type (IBC-NST) (grade 1–2) from 11 patients were assessed. First, tissue fragments were classified into small (smaller than 60 × 102 μm2), medium, and large (100 × 102 μm2 or larger), and the appearance rate of each size was determined. Second, for FKT, the luminance value of tissue fragment chromasia, the unevenness and fractal value, and the tissue fragment inner structure complexity were determined. In statistical analysis, the Steel-Dwass test, nonlinear discriminant analysis, and receiver operating characteristic analysis were performed, setting the significance level at p < 0.05. Results: “Unevenness of the tissue fragment shape,” “fractal value of the tissue fragment shape,” and “fractal value of the tissue fragment inner structure” were significantly higher in small and large tissue fragments in IBC-NST compared with those in FA. The specificity and sensitivity were the highest (100%) in small tissue fragments in multivariate analysis using 4 variables (“luminance value of tissue fragment chromasia,” “unevenness of tissue fragment shape,” “fractal value of the tissue fragment shape,” and “fractal value of the tissue fragment inner structure”). Conclusion: FKT, which evaluates “tissue fragment darkness,” “tissue fragment shape unevenness,” and “tissue fragment inner structure complexity” focusing on small tissue fragments of HCG in breast FNAB, is useful as a system that assists cytopathological assessment of breast FNAB.

BACKGROUND AND AIM Direct-acting antivirals (DAAs) have contributed to the improvement of outcomes for all patients with chronic hepatitis C. The aim of this study was to evaluate the long-term hepatic benefits of hepatitis C virus (HCV) cure by DAAs in patients with compensated cirrhosis. METHODS This multicenter cohort study consisted of consecutive patients with compensated cirrhosis who initiated interferon-free DAA treatment before September 2016. The impact of treatment on long-term hepatic function was followed for at least 4 years after the end of treatment, and the progression to decompensation was evaluated. RESULTS The data of 394 patients were available for study. The median age was 70, and 41% had modified albumin-bilirubin (ALBI) grade 2b. During a short-term follow-up 1 year after the end of treatment, FIB-4 index and ALBI score significantly improved. The achievement rates of FIB-4

OBJECTIVE AND METHOD Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma with poor prognosis. We retrospectively reviewed the medical records of 312 patients with aggressive ATL and analyzed the effect of chemotherapy dose intensity on prognosis in clinical practice. RESULT As first-line therapy, 62 patients underwent best supportive care (BSC) or single-agent chemotherapy, and 235 underwent intensive chemotherapy. The median survival time (MST) was 0.58 years in the 312 total patients, and 0.13 years and 0.75 years in the BSC/single-agent chemotherapy group and intensive chemotherapy group, respectively. The median average relative dose intensity (ARDI) of patients who received intensive chemotherapy was 60%. We divided patients into 3 groups according to ARDI. Those in the top tertile of ARDI (ARDI ≥ 75%, n = 82) had better overall survival compared with those in the intermediate tertile (45% ≤ ARDI

A close-fitting assisted walking device (RE-Gait) designed to assist ankle movements might be a novel approach for acquiring the forefoot rocker function in the gait cycle. The purpose of the present study was to investigate the effects of using RE-Gait by evaluating the intramuscular coherence (IMC) of the two parts of the tibialis anterior muscles (TA), which could indicate whether a common synaptic drive is present. Seventeen healthy volunteers walked on a treadmill at a comfortable speed before, during, and immediately after 15-minute RE-Gait intervention. After RE-Gait intervention, IMC of the two parts of the TA muscles in the beta frequency band in the initial swing phase was significantly enhanced during RE-Gait intervention. In addition, IMCs in the beta and low-gamma frequency bands were significantly correlated with the enhancement ratio of the step length. These results suggest that robotic ankle plantar flexion and dorsiflexion assistance in the initial swing phase may be effective for improving gait function with enhancement of the functioning of the sensorimotor loop.

