Activin A signaling stimulates neutrophil activation and macrophage migration in pancreatitis.

Acute Pancreatitis (AP) is associated with high mortality and current treatment options are limited to supportive care. We found that blockade of activin A (activin) in mice improves outcomes in two murine models of AP. To test the hypothesis that activin is produced early in response to pancreatitis and is maintained throughout disease progression to stimulate immune cells, we first performed digital spatial profiling (DSP) of human chronic pancreatitis (CP) patient tissue. Then, transwell migration assays using RAW264.7 mouse macrophages and qPCR analysis of "neutrophil-like" HL-60 cells were used for functional correlation. Immunofluorescence and western blots on cerulein-induced pancreatitis samples from pancreatic acinar cell-specific Kras knock-in (Ptf1aCreER™; LSL-KrasG12D) and functional WT Ptf1aCreER™ mouse lines mimicking AP and CP to allow for in vivo confirmation. Our data suggest activin promotes neutrophil and macrophage activation both in situ and in vitro, while pancreatic activin production is increased as early as 1 h in response to pancreatitis and is maintained throughout CP in vivo. Taken together, activin is produced early in response to pancreatitis and is maintained throughout disease progression to promote neutrophil and macrophage activation.

Left atrial to coronary sinus shunting for treatment of heart failure with mildly reduced or preserved ejection fraction: The ALT FLOW Early Feasibility Study 1-year results.

AIMS: Patients with heart failure and mildly reduced or preserved ejection fraction have limited therapeutic options. The ALT-FLOW Early Feasibility Study evaluated safety, haemodynamics and outcomes for the APTURE transcatheter shunt system, a novel left atrium to coronary sinus shunt in these patients. METHODS AND RESULTS: Safety and shunt implantation success was evaluated for all 116 enrolled patients. An analysis population of implanted patients with a left ventricular ejection fraction (LVEF) >40% (n = 95) was chosen to assess efficacy via paired comparison between baseline and follow-up haemodynamic (3 and 6 months), and echocardiographic, clinical and functional outcomes (6 months and 1 year). Health status and quality of life outcomes were assessed using the Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS). The primary safety endpoint, major adverse cardiac, cerebral, and renal events, and reintervention through 30 days, occurred in 3/116 patients (2.6%). All implanted shunts were patent at 1 year. In patients with LVEF >40%, the mean (95% confidence interval) reduction in exercise pulmonary capillary wedge pressure (PCWP) at 20 W was -5.7 (-8.6, -2.9) mmHg at 6 months (p < 0.001). At baseline, 8% had New York Heart Association class I-II status and improved to 68% at 1 year (p < 0.001). KCCQ-OSS at baseline was 39 (35, 43) and improved at 6 months and 1 year by 25 (20-30) and 27 (22-32) points, respectively (both p < 0.0001). No adverse changes in haemodynamic and echocardiographic indices of right heart function were observed at 1 year. Overall, the reduction in PCWP at 20 W and improvement in KCCQ-OSS in multiple subgroups were consistent with those observed for the entire population. CONCLUSIONS: In patients with heart failure and LVEF >40%, the APTURE shunt demonstrated an acceptable safety profile with significant sustained improvements in haemodynamic and patient-centred outcomes, underscoring the need for further evaluation of the APTURE shunt in a randomized trial.

Nationwide Trends and Outcomes for Coronary Artery Bypass Grafting in End-Stage Kidney Disease and Stable Coronary Artery Disease.

Patients with end-stage kidney disease (ESKD) on dialysis have an increased burden of coronary artery disease (CAD). This study assessed the trend and outcomes for coronary artery bypass surgery (CABG) in patients with ESKD and stable CAD. We conducted a longitudinal study using the United States Renal Data System of patients with ESKD and stable CAD who underwent CABG from the years 2009 to 2017. The outcomes included in-hospital, long-term mortality, and repeat revascularization. The follow-up was until death, end of Medicare AB coverage, or December 31, 2018. A total of 11,952 patients were identified. The mean age was 62.8 years, 68% were male, and 67% were white. The common co-morbidities included hypertension (97%), diabetes mellitus (75%), and congestive heart failure (53%). A significant decrease in CABG procedures from 2.9 to 1.3 procedures per 1,000 patients with ESKD (p <0.001) was noted during the years studied. The overall in-hospital mortality rate was 5.9%, and there was a significant decrease over the study period (p = 0.01). Although the 30-day mortality rate was 6.9% and remained steady (p = 0.14), the 1-year mortality rate was 22.8% and decreased significantly (p <0.001). At 5 years, the overall survival rate was 35%, and patients with internal mammary artery grafts showed better survival than those without (36% vs 25%). In conclusion, there has been a decrease in CABG procedures performed in patients with ESKD with stable CAD with decreasing in-hospital and 1-year mortality. Those with an internal mammary artery graft do better, but the overall long-term survival remains dismal in this population. There remains need for caution and individualization of revascularization decisions in this high-risk population.

