Associations between circulating levels of FABP4 and TNF receptors are more evident in patients with type 2 diabetes mellitus than in patients with type 1 diabetes mellitus.

BACKGROUND: Fatty acid-binding protein 4 (FABP4) is an adipokine that plays significant roles in the development of insulin resistance and atherosclerosis. High levels of soluble tumor necrosis factor receptors (TNFRs) including TNFR1 and TNFR2 are associated with renal dysfunction and increased mortality in patients with diabetes mellitus (DM). However, the association between circulating levels of FABP4 and TNFRs remains unclear. METHODS: We investigated the associations of FABP4 with TNFRs and metabolic markers in Japanese patients with type 1 DM (T1DM, n=76, men/women: 31/45) and type 2 DM (T2DM, n=575, men/women: 312/263). RESULTS: FABP4 concentration was positively correlated with levels of TNFR1 and TNFR2 in both patients with T1DM and those with T2DM. Multivariable regression analyses showed that there were independent associations of FABP4 concentration with body mass index (BMI) and estimated glomerular filtration rate (eGFR) after adjustment of age and sex in both patients with T1DM and those with T2DM. FABP4 concentration was independently associated with circulating levels of TNFR1 and TNFR2 after adjustment of the confounders in patients with T2DM but not in those with T1DM. Similarly, levels of TNFR1 and TNFR2 were independently associated with FABP4 concentration after adjustment of age, sex, systolic blood pressure, duration of DM and levels of eGFR, high-density lipoprotein cholesterol and C-reactive protein in patients with T2DM but not in those with T1DM. CONCLUSION: FABP4 concentration is independently associated with levels of TNFRs in patients with DM, but the association is more evident in patients with T2DM than in those with T1DM.

Influence of the COVID-19 pandemic on the achievement of guideline targets for HbA1c, blood pressure, and LDL cholesterol in people with diabetes in Japan.

Objective: In this study, we investigated whether the COVID-19 pandemic affected achievement of guideline targets for HbA1c, blood pressure (BP), and low-density lipoprotein (LDL) cholesterol in people with diabetes mellitus (DM). Materials and methods: Data for 556 people with DM who were treated regularly for 4 years before and during the COVID-19 pandemic in Japan were analyzed in this retrospective study. Achieved targets were defined as HbA1c < 7.0%, BP < 130/80 mmHg, and LDL cholesterol < 100 or < 120 mg/dL depending on the presence or absence of coronary artery disease. Results: In 2019, before the start of the COVID-19 pandemic, achievement rates of guideline targets for HbA1c, BP and LDL cholesterol were 53.4%, 45.9% and 75.7%, respectively. In 2020, the achievement rates for HbA1c and BP targets were significantly decreased to 40.8% and 31.3%, respectively. The achievement rates for the HbA1c target gradually recovered to 49.3% in 2021 and to 51.1% in 2022. However, recovery in achieving the BP target was slow, remaining at 40.5% even in 2022. On the other hand, the achievement rate for the LDL cholesterol target was not affected and remained relatively high during the COVID-19 pandemic. Conclusions: The rates of achieving therapeutic targets for HbA1c and BP have not been high enough in people with DM, and the rates were further reduced by lifestyle changes due to the COVID-19 pandemic. Although there has been a trend toward improvement with the lifting of behavioral restrictions, more intensified treatment is necessary to achieve good control. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-024-00715-8.

Metabolic dysfunction-associated steatotic liver disease (SLD) and alcohol-associated liver disease, but not SLD without metabolic dysfunction, are independently associated with new onset of chronic kidney disease during a 10-year follow-up period.

