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To test the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss-independent mechanisms.Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase-4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo-controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. The primary outcomes were measures of endothelial function: flow-mediated vasodilation (FMD), plasminogen activator inhibitor-1 (PAI-1) and urine albumin-to-creatinine ratio (UACR).Eighty-eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI-1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP-1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1).Liraglutide and diet reduce weight, insulin resistance and PAI-1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1, indicating that this beneficial effect is independent of weight loss.

Background: DPP4 (dipeptidyl peptidase-4) inhibitors comprise a class of oral diabetes medication that have the potential for off-target cardiovascular effects. We previously showed that DPP4 inhibition attenuates the hypotensive effect of acute ACE (angiotensin-converting enzyme) inhibition and increases norepinephrine. Here, we investigated the effects of DPP4 during sustained ACE inhibition compared with during therapy with an ARB (angiotensin receptor blocker) or calcium channel blocker (neutral comparator) in a randomized, double-blinded crossover study. Methods: We enrolled 106 adults with type 2 diabetes and hypertension and 100 received intervention. Subjects were randomized to one of 3 blood pressure arms: ramipril, valsartan, or amlodipine for a total of 15 weeks and received 3 one-week crossover therapies in random order: placebo + placebo, sitagliptin + placebo, and sitagliptin + aprepitant separated by 4-week washout. Results: We found that DPP4 inhibition increased norepinephrine during ramipril but did not increase blood pressure. Aprepitant, a NK1 (substance P) receptor blocker, lowered standing heart rate during renin-angiotensin-aldosterone system blockade with ramipril or valsartan. Conclusions: Increased catecholamines during concurrent ACE and DPP4 inhibition may contribute to cardiovascular complications in patients predisposed to heart failure.

Contemporary anticancer drugs have significantly improved cancer survival at the expense of cardiovascular toxicities, including heart disease, thromboembolic disease, and hypertension. One of the most common side effects of these drugs is hypertension, especially in patients treated with vascular endothelial growth factor inhibitors, as well as tyrosine kinase inhibitors and proteasome inhibitors. Adjunctive therapy, including corticosteroids, calcineurin inhibitors, and nonsteroidal anti-inflammatories, as well as anti-androgen hormone therapy for prostate cancer, may further increase blood pressure in these patients. Cancer therapy-induced hypertension is often dose limiting, increases cardiovascular mortality in cancer survivors, and is usually reversible after interruption or discontinuation of treatment. The exact molecular mechanisms underlying hypertension are unclear, but recent discoveries indicate an important role for reduced nitric oxide generation, oxidative stress, endothelin-1, prostaglandins, endothelial dysfunction, increased sympathetic outflow, and microvascular rarefaction. In addition, genetic polymorphisms in vascular endothelial growth factor receptors are implicated in vascular endothelial growth factor inhibitor-induced hypertension. Diagnosis, management, and follow-up of cancer therapy-induced hypertension follow national hypertension guidelines because evidence-based clinical trials specifically addressing patients who develop hypertension as a result of cancer therapy are currently lacking. Rigorous baseline assessment of patients before therapy is started requires particular emphasis on assessing and treating cardiovascular risk factors. Hypertension management follows guidelines for the general population, although special attention should be given to rebound hypotension after termination of cancer therapy. Management of these complex patients requires collaborative care involving oncologists, cardiologists, hypertension specialists, primary care professionals, and pharmacists to ensure the optimal therapeutic effect from cancer treatment while minimizing competing cardiovascular toxicities.