Outcomes of peripheral artery disease and polyvascular disease in patients with end-stage kidney disease.

OBJECTIVE: Patients with peripheral artery disease (PAD) and end-stage kidney disease are a high-risk population, and concomitant atherosclerosis in coronary arteries (CAD) or cerebral arteries (CVD) is common. The aim of the study was to assess long-term outcomes of PAD and the impact of coexistent CAD and CVD on outcomes. METHODS: The United States Renal Data System was used to identify patients with PAD within 6 months of incident dialysis. Four groups were formed: PAD alone, PAD with CAD, PAD with CVD, and PAD with CAD and CVD. PAD-specific outcomes (chronic limb-threatening ischemia, major amputation, percutaneous/surgical revascularization, and their composite, defined as major adverse limb events [MALE]) as well as all-cause mortality, myocardial infarction, and stroke were studied. RESULTS: The study included 106,567 patients (mean age, 71.2 years; 40.8% female) with a median follow-up of 546 days (interquartile range, 214-1096 days). Most patients had PAD and CAD (49.8%), 25.8% had PAD alone, and 19.2% had all three territories involved. MALE rate in patients with PAD was 22.3% and 35.0% at 1 and 3 years, respectively. In comparison to PAD alone, the coexistence of both CAD and CVD (ie, polyvascular disease) was associated with a higher adjusted rates of all-cause mortality (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.24-1.31), myocardial infarction (HR, 1.78; 95% CI, 1.69-1.88), stroke (HR, 1.66; 95% CI, 1.52,1.80), and MALE (HR, 1.07; 95% CI, 1.04-1.11). CONCLUSIONS: Patients with end-stage kidney disease have a high burden of PAD with poor long-term outcomes, which worsen, in an incremental fashion, with the involvement of each additional diseased arterial bed.

Impact of preexisting coronary artery and peripheral artery disease on outcomes in diabetic patients after kidney transplant.

BACKGROUND: Atherosclerotic cardiovascular disease is highly prevalent in patients with end-stage kidney disease (ESKD). Kidney transplant (KT) improves patient survival and cardiovascular outcomes. The impact of preexisting coronary artery disease (CAD) and peripheral artery disease (PAD) on posttransplant outcomes remains unclear. METHODS: This is a retrospective study utilizing the United States Renal Data System. Adult diabetic dialysis patients who underwent first KT between 2006 and 2017 were included. The study population was divided into four cohorts based on presence of CAD/PAD: (1) polyvascular disease (CAD + PAD); (2) CAD without PAD; (3) PAD without CAD; (4) no CAD or PAD (reference cohort). The primary outcome was 3-year all-cause mortality. Secondary outcomes were incidence of posttransplant myocardial infarction (MI), cerebrovascular accidents (CVA), and graft failure. RESULTS: The study population included 19,329 patients with 64.4% men, mean age 55.4 years, and median dialysis duration of 2.8 years. Atherosclerotic cardiovascular disease was present in 28% of patients. The median follow up was 3 years. All-cause mortality and incidence of posttransplant MI were higher with CAD and highest in patients with polyvascular disease. The cohort with polyvascular disease had twofold higher all-cause mortality (16.7%, adjusted hazard ratio (aHR) 1.5, p < 0.0001) and a fourfold higher incidence of MI (12.7%, aHR 3.3, p < 0.0001) compared to the reference cohort (8.0% and 3.1%, respectively). There was a higher incidence of posttransplant CVA in the cohort with PAD (3.4%, aHR 1.5, p = 0.01) compared to the reference cohort (2.0%). The cohorts had no difference in graft failure rates. CONCLUSIONS: Preexisting CAD and/or PAD result in worse posttransplant survival and cardiovascular outcomes in patients with diabetes mellitus and ESKD without a reduction in graft survival.