AIMS: The new nomenclature of steatotic liver disease (SLD) including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) has recently been proposed. We aimed to elucidate the relationship between each category of SLD and chronic kidney disease (CKD). METHODS: We investigated the effects of various SLDs on the development of CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or positive for urinary protein, during a 10-year period in 12 138 Japanese subjects (men / women, 7984/4154; mean age, 48 years) who received annual health examinations including abdominal ultrasonography. RESULTS: The prevalences of SLD without metabolic dysfunction (SLD-MD[-]), MASLD, MetALD, and ALD were 1.7%, 26.3%, 4.9%, and 1.9%, respectively. During the follow-up period, 1963 subjects (16.2%) (men / women, 1374 [17.2%]/589 [14.2%]) had new onset of CKD. Multivariable Cox proportional hazard model analyses after adjustment of age, sex, eGFR, current smoking habit, diabetes mellitus, hypertension, and dyslipidemia showed that the hazard ratios (HR [95% confidence interval]) for the development of CKD in subjects with MASLD (1.20 [1.08-1.33], p = 0.001) and those with ALD (1.41 [1.05-1.88], p = 0.022), but not those with MetALD (1.11 [0.90-1.36], p = 0.332), were significantly higher than the HR in subjects with non-SLD. Interestingly, subjects with SLD-MD[-] had a significantly lower HR (0.61 [0.39-0.96], p = 0.034) than that in subjects with non-SLD. The addition of the novel classification of SLDs into traditional risk factors for the development of CKD significantly improved the discriminatory capacity. CONCLUSIONS: MASLD and ALD, but not SLD-MD[-], are independently associated with the development of CKD.

Straightforward and immediate ultrasound-guided kidney biopsy using a guide needle technique to get adequate tissue with reduced procedural time.

BACKGROUND: A streamlined and effective renal biopsy technique is essential for all nephrologists, particularly those who are less experienced, such as residents. Herein, we report the efficacy of a Straightforward and Immediate ultrasound-guided kidney biopsy using a Guide Needle (SIGN) technique, which allows operators to insert a biopsy gun through a guide needle placed into the fascia of the posterior abdominal wall. METHODS: A retrospective cross-sectional study was conducted at a nephrology training institution to compare the time spent on the procedure and the number of glomeruli obtained between a group using the SIGN (n = 81) and a group using the conventional ultrasound-guided kidney biopsy technique with a needle guide device (n = 143). RESULTS: The median procedure time in the SIGN group (2 min, interquartile range [IQR]: 1-3 min) was significantly shorter than that in the conventional group (3 min, IQR: 2-4 min) (P < 0.001). Multivariable linear regression and logistic regression analyses adjusted for covariates, including operators (board-certificated nephrologists or nephrology residents), showed that the use of the SIGN technique was independently associated with a high number of glomeruli obtained and a procedure time above 2 min as the median value (odds ratio: 0.17, 95% confidence interval CI 0.09-0.34). The prevalence of complications was comparable between the two groups (P = 0.681). CONCLUSION: The SIGN technique reduces the procedure time and obtains adequate biopsy tissue regardless of the operator's experience. SIGN can be applied in nephrology training programs and used as a standard biopsy technique.

Endoscopic ultrasound-guided hepaticogastrostomy and endoscopic retrograde cholangiopancreatography-guided biliary drainage for distal malignant biliary obstruction due to pancreatic cancer with asymptomatic duodenal invasion: a retrospective, single-center study in Japan.

Background/Aims: Duodenal invasion (DI) is a risk factor for early recurrent biliary obstruction (RBO) in endoscopic retrograde cholangiopancreatography-guided biliary drainage (ERCP-BD). Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) may reduce early RBO in cases of asymptomatic DI, even when ERCP is possible. Methods: We enrolled 56 patients with pancreatic cancer and asymptomatic DI who underwent EUS-HGS (n=25) or ERCP-BD (n=31). Technical and clinical success, early (<3 months) and overall RBO rates, time to RBO (TRBO), and adverse events (AEs) were compared between the EUS-HGS and ERCP-BD groups. Risk factors for early RBO were also evaluated. Results: Baseline characteristics were similar between the groups. Both procedures demonstrated 100% technical and clinical success rates, with a similar incidence of AE (48% vs. 39%, p=0.59). While the median TRBO was comparable (5.7 vs. 8.8 months, p=0.60), EUS-HGS was associated with a lower incidence of early RBO compared to ERCP-BD (8% vs. 29%, p=0.09). The major causes of early RBO in ERCP-BD were sludge and food impaction, rarely occurring in EUS-HGS. EUS-HGS was potentially reduced early RBO (odds ratio, 0.32; p=0.07). Conclusions: EUS-HGS can be a viable option for treating pancreatic cancer with asymptomatic DI.

