Age and sex-related differences in outcomes of OHCA patients after adjustment for sex-based in-hospital management disparities.

OBJECTIVES: Out-of-hospital cardiac arrest (OHCA) survival differences due to sex remain controversial. Previous studies adjusted for prehospital variables, but not sex-based in-hospital management disparities. We aimed to investigate age and sex-related differences in survival outcomes in OHCA patients after adjustment for sex-based in-hospital management disparities. METHODS: This retrospective observational study used a prospective multicenter OHCA registry to review data of patients from October 2015 to December 2020. The primary outcome was good neurological outcome defined as cerebral performance category score 1 or 2. We performed multivariable logistic regression and restricted cubic spline analysis according to age. RESULTS: Totally, 8988 patients were analyzed. Women showed poorer prehospital characteristics and received fewer coronary angiography, percutaneous coronary interventions, targeted temperature management, and extracorporeal membrane oxygenation than men. Good neurological outcomes were lower in women than in men (5.8% vs. 12.2%, p < 0.001). After adjustment for age, prehospital variables, and in-hospital management, women were more likely to have good neurological outcomes than men (adjusted odds ratio [aOR] 1.37, 95% confidence interval [CI] 1.07-1.74, p = 0.012). The restricted cubic spline curve showed a reverse sigmoid pattern of adjusted predicted probability of outcomes and dynamic associations of sex and age-based outcomes. CONCLUSIONS: Women with OHCA were more likely to have good neurological outcome after adjusting for age, prehospital variables, and sex-based in-hospital management disparities. There were non-linear associations between sex and survival outcomes according to age and age-related sex-based differences.

Deletion of adipose triglyceride lipase abolishes blood flow increase after ß3-adrenergic stimulation in visceral adipose tissue of mice.

Dynamic changes in adipose tissue blood flow (ATBF) with nutritional status play a role in the regulation of metabolic and endocrine functions. Activation of the sympathetic nervous system via ß-adrenergic receptors (ß-AR) contributes to the control of postprandial enhancement of ATBF. Herein, we sought to identify the role of each ß-AR subtype in the regulation of ATBF in mice. We monitored the changes in visceral epididymal ATBF (VAT BF), induced by local infusion of dobutamine, salbutamol, and CL316,243 (a selective ß1-, ß2-, and ß3-AR agonist, respectively) into VAT of lean CD-1 mice and global adipose triglyceride lipase (ATGL) knockout (KO) mice, using laser Doppler flowmetry. Administration of CL316,243, known to promote lipolysis in adipocytes, significantly increased VAT BF of CD-1 mice to a greater extent compared to that of the vehicle, whereas administration of dobutamine or salbutamol did not produce significant differences in VAT BF. The increase in VAT BF induced by ß3-AR stimulation disappeared in ATGL KO mice as opposed to their wild-type (WT) littermates, implying a role of ATGL-mediated lipolysis in the regulation of VAT BF. Different vascular reactivities occurred despite no significant differences in vessel density and adiposity between the groups. Additionally, the expression levels of the angiogenesis-related genes were significantly higher in VAT of ATGL KO mice than in that of WT, implicating an association of ATBF responsiveness with angiogenic activity in VAT. Our findings suggest a potential role of ß3-AR signaling in the regulation of VAT BF via ATGL-mediated lipolysis in mice.

Thigh muscle mass evaluated by point-of-care ultrasound is associated with short-term mortality in patients with sepsis in the emergency department.