Acute Pancreatitis: Current Clinical Approaches, Molecular Pathophysiology, and Potential Therapeutics.

OBJECTIVE: Severe acute pancreatitis (SAP), pancreatic inflammation leading to multiorgan failure, is associated with high morbidity and mortality. There is a critical need to identify novel therapeutic strategies to improve clinical outcomes for SAP patients. MATERIALS AND METHODS: A comprehensive literature review was performed to identify current clinical strategies, known molecular pathophysiology, and potential therapeutic targets for SAP. RESULTS: Current clinical approaches focus on determining which patients will likely develop SAP. However, therapeutic options are limited to supportive care and fluid resuscitation. The application of a novel 5-cytokine panel accurately predicting disease outcomes in SAP suggests that molecular approaches will improve impact of future clinical trials in AP. CONCLUSIONS: Inflammatory outcomes in acute pancreatitis are driven by several unique molecular signals, which compound to promote both local and systemic inflammation. The identification of master cytokine regulators is critical to developing therapeutics, which reduce inflammation through several mechanisms.

Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance.

We have shown that activin A (activin), a TGF-ß superfamily member, has pro-metastatic effects in colorectal cancer (CRC). In lung cancer, activin activates pro-metastatic pathways to enhance tumor cell survival and migration while augmenting CD4+ to CD8+ communications to promote cytotoxicity. Here, we hypothesized that activin exerts cell-specific effects in the tumor microenvironment (TME) of CRC to promote anti-tumoral activity of immune cells and the pro-metastatic behavior of tumor cells in a cell-specific and context-dependent manner. We generated an Smad4 epithelial cell specific knockout (Smad4-/-) which was crossed with TS4-Cre mice to identify SMAD-specific changes in CRC. We also performed IHC and digital spatial profiling (DSP) of tissue microarrays (TMAs) obtained from 1055 stage II and III CRC patients in the QUASAR 2 clinical trial. We transfected the CRC cells to reduce their activin production and injected them into mice with intermittent tumor measurements to determine how cancer-derived activin alters tumor growth in vivo. In vivo, Smad4-/- mice displayed elevated colonic activin and pAKT expression and increased mortality. IHC analysis of the TMA samples revealed increased activin was required for TGF-ß-associated improved outcomes in CRC. DSP analysis identified that activin co-localization in the stroma was coupled with increases in T-cell exhaustion markers, activation markers of antigen presenting cells (APCs), and effectors of the PI3K/AKT pathway. Activin-stimulated PI3K-dependent CRC transwell migration, and the in vivo loss of activin lead to smaller CRC tumors. Taken together, activin is a targetable, highly context-dependent molecule with effects on CRC growth, migration, and TME immune plasticity.

Left Atrial to Coronary Sinus Shunting for Treatment of Symptomatic Heart Failure.

BACKGROUND: Heart failure (HF) is associated with both mortality and a significant decline in health status. Interatrial shunting is increasingly being investigated as a novel therapeutic option. OBJECTIVES: The ALT FLOW Early Feasibility Study was designed to evaluate the safety of the Edwards left atrial to coronary sinus APTURE Transcatheter Shunt System in patients with symptomatic HF. METHODS: A total of 18 centers enrolled patients with symptomatic HF with a pulmonary capillary wedge pressure >15 mm Hg at rest or 25 mm Hg during exercise. RESULTS: Between May 2018 and September 2022, 87 patients underwent attempted APTURE shunt implantation. Mean age was 71 years, and 53% were male. At baseline, mean left ventricular ejection fraction was 59% with 90% of the patients being in NYHA functional class III. Device success was achieved in 78 patients (90%), with no device occlusions or associated adverse events identified after implantation. The primary safety outcome occurred in only 2 patients (2.3%) at 30 days. At 6 months, health status improved: 67% of participants achieved NYHA functional class I to II status, with a 23-point improvement (P < 0.0001; 95% CI: 17-29 points) in the Kansas City Cardiomyopathy Questionnaire overall summary score. Also at 6 months, 20-W exercise pulmonary capillary wedge pressure was 7 mm Hg lower (P < 0.0001; 95% CI: -11 to -4 mm Hg) without change in right atrial pressure or other right heart function indices. CONCLUSIONS: In this single-arm experience, the APTURE Transcatheter Shunt System in patients with symptomatic HF was observed to be safe and resulted in reduction in pulmonary capillary wedge pressure and clinically meaningful improvements in HF symptoms and quality of life indices.