Risk stratification is required to improve the management of pouchitis with ulcerative colitis (UC) patients who undergo ileal pouch-anal anastomosis (IPAA). Recently, the colectomy risk score (CRS) has been used to assess UC severity and predict the need for surgery. We explored whether the CRS predicted pouchitis in patients with UC who underwent IPAA. This retrospective study included 168 UC patients who underwent IPAA. Pouchitis was diagnosed according to the pouchitis disease activity index. The primary endpoint was the cumulative incidence of pouchitis. The risk factors for pouchitis using preoperatively obtained data, including the CRS, were investigated. Based on their CRS, patients were assigned to low- (scores 0-3), intermediate- (scores 4-6), and high-risk (scores 7-9) groups. The incidence of pouchitis was estimated using the Kaplan-Meier curve. CRS validity was assessed using the Cox proportional hazards model. During the median 7.2 (interquartile range [IQR] 2.8-11.1) years' follow-up, 37 (28.5%) patients were diagnosed with pouchitis. Patients with pouchitis had significantly higher CRS than patients without pouchitis (median 7.0; IQR, 4.0-7.0 vs median 5.0; IQR, 3.0-7.0). The cumulative incidences of pouchitis in the low-, intermediate-, and high-risk groups were 10.3%, 18.3%, and 36.1% at 5 years, respectively. Thus, the incidence trended to increase significantly as CRS increased. Multivariate analysis revealed high-risk CRS status was an independent predictor of pouchitis (hazard ratio: 18.03; 95% confidence interval 1.55-210.05). CRS is useful in risk stratification for the development of subsequent pouchitis in patients with UC undergoing IPAA.

Aphasic status epilepticus (ASE) is a subtype of focal nonconvulsive status epilepticus, in which language disturbance is the only objective clinical manifestation. We present two cases of patients who experienced delayed onset of temporal aphasia after the removal of glioma at the language-dominant hemisphere. In both cases, arterial spin labeling was useful for diagnosis and antiepileptic drug was effective. ASE should be considered a cause of persistent aphasia after glioma resection at or near the language area.

OBJECTIVES The aim of this study was to clarify the mechanisms of the transient increase in neutrophils after running standard marathon races by measurement of cytokines involved in the production and survival of neutrophils, and cortisol. METHODS Fourteen male runners who participated in the Hokkaido Marathon, which is the sole marathon race held in summer in Japan, and finished the standard marathon were analyzed sequentially from the start until a maximum of 8 days after the finish. RESULTS Neutrophilia was observed in all runners just after they reached the goal (mean neutrophils: 13 226/μL). IL-6, G-CSF, and cortisol, but not GM-CSF, increased at the same time. Time-course studies with complete blood counts, biochemical markers, cytokines, and cortisol showed transient increases in neutrophils, monocytes, myoglobin, high-sensitivity C-reactive protein (hsCRP), G-CSF, IL-6, and cortisol. The increase in hsCRP was delayed 6 hours from the first increase in neutrophils. Correlations were observed between the neutrophil count and G-CSF, IL-6, and cortisol (G-CSF; r = .667, IL-6; r = .667, cortisol; r = .623). CONCLUSION These results suggest that G-CSF is directly involved, and IL-6 is involved via cortisol in the transient neutrophilia that occurs after marathon races.

Aims/Introduction This study examined the effect of daily walking steps on glycated hemoglobin, body mass index (BMI) and body composition while taking into consideration sedentary time (ST) in Japanese type 2 diabetes patients over a period of 12 months. Materials and Methods Self‐administered ST values and information regarding daily walking steps were obtained and analyzed for 236 patients with type 2 diabetes who regularly visited the outpatient clinic. The patients – divided into three categories of daily walking steps: non‐step counter user, This prospective observational study clarified that number of daily walking steps affected both bodyweight and body composition among patients with type 2 diabetes in a group of participants with high sedentary time. The results suggest that sedentary status should be taken into consideration for the successful practice of physical activity such as daily walking to prevent Japanese patients with type 2 diabetes from becoming overweight or obese and thereby exacerbate their diabetes condition.