Muscle mass depletion is associated with mortality and morbidity in various conditions including sepsis. However, few studies have evaluated muscle mass using point-of-care ultrasound in patients with sepsis. This study aimed to evaluate the association between thigh muscle mass, evaluated using point-of-care ultrasound with panoramic view in patients with sepsis in the emergency department, and mortality. From March 2021 to October 2022, this prospective observational study used sepsis registry. Adult patients who were diagnosed with sepsis at the emergency department and who underwent point-of-care ultrasounds for lower extremities were included. The thigh muscle mass was evaluated by the cross-sectional area of the quadriceps femoris (CSA-QF) on point-of-care ultrasound using panoramic view. The primary outcome was 28 day mortality. Multivariable Cox proportional hazard model was performed. Of 112 included patients with sepsis, mean CSA-QF was significantly lower in the non-surviving group than surviving group (49.6 [34.3-56.5] vs. 63.2 [46.9-79.6] cm2, p = 0.002). Each cm2 increase of mean CSA-QF was independently associated with decreased 28 day mortality (adjusted hazard ratio 0.961, 95% CI 0.928-0.995, p = 0.026) after adjustment for potential confounders. The result of other measurements of CSA-QF were similar. The muscle mass of the quadriceps femoris evaluated using point-of-care ultrasound with panoramic view was associated with mortality in patients with sepsis. It might be a promising tool for determining risk factors for mortality in sepsis patients in the early stages of emergency department.

Ischemia-Modified Albumin, Lactate, and Combination for Predicting Mortality in Patients with Septic Shock in the Emergency Department.

Ischemia-modified albumin (IMA) is produced during ischemia and reactive oxygen species production. This study aimed to evaluate the association between IMA and mortality in a larger population and the prognostic value of the combination of IMA and lactate for predicting mortality in septic shock patients in the emergency department. This retrospective observational study included adult septic shock patients between October 2019 and December 2021. A multivariable Cox proportional hazards model was performed. IMA was significantly higher in the non-surviving group than in the surviving group (89.1 ± 7.2 vs. 83.8 ± 6.2 U/mL, p < 0.001). IMA was independently associated with 28-day mortality after adjustments (adjusted hazard ratio [aHR]: 1.075, 95% confidence interval [CI]: 1.016-1.138, p = 0.012). The area under the ROC curve (AUROC) of IMA was 0.712 (95% CI: 0.648-0.775, p < 0.001) and was comparable to that of lactate. The AUROC of the combination of IMA and lactate was 0.838 (95% CI: 0.786-0.889, p < 0.001). The group with both high lactate and high IMA levels showed an extremely high risk of mortality than other groups (86.1%; aHR 8.956, 95% CI 4.071-19.70, p < 0.001). The elevation of IMA was associated with mortality in septic shock patients. The combination of IMA and lactate can be a helpful tool for early risk stratification of septic shock patients.

Comprehensive molecular characterization of TFE3-rearranged renal cell carcinoma.

TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC.

Sex differences in in-hospital management in patients with sepsis and septic shock: a prospective multicenter observational study.

Sex differences in the in-hospital management of sepsis exist. Previous studies either included patients with sepsis that was defined using previous definitions of sepsis or evaluated the 3-h bundle therapy. Therefore, this study sought to assess sex differences in 1-h bundle therapy and in-hospital management among patients with sepsis and septic shock, defined according to the Sepsis-3 definitions. This observational study used data from Korean Shock Society (KoSS) registry, a prospective multicenter sepsis registry. Adult patients with sepsis between June 2018 and December 2021 were included in this study. The primary outcome was adherence to 1-h bundle therapy. Propensity score matching (PSM) and multivariable logistic regression analyses were performed. Among 3264 patients with sepsis, 3129 were analyzed. PSM yielded 2380 matched patients (1190 men and 1190 women). After PSM, 1-h bundle therapy was performed less frequently in women than in men (13.0% vs. 19.2%; p < 0.001). Among the bundle therapy components, broad-spectrum antibiotics were administered less frequently in women than in men (25.4% vs. 31.6%, p < 0.001), whereas adequate fluid resuscitation was performed more frequently in women than in men (96.8% vs. 95.0%, p = 0.029). In multivariable logistic regression analysis, 1-h bundle therapy was performed less frequently in women than in men [adjusted odds ratio (aOR) 1.559; 95% confidence interval (CI) 1.245-1.951; p < 0.001] after adjustment. Among the bundle therapy components, broad-spectrum antibiotics were administered less frequently to women than men (aOR 1.339, 95% CI 1.118-1.605; p = 0.002), whereas adequate fluid resuscitation was performed more frequently for women than for men (aOR 0.629, 95% CI 0.413-0.959; p = 0.031). Invasive arterial blood pressure monitoring was performed less frequently in women than in men. Resuscitation fluid, vasopressor, steroid, central-line insertion, ICU admission, length of stay in the emergency department, mechanical ventilator use, and renal replacement therapy use were comparable for both the sexes. Among patients with sepsis and septic shock, 1-h bundle therapy was performed less frequently in women than in men. Continuous efforts are required to increase adherence to the 1-h bundle therapy and to decrease sex differences in the in-hospital management of patients with sepsis and septic shock.