Burden of Hypertensive Crisis in Patients With End-Stage Kidney Disease on Maintenance Dialysis: Insights From United States Renal Data System Database.

BACKGROUND: There is paucity of information on the incidence, clinical characteristics, admission trends, and outcomes of hypertensive crisis (HTN-C) in patients with end-stage kidney disease (ESKD) who are on maintenance dialysis. METHODS: We conducted a retrospective observational study of HTN-C admissions in patients with end-stage kidney disease using the United States Renal Data System. We identified patients with end-stage kidney disease aged ≥18 years on dialysis and were hospitalized for HTN-C from January 2006 to August 2015. RESULTS: A total of 54 483 patients with end-stage kidney disease were hospitalized for HTN-C during the study period. After study exclusions, 37 214 patients were included in the analysis. A majority of patients were Black, there were more women than men and the South region of the country accounted for a great majority of patients. During the study period, hospitalization rates increased from 1060 per 100 000 beneficiary years to 1821 (Ptrend<0.0001). Overall, in-hospital mortality, 30-day, and 1-year mortality were 0.6%, 2.3%, and 21.8%, respectively, and 30-day readmission rate was 31.1%. During the study period, most study outcomes showed a significant decreasing trend (in-hospital mortality 0.6%-0.5%, 30-day mortality 2.4%-1.9%, 1-year mortality 23.9%-19.7%, Ptrend<0.0001 for all). CONCLUSIONS: Hospitalizations for HTN-C have increased consistently during the decade studied. Although temporal trends showed improving mortality and readmission rates, the absolute rates were still high with 1 in 3 patients readmitted within 30 days and 1 in 5 patients dying within 1 year of index hospitalization.

Cachexia Is Associated With Adverse Outcomes in Patients Admitted With Heart Failure.

Cachexia is often seen in patients with heart failure (HF). This study aimed to examine the association between cachexia and clinical outcomes in patients hospitalized for HF. We extracted all adult cases with a primary diagnosis of HF that were discharged between January and November, identified in the Nationwide Readmissions Database for 2016 through 2019. Exclusion criteria included cases with missing data or a diagnosis of acquired immunodeficiency syndrome, advanced liver disease, end-stage renal disease, chronic lung disease, or malignancy. Appropriate weighting was used to obtain national estimates. Primary outcomes were inpatient mortality, length of stay, and 30-day readmission in patients with HF with cachexia compared with patients with no cachexia. Multivariable logistic regression was used to estimate the association between cachexia and clinical outcomes. Survey procedures were applied using Statistical Analysis Software 9.4. The final analysis included 2,360,307 HF-related hospitalizations. Cachexia was present in about 7% of the study population. A greater percentage of patients with cachexia were female and older than patients without cachexia (52% vs 47% female, the mean age of 77 vs 72 years, respectively). However, after adjusting for demographics and co-morbidities, including coronary artery disease and atrial fibrillation, patients with cardiac cachexia had higher inpatient mortality (odds ratio 3.01, 95% confidence interval 2.88 to 3.15, p <0.001), prolonged hospital stays (9 vs 5 days, p <0.0001), and greater all-cause 30-day readmissions (23% vs 21%, p <0.0001). HF-related cachexia is associated with increased inpatient mortality, greater resource use, and additional healthcare costs.

Diet-Induced Gut Barrier Dysfunction Is Exacerbated in Mice Lacking Cannabinoid 1 Receptors in the Intestinal Epithelium.