OBJECTIVES: Health-related quality of life (HRQoL) measures capture the patient’s experience of the burden of chronic disease and are strongly associated with adverse health-related outcomes across multiple populations. The SF-36 score is the most widely used HRQoL measure among patients with end-stage renal disease (ESRD). Current understanding of determinants of the physical component summary (PCS) and the mental component summary (MCS) and their association with objectively measured physical performance and activity is limited. DESIGN: Cross-sectional study. SETTING AND SUBJECTS: As an index of HRQoL, we prospectively examined the association of SF-36 and its component scores with physical function among 155 incident dialysis patients from the Hemodialysis Center. We investigated associations of HRQoL with the physical performance-based components of the frailty using multivariate linear and logistic regression after adjustment for confounders. PREDICTOR: HRQoL score. MAIN OUTCOME: Impaired physical performance was defined as having either slow usual gait speed or weak handgrip strength based on standardized and validated criteria derived from a large cohort study of older adults. RESULTS: The patients had a mean age of 65 ± 11 years, and 52.3% were male. After adjusting confounders, lower PCS was independently associated with decreased physical performance and reduced physical activity, but MCS was not associated. Among the PCS subscales, only physical functioning 10 (PF-10) was consistently associated with outcomes, and every 1 point increase in PF-10 score was associated with 4% lower odds of impaired physical performance (95%CI: 2 to 7%; P=0.01) after adjustment. CONCLUSIONS: SF-36, especially PF-10, is a valid surrogate that discriminates low physical performance and physical inactivity in the absence of formal physical function testing in patients on hemodialysis. The routine implementation of the PF-10 in clinical care has important clinical implications for medical management and therapeutic decision-making in patients undergoing hemodialysis.

Gaucher disease is a rare genetic disorder caused by the deficiency of acid β-glucosidase to effectively catalyze the degradation of glucosylceramide to glucose and ceramide. We report here the case of a 31-year-old male Japanese patient with Gaucher disease who switched from enzyme replacement therapy (ERT) to substrate reducing therapy (SRT). Liver dysfunction was identified at a routine medical checkup, and the patient was referred to our hospital with “idiopathic liver disease.” Clinical laboratory tests indicated thrombocytopenia and splenomegaly, which are characteristic symptoms of Gaucher disease. To definitively diagnose Gaucher disease, a bone marrow biopsy and acid β-glucosidase activity measurement were conducted; the results supported a diagnosis of Gaucher disease. This case emphasizes that it is possible for periodic medical checkups in adults to lead to the diagnosis of rare genetic disorders. The patient underwent ERT treatment with imiglucerase for 5 years; the platelet count rapidly increased and the spleen size rapidly decreased, indicating a good response to the drug. However, the patient increasingly felt the burden of visiting the hospital for 2 h of infusion ERT every 2 weeks. Consequently, it was jointly decided that he should switch from ERT to SRT with an oral drug. This switch was successful with no deterioration of laboratory data. This case report is the first to describe a Japanese Gaucher disease patient treated with eliglustat for >2 years. We showed that SRT is a well-tolerated and effective option for the treatment of Gaucher disease.

Aim Glyphosate‐containing herbicides are less toxic than paraquat and are one of the most widely used herbicides today. Case presentation We report a case of ingestion of a pesticide containing glyphosate in a suicide attempt. The patient was admitted to the psychiatric department because of persistent suicidal thoughts. He suffered from short‐term memory impairment on day 3. Magnetic resonance imaging (MRI) showed swelling in the bilateral medial temporal lobes and hippocampi and high signal on T2‐weighted images. Gradually, the patient's cognitive impairments improved, and he was discharged on day 33. Conclusion A physician should examine the patient with the possibility of glyphosate encephalopathy in mind., The patient presented with delayed and transient short‐term memory impairment due to glyphosate medication. MRI showed bilateral medial temporal lobe and hippocampal swelling and high signal on T2‐weighted images, high signal in the right predominant insular cortex on diffusion‐weighted images, and high signal in the hippocampus and insular cortex on T2FLAIR.

