Development of branchial ionocytes in embryonic and larval stages of cloudy catshark, Scyliorhinus torazame.

In teleost fish, branchial ionocytes are important sites for osmoregulation and acid-base regulation by maintaining ionic balance in the body fluid. During the early developmental stages before the formation of the gills, teleost ionocytes are localized in the yolk-sac membrane and body skin. By comparing with teleost fish, much less is known about ionocytes in developing embryos of elasmobranch fish. The present study investigated the development of ionocytes in the embryo and larva of cloudy catshark, Scyliorhinus torazame. We first observed ionocyte distribution by immunohistochemical staining with anti-Na+/K+-ATPase (NKA) and anti-vacuolar-type H+-ATPase (V-ATPase) antibodies. The NKA- and V-ATPase-rich ionocytes appeared as single cells in the gill filaments from stage 31, the stage of pre-hatching, while the ionocytes on the body skin and yolk-sac membrane were also observed. From stage 32, in addition to single ionocytes on the gill filaments, some outstanding follicular structures of NKA-immunoreactive cells were developed to fill the inter-filament region of the gill septa. The follicular ionocytes possess NKA in the basolateral membrane and Na+/H+ exchanger 3 in the apical membrane, indicating that they are involved in acid-base regulation like single NKA-rich ionocytes. Three-dimensional analysis and whole-mount immunohistochemistry revealed that the distribution of follicular ionocytes was limited to the rostral side of gill septum. The rostral sides of gill septum might be exposed to faster water flow than caudal side because the gills of sharks gently curved backward. This dissymmetric distribution of follicular ionocytes is considered to facilitate efficient body-fluid homeostasis of catshark embryo.

Simple mathematical model for predicting COVID-19 outbreaks in Japan based on epidemic waves with a cyclical trend.

BACKGROUND: Several models have been used to predict outbreaks during the COVID-19 pandemic, with limited success. We developed a simple mathematical model to accurately predict future epidemic waves. METHODS: We used data from the Ministry of Health, Labour and Welfare of Japan for newly confirmed COVID-19 cases. COVID-19 case data were summarized as weekly data, and epidemic waves were visualized and identified. The periodicity of COVID-19 in each prefecture of Japan was confirmed using time-series analysis and the autocorrelation coefficient, which was used to investigate the longer-term pattern of COVID-19 cases. Outcomes using the autocorrelation coefficient were visualized via a correlogram to capture the periodicity of the data. An algorithm for a simple prediction model of the seventh COVID-19 wave in Japan comprised three steps. Step 1: machine learning techniques were used to depict the regression lines for each epidemic wave, denoting the "rising trend line"; Step 2: an exponential function with good fit was identified from data of rising straight lines up to the sixth wave, and the timing of the rise of the seventh wave and speed of its spread were calculated; Step 3: a logistic function was created using the values calculated in Step 2 as coefficients to predict the seventh wave. The accuracy of the model in predicting the seventh wave was confirmed using data up to the sixth wave. RESULTS: Up to March 31, 2023, the correlation coefficient value was approximately 0.5, indicating significant periodicity. The spread of COVID-19 in Japan was repeated in a cycle of approximately 140 days. Although there was a slight lag in the starting and peak times in our predicted seventh wave compared with the actual epidemic, our developed prediction model had a fairly high degree of accuracy. CONCLUSION: Our newly developed prediction model based on the rising trend line could predict COVID-19 outbreaks up to a few months in advance with high accuracy. The findings of the present study warrant further investigation regarding application to emerging infectious diseases other than COVID-19 in which the epidemic wave has high periodicity.

Extremely Poor Post-discharge Prognosis in Aspiration Pneumonia and Its Prognostic Factors: A Retrospective Cohort Study.