The gut barrier provides protection from pathogens and its function is compromised in diet-induced obesity (DIO). The endocannabinoid system in the gut is dysregulated in DIO and participates in gut barrier function; however, whether its activity is protective or detrimental for gut barrier integrity is unclear. We used mice conditionally deficient in cannabinoid receptor subtype-1 (CB1R) in the intestinal epithelium (intCB1-/-) to test the hypothesis that CB1Rs in intestinal epithelial cells provide protection from diet-induced gut barrier dysfunction. Control and intCB1-/- mice were placed for eight weeks on a high-fat/sucrose Western-style diet (WD) or a low-fat/no-sucrose diet. Endocannabinoid levels and activity of their metabolic enzymes were measured in the large-intestinal epithelium (LI). Paracellular permeability was tested in vivo, and expression of genes for gut barrier components and inflammatory markers were analyzed. Mice fed WD had (i) reduced levels of endocannabinoids in the LI due to lower activity of their biosynthetic enzymes, and (ii) increased permeability that was exacerbated in intCB1-/- mice. Moreover, intCB1-/- mice fed WD had decreased expression of genes for tight junction proteins and increased expression of inflammatory markers in LI. These results suggest that CB1Rs in the intestinal epithelium serve a protective role in gut barrier function in DIO.

Outcomes in patients with history of cocaine use presenting with chest pain to the emergency department: Insights from the Nationwide Emergency Department Sample 2016-2018.

OBJECTIVES: Cocaine use (CU) related chest pain (CP) is a common cause of emergency department (ED) visits in the United States. However, information on disposition and outcomes in these patients is scarce. We conducted a nationwide study to assess disposition from ED, hospitalization rates, in-hospital outcomes, and health care costs in patients with history of CU who presented to the ED with CP. METHODS: We queried the Nationwide Emergency Department Sample database from 2016-2018 for adult patients with CU presenting to the ED with CP. International Classification of Diseases, Tenth Revision codes were used to identify study patients. RESULTS: We identified 149,372 patients. The majority were male (76%), presented to metropolitan centers (91.3%), and had a high prevalence of cardiovascular risk factors (48.1% with hypertension, 24.4% with coronary artery disease, 18.2% with diabetes) and psychiatric illnesses (21%). Overall, 21.4% of patients were hospitalized, 68.6% were discharged from ED and 6.6% left against medical advice. Patients requiring admission were older (51.8 vs 45.0; P < 0.0001) and had a higher prevalence of coronary artery disease, peripheral arterial disease, hypertension, diabetes, and chronic kidney disease. Of those admitted, 45.7% were diagnosed with myocardial infarction (MI), constituting 9.7% of the total study population. Over 80% of these patients underwent coronary angiography and 38.6% had coronary intervention. Mortality was 1.2%. CONCLUSION: CU patients who present to ED are predominantly male, are from lower economic strata, and have significant comorbidity burden. One in 5 patients requires hospitalization and has more prevalent cardiovascular risk factors and comorbidities. In-hospital mortality is low, but incidence of MI and subsequent invasive procedures is high. CU may be considered a cardiac risk factor as it is associated with high rates of in-hospital MI.

Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice.

BACKGROUND: Individuals with Fragile X syndrome (FXS) and autism spectrum disorder (ASD) exhibit an array of symptoms, including sociability deficits, increased anxiety, hyperactivity, and sensory hyperexcitability. It is unclear how endocannabinoid (eCB) modulation can be targeted to alleviate neurophysiological abnormalities in FXS as behavioral research reveals benefits to inhibiting cannabinoid (CB) receptor activation and increasing endocannabinoid ligand levels. Here, we hypothesize that enhancement of 2-arachidonoyl-sn-glycerol (2-AG) in Fragile X mental retardation 1 gene knock-out (Fmr1 KO) mice may reduce cortical hyperexcitability and behavioral abnormalities observed in FXS. METHODS: To test whether an increase in 2-AG levels normalized cortical responses in a mouse model of FXS, animals were subjected to electroencephalography (EEG) recording and behavioral assessment following treatment with JZL-184, an irreversible inhibitor of monoacylglycerol lipase (MAGL). Assessment of 2-AG was performed using lipidomic analysis in conjunction with various doses and time points post-administration of JZL-184. Baseline electrocortical activity and evoked responses to sound stimuli were measured using a 30-channel multielectrode array (MEA) in adult male mice before, 4 h, and 1 day post-intraperitoneal injection of JZL-184 or vehicle. Behavior assessment was done using the open field and elevated plus maze 4 h post-treatment. RESULTS: Lipidomic analysis showed that 8 mg/kg JZL-184 significantly increased the levels of 2-AG in the auditory cortex of both Fmr1 KO and WT mice 4 h post-treatment compared to vehicle controls. EEG recordings revealed a reduction in the abnormally enhanced baseline gamma-band power in Fmr1 KO mice and significantly improved evoked synchronization to auditory stimuli in the gamma-band range post-JZL-184 treatment. JZL-184 treatment also ameliorated anxiety-like and hyperactivity phenotypes in Fmr1 KO mice. CONCLUSIONS: Overall, these results indicate that increasing 2-AG levels may serve as a potential therapeutic approach to normalize cortical responses and improve behavioral outcomes in FXS and possibly other ASDs.