Association of prehospital advanced airway and epinephrine with survival in patients with out-of-hospital cardiac arrest.

Survival benefits of prehospital advanced airway and epinephrine in out-of-hospital cardiac arrest (OHCA) patients are controversial, but few studies evaluated this together. This study evaluated association of prehospital advanced airway and epinephrine with survival outcomes in OHCA patients. This was observational study using a prospective multicentre KoCARC registry. Adult OHCA patients between October 2015 and December 2021 were included. The variables of interest were prehospital managements, which was classified into basic life support (BLS)-only, BLS + advanced airway, and BLS + advanced airway + epinephrine. In total, 8217 patients were included in analysis. Survival to discharge and good neurological outcomes were lowest in the BLS + advanced airway + epinephrine group (22.1% in BLS-only vs 13.2% in BLS + advanced airway vs 7.5% in BLS + advanced airway + epinephrine, P < 0.001 and 17.1% in BLS-only vs 9.2% in BLS + advanced airway vs 4.3% in BLS + advanced airway + epinephrine, P < 0.001, respectively). BLS + advanced airway + epinephrine group was less likely to survive to discharge and have good neurological outcomes (aOR 0.39, 95% CI 0.28-0.55, P < 0.001 and aOR 0.33, 95% CI 0.21-0.51, P < 0.001, respectively) than BLS-only group after adjusting for potential confounders. In prehospital settings with intermediate EMS providers and prehospital advanced airway insertion is performed followed by epinephrine administration, prehospital management with BLS + advanced airway + epinephrine in OHCA patients was associated with lower survival to discharge rate compared to BLS-only.

Association between metformin and survival outcomes in in-hospital cardiac arrest patients with diabetes.

INTRODUCTION: Metformin has shown cardioprotective and neuroprotective effects in cardiac arrest and ischemia-reperfusion injury animal models. Therefore, this study aimed to determine the association between diabetes medication and survival outcomes in in-hospital cardiac arrest (IHCA) patients with type 2 DM (T2DM). METHODS: This retrospective observational study included adult IHCA patients with T2DM between April 2017 and March 2022. The variable of interest was administration of diabetes medications within 24 h before cardiac arrest. Multivariable logistic regression analysis was performed. RESULTS: In the 377 included patients, administration of metformin within 24 h before IHCA was associated with a higher rate of survival to discharge and good neurologic outcome (41.5% vs 11.7%, P < 0.001 and 18.9% vs 6.2%, P = 0.004, respectively). Administration of metformin within 24 h before IHCA was independently associated with survival to discharge and good neurologic outcome (aOR: 5.37, 95% CI: 2.13-13.53, P < 0.001 and aOR: 3.57, 95% CI: 1.14-11.17, P = 0.029). The rate of survival to discharge was the highest in patients who were administered 500-1000 mg/day metformin (P < 0.001). CONCLUSIONS: In IHCA patients with T2DM, administration of metformin within 24 h before IHCA was independently associated with survival to discharge.

Inhibition of adipose tissue angiogenesis prevents rebound weight gain after caloric restriction in mice fed a high-fat diet.