Intraocular fatty acids induce reinforcement of barrier functions on the outer blood-retinal barrier.

The aim of the present study was to elucidate unknown effects of intraocular fatty acids (ioFAs) including palmitic acid (C16:0), stearic acid (C18:0), oleic acid (C18:1), linoleic acid (C18:2), arachidonic acid (C20:4), eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6) on the outer blood-retinal barrier (oBRB). For this purpose, human retinal pigment epithelium cell line ARPE19 was subjected to analyses for evaluating the following biological phenotypes: (1) cell viability, (2) cellular metabolic functions, (3) barrier functions by trans-epithelial electrical resistance (TEER), and (4) expression of tight junction (TJ) molecules. In the presence of 100 nM ioFAs, no significant effects on cell viability of ARPE19 cells was observed. While treatment with EPA or DHA tended to reduce non-mitochondrial oxygen consumption, most indices in mitochondrial functions were not markedly affected by treatment with ioFAs in ARPE19 cells. On the other hand, ioFAs except for palmitic acid and stearic acid significantly increased basal extracellular acidification rates, suggesting activated glycolysis or increased lactate production. Interestingly, TEER values of planar ARPE19 monolayer were significantly increased by treatment any ioFAs. Consistently, gene expression levels of TJ proteins were increased by treatment with ioFAs. Collectively, the findings presented herein suggest that ioFAs may contribute to reinforcement of barrier functions of the oBRB albeit there are some differences in biological effects depending on the type of ioFAs.

Older Age as a Worrisome Feature in Patients With Intraductal Papillary Mucinous Neoplasms: A Long-Term Surveillance Study.

INTRODUCTION: Aging has been implicated in the development of various cancer types. No study has specifically investigated age at intraductal papillary mucinous neoplasm (IPMN) diagnosis in relation to the long-term risk of pancreatic carcinogenesis. METHODS: Within a prospective cohort of 4,104 patients diagnosed with pancreatic cysts, we identified 3,142 patients with IPMNs and examined an association of age at IPMN diagnosis with the incidence of pancreatic carcinoma. Using the multivariable competing-risks proportional hazards regression model, we estimated subdistribution hazard ratios (SHRs) and 95% confidence intervals (CIs) for pancreatic carcinoma incidence according to age at IPMN diagnosis. RESULTS: During 22,187 person-years of follow-up, we documented 130 patients diagnosed with pancreatic carcinoma (64 with IPMN-derived carcinoma and 66 with concomitant ductal adenocarcinoma). Older age at IPMN diagnosis was associated with a higher risk of pancreatic cancer incidence ( Ptrend = 0.002). Compared with patients younger than 55 years, patients aged 55-64, 65-74, and ≥ 75 years had adjusted SHRs of 1.80 (95% CI, 0.75-4.32), 2.56 (95% CI, 1.10-5.98), and 3.31 (95% CI, 1.40-7.83), respectively. Patients aged 70 years and older had a numerically similar adjusted SHR compared with patients younger than 70 years with worrisome features defined by the international consensus guidelines (1.73 [95% CI, 1.01-2.97] and 1.66 [95% CI, 0.89-3.10], respectively). DISCUSSION: Older patients with IPMNs were at a higher risk of developing pancreatic carcinoma during surveillance. Surgically fit elderly patients may be good candidates for periodic surveillance aimed at a reduction of pancreatic cancer-related deaths.

Inhibition of mTOR differently modulates planar and subepithelial fibrogenesis in human conjunctival fibroblasts.