UPLC-MS/MS Method for Analysis of Endocannabinoid and Related Lipid Metabolism in Mouse Mucosal Tissue.

The endocannabinoid system is expressed in cells throughout the body and controls a variety of physiological and pathophysiological functions. We describe robust and reproducible UPLC-MS/MS-based methods for analyzing metabolism of the endocannabinoids, 2-arachidonoyl-sn-glycerol and arachidonoyl ethanolamide, and related monoacylglycerols (MAGs) and fatty acid ethanolamides (FAEs), respectively, in mouse mucosal tissues (i.e., intestine and lung). These methods are optimized for analysis of activity of the MAG biosynthetic enzyme, diacylglycerol lipase (DGL), and MAG degradative enzymes, monoacylglycerol lipase (MGL) and alpha/beta hydrolase domain containing-6 (ABHD6). Moreover, we describe a novel UPLC-MS/MS-based method for analyzing activity of the FAE degradative enzyme, fatty acid amide hydrolase (FAAH), that does not require use of radioactive substrates. In addition, we describe in vivo pharmacological methods to inhibit MAG biosynthesis selectively in the mouse small-intestinal epithelium. These methods will be useful for profiling endocannabinoid metabolism in rodent mucosal tissues in health and disease.

Cannabinoid Receptor Subtype-1 Regulates Allergic Airway Eosinophilia During Lung Helminth Infection.

Introduction: Over 1 billion humans carry infectious helminth parasites that can lead to chronic comorbidities such as anemia and growth retardation in children. Helminths induce a T-helper type 2 (Th2) immune response in the host and can cause severe tissue damage and fibrosis if chronic. We recently reported that mice infected with the soil-transmitted helminth, Nippostrongylus brasiliensis, displayed elevated levels of endocannabinoids (eCBs) in the lung and intestine. eCBs are lipid-signaling molecules that control inflammation; however, their function in infection is not well defined. Materials and Methods: A combination of pharmacological approaches and genetic mouse models was used to investigate roles for the eCB system in inflammatory responses and lung injury in mice during parasitic infection with N. brasiliensis. Results: Hemorrhaging of lung tissue in mice infected with N. brasiliensis was exacerbated by inhibiting peripheral cannabinoid receptor subtype-1 (CB1Rs) with the peripherally restricted CB1R antagonist, AM6545. In addition, these mice exhibited an increase in nonfunctional alveolar space and prolonged airway eosinophilia compared to vehicle-treated infected mice. In contrast to mice treated with AM6545, infected cannabinoid receptor subtype-2-null mice (Cnr2-/-) did not display any changes in these parameters compared to wild-type mice. Conclusions: Roles for the eCB system in Th2 immune responses are not well understood; however, increases in its activity in response to infection suggest an immunomodulatory role. Moreover, these findings suggest a role for eCB signaling at CB1Rs but not cannabinoid receptor subtypes-2 in the resolution of Th2 inflammatory responses, which become host destructive over time.

Cannabinoid CB1 Receptors in the Intestinal Epithelium Are Required for Acute Western-Diet Preferences in Mice.