Background Various adrenal disorders including primary aldosteronism and Cushing’s syndrome lead to the cause of hypertension. Although primary aldosteronism is sometimes complicated with preclinical Cushing’s syndrome, concurrence of overt Cushing’s syndrome and primary aldosteronism is very rare. In addition, it has been drawing attention recently that primary aldosteronism is brought about by the presence of aldosterone-producing cell cluster in adjacent adrenal cortex rather than the presence of aldosterone-producing adenoma. Case presentation A 67-year-old Japanese female was referred to our institution due to moon face and central obesity. Based on various clinical findings and data, we diagnosed this subject as overt Cushing’s syndrome and primary aldosteronism. Furthermore, in immunostaining for cytochrome P450 (CYP) 11B1, a cortisol-producing enzyme, diffuse staining was observed in tumorous lesion. Also, in immunostaining for CYP11B2, an aldosterone-producing enzyme, CYP11B2 expression was not observed in tumorous lesion, but strong CYP11B2 expression was observed in adjacent adrenal cortex, indicating the presence of aldosterone-producing cell cluster. Conclusions We should bear in mind the possibility that concurrence of overt Cushing’s syndrome and primary aldosteronism is accompanied by aldosterone-producing cell cluster in adjacent adrenal cortex.

BACKGROUND Aripiprazole is regarded as the first-line antipsychotic medication. Long-term aripiprazole therapy can cause hypoprolactinemia, which may result from its activity as a dopamine agonist. However, there is little information on hypoprolactinemia and steady-state aripiprazole concentrations. METHODS The subjects included 66 male and 177 female patients diagnosed with schizophrenia who were treated with aripiprazole. The plasma concentrations of aripiprazole and dehydroaripiprazole and the plasma concentration of prolactin were measured using high-performance liquid chromatography and enzyme immunoassay, respectively. A prolactin concentration of

Background Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by pituitary neoplasia, primary hyperparathyroidism and pancreatic endocrine tumor. Here we show a case of MEN1 with a germline frameshift mutation in its gene accompanied by a giant cervical lipoma and multiple fatty deposits in the pancreas. Case presentation A 28-year-old man noticed the decreased visual acuity of both eyes and visited our institution. Since he was diagnosed as visual disturbance and brain computer tomography (CT) showed a mass in the pituitary fossa, he was hospitalized in our institution. Endoscopic trans-sphenoidal hypophysectomy and total parathyroidectomy with auto-transplantation were performed, and a giant cervical lipoma was resected. Furthermore, in genetic search, we found a germline frameshift mutation in MEN1 gene leading to the appearance of a new stop codon. Conclusions We should bear in m ind that giant skin lipoma and multiple abnormal fatty deposits in the pancreas could be complicated with MEN1.

Background Endocytoscope systems (ECS) can visualize cellular nuclei of the mucosa of the gastrointestinal tract and are predicted to provide real-time microscopic diagnosis. However, their practical diagnostic performance remains unclear. Therefore, we conducted a multicenter prospective study to evaluate the visualization of superficial esophageal neoplasm in vivo using an ECS, and its diagnostic capability. Methods The study target was histologically confirmed squamous cell carcinoma (SCC) and high-grade intraepithelial neoplasia (HGIN). An integrated ECS was used to obtain ECS images. In each patient, three ECS images of cancerous and corresponding noncancerous regions were selected for evaluation. A pathological review board of five certified pathologists made the final diagnosis of the images. The primary endpoint was the sensitivity of ECS diagnosis by pathologists. Results ECS images of 68 patients were assessed: 42 lesions were mucosal SCC, 13 were submucosal SCC, and 13 were HGIN. The rate of assessable images was 96% (95% CI 87.6–99.1). The sensitivity of ECS diagnosis by pathologists was 88% (95% CI 77.2–94.5). Conclusions ECS can provide high-quality images of cancerous lesions and a high diagnostic accuracy by pathologists, and could be useful for real-time endoscopic histological diagnosis of SCC and HGIN. Trial registration The UMIN Clinical Trials Registry Identification Number: 000004218