PURPOSE: In the current investigation, the effects of the mTOR inhibitors, Rapa and Torin1 on the TGF-ß2-induced conjunctival fibrogenesis were studied. STUDY DESIGN: Experimental research. METHODS: 2D and 3D cultures of HconF were subjected to the following analyses; (1) planar proliferation evaluated by TEER (2D), (2) Seahorse metabolic analyses (2D), (3) subepithelial proliferation evaluated by the 3D spheroids' size and hardness, and (4) the mRNA expression of ECM proteins and their regulators (2D and 3D). RESULT: Rapa or Torin1 both significantly increased planar proliferation in the non-TGF-ß2-treated 2D HconF cells, but in the TGF-ß2-treated cells, this proliferation was inhibited by Rapa and enhanced by Torin1. Although Rapa or Torin1 did not affect cellular metabolism in the non-TGF-ß2-treated HconF cells, mTOR inhibitors significantly decreased and increased the mitochondrial respiration and the glycolytic capacity, respectively, under conditions of TGF-ß2-induced fibrogenesis. Subepithelial proliferation, as evidenced by the hardness of the 3D spheroids, was markedly down-regulated by both Rapa and Torin1 independent of TGF-ß2. The mRNA expressions of several ECM molecules and their regulators fluctuated in the cases of 2D vs 3D and TGF-ß2 untreated vs treated cultures. CONCLUSION: The present findings indicate that mTOR inhibitors have the ability to increase and to reduce planar and subepithelial proliferation in HconF cells, depending on the inhibitor being used.

Contribution of MLKL to the development of doxorubicin-induced cardiomyopathy and its amelioration by rapamycin.

Necroptosis, necrosis characterized by RIPK3-MLKL activation, has been proposed as a mechanism of doxorubicin (DOX)-induced cardiomyopathy. We showed that rapamycin, an mTORC1 inhibitor, attenuates cardiomyocyte necroptosis. Here we examined role of MLKL in DOX-induced myocardial damage and protective effects of rapamycin. Cardiomyopathy was induced in mice by intraperitoneal injections of DOX (10 mg/kg, every other day) and followed for 7 days. DOX-treated mice showed a significant decline in LVEF assessed by cardiac MRI (45.5 ± 5.1% vs. 65.4 ± 4.2%), reduction in overall survival rates, and increases in myocardial RIPK3 and MLKL expression compared with those in vehicle-treated mice, and those changes were prevented by administration of rapamycin (0.25 mg/kg) before DOX injection. In immunohistochemical analyses, p-MLKL signals were detected in the cardiomyocytes of DOX-treated mice, and the signals were reduced by rapamycin. Mlkl+/- and Mlkl-/- mice were similarly resistant to DOX-induced cardiac dysfunction, indicating that a modest reduction in MLKL level is sufficient to prevent the development of DOX-induced cardiomyopathy. However, evidence of cardiomyocyte necrosis assessed by C9 immunostaining, presence of replacement fibrosis, and electron microscopic analyses was negligible in the myocardium of DOX-treated mice. Thus, MLKL-mediated signaling contributes to DOX-induced cardiac dysfunction primarily by a necrosis-independent mechanism, which is inhibitable by rapamycin.

High Intraocular Pressure Is Independently Associated With New-Onset Systemic Hypertension Over a 10-Year Period.

BACKGROUND: Systemic hypertension (HT) is associated with the development of increased intraocular pressure (IOP), a risk factor for glaucoma. However, it remains unclear whether high IOP is a risk factor for HT.Methods and Results: We investigated 7,487 Japanese individuals (4,714 men, 2,773 women; mean [±SD] age 49±9 years) who underwent annual health checkups in 2006. Over the 10-year follow-up period, 1,232 (24.3%) men and 370 (11.5%) women developed new-onset HT, defined as initiation of antihypertensive drug treatment or blood pressure ≥140/90 mmHg. After dividing IOP into tertiles (T1-T3), Cox proportional hazards analysis (adjusted for age, sex, systolic blood pressure, obesity, current smoking, alcohol consumption, family history of HT, estimated glomerular filtration rate, and diabetes and dyslipidemia diagnoses at baseline) revealed a significantly higher risk of newly developed HT in T3 (IOP ≥14 mmHg; hazard ratio 1.14; 95% confidence interval 1.01-1.29; P=0.038) using T1 (IOP ≤11 mmHg) as the reference group. There was no significant interaction between sex and IOP tertile (P=0.153). A restricted cubic spline model showed a gradual but robust increase in the hazard ratio for new-onset HT with increasing IOP. CONCLUSIONS: High IOP is an independent risk factor for the development of HT over a 10-year period.

Fatty Acid-Binding Protein 4-Mediated Regulation Is Pivotally Involved in Retinal Pathophysiology: A Review.