The endocannabinoid system plays an important role in the intake of palatable food. For example, endocannabinoid signaling in the upper small-intestinal epithelium is increased (i) in rats after tasting dietary fats, which promotes intake of fats, and (ii) in a mouse model of diet-induced obesity, which promotes overeating via impaired nutrient-induced gut-brain satiation signaling. We now utilized a combination of genetic, pharmacological, and behavioral approaches to identify roles for cannabinoid CB1Rs in upper small-intestinal epithelium in preferences for a western-style diet (WD, high-fat/sucrose) versus a standard rodent diet (SD, low-fat/no sucrose). Mice were maintained on SD in automated feeding chambers. During testing, mice were given simultaneous access to SD and WD, and intakes were recorded. Mice displayed large preferences for the WD, which were inhibited by systemic pretreatment with the cannabinoid CB1R antagonist/inverse agonist, AM251, for up to 3 h. We next used our novel intestinal epithelium-specific conditional cannabinoid CB1R-deficient mice (IntCB1-/-) to investigate if intestinal CB1Rs are necessary for WD preferences. Similar to AM251 treatment, preferences for WD were largely absent in IntCB1-/- mice when compared to control mice for up to 6 h. Together, these data suggest that CB1Rs in the murine intestinal epithelium are required for acute WD preferences.

Vascular complications associated with percutaneous left ventricular assist device placement: A 10-year US perspective.

BACKGROUND: Over the last decade, there has been a significant increase in the use of percutaneous left ventricular assist devices(p-LVADs). p-LVADs are being increasingly used during complex coronary interventions and for acute cardiogenic shock. These large bore percutaneous devices have a higher risk of vascular complications. We examined the vascular complication rates from the use of p-LVAD in a national database. METHODS: We conducted a secondary analysis of the National In-patient Sample (NIS) dataset from 2005 till 2015. We used the ICD-9-CM procedure codes 37.68 and 37.62 for p-LVAD placement regardless of indications. We investigated common vascular complications, defining them by the validated ICD 9 CM codes. χ2 test and t test were used for categorical and continuous variables, respectively for comparison. RESULTS: A total of 31,263 p-LVAD placements were identified during the period studied. A majority of patients were male (72.68%) and 64.44% were white. The overall incidence of vascular complications was 13.53%, out of which 56% required surgical treatment. Acute limb thromboembolism and bleeding requiring transfusion accounted for 27.6% and 21.8% of all vascular complications. Occurrence of a vascular complication was associated with significantly higher in-hospital mortality (37.77% vs. 29.95%, p < .001), length of stay (22.7 vs. 12.2 days, p < .001) and cost of hospitalization ($ 161,923 vs. $ 95,547, p < .001). CONCLUSIONS: There is a high incidence of vascular complications with p-LVAD placement including need for vascular surgery. These complications are associated with a higher in-hospital, LOS and hospitalization costs. These findings should be factored into the decision-making for p-LVAD placement.

Impact of short term oral steroid use for intravenous contrast media hypersensitivity prophylaxis in diabetic patients undergoing nonemergent coronary angiography or interventions.

OBJECTIVES: Oral steroids are routinely administered in the United States for prophylaxis of iodinated contrast media hypersensitivity (ICMH). We studied the impact of short-term steroid use in diabetic patients with ICMH undergoing nonemergent coronary angiography. METHODS: We retrospectively analyzed records of diabetic patients with and without ICMH who underwent nonemergent coronary angiography at our center. Primary study endpoint was 30-day major adverse cardiac events (MACE) and secondary endpoints were pre- and postprocedure fasting blood glucose (FBG), highest in hospital blood glucose, pre- and postprocedure systolic blood pressure (SBP), and use of intravenous insulin and antihypertensive medications. RESULTS: A total of 88 diabetics with ICMH (study group) and 76 diabetics without ICMH (control group) undergoing angiography were enrolled. Demographics and hemoglobin A1c values were similar in both groups. Preprocedural FBG was significantly higher in the study group. The study group had significantly higher post angiography FBG (239.93 + 96.88 mg/dl vs. 156.6 + 59.88 mg/dl) and greater use of intravenous (IV) insulin (67.27% vs. 32.43%). Further, those who received steroids had significantly higher systolic SBP postprocedure (146.16 + 25.35 mmHg vs. 130.8 + 21.59 mmHg), a higher incidence of severe hypertension and use of IV antihypertensive medications (80.95% vs. 19.05%) periprocedurally. There were no differences in 30-day MACE between groups. CONCLUSION: Short-term steroid use for ICMH results in a significant increase in surrogate markers for adverse clinical events after coronary procedures. Study findings highlight the need for better periprocedural management of these patients and to limit steroid prophylaxis to those with only true ICMH.