CD163 is one of the scavenger receptors expressed on macrophages. However, several immunohistochemical studies have demonstrated that CD163 is also detected on cancer cells, and is associated with a poor prognosis. In the present study, we detected CD163 staining on cancer cells in lung adenocarcinoma and squamous cell carcinoma (SCC), and investigated the relationship between CD163 on cancer cells and the clinical prognosis. CD163 staining was seen in 128 of 342 adenocarcinoma cases and 35 of 103 SCC cases. Among the lung adenocarcinoma cases, the progression-free survival and overall survival were significantly shorter in the CD163 high group than the CD163 low group. A similar trend was observed among the SCC cases, but the difference was not statistically significant. Additionally, a higher number of macrophages was detected in areas with CD163-positive cancer cells when compared to areas with CD163-negative cancer cells. In summary, we found that CD163-positive cancer cells are a predictor of a worse clinical course in lung adenocarcinoma and SCC.

We proposed a new primary calibration method of a laser Doppler vibrometer (LDV) using the optical modulated excitation of an electro-optical modulator and validated this approach by comparing mechanical modulated excitation with homodyne laser interferometer at the National Metrology Institute of Japan (NMIJ). The velocity sensitivity of the LDV was evaluated with the uncertainty budget at a high-frequency range up to 1 MHz, which is indicated as the upper limit of 50 kHz in ISO (International Organization for Standardization) 16063–41. As the results, we confirmed that velocity sensitivities between optical and mechanical modulated excitations are flat within their uncertainty from 100 Hz up to 1 MHz. Moreover, in order to evaluate the accurate phase shift of the accelerometer up to 20 kHz using optical modulated excitation, we also revealed the reliability of two time shifts between homodyne and heterodyne laser interferometers.

Conventional neuronal network pattern formation techniques cannot control the arrangement of axons and dendrites because network structures must be fixed before neurite differentiation. To overcome this limitation, we developed a non-destructive stepwise microfabrication technique that can be used to alter microchannels within agarose to guide neurites during elongation. Micropatterns were formed in thin agarose layer coating of a cultivation dish using the tip of a 0.7 $$\upmu \mathrm{m}$$ μ m -diameter platinum-coated glass microneedle heated by a focused 1064-nm wavelength infrared laser, which has no absorbance of water. As the size of the heat source was 0.7 $$\upmu \mathrm{m}$$ μ m , which is smaller than the laser wavelength, the temperature fell to 45 $$^\circ \hbox {C}$$ ∘ C within a distance of 7.0 $$\upmu \mathrm{m}$$ μ m from the edge of the etched agarose microchannel. We exploited the fast temperature decay property to guide cell-to-cell connection during neuronal network cultivation. The first neurite of a hippocampal cell from a microchamber was guided to a microchannel leading to the target neuron with stepwise etching of the micrometer resolution microchannel in the agarose layer, and the elongated neurites were not damaged by the heat of etching. The results indicate the potential of this new technique for fully direction-controlled on-chip neuronal network studies.

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.

Aim Several reports have shown that risperidone increases prolactin concentrations, while aripiprazole decreases prolactin concentrations. The frequency of abnormal prolactin concentrations in patients with schizophrenia receiving these drugs is still unknown. Furthermore, although hyperprolactinemia leads to sexual dysfunction, the relationship between hyperprolactinemia and testosterone, which may be directly related to male sexual function, is not well understood. Methods The subjects were 94 male schizophrenia outpatients receiving risperidone or paliperidone (risperidone group) and 83 male schizophrenia outpatients receiving aripiprazole. We measured the serum prolactin and total and free testosterone concentrations. We compared the prolactin and testosterone levels in patients receiving risperidone or paliperidone and patients receiving aripiprazole. Results The average serum prolactin concentration was 27.5 ± 13.1 ng/mL for the risperidone group and 3.9 ± 3.5 ng/mL for the aripiprazole group, and the concentrations were significantly different (P, There were very common hyperprolactinemia and hypoprolactinemia in the risperidone group and aripiprazole group, respectively. Free testosterone concentrations were associated with elevated prolactin levels in patients receiving risperidone or paliperidone.