BACKGROUND: B-type natriuretic peptide (BNP) immunoassays (ia) do not differentiate active and inactive forms. Inactive NT-proBNP is used to track heart failure (HF) during treatment with sacubitril/valsartan, which inhibits BNP degradation. Mass spectrometry (MS) may better assess effects of HF treatment on biologically active BNP1–32. METHODS AND RESULTS: We developed a MS assay with immediate protease inhibition to quantify BNP1–32 over a linear range, using labeled recombinant BNP standard. In four healthy volunteers, BNP1–32 by MS (BNP(MS)) rose from below the 5 pg/ml detection limit to 228 pg/mL after nesiritide. In patients with HF, BNP(MS) was measured in parallel with BNP and NT-proBNP immunoassays before and during sacubitril/valsartan treatment. BNP(MS) was 4.4-fold lower than BNP(ia) in patients with HF. Among patients not taking sacubitril/valsartan and without ESRD, BNP(MS) correlated with BNP(ia) (r(s)=0.77, p

Hardhead catfish Ariopsis felis are a common marine catfish in the coastal waters of the Gulf of Mexico (GOM). The low economic value of this species has depressed interest and research, and although the species is known for its extremely low fecundity and large oocytes, little else is known about this catfish species. A total of 1230 samples across all months of the year from 2016 to 2018 resulted in 681 females, and analysis of gonado-somatic index (IG ) revealed 1% to be a clear cut-off indicating maturity. Females are considered capable of spawning from April to June when IG averaged 4-8%. Both atresia and post-ovulatory follicles were present in July, suggesting that spawning ends in July in the northern GOM. The 1% IG cut-off was used to designate maturity, and from that an L50 of 253 mm was estimated. Batch fecundity from 41 females estimated a mean batch size of 36 oocytes. Perhaps the most interesting finding was the presence of secondary growth stage oocytes (e.g., cortical alveoli) from July through November, well outside the spawning capable period. Furthermore, 78% of females had some early vitellogenic oocytes present during the non-spawning season, and the distribution of these relatively large (2-5 mm) oocytes did not change over time. The results here are not only important as reproductive biology information for a common and abundant species, but also present interesting and unusual patterns of non-spawning season oocyte development that is not commonly seen in Western Hemisphere subtropical fish species.

Background Natriuretic peptide (NP) hormones, atrial NP (ANP) and B-type NP (BNP), exert cardiovascular and metabolically protective effects. When measured by conventional immunoassay methods, NP levels are lower in obese, black, and insulin-resistant individuals, suggesting these groups may experience a relative NP deficiency. However, immunoassay measurements are likely poor determinants of physiologically relevant NPs as the immunoassay inadvertently captures predominantly inactive truncated peptides due to poor specificity and rapid degradation of the bioactive form. We have developed and validated a novel ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay1 that specifically measures bioactive BNP (BNPMS) and ANP (ANPMS). Relationships between bioactive NPs measured by mass spectrometry (MS) with BMI, race, and glucose metabolism are not well-understood. Methods We measured bioactive BNP and ANP using a novel UPLC-MS/MS assay in 26 veterans without heart failure, diabetes, or significant cardiac/pulmonary/renal/hepatic disease. We also determined BNP using conventional immunoassay (BNPia), age, sex, race, BMI, fasting glucose, and HbA1c. We assessed relationships of NPs with continuous variables using Spearman's correlation and multivariable linear regression, and with categorical variables using Wilcoxon rank-sum. Results Among 26 veterans (aged 25-55, 69% male), 8 were lean (BMI 23.1 +/- 1.4 kg/m2) and 18 were obese (BMI 34 +/- 2.9 kg/m2). ANPMS was negatively associated with BMI (rs=-0.59, p=0.0015). Moreover, when analyzed by BMI category, ANPMS was lower in obese compared with lean individuals (mean 113.9 +/- 74.9 vs. mean 220 +/- 173.7 pg/mL, respectively, p=0.020). BNPMS was lower in blacks; all 5 black individuals had undetectably low BNPMS ( Discussion Using a novel UPLC-MS/MS technique, we found that ANPMS is lower in obesity, and BNPMS is lower in black individuals and in those with higher fasting glucose. Our results are consistent with relationships of NPs assessed by traditional immunoassay methods from large epidemiologic studies. Our findings are particularly striking as our sample size was relatively small compared with epidemiologic studies. Our analyses of bioactive NP levels by this specific methodology support the emerging hypothesis that obese and black individuals experience a relative NP deficiency. Future large-scale studies quantifying bioactive NPs by MS are warranted to refine the phenotyping of individuals with relative NP deficiency and determine whether relative NP deficiency contributes to greater cardiometabolic risk. 1Reference: Dillon EM et al. Active BNP Measured by Mass Spectrometry and Response to Sacubitril/Valsartan. Journal of Cardiac Failure. 2021 Nov. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:12 p.m. - 1:17 p.m.