AIMS: We investigated whether modulation of white adipose tissue (WAT) vasculature regulates rebound weight gain (RWG) after caloric restriction (CR) in mice fed a high-fat diet (HFD). MAIN METHODS: We compared changes in energy balance, hypothalamic neuropeptide gene expression, and characteristics of WAT by RT-qPCR, ELISA, immunohistochemistry, and adipose-derived stromal vascular fraction spheroid sprouting assay in obese mice fed a HFD ad libitum (HFD-AL), mice under 40 % CR for 3 or 4 weeks, mice fed HFD-AL for 3 days after CR (CRAL), and CRAL mice treated with TNP-470, an angiogenic inhibitor. KEY FINDINGS: WAT angiogenic genes were expressed at low levels, but WAT vascular density was maintained in the CR group compared to that in the HFD-AL group. The CRAL group showed RWG, fat regain, and hyperphagia with higher expression of angiogenic genes and reduced pericyte coverage of the endothelium in WAT on day 3 after CR compared to the CR group, indicating rapidly increased angiogenic activity after CR. Administration of TNP-470 suppressed RWG, fat regain, and hyperphagia only after CR compared to the CRAL group. Changes in circulating leptin levels and hypothalamic neuropeptide gene expression were correlated with changes in weight and fat mass, suggesting that TNP-470 suppressed hyperphagia independently of the hypothalamic melanocortin system. Additionally, TNP-470 increased gene expression related to thermogenesis, fuel utilization, and browning in brown adipose tissue (BAT) and WAT, indicating TNP-470-induced increase in thermogenesis. SIGNIFICANCE: Modulation of the WAT vasculature attenuates RWG after CR by suppressing hyperphagia and increasing BAT thermogenesis and WAT browning.

Metformin acts as a dual glucose regulator in mouse brain.

Aims: Metformin improves glucose regulation through various mechanisms in the periphery. Our previous study revealed that oral intake of metformin activates several brain regions, including the hypothalamus, and directly activates hypothalamic S6 kinase in mice. In this study, we aimed to identify the direct effects of metformin on glucose regulation in the brain. Materials and methods: We investigated the role of metformin in peripheral glucose regulation by directly administering metformin intracerebroventricularly in mice. The effect of centrally administered metformin (central metformin) on peripheral glucose regulation was evaluated by oral or intraperitoneal glucose, insulin, and pyruvate tolerance tests. Hepatic gluconeogenesis and gastric emptying were assessed to elucidate the underlying mechanisms. Liver-specific and systemic sympathetic denervation were performed. Results: Central metformin improved the glycemic response to oral glucose load in mice compared to that in the control group, and worsened the response to intraperitoneal glucose load, indicating its dual role in peripheral glucose regulation. It lowered the ability of insulin to decrease serum glucose levels and worsened the glycemic response to pyruvate load relative to the control group. Furthermore, it increased the expression of hepatic G6pc and decreased the phosphorylation of STAT3, suggesting that central metformin increased hepatic glucose production. The effect was mediated by sympathetic nervous system activation. In contrast, it induced a significant delay in gastric emptying in mice, suggesting its potent role in suppressing intestinal glucose absorption. Conclusion: Central metformin improves glucose tolerance by delaying gastric emptying through the brain-gut axis, but at the same time worsens it by increasing hepatic glucose production via the brain-liver axis. However, with its ordinary intake, central metformin may effectively enhance its glucose-lowering effect through the brain-gut axis, which could surpass its effect on glucose regulation via the brain-liver axis.

Vascular reactivity contributes to adipose tissue remodeling in obesity.