There is little evidence regarding the long-term prognosis of patients with aspiration pneumonia. This study aimed to investigate post-discharge survival time and prognostic factors in older patients hospitalized for aspiration pneumonia. This retrospective cohort study included patients aged ≥ 65 years hospitalized for aspiration pneumonia and discharged alive from a tertiary care hospital in Japan between April 2009 and September 2014. Candidate prognostic factors were patient's age, sex, body mass index (BMI), performance status, chronic conditions, CURB-65 score, serum albumin level, hematocrit concentration, nutritional pathway at discharge, and discharge location. Kaplan-Meier curves were determined and multivariable survival analysis using Cox regression model was performed to analyze the effect of each factor on mortality. In total, 209 patients were included in this study. The median age was 85 years, 58% of the patients were males, 33% had a performance status of 4 and 34% were discharged home. Among the patients, 65% received oral intake, 23% received tube feeding, and 21% received parenteral nutrition at discharge. During the follow-up period, 77% of the patients died, and the median post-discharge survival time was 369 days. Besides male sex and low BMI, tube feeding (adjusted hazard ratio (aHR) = 1.70, 95% confidence interval (CI) 1.11-2.59) and parenteral nutrition (aHR = 4.42, 95% CI 2.57-7.60) were strongly associated with mortality. Long-term prognosis of patients hospitalized for aspiration pneumonia was extremely poor. The nutritional pathway at discharge was a major prognostic factor. These results may be useful for future care and research.

Photo-Electro-Biochemical H2 Production Using the Carbon Material-Based Cathode Combined with Genetically Engineered Escherichia coli Whole-Cell Biocatalysis.

Abio/bio hybrids, which incorporate biocatalysts that promote efficient and selective material conversions under mild conditions into existing catalytic reactions, have attracted considerable attention for developing new catalytic systems. This study constructed a H2 -forming biocathode based on a carbon material combined with whole-cell biocatalysis of genetically-engineered-hydrogenase-overproducing Escherichia coli for the photoelectrochemical water splitting for clean H2 production. Low-cost and abundant carbon materials are generally not suitable for H2 -forming cathode due to their high overpotential for proton reduction; however, the combination of the reduction of an organic electron mediator on the carbon electrode and the H2 formation with the reduced mediator by the redox enzyme hydrogenase provides a H2 -forming cathodic reaction comparable to that of the noble metal electrode. The present study demonstrates that the recombinant E. coli whole cell can be employed as a part of the H2 -forming biocathode system, and the biocathode system wired with TiO2 photoanode can be a photoelectrochemical water-splitting system without external voltage assistance under natural pH. The findings of this study expand the feasibility of applications of whole-cell biocatalysis and contribute to obtaining solar-to-chemical conversions by abio/bio hybrid systems, especially for low-cost, noble-metal-free, and clean H2 production.

Granulocyte colony-stimulating factor-induced aortitis with temporal arteritis and monoarthritis.

We present the case of a patient in his 80s receiving gemcitabine-cisplatin therapy for bladder cancer who developed neutropenia and was treated with filgrastim. In 10 days, the patient developed a mild fever with left jaw claudication and right knee arthritis. Contrast-enhanced CT findings indicated aortitis. Prednisolone was started for granulocyte colony-stimulating factor (G-CSF)-induced aortitis, and symptoms and elevated serum inflammatory markers resolved rapidly, allowing early discontinuation of prednisolone. Right knee arthritis relapsed at the initial follow-up. Contrast-enhanced CT revealed aortitis had disappeared. Therefore, recurrence of G-CSF-induced arthritis was suspected; prednisolone was resumed for 29 days without relapse. Most previous reports of G-CSF-induced aortitis have described inflammation of the aorta, carotid arteries and subclavian arteries; however, G-CSF-induced aortitis may present with more peripheral symptoms, such as temporal arteritis and knee arthritis. Furthermore, G-CSF-induced aortitis reportedly responds well and rapidly to prednisolone, although early discontinuation may lead to relapse.

Multimorbidity patterns and the relation to self-rated health among older Japanese people: a nationwide cross-sectional study.

OBJECTIVES: Classifying individuals into multimorbidity patterns can be useful to identify the target population with poorer clinical outcomes. Self-rated health (SRH) is one of the core outcomes in multimorbidity patients. Although studies have reported that multimorbidity is associated with poor SRH, whether certain patterns have stronger associations remains unknown. Therefore, this study aimed to identify the prevalence and patterns of multimorbidity and investigate the association between multimorbidity patterns and SRH in an older Japanese population. DESIGN: Cross-sectional study. SETTING: Data were obtained from the 2013 Comprehensive Survey of Living Conditions, a nationally representative survey of the general Japanese population. PARTICIPANTS: This study mainly examined 23 730 participants aged ≥65 years who were not hospitalised or institutionalised. PRIMARY OUTCOME MEASURE: Poor SRH was defined as choosing 'not very good' or 'bad' from five options: 'excellent', 'fairly good', 'average', 'not very good' and 'bad'. RESULTS: The prevalence of multimorbidity was 40.9% and that of poor SRH was 23.8%. Three multimorbidity patterns were identified by exploratory factor analysis: (1) degenerative/mental health, (3) malignant/digestive/urological/haematological and (3) cardiovascular/metabolic. Multivariable modified Poisson regression analysis revealed that high malignant/digestive/urological/haematological, degenerative/mental health and cardiovascular/metabolic pattern scores, corresponding to the number of affected body systems in each pattern, were significantly associated with poor SRH (adjusted risk ratio (aRR)=1.68, 95% CI: 1.60 to 1.76; aRR=1.63, 95% CI: 1.58 to 1.69; and aRR=1.31, 95% CI: 1.26 to 1.36, respectively). When including the Kessler 6 score, a screening scale for psychological distress, in the analysis, the association between each multimorbidity pattern score and poor SRH decreased. CONCLUSIONS: Malignant/digestive/urological/haematological and degenerative/mental health patterns may be associated with a high risk for poor SRH. Further research should focus on interventions to improve SRH in multimorbidity patients.