Background GLP-1 receptor (GLP1R) agonists reduce glucose, weight and cardiovascular risk. Understanding the weight loss-dependent mechanisms of these benefits will inform treatment and drug development. This study compared metabolic responses among GLP1R agonist (liraglutide), DPP4 inhibitor (sitagliptin), and hypocaloric diet treatments. Methods We randomized 88 obese, pre-diabetic individuals in a 2: 1: 1 ratio to liraglutide, sitagliptin, or diet for 14 weeks. Treatment was double-blinded and placebo-controlled for drug. Individuals completed a mixed meal at baseline, 2 and 14 weeks. The GLP1R antagonist exendin (9-39) and vehicle were infused in a randomized crossover design at 2 and 14 weeks. Within-subject change was assessed using paired t-test. Between-treatment effects were analyzed using generalized least squares linear regression. Results Baseline characteristics were similar (mean age 50, 32% men, 13% black). Liraglutide and diet caused weight loss at 14 weeks (L: -2.7kg 95%CI [-3.8, -1.7], P Conclusions Liraglutide lowered glucose and increased peak post-prandial GLP-1 in obese pre-diabetic individuals without raising insulin. GLP1R antagonism increased glucose and insulin in all, and increased post-prandial GLP-1 levels to a greater extent in sitagliptin-treated than in liraglutide-treated individuals. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous glucagon-like peptide-1 (GLP-1). We hypothesized that genetic variation in the gene encoding the GLP-1 receptor (GLP1R) could affect the metabolic response to DPP-4 inhibition. To evaluate the relationship between the GLP1R rs6923761 variant (G-to-A nucleic acid substitution) and metabolic responses, we performed mixed meal studies in individuals with type 2 diabetes mellitus and hypertension after 7-day treatment with placebo and the DPP-4 inhibitor sitagliptin. This analysis is a substudy of NCT02130687. The genotype frequency was 13:12:7 GG:GA:AA among individuals of European ancestry. Postprandial glucose excursion was significantly decreased in individuals carrying the rs6923761 variant (GA or AA) as compared with GG individuals during both placebo (P = 0.001) and sitagliptin treatment (P = 0.045), while intact GLP-1 levels were similar among the genotype groups. In contrast, sitagliptin lowered postprandial glucose to a greater degree in GG as compared with GA/AA individuals (P = 0.035). The relationship between GLP1R rs6923761 genotype and therapies that modulate GLP-1 signalling merits study in large populations.

Waste-to-energy systems can play an important role in diverting organic waste from landfills. However, real-world waste management can differ from idealized practices, and emissions driven by microbial communities and complex chemical processes are poorly understood. This study presents a comprehensive life-cycle assessment, using reported and measured data, of competing management alternatives for organic municipal solid waste including landfilling, composting, dry anaerobic digestion (AD) for the production of renewable natural gas (RNG), and dry AD with electricity generation. Landfilling is the most greenhouse gas (GHG)-intensive option, emitting nearly 400 kg CO2e per tonne of organic waste. Composting raw organics resulted in the lowest GHG emissions, at -41 kg CO2e per tonne of waste, while upgrading biogas to RNG after dry AD resulted in -36 to -2 kg CO2e per tonne. Monetizing the results based on social costs of carbon and other air pollutant emissions highlights the importance of ground-level NH3 emissions from composting nitrogen-rich organic waste or post-AD solids. However, better characterization of material-specific NH3 emissions from landfills and land-application of digestate is essential to fully understand the trade-offs between alternatives.

