Citations

Abstract Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

Introduction: Renin-Angiotensin System (RAS) regulates the cardiovascular system and has been implicated in the development of abdominal aortic aneurysm (AAA). RAS modulates function via balancing the ACE/Chymase/AngII-AT1 receptor and ACE-2/Ang(1-7)-Mas receptor axis. Preferential activation of the ACE/Chymase/AngII-AT1 receptor pathway of the RAS contributes to dysregulation of cardiovascular system and disease while the Ang(1-7)-MasR axis contributes to anti-inflammatory pathways. Therefore, identifying the RAS axis mechanism involved in growth, progression, or the risk of rupture in AAA humans could bring a novel treatment perspective. Hypothesis: We hypothesize that in the AAA, the local RAS is altered such as it favours the ACE/AngII/AT1R axis while decreasing the ACE-2/Ang(1-7)/MasR pathway, with consequent AAA development. Objective: We sought to investigate the expression of RAS components in the AAA human aorta. Methods: Aorta tissue from AAA patients (n=21) was collected during the AAA conventional repair surgery, and aorta control aortas were obtained from organ donors (Control, n=11). Protein expression of renin, chymase, ACE, ACE-2 AT1, AT2, and MAS receptors was analyzed by Western Blotting. Results: Our AAA cohort consisted mostly males (76.6% AAA vs. 63.6% Control, p=0.68), smokers or ex-smokers (90.4% AAA vs. 36.3% Control, p=0.002) and most of them had hypertension(71.4% AAA vs. 36.3% Control, p=0.07). Analysis of protein expression in the AAA group showed that ACE and AT1 receptors were upregulated compared with Control (p=0.05; p=0.02, respectively,), while chymase expression was decreased in AAA compared to the control (p=0.03). Additionally, the AAA group showed downregulation in ACE-2 and AT2 compared with Control (respectively, p=0.01, p=0.03). There was no significant difference in the expression of renin and MAS receptors between groups (p=0.52, p=0.41, respectively,). Conclusions: Our data show that the ACE/AT1R axis was upregulated while ACE-2 and AT2 receptors were downregulated in the AAA aorta. Our results implicate local RAS in AAA development and warrant further studies.

ABSTRACT Snapping proximal hamstring is an uncommon phenomenon, with few case reports documenting surgical treatment. The purpose of this study is to report snapping resolution, minimum 2-year post-operative patient-reported outcome (PRO), satisfaction scores and complications from patients who underwent surgical release of the conjoint tendon from the sacrotuberous ligament with reattachment to the ischial tuberosity. Prospectively collected data from two institutional databases were retrospectively reviewed for patients who underwent hamstring repair for partial- or full-thickness tears. Patients were included if they demonstrated ‘snapping proximal hamstrings’ on preoperative physical examination, including ultrasound confirmation, and repair subsequently performed. Patients were excluded if they had reconstruction of the proximal hamstring tendon or claimed worker’s compensation. With a total of 20 patients (15 females and 5 males), successful resolution of snapping was reported in 100% of the cohort. For patients with pre- and post-surgical lower-extremity functional scores (LEFS), post-surgical LEFS were significantly higher than pre-surgical LEFS (pre-surgical: 17.0 ± 4.0, post-surgical: 73.6 ± 3.3, P < 0.001). Average post-operative PROs were as follows: International Hip Outcome Tool-12, 92.3 ± 8.3; modified Harris Hip Score, 93.2 ± 7.8; Non-arthritic Hip Score, 92.5 ± 6.8; Hip Outcome Score-Sports Specific Subscale, 94.4 ± 6.7; LEFS, 73.9 ± 3.4; and median visual analog scale of 0 with an interquartile range of 0-1. Patient satisfaction was ‘very satisfied’ in 19 (95%) patients and ‘satisfied’ in 1 (5%) patient. At a minimum 2-year follow-up, patients who underwent surgical treatment for chronic snapping of the proximal hamstrings demonstrated complete resolution of painful posterior snapping, reported high PROs and satisfaction, and had no reported post-operative complications.

e19078 Background: MECOM (EVI1) rearrangements in MDS/AML are rare and carry an unfavorable prognosis. Although allogeneic stem cell transplantation (allo-HSCT) may prolong survival, factors impacting outcomes are not known. We conducted a retrospective analysis of patients with MECOM (EVI1) to associate clinicopathologic variables with prognosis. Methods: This study was approved by the Mayo Clinic IRB. Patients >18 years of age with MDS or AML and MECOM EVI1 at Mayo Clinic between 01/2012 and 12/2022 were included. Response was defined by ELN criteria. Intensive chemotherapy was defined as 7+3 or high dose cytarabine. Non-intensive chemotherapy included hypomethylating agents with or without venetoclax. Median overall survival (OS) and median leukemia free survival (LFS) were estimated using the Kaplan-Meier method. Outcome differences between sub-groups and univariate analyses were assessed with Cox regression. Results: Sixty patients met criteria for inclusion. Sixty-three percent (n = 38) were male and the median age at diagnosis was 67.8 yrs (range, 56 – 75). Eighty percent had AML (n = 48) and 18% had MDS (n = 11). Sixty-seven percent of patients had secondary AML/MDS (n = 40). Inv(3)/t(3;3) was present in 65% (n = 39) and t(3;21) was present in 12% (n = 7). Thirty-eight percent (n = 23) of patients had cooccurring monosomy 7 or 7q deletion and 5% had complex karyotype (n = 3). SF3B1 was the most common cooccurring mutation in 31% (n = 10), followed by KRAS in 19% (n = 6). Thirty-eight percent of patients (n = 23) received intensive chemotherapy. Complete response (CR) rates were 36% with intensive treatment (n = 8) and 4% with non-intensive treatment (n = 1; p = 0.007). Thirty percent (n = 18) underwent SCT (78% in CR1 and 22% in CR2) and of those, myeloablative conditioning (MAC) was used in 38% while 61% received reduced intensity conditioning (RIC). The mOS in the entire cohort was 11 months (95% CI 6.2, 17). Patients who received a SCT had longer mOS compared to patients who did not (19 vs 6.2 months, HR = 0.31, 95% CI 0.16,0.64; p = 0.001). AML-MRC was a poor prognostic factor in the HCST group for OS (HR = 4.23, 95% CI 1.02, 17.5, p = 0.047). Intensive vs. non-intensive chemotherapy, response prior to transplant (CR vs. no CR), or having 2 or more mutations on NGS did not significantly impact OS or LFS. Conclusions: In line with previous reports, allo-HSCT was associated with improved survival outcomes. Our results showed a high frequency of secondary AML/MDS, but only AML-MRC was associated with decreased survival outcomes. Regardless of therapy type, outcomes were poor. Novel therapies are urgently needed for these patients.