A 10-year (2008-2017) retrospective canine-mediated human rabies epidemiology was studied to assess the burden of rabies in Nepal. To this end, the number of dog bites, the use of post-exposure prophylaxis (PEP), and human death records from 2008 to 2017 were retrieved from Sukraraj Tropical Hospital, Kathmandu, Nepal. The findings revealed that the number of human rabies occurrences was consistent with minor fluctuations throughout the study period. There were 252,297 dog bite cases in humans recorded between 2008 and 2017. Every month, 2,102 people were bitten by mostly stray dogs. There was a gradual increase in PEP use throughout 10 years. On average, 36,995 PEP dosages were used per year for stray dog bites. The PEP consumption and the number of human deaths were negatively correlated. A total of 482 human rabies deaths were recorded in Nepal during the study period. On average, 49 people died of canine-mediated rabies each year. Although there was an increase in the use of PEP, the number of human deaths and street dog bites recorded were still high. The high mortality due to rabies could then be attributed to the flawed surveillance system and stray dog population management, and not merely the lack of PEP services. Hence, it is recommended that the government agencies and other concerned stakeholders should organize mass vaccination and population management program for stray dogs in order to reduce the country’s rabies burden.

Sandwich structures have several potential applications in structural engineering because of the different material properties of the skin and core. In particular, sandwich structures with heteromorphic cores can satisfy the special requirements of engineering and structural design. In this study, to enhance the critical thermal buckling behavior of sandwich structures with heteromorphic cores, we developed a free-form optimization system based on a gradient method to optimize the core shapes under a volume constraint. The free-form optimization system combined with a finite element method code and an in-house program consists of thermal buckling analysis, initial thermal stress analysis, the derivation of the sensitivity function, velocity analysis, and shape update. According to the optimal results of the design examples, the developed free-form optimization system could significantly enhance the thermal buckling behavior of sandwich structures. In particular, by simply specifying the constraint conditions in the velocity analysis, we could maintain the initial shape of the specified parts in the heteromorphic core during the free-form optimization process to satisfy special requirements.

Introduction This study aimed to examine retrospectively the clinical backgrounds of Japanese patients with type 2 diabetes (T2D) who successfully withdrew from insulin use after being started on basal insulin in an outpatient setting. Methods The study population comprised 376 insulin-naïve patients who were started on basal insulin (glargine U100, glargine U300, or degludec) for the management of T2D and followed the treatment regimen for at least 6 months in 13 institutions in Japan. The clinical courses of the study participants were compared based on outpatient clinic medical records for the three different types of basal insulin prescribed by categorizing the participants into two groups retrospectively: those who successfully withdrew from insulin therapy and those who did not, during a 6-month observation period. The clinical determinants for insulin withdrawal were assessed using a Cox proportional hazard model. Results Glycated hemoglobin was improved in all participants regardless of basal insulin type. Of the 376 study participants, 61 successfully withdrew from basal insulin therapy. After adjustment was made for several confounders, the positive determinant factors for successful withdrawal of insulin were short duration of diabetes and high body mass index at the start of study, and the negative determinant factor was use of insulin secretagogues at the start. The types of basal insulin used by the study participants were not significant determinants of successful insulin withdrawal in this study. Conclusions Use of basal insulin is a powerful option for the treatment of T2D. In patients with high BMI and/or short duration of diabetes, short-term insulin therapy is a promising strategy for the treatment of T2D before the initiation of insulin secretagogues, since such patients have the potential to successfully withdraw from basal insulin use even in an outpatient setting.

Patients with stroke experience declined physical functions and aim to recover by rehabilitation. It is important to improve their functions in the subacute period. Hemiplegic patients who can stan...