Fatty acid-binding proteins (FABPs), a family of lipid chaperone molecules that are involved in intracellular lipid transportation to specific cellular compartments, stimulate lipid-associated responses such as biological signaling, membrane synthesis, transcriptional regulation, and lipid synthesis. Previous studies have shown that FABP4, a member of this family of proteins that are expressed in adipocytes and macrophages, plays pivotal roles in the pathogenesis of various cardiovascular and metabolic diseases, including diabetes mellitus (DM) and hypertension (HT). Since significant increases in the serum levels of FABP4 were detected in those patients, FABP4 has been identified as a crucial biomarker for these systemic diseases. In addition, in the field of ophthalmology, our group found that intraocular levels of FABP4 (ioFABP4) and free fatty acids (ioFFA) were substantially elevated in patients with retinal vascular diseases (RVDs) including proliferative diabetic retinopathy (PDR) and retinal vein occlusion (RVO), for which DM and HT are also recognized as significant risk factors. Recent studies have also revealed that ioFABP4 plays important roles in both retinal physiology and pathogenesis, and the results of these studies have suggested potential molecular targets for retinal diseases that might lead to future new therapeutic strategies.

High-intensity interval training using electrical stimulation ameliorates muscle fatigue in chronic kidney disease-related cachexia by restoring mitochondrial respiratory dysfunction.

Background: Exercise, especially high-intensity interval training (HIIT), can increase mitochondrial respiratory capacity and enhance muscular endurance, but its systemic burden makes it difficult to safely and continuously prescribe for patients with chronic kidney disease (CKD)-related cachexia who are in poor general condition. In this study, we examined whether HIIT using electrical stimulation (ES), which does not require whole-body exercise, improves muscle endurance in the skeletal muscle of 5/6 nephrectomized rats, a widely used animal model for CKD-related cachexia. Methods: Male Wistar rats (10 weeks old) were randomly assigned to a group of sham-operated (Sham) rats and a group of 5/6 nephrectomy (Nx) rats. HIIT was performed on plantar flexor muscles in vivo with supramaximal ES every other day for 4 weeks to assess muscle endurance, myosin heavy-chain isoforms, and mitochondrial respiratory function in Nx rats. A single session was also performed to identify upstream signaling pathways altered by HIIT using ES. Results: In the non-trained plantar flexor muscles from Nx rats, the muscle endurance was significantly lower than that in plantar flexor muscles from Sham rats. The proportion of myosin heavy chain IIa/x, mitochondrial content, mitochondrial respiratory capacity, and formation of mitochondrial respiratory supercomplexes in the plantaris muscle were also significantly decreased in the non-trained plantar flexor muscles from Nx rats than compared to those in plantar flexor muscles from Sham rats. Treatment with HIIT using ES for Nx rats significantly improved these molecular and functional changes to the same degrees as those in Sham rats. Furthermore, a single session of HIIT with ES significantly increased the phosphorylation levels of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK), pathways that are essential for mitochondrial activation signaling by exercise, in the plantar muscles of both Nx and Sham rats. Conclusion: The findings suggest that HIIT using ES ameliorates muscle fatigue in Nx rats via restoration of mitochondrial respiratory dysfunction with activation of AMPK and p38 MAPK signaling. Our ES-based HIIT protocol can be performed without placing a burden on the whole body and be a promising intervention that is implemented even in conditions of reduced general performance status such as CKD-related cachexia.

[Ectopic Injection of Hydrogel Spacer in IMRT for Prostate Cancer-A Case Study].

A hydrogel spacer injection between the prostate and rectum is reported to reduce the risk of rectal toxicity in radiotherapy for prostate cancer. We present a case of an ectopic injection of hydrogel spacer. The patient was a 77-year-old male with intermediate-risk prostate cancer. It was planned that he would receive intensity modulated radiation therapy(IMRT), and a hydrogel spacer was inserted. Three days after insertion, the patient had a fever of 38.6℃ and presented frequent urination and perineal pain. Swelling and heat sensation were observed in the perineum. CRP was 12.00 mg/dL and the white blood cell count was as high as 9,300/µL. T2-weighted images showed a 5.3×1.9 cm high-intensity area around the lower urethra. Ectopic injection of hydrogel spacer and concomitant infection were diagnosed. Upon administering antibiotic treatment, his symptoms and inflammation improved immediately. Four months after hydrogel spacer insertion, T2-weighted images showed a high-intensity area in the lower urethra and around the ischial bone, which was attributed to the remaining hydrogel spacer. The hydrogel spacer and his symptoms completely disappeared at 9 months after hydrogel spacer insertion.