Vascular reactivity of adipose tissue (AT) is hypothesized to play an important role in the development of obesity. However, the exact role of vascular reactivity in the development of obesity remains unclear. In this study, we investigated the chronological changes in vascular reactivity and the microenvironments of the visceral AT (VAT) and subcutaneous AT (SAT) in lean and obese mice. Changes in blood flow levels induced by a ß-adrenoceptor agonist (isoproterenol) were significantly lower in the VAT of the mice fed a high-fat diet (HFD) for 1 and 12 weeks than those in the VAT of the mice fed a low-fat diet (LFD) for the same period; no significant change was observed in the SAT of any mouse group, suggesting depot-specific vascular reactivity of AT. Moreover, the hypoxic area and the expression of genes associated with angiogenesis and macrophage recruitment were increased in the VAT (but not in the SAT) of mice fed an HFD for 1 week compared with mice fed an LFD. These changes occurred with no morphological changes, including those related to adipocyte size, AT vessel density, and the diameter and pericyte coverage of the endothelium, suggesting a determinant role of vascular reactivity in the type of AT remodeling. The suppression of vascular reactivity was accompanied by increased endothelin1 (Edn1) gene expression and extracellular matrix (ECM) stiffness only in the VAT, implying enhanced contractile activities of the vasculature and ECM. The results suggest a depot-specific role of vascular reactivity in AT remodeling during the development of obesity.

The effect of metformin on neuronal activity in the appetite-regulating brain regions of mice fed a high-fat diet during an anorectic period.

Metformin reduces body weight by decreasing food intake in humans and animals. However, the brain regions involved in metformin-induced anorexia remain unclear. Therefore, we investigated c-Fos expression (FOS), a marker of neuronal activity, in the appetite-regulating brain regions after oral administration of metformin (PO, 300mg/kg daily for 1 or 3days) or vehicle. The body weight and food intake decreased in mice treated with metformin for 3days (RM group) and mice that had the same amount of food as the RM group (Pair-fed group; PF) compared to the control group. FOS expression levels increased in the paraventricular nucleus, area postrema, and central amygdala of mice administered an acute single dose of metformin (SM group) compared to the control mice. In the nucleus tractus solitarius, the FOS expression levels increased in both the SM and RM groups compared to the control group. The FOS expression levels also increased in the nucleus accumbens of the RM group compared to other groups. The FOS expression levels decreased in the ventromedial hypothalamic nucleus in the PF group, but not the RM group, compared to the control group, suggesting a potential hypothalamic area involvement for metformin-induced anorexia. These results suggest that both the hypothalamic and extra-hypothalamic regions are associated with metformin-induced anorexia, which is dependent on metformin treatment duration.

Depot-specific differences in angiogenic capacity of adipose tissue in differential susceptibility to diet-induced obesity.

OBJECTIVE: Adipose tissue (AT) expansion requires AT remodeling, which depends on AT angiogenesis. Modulation of AT angiogenesis could have therapeutic promise for the treatment of obesity. However, it is unclear how the capacity of angiogenesis in each adipose depot is affected by over-nutrition. Therefore, we investigated the angiogenic capacity (AC) of subcutaneous and visceral fats in lean and obese mice. METHODS: We compared the AC of epididymal fat (EF) and inguinal fat (IF) using an angiogenesis assay in diet-induced obese (DIO) mice and diet-resistant (DR) mice fed a high-fat diet (HFD). Furthermore, we compared the expression levels of genes related to angiogenesis, macrophage recruitment, and inflammation using RT-qPCR in the EF and IF of lean mice fed a low-fat diet (LFD), DIO mice, and DR mice fed a HFD. RESULTS: DIO mice showed a significant increase in the AC of EF only at 22 weeks of age compared to DR mice. The expression levels of genes related to angiogenesis, macrophage recruitment, and inflammation were significantly higher in the EF of DIO mice than in those of LFD mice and DR mice, while expression levels of genes related to macrophages and their recruitment were higher in the IF of DIO mice than in those of LFD and DR mice. Expression of genes related to angiogenesis (including Hif1a, Vegfa, Fgf1, Kdr, and Pecam1), macrophage recruitment, and inflammation (including Emr1, Ccr2, Itgax, Ccl2, Tnf, and Il1b) correlated more strongly with body weight in the EF of HFD-fed obese mice compared to that of IF. CONCLUSIONS: These results suggest depot-specific differences in AT angiogenesis and a potential role in the susceptibility to diet-induced obesity.