Development of a culturally adaptable internet-based cognitive behavioral therapy for Japanese women with bulimia nervosa.

Background: The process of cultural adaptation of internet-based cognitive behavioral therapy (ICBT) programs for bulimia nervosa (BN) have rarely been reported despite the potential influence of cultural adaptation of psychosocial interventions on therapeutic response. Aim: This study aimed to illustrate development process of an ICBT program for Japanese women with bulimia nervosa (BN). Methods: A mixed methods approach was used to assess cultural adaptation of the prototype of an original ICBT program by using the Cultural Relevance Questionnaire (CRQ). Five women with BN and seven clinicians were interviewed using the CRQ. Results: Quantitative analyses were conducted to assess cultural adaptation of the prototype of the program and participants rated cultural adaptation as high. A qualitative analysis of the mixed method supported the culturally sensitive changes implemented. Conclusions: The results of this study show that a series of processes can make ICBT programs more culturally adapted.

Effectiveness of angiotensin converting enzyme inhibitors in preventing pneumonia: A systematic review and meta-analysis.

We performed a systematic review and meta-analysis to re-evaluate the effectiveness of angiotensin-converting enzyme inhibitors (ACE-I) in the reduction of pneumonia risk. We searched relevant publications in five databases. All studies included patients older than 18 years, who had used ACE-I as an intervention, and had assessed pneumonia. Seven RCTs (n = 8704) and 38 observational studies (n = 1,705,030) were included. The overall risk of bias was high. ACE-I-treated patients were associated with a slightly lower risk of pneumonia, both from pooled estimates of RCTs [pooled odds ratio (OR), 0.75; 95% confidence interval (CI), 0.62-0.90; low certainty of evidence] and observational studies (pooled OR, 0.85; 95% CI, 0.78-0.92; very low certainty of evidence). Considering the small effect size of ACE-I in preventing pneumonia and the low quality of the evidence, routine use of ACE-I for pneumonia prevention is not recommended.

Sustainable Approach for Peroxygenase-Catalyzed Oxidation Reactions Using Hydrogen Peroxide Generated from Spent Coffee Grounds and Tea Leaf Residues.

Peroxygenases are promising catalysts for use in the oxidation of chemicals as they catalyze the direct oxidation of a variety of compounds under ambient conditions using hydrogen peroxide (H2O2) as an oxidant. Although the use of peroxygenases provides a simple method for oxidation of chemicals, the anthraquinone process currently used to produce H2O2 requires significant energy input and generates considerable waste, which negatively affects process sustainability and production costs. Thus, generating H2O2 for peroxygenases on site using an environmentally benign method would be advantageous. Here, we utilized spent coffee grounds (SCGs) and tea leaf residues (TLRs) for the production of H2O2. These waste biomass products reacted with molecular oxygen and effectively generated H2O2 in sodium phosphate buffer. The resulting H2O2 was utilized by the bacterial P450 peroxygenase, CYP152A1. Both SCG-derived and TLR-derived H2O2 promoted the CYP152A1-catalyzed oxidation of 4-methoxy-1-naphthol to Russig's blue as a model reaction. In addition, when CYP152A1 was incubated with styrene, the SCG and TLR solutions enabled the synthesis of styrene oxide and phenylacetaldehyde. This new approach using waste biomass provides a simple, cost-effective, and sustainable oxidation method that should be readily applicable to other peroxygenases for the synthesis of a variety of valuable chemicals.