Body mass index and survival among patients with advanced biliary tract cancer: a single-institutional study with nationwide data-based validation.

BACKGROUND: Excess body weight may modulate the progression of various cancer types. The prognostic relevance of body mass index (BMI) has not been fully examined in patients with biliary tract cancer. METHODS: Using a single-institutional cohort of 360 patients receiving gemcitabine-based chemotherapy for advanced biliary tract cancer, we examined the association of BMI with overall survival (OS). Using the Cox regression model with adjustment for potential confounders, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for OS according to BMI. The findings were validated using a Japanese nationwide inpatient database including 8324 patients treated at 201 hospitals. RESULTS: In the clinical cohort, BMI was not associated with OS (Ptrend = 0.34). Compared to patients with BMI = 18.5-24.9 kg/m2, patients with BMI < 18.5 kg/m2 and ≥ 25.0 kg/m2 had adjusted HRs for OS of 1.06 (95% CI, 0.78-1.45) and 1.01 (95% CI, 0.74-1.39), respectively. There was no evidence on a non-linear relationship between BMI and OS (Pnonlinearity = 0.63). In the nationwide cohort, the null findings were validated (Ptrend = 0.18) with adjusted HRs of 1.07 (95% CI, 0.98-1.18) for BMI < 18.5 kg/m2 and 1.05 (95% CI, 0.96-1.14) for BMI ≥ 25.0 kg/m2 (vs. BMI = 18.5-24.9 kg/m2). In the clinical cohort, BMI was not associated with progression-free survival (Ptrend = 0.81). CONCLUSIONS: BMI was not associated with survival outcomes of patients with advanced biliary tract cancer. Further research is warranted incorporating more detailed body composition metrics to explore the prognostic role of adiposity in biliary tract cancer.

Lysophosphatidic Acid Modulates TGF-ß2-Induced Biological Phenotype in Human Conjunctival Fibroblasts.

BACKGROUND: Although lysophosphatidic acid (LPA) is known to have multiple pathophysiological roles, its contributions to ocular tissues, especially conjunctival fibrogenesis, remain to be elucidated. METHODS: To study this issue, the effects of LPA on transforming growth factor-ß2 (TGF-ß2)-induced fibrogenesis of two-dimensional (2D) and three-dimensional (3D) cultures of human conjunctival fibroblasts (HconF) were examined by the following analyses: (1) planar proliferation determined by transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC)-dextran permeability measurements, (2) real-time metabolic analyses, (3) measurements of the size and stiffness of 3D spheroids, and (4) mRNA expression of extracellular matrix (ECM) molecules and their modulators. RESULTS: LPA had no effect on TGF-ß2-induced increase in the planar proliferation of HconF cells. LPA induced a more quiescent metabolic state in 2D HconF cells, but this metabolic suppression by LPA was partially blunted in the presence of TGF-ß2. In contrast, LPA caused a substantial decrease in the hardness of 3D HconF spheroids independently of TGF-ß2. In agreement with these different LPA-induced effects between 2D and 3D cultured HconF cells, mRNA expressions of ECM and their modulators were differently modulated. CONCLUSION: The findings that LPA induced the inhibition of both TGF-ß2-related and -unrelated subepithelial proliferation of HconF cells may be clinically applicable.

The Correlation between the Severity of Obstructive Sleep Apnea and Insulin Resistance in a Japanese Population.