Introduction In recent years, a shortage of surgeons and anesthesiologists, particularly in regional hospitals, has become a social issue in Japan. In such hospitals, urgent surgery at night has been performed with difficulty. Therefore, we retrospectively assessed the outcomes of appendectomies for the patients visited at nighttime in our hospital categorized as a local university hospital. Methods A retrospective review was conducted on 82 patients of acute appendicitis presented to our hospital between 5:30 p.m. to 8:30 a.m., between January 2014 and April 2019. We compared patients who underwent urgent nighttime appendectomy (group A) and patients who underwent appendectomy during the daytime, or so-called short interval appendectomy (group B). The evaluated factors were preoperative characteristics (age, sex, body mass index, cardiopulmonary complications, laboratory data, body temperature, presence of the Blumberg sign, and CT findings), operation characteristics, and postoperative characteristics (surgical-site infection [SSI], complications, and length of hospital stay). Results Patients in group A were significantly younger than patients in group B. Patients in group A were significant more likely to experience an SSI. Discussion Patients diagnosed with acute appendicitis during the nighttime can undergo short interval appendectomy, which leads to a decreased risk of SSI, has no effect on length of hospital stay after surgery, and lessens medical staff burden.

The Colonoscopy Screening and Surveillance Guidelines were developed by the Japan Gastroenterological Endoscopy Society as basic guidelines based on the scientific methods. The importance of endoscopic screening and surveillance for both detection and post-treatment follow-up of colorectal cancer has been recognized as essential to reduce disease mortality. There is limited high-level evidence in this field; therefore, we had to focus on the consensus of experts. These clinical practice guidelines consist of 20 clinical questions and eight background knowledge topics that have been determined as the current guiding principles.

Background: Previous studies have linked residential displacement as a result of the 2011 East Japan Earthquake to increases in body weight. However, no study has examined longer-term trajectories of body weight among displaced survivors. We compared body weight change between survivors relocated to temporary housing (TH) group versus other types of accommodation for up to 5 years after the Great East Japan Earthquake. Methods: Longitudinal follow-up was conducted from 2011 to 2015 in a cohort of 9,909 residents of 42,831. We compared trends in body weight in the TH group (n = 3,169) and the non-TH group (n = 6,740) using a mixed linear regression model stratified by sex (mean age, 61.0 years old; male, 38.9%). Results: In age-adjusted analysis, the body weight in the 2011 survey was not significantly different between two groups for either sex. In men, the TH group significantly increased body weight compared to the non-TH group since 2012. In women, body weight sharply increased in the TH group while body weight did not change in the non-TH group during survey time points. The interaction of living conditions and survey years was statistically significant in both sexes (men; F-value, 6.958; P < 0.001: women; F-value, 19.127; P < 0.001). Conclusion: Survivors relocated to temporary housing had an increased risk of weight gain. The weight gain in this group is a potential risk factor for metabolic syndrome in the post-disaster period.

Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real‐world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1–75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2–357). Adverse events occurred in 12.7%. Life‐threatening complications occurred in 0.5%, but there were no treatment‐related deaths. During a median follow‐up period of 46.1 months (range 1–113), the 3‐year overall survival rate, relapse‐free survival rate, cause‐specific survival rate, and larynx‐preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment. Clinical trials registry number: UMIN000008276., This is the first report on nationwide survival data and pathological criteria of superficial head and neck cancer. Transoral surgery for superficial head and neck cancer was safe and offered highly curative minimally invasive treatment preserving organs and their function. Subepithelial invasion was clinically useful predictor of recurrence after transoral surgery.