Chronic kidney disease is a key predictive factor for potential myocardial ischaemia and poor prognosis in asymptomatic patients with diabetes mellitus.

Some asymptomatic patients with diabetes mellitus (DM) have critical coronary artery disease (CAD), although the guidelines do not recommend aggressive screening for CAD in asymptomatic patients. Chronic kidney disease (CKD) is among the serious co-morbidities of severe systemic atherosclerosis. Thus, CKD may be associated with potential myocardial ischaemia. Therefore, the present study aimed to determine the impact of CKD on the incidence of silent myocardial ischaemia (SMI) and the long-term outcomes in asymptomatic patients with DM. This study investigated 461 consecutive patients with DM. All patients who were asymptomatic and self-sufficient in daily life underwent the ergometer exercise (ERG) test. Coronary angiography was performed if the stress test was positive, or if the patient did not achieve 90% of the target heart rate. The primary end point included major adverse cardiac and cerebrovascular events (MACCE) including death, non-fatal myocardial infarction and stroke. The median follow-up duration after study enrolment was 35 months for the entire cohort of 461 patients. Eighty-one patients were diagnosed with SMI. The estimated glomerular filtration rate was significantly lower in the SMI group (70.5 ± 23.8 vs. 81.8 ± 30.0 mL/min/1.73 m2, P < 0.001). SMI occurred more frequently in patients with advanced CKD [27/103, (26.2%) in stages 3-5], whereas only 5/68 (7.3%) patients without CKD, 13/81 (16.0%) patients with stage 1 CKD and 36/209, (17.2%) in stage 2, had SMI. The Kaplan-Meier curves revealed that, patients with SMI had poor clinical outcomes (log-rank: P = 0.016). The incidence of MACCE (log-rank: P = 0.009) was higher in patients with severe CKD > stage 3a in the SMI subgroup. Urinary albumin (mg/gCr) was associated with MACCE in the SMI subgroup [HR 3.37, 95%CI (1.170-9.521), P = 0.025] after adjusting for age, sex, and conventional risk factors. SMI was more prevalent in patients with CKD and the incidence was proportional to the CKD stage in asymptomatic patients with DM. Those Patients with CKD and SMI exhibited poor clinical outcomes. CKD may be a key factor for the identification and management of SMI in asymptomatic patients with DM in routine clinical practice.Trial Registration: UMIN000038340.

Intravascular large B-cell lymphoma causing hypopituitarism and respiratory failure due to infiltration into pulmonary capillaries.

We report a rare case of intravascular large B-cell lymphoma (IVLBCL) with hypopituitarism and respiratory failure. A man in his 80s presented with hypotension and respiratory failure but was unsuccessfully treated for septic shock. Biological investigations were performed, and he was diagnosed with hypopituitarism due to insufficient secretion of anterior pituitary hormone. Although his condition temporarily improved following hormone replacement therapy, he eventually died of progressive respiratory failure. The lymphoma was only discovered during the autopsy, where it was observed to have spread to the pituitary gland and lung capillaries. Therefore, we concluded that the lymphoma had caused respiratory failure and hypopituitarism. The patient was thus diagnosed with IVLBCL posthumously. In conclusion, IVLBCL can cause hypopituitarism and respiratory failure due to pituitary and pulmonary capillary invasion by lymphoma cells.

Transition-Metal-Free O-Arylation of Alcohols and Phenols with S-Arylphenothiaziniums.

Herein, we report the transition-metal-free O-arylation of alcohols and phenols with S-arylphenothiaziniums, which can be easily synthesized from boronic acids. Aryl substituents derived from arylboronic acids were selectively introduced into the hydroxy groups in alcohols and phenols, and a variety of aryl ethers were synthesized. This selectivity is supported by theoretical calculations.

Molecular mechanism of nutrient uptake in developing embryos of oviparous cloudy catshark (Scyliorhinus torazame).