Background: Repetitive episodes of apnea and hypopnea during sleep in patients with obstructive sleep apnea (OSA) are known to increase the risk of atherosclerosis. Underlying obesity and related disorders, such as insulin resistance, are indirectly related to the development of atherosclerosis. In addition, OSA is independently associated with insulin resistance; however, data regarding this relationship are scarce in Japanese populations. Methods: This study aimed to examine the relationship between the severity of OSA and insulin resistance in a Japanese population. We analyzed the data of consecutive patients who were referred for polysomnography under clinical suspicion of developing OSA and who did not have diabetes mellitus or any cardiovascular disease. Multiple regression analyses were performed to determine the relationship between the severity of OSA and insulin resistance. Results: The data from a total of 483 consecutive patients were analyzed. The median apnea-hypopnea index (AHI) was 40.9/h (interquartile range: 26.5, 59.1) and the median homeostasis model assessment for insulin resistance (HOMA-IR) was 2.00 (interquartile range: 1.25, 3.50). Multiple regression analyses revealed that the AHI, the lowest oxyhemoglobin saturation (SO2), and the percentage of time spent on SO2 < 90% were independently correlated with HOMA-IR (an adjusted R-squared value of 0.01278821, p = 0.014; an adjusted R-squared value of -0.01481952, p = 0.009; and an adjusted R-squared value of 0.018456581, p = 0.003, respectively). Conclusions: The severity of OSA is associated with insulin resistance assessed by HOMA-IR in a Japanese population.

Computed tomography-based prediction of pancreatitis following biliary metal stent placement with the convolutional neural network.

Background and study aims Pancreatitis is a potentially lethal adverse event of endoscopic transpapillary placement of a self-expandable metal stent (SEMS) for malignant biliary obstruction (MBO). Deep learning-based image recognition has not been investigated in predicting pancreatitis in this setting. Patients and methods We included 70 patients who underwent endoscopic placement of a SEMS for nonresectable distal MBO. We constructed a convolutional neural network (CNN) model for pancreatitis prediction using a series of pre-procedure computed tomography images covering the whole pancreas (≥ 120,960 augmented images in total). We examined the additional effects of the CNN-based probabilities on the following machine learning models based on clinical parameters: logistic regression, support vector machine with a linear or RBF kernel, random forest classifier, and gradient boosting classifier. Model performance was assessed based on the area under the curve (AUC) in the receiver operating characteristic analysis, positive predictive value (PPV), accuracy, and specificity. Results The CNN model was associated with moderate levels of performance metrics: AUC, 0.67; PPV, 0.45; accuracy, 0.66; and specificity, 0.63. When added to the machine learning models, the CNN-based probabilities increased the performance metrics. The logistic regression model with the CNN-based probabilities had an AUC of 0.74, PPV of 0.85, accuracy of 0.83, and specificity of 0.96, compared with 0.72, 0.78, 0.77, and 0.96, respectively, without the probabilities. Conclusions The CNN-based model may increase predictability for pancreatitis following endoscopic placement of a biliary SEMS. Our findings support the potential of deep learning technology to improve prognostic models in pancreatobiliary therapeutic endoscopy.

The Specific ROCK2 Inhibitor KD025 Alleviates Glycolysis through Modulating STAT3-, CSTA- and S1PR3-Linked Signaling in Human Trabecular Meshwork Cells.

To investigate the biological significance of Rho-associated coiled-coil-containing protein kinase (ROCK) 2 in the human trabecular meshwork (HTM), changes in both metabolic phenotype and gene expression patterns against a specific ROCK2 inhibitor KD025 were assessed in planar-cultured HTM cells. A seahorse real-time ATP rate assay revealed that administration of KD025 significantly suppressed glycolytic ATP production rate and increased mitochondrial ATP production rate in HTM cells. RNA sequencing analysis revealed that 380 down-regulated and 602 up-regulated differentially expressed genes (DEGs) were identified in HTM cells treated with KD025 compared with those that were untreated. Gene ontology analysis revealed that DEGs were more frequently related to the plasma membrane, extracellular components and integral cellular components among cellular components, and related to signaling receptor binding and activity and protein heterodimerization activity among molecular functions. Ingenuity Pathway Analysis (IPA) revealed that the detected DEGs were associated with basic cellular biological and physiological properties, including cellular movement, development, growth, proliferation, signaling and interaction, all of which are associated with cellular metabolism. Furthermore, the upstream regulator analysis and causal network analysis estimated IL-6, STAT3, CSTA and S1PR3 as possible regulators. Current findings herein indicate that ROCK2 mediates the IL-6/STAT3-, CSTA- and S1PR3-linked signaling related to basic biological activities such as glycolysis in HTM cells.