Abstract Funding Acknowledgements Type of funding sources: Private hospital(s). Main funding source(s): Mayo Clinic Background/Introduction Syncope is a common presentation in heart failure (HF) patients. However, the associations between syncope and prognosis in HF patients with the cardiac implantable electronic device (CIED) have not been demonstrated. It is unclear whether syncope increases all-cause mortality in HF patients with CIED. Purpose We aimed to examine the association between syncope and all-cause mortality in the largest cohort of HF with reduced ejection fraction (HFrEF), mid-ranged ejection fraction (HFmEF), and preserved ejection fraction (HFpEF) patients with and without CIED. Methods A retrospective cohort of patients with HF and syncope at our hospital between 2010 and 2015 were identified, and 1:1 propensity was matched with a control group of HF patients without syncope. A chart review was conducted. The multivariate Cox regression model was applied to estimate the association between syncope and the all-cause mortality endpoint. Results 3,449 HF patients were diagnosed with syncope (mean age, 72.8±14.5 years; 41.5% women), and the propensity-matched control HF patients without syncope (n=3,449) aged 72.8±14.3 years, and 42.5% women were selected. Cardiac implantable electronic devices were implanted more in HF patients with syncope (32.5% versus 13.7%, p<0.001). Implantable cardioverter defibrillators were implanted more in HF patients with syncope (15.6% versus 8.3%, p<0.001) as well as pacemakers (16.9% versus 7.5%, p<0.001) and cardiac resynchronization therapy devices (6.9% versus 4.8%, p=0.015). Among HF patients with CIED, syncope significantly increased the risk of all-cause mortality in HFrEF patients (hazard ratio [HR]=1.479, 95% confidence interval [CI]: 1.197-1.828, p<0.001) but not in HFpEF (HR=0.980, 95%CI: 0.793-1.210, p=0.849)(Figure 1). Syncope also tended to increase the risk of all-cause mortality in HFmEF patients with CIED but was not significant (HR=1.193, 95%CI: 0.762-1.865, p=0.762)(Figure 1). Among HF patients without CIED, syncope did not increase the risk of all-cause mortality in HFrEF (HR=0.923, 95%CI: 0.806-1.057, p=0.247), HFmEF (HR=1.074, 95%CI: 0.848-1.360, p=0.554), or HFpEF (HR=0.964, 95%CI: 0.883-1.052, p=0.406). Conclusions Syncope significantly increased the risk of all-cause mortality in HFrEF patients but not in HFmEF or HFpEF patients with CIED. The association of syncope and increased mortality in HFrEF patients with CIED suggests that syncope may be a marker and a factor of mortality and warrants further investigation.

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women’s worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women’s brains and provide initial evidence for neuroscience-informed policies for gender equality.

Abstract Health-related quality of life (HRQoL) and vulnerability are variably affected in patients with myelodysplastic syndromes (MDS) and other cytopenic states; however, the heterogeneity of these diseases has limited our understanding of these domains. The National Heart, Lung, and Blood Institute-sponsored MDS Natural History Study is a prospective cohort enrolling patients undergoing workup for suspected MDS in the setting of cytopenias. Untreated patients undergo bone marrow assessment with central histopathology review for assignment as MDS, MDS/myeloproliferative neoplasm (MPN), idiopathic cytopenia of undetermined significance (ICUS), acute myeloid leukemia (AML) with <30% blasts, or “At-Risk.” HRQoL data are collected at enrollment, including the MDS-specific Quality of Life in Myelodysplasia Scale (QUALMS). Vulnerability is assessed with the Vulnerable Elders Survey. Baseline HRQoL scores from 449 patients with MDS, MDS/MPN, AML <30%, ICUS or At-Risk were similar among diagnoses. In MDS, HRQoL was worse for vulnerable participants (eg, mean Patent-Reported Outcomes Management Information Systems [PROMIS] Fatigue of 56.0 vs 49.5; P < .001) and those with worse prognosis (eg, mean Euroqol-5 Dimension-5 Level [EQ-5D-5L] of 73.4, 72.7, and 64.1 for low, intermediate, and high-risk disease; P = .005). Among vulnerable MDS participants, most had difficulty with prolonged physical activity (88%), such as walking a quarter mile (74%). These data suggest that cytopenias leading to MDS evaluation are associated with similar HRQoL, regardless of eventual diagnosis, but with worse HRQoL among the vulnerable. Among those with MDS, lower-risk disease was associated with better HRQoL, but the relationship was lost among the vulnerable, showing for the first time that vulnerability trumps disease risk in affecting HRQoL. This study is registered at www.clinicaltrials.gov as NCT02775383.