Forms of embryonic nutrition are highly diverse in cartilaginous fishes, which contain oviparity, yolk-sac viviparity and several types of matrotrophic viviparity (histotrophy, oophagy, and placentotrophy). The molecular mechanisms of embryonic nutrition are poorly understood in these animals as few species are capable of reproducing in captivity. Oviparous cartilaginous fishes solely depend on yolk nutrients for their growth and development. In the present study, we compared the contribution to embryonic nutrition of the embryonic intestine with the yolk sac membrane (YSM). RNA-seq analysis was performed on the embryonic intestine and YSM of the oviparous cloudy catshark Scyliorhinus torazame to identify candidate genes involved in nutrient metabolism to further the understanding of nutrient utilization of developing embryos. RNA-seq discovery was subsequently confirmed by quantitative PCR analysis and we identified increases in several amino acid transporter genes (slc3a1, slc6a19, slc3a2, slc7a7) as well as genes involved in lipid absorption (apob and mtp) in the intestine after 'pre-hatching', which is a developmental event marked by an early opening of the egg case about 4 months before hatching. Although a reciprocal decrease in the nutritional role of YSM was expected after the intestine became functional, we observed similar increases in gene expression among amino acid transporters, lipid absorption molecules, and lysosomal cathepsins in the extraembryonic YSM in late developmental stages. Ultrastructure of the endodermal cells of YSM showed that yolk granules were incorporated by endocytosis, and the number of granules increased during development. Furthermore, the digestion of yolk granules in the YSM and nutrient transport through the basolateral membrane of the endodermal cells appeared to be enhanced after pre-hatching. These findings suggest that nutrient digestion and absorption is highly activated in both intestine and YSM after pre-hatching in catshark embryos, which supports the rapid growth at late developmental stages.

N-Methylphenothiazine S-Oxide Enabled Oxidative C(sp2)-C(sp2) Coupling of Boronic Acids with Organolithiums via Phenothiaziniums.

Herein, we report the development of a transition-metal-free oxidative C(sp2)-C(sp2) coupling of readily available boronic acids and organolithiums via phenothiazinium ions. Various biaryl, styrene, and diene derivatives were obtained using this reaction system. The key to this process is N-methylphenothiazine S-oxide (PTZSO), which allows efficient conversion of boronic acids to phenothiazinium ions. The mechanism of phenothiazinium formation using PTZSO was investigated using theoretical calculations and experiments, which provided insight into the unique reactivity of PTZSO.

PD-L1 on mast cells suppresses effector CD8+ T-cell activation in the skin in murine contact hypersensitivity.

BACKGROUND: The programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) pathway is known to inhibit the activation of effector CD8+ T cells. However, just how this regulatory pathway is involved in the pathophysiology of CD8+ T-cell-mediated inflammatory skin diseases remains unclear. OBJECTIVE: Our aim was to elucidate the mechanisms by which the PD-1/PD-L1 pathway exerts its regulatory roles in CD8+ T-cell-mediated cutaneous immune responses. METHODS: PD-L1-deficient (Pdl1-/-) mice were used for the murine contact hypersensitivity model. Inflammatory responses such as IFN-γ production from CD8+ T cells in the skin was evaluated by flow cytometry. RESULTS: Compared with wild-type mice, Pdl1-/- mice exhibited exacerbated ear swelling and increased numbers of IFN-γ+ CD8+ T cells in the skin. Adoptive T-cell transfer experiments revealed the involvement of the PD-1/PD-L1 pathway in the elicitation phase of contact hypersensitivity. Bone marrow chimera experiments showed that PD-L1 on radioresistant cells was responsible for this regulatory pathway. Flow cytometric analysis revealed that among the radioresistant cells in the skin, PD-L1 was most highly expressed on mast cells (MCs) before and after elicitation. Administration of anti-PD-L1 blocking antibody during the elicitation phase significantly enhanced ear swelling responses and increased the number of IFN-γ+CD8+ T cells in the skin of wild-type mice, whereas no significant effects were observed in MC-deficient (WBB6F1/J-KitW/KitW-v/J and C57BL/6-KitW-sh/W-sh) mice. The high level of expression of PD-L1 on human skin MCs was confirmed by database analysis and immunohistochemical analysis. CONCLUSION: PD-L1 on MCs negatively regulates CD8+ T-cell activation in the skin.

Enhanced image sensing with avalanche multiplication in hybrid structure of crystalline selenium photoconversion layer and CMOSFETs.

The recent improvements of complementary metal-oxide-semiconductor (CMOS) image sensors are playing an essential role in emerging high-definition video cameras, which provide viewers with a stronger sensation of reality. However, the devices suffer from decreasing sensitivity due to the shrinkage of pixels. We herein address this problem by introducing a hybrid structure comprising crystalline-selenium (c-Se)-based photoconversion layers and 8 K resolution (7472 × 4320 pixels) CMOS field-effect transistors (FETs) to amplify signals using the avalanche multiplication of photogenerated carriers. Using low-defect-level NiO as an electric field buffer and an electron blocking layer, we confirmed signal amplification by a factor of approximately 1.4 while the dark current remained low at 2.6 nA/cm2 at a reverse bias voltage of 22.6 V. Furthermore, we successfully obtained a brighter image based on the amplified signals without any notable noise degradation.