Stroke, spinal cord injury and other neuromuscular disorders lead to impairments in the human body. Upper limb impairments, especially hand impairments affect activities of daily living (ADL) and reduce the quality of life. The purpose of this review is to compare and evaluate the available robotic rehabilitation and assistive devices that can lead to motor recovery or maintain the current motor functional level.A systematic review was conducted of the literature published in the years from 2016-2021, to focus on the most recent rehabilitation and assistive devices available in the market or research environments.A total of 230 studies published between 2016 and 2021 were identified from various databases. 107 were excluded with various reasons. Twenty-eight studies were taken into detailed review, to determine the efficacy of robotic devices in improving upper limb impairments or maintaining the current level from getting worse.It was concluded that with a good strategy and treatment plan; appropriate and regular use of these robotic rehabilitation and assistive devices do lead to improvements in current conditions of most of the subjects and prolonged use may lead to motor recovery.Implications for RehabilitationStroke, accidents, spinal cord injuries and other neuromuscular disorders lead to impairments. Upper limb impairments have a tremendous adverse affect on ADL and reduces quality of life drastically.Advancement in technology has led to the designing of many robotic assistive and rehabilitation devices to assist in motor recovery or aid in ADL.This review analyses different available devices for rehabilitation and assistance and points out that use of these devices in time does help in motor recovery. Most of the studies reviewed showed improvements for the user.Future devices should be more portable and easier to use from home.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tickborne infectious disease caused by SFTS virus (SFTSV). We report 7 cases of spontaneous fatal SFTS in felines. Necropsies revealed characteristic lesions, including necrotizing lymphadenitis in 5 cases and necrotizing splenitis and SFTSV-positive blastic lymphocytes in all cases. We detected hemorrhagic lesions in the gastrointestinal tract in 6 cases and lungs in 3 cases, suggesting a more severe clinical course of SFTS in felids than in humans. We noted necrotic or ulcerative foci in the gastrointestinal tract in 3 cases, the lung in 2 cases, and the liver in 4 cases. We clarified that blastic lymphocytes are predominant targets of SFTSV and involved in induction of necrotic foci. We also found that thymic epithelial cells were additional targets of SFTSV. These results provide insights for diagnosing feline SFTS during pathological examination and demonstrate the similarity of feline and human SFTS cases.

Background Depopulation accompanied by population aging is a major public health concern in Japan. Although adequate allocation of mental healthcare resources is needed, there have been few studies on the impact of population change on the supply–demand balance for mental illness in Japan. The aim of this study is to predict psychiatrists' distribution for patients with mental illness via a utilization-based approach. Methods We set patients with schizophrenia, mood disorders, vascular dementia or Alzheimer’s disease as study subjects and conducted analyses for 2015, 2025, 2035, and 2045 across all prefectures. Moreover, we evaluated the regional maldistribution of demand and supply by calculating the number of psychiatrists per patient, Gini coefficients (GC), and Herfindahl–Hirschman Index (HHI). Results The mean number of psychiatrists per patient for patients with schizophrenia, mood disorders, vascular dementia, and Alzheimer’s disease in 2025, 2035, and 2045 was significantly lower than in 2015. For all of the abovementioned diseases, both the GC and HHI will increase until 2045. Conclusion If psychiatrists are allocated at the current population-to-psychiatrist ratio, the shortage of psychiatrists will continue to worsen in the future. To overcome this inequity, policy makers should make plans to shift responsibilities from psychiatrists to other mental health workers and to ensure the adequate geographical allocation of healthcare resources.

The prognosis of multiple myeloma (MM) has improved with the introduction of novel agents. These data are largely derived from clinical trials and might not reflect real-world patient outcomes accurately. We surveyed real-world data from 284 patients newly diagnosed with MM between 2010 and 2018 in Miyazaki Prefecture. The median follow-up period was 32.8 months. The median age at diagnosis was 71 years, with 68% of patients aged &gt, 65 years. The International Staging System (ISS) stage at diagnosis was I in 18.4% of patients, II in 34.1%, and III in 47.5%. Bortezomib-containing regimens were preferred as initial treatment, they were used in 147 patients (51.8%). In total, 80% of patients were treated with one or more novel agents (thalidomide, lenalidomide, or bortezomib). Among 228 patients who were treated with novel agents as an initial treatment, the overall response rate (partial response (PR) or better) to initial treatment was 78.4%, and the median time to next treatment (TTNT) was 11.6 months. In the multivariate analysis, PR or better responses to initial treatment were independently favorable prognostic factors for TTNT. The median survival time after initial therapy for patients with novel agents was 56.4 months and 3-year overall survival (OS) was 70.4%. In multivariate analysis, ISS stage I/II disease and PR or better response to initial treatment, and autologous stem cell transplantation (ASCT) were identified as independent prognostic factors for overall survival (OS).

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.