Photo-biohydrogen Production by Photosensitization with Biologically Precipitated Cadmium Sulfide in Hydrogen-Forming Recombinant Escherichia coli.

An inorganic-biological hybrid system that integrates features of both stable and efficient semiconductors and selective and efficient enzymes is attractive for facilitating the conversion of solar energy to hydrogen. In this study, we aimed to develop a new photocatalytic hydrogen-production system based on Escherichia coli whole-cell genetically engineered as a biocatalysis for highly active hydrogen formation. The photocatalysis part was obtained by bacterial precipitation of cadmium sulfide (CdS), which is a visible-light-responsive semiconductor. The recombinant E. coli cells were sequentially subjected to CdS precipitation and heterologous [FeFe]-hydrogenase synthesis to yield a CdS@E. coli hybrid capable of light energy conversion and hydrogen formation in a single cell. The CdS@E. coli hybrid achieved photocatalytic hydrogen production with a sacrificial electron donor, thus demonstrating the feasibility of our system and expanding the current knowledge of photosensitization using a whole-cell biocatalyst with a bacterially precipitated semiconductor.

Morphological and functional development of the spiral intestine in cloudy catshark (Scyliorhinus torazame).

Cartilaginous fish have a comparatively short intestine known as the spiral intestine that consists of a helical spiral of intestinal mucosa. However, morphological and functional development of the spiral intestine has not been fully described. Unlike teleosts, cartilaginous fish are characterized by an extremely long developmental period in ovo or in utero; for example, in the oviparous cloudy catshark (Scyliorhinus torazame), the developing fish remains inside the egg capsule for up to 6 months, suggesting that the embryonic intestine may become functional prior to hatching. In the present study, we describe the morphological and functional development of the spiral intestine in the developing catshark embryo. Spiral formation of embryonic intestine was completed at the middle of stage 31, prior to 'pre-hatching', which is a developmental event characterized by the opening of the egg case at the end of the first third of development. Within 48 h of the pre-hatching event, egg yolk began to flow from the external yolk sac into the embryonic intestine via the yolk stalk. At the same time, there was a rapid increase in mRNA expression of the peptide transporter pept1 and neutral amino acid transporter slc6a19 Secondary folds in the intestinal mucosa and microvilli on the apical membrane appeared after pre-hatching, further supporting the onset of nutrient absorption in the developing intestine at this time. We demonstrate the acquisition of intestinal nutrient absorption at the pre-hatching stage of an oviparous elasmobranch.

Influence of sex on the incidence of potential coronary artery disease and long-term outcomes in asymptomatic patients with diabetes mellitus.

BACKGROUND: Diabetic patients often have coronary artery disease (CAD) without symptoms. It is known that females tend to have silent or less chest pain and worse prognoses when they develop acute coronary syndrome. Thus, sex differences may impact long-term outcomes in diabetes mellitus (DM) patients with silent myocardial ischemia (SMI). The present study aimed to assess the influence of sex on long-term outcomes in DM patients with SMI. METHODS: A total of 461 consecutive asymptomatic and self-sufficient DM patients seen at our hospital from 2011 to 2017 were prospectively reviewed. Patients underwent an ergometer exercise test. When the exercise test was positive or the patient could not achieve 90% of their target heart rate, coronary angiography was performed. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCEs), including death, non-fatal myocardial infarction, and stroke. RESULTS: SMI was diagnosed in 81 patients. The median follow-up duration from diagnosis was 35 (15-57) months. The incidence of SMI was similar in females and males [34/170 (20%) vs. 47/291 (16.2%), p = 0.36]. Enrolled patients were divided into four groups according to sex and the presence/absence of SMI. Female patients with SMI showed worse clinical outcomes. After adjustment for age and coronary risk factors, female SMI was independently associated with MACCEs [hazard ratio 2.59, 95% confidence interval 1.07-5.68, p = 0.024], while male SMI was not. CONCLUSIONS: Female SMI was associated with worse long-term outcomes in DM patients. Early diagnosis of potential SMI and appropriate care are required in female DM patients. (UMIN000038340).