Background Mechanisms of postoperative delirium remain poorly understood, limiting development of effective treatments. We tested the hypothesis that intraoperative oxidative damage is associated with delirium and neuronal injury and that disruption of the blood–brain barrier modifies these associations. Methods In a prespecified cohort study of 400 cardiac surgery patients enrolled in a clinical trial of atorvastatin to reduce kidney injury and delirium, we measured plasma concentrations of F2-isoprostanes and isofurans using gas chromatography-mass spectrometry to quantify oxidative damage, ubiquitin carboxyl-terminal hydrolase isozyme L1 to quantify neuronal injury, and S100 calcium-binding protein B using enzyme-linked immunosorbent assays to quantify blood–brain barrier disruption before, during, and after surgery. We performed the Confusion Assessment Method for the Intensive Care Unit twice daily to diagnose delirium. We measured the independent associations between intraoperative F2-isoprostanes and isofurans and delirium (primary outcome) and postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (secondary outcome), and we assessed if S100 calcium-binding protein B modified these associations. Results Delirium occurred in 109 of 400 (27.3%) patients for a median (10th, 90th percentile) of 1.0 (0.5, 3.0) days. In the total cohort, plasma ubiquitin carboxyl-terminal hydrolase isozyme L1 concentration was 6.3 ng/ml (2.7, 14.9) at baseline and 12.4 ng/ml (7.9, 31.2) on postoperative day 1. F2-isoprostanes and isofurans increased throughout surgery, and the log-transformed sum of intraoperative F2-isoprostanes and isofurans was independently associated with increased odds of postoperative delirium (odds ratio, 3.70 [95% CI, 1.41 to 9.70]; P = 0.008) and with increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (ratio of geometric means, 1.42 [1.11 to 1.81]; P = 0.005). The association between increased intraoperative F2-isoprostanes and isofurans and increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 was amplified in patients with elevated S100 calcium-binding protein B (P = 0.049). Conclusions Intraoperative oxidative damage was associated with increased postoperative delirium and neuronal injury, and the association between oxidative damage and neuronal injury was stronger among patients with increased blood–brain barrier disruption. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

The reproductive characteristics, movement patterns and courtship behaviors associated with a yellowfin grouper (Mycteroperca venenosa, Linnaeus, 1758) fish spawning aggregation (FSA) were assessed between 2004 and 2014. The FSA was located on the Grammanik Bank, a seasonally closed area on the edge of the Puerto Rico platform, south of St. Thomas, US Virgin Islands. Fish arrived at the FSA site around full moon and departed 10–12 days after full moon (dafm), during two or three consecutive months, from January to May each year. Males were significantly larger than females and preceded females at the spawning site. Courtship coloration and behaviors showed distinct patterns relative to lunar date and time of day. Spawning was observed for several days each month in 2008, 2009, 2011 and 2014, from 6 to 10 dafm. Female gonadosomatic index (GSI) values were highest from 4 to 7 dafm. Spawning, which began at sunset, consisted of 7 to 12 males following one female along the bottom before ascending 10–20 m, then "rushing" upward to release gametes. Histological analysis of ovaries indicated females spawned every 2–3 nights, although 11.6% were capable of spawning two consecutive nights. Total spawning population size of yellowfin grouper fluctuated from 600 to 1100 fish during the study period, but consistent annual population assessments using scuba were difficult to carry out due to ocean conditions. Based on size-frequency analysis and other metrics, the M. venenosa spawning population at the Grammanik bank appears to be stable at this time with existing regulations.

Aims/HypothesisGLP-1 receptor (GLP1R) agonists cause weight loss in obese individuals and decrease cardiovascular events in patients with type 2 diabetes. The objective of this study was to test the hypothesis that GLP1R agonists have beneficial effects on vascular endothelial function, fibrinolysis, and inflammation in obesity through weight loss-independent (GLP1R-dependent) mechanism(s).MethodsWe conducted a randomized, parallel-group, three-arm double-blinded controlled trial at a single center in the United States. Eligibility criteria were as follows: age 18-65 years, body mass index ≥ 30kg/m2, and pre-diabetes defined by the American Diabetes Association criteria. Participants were randomized in a 2:1:1 ratio to 14 weeks of the GLP1R agonist liraglutide, hypocaloric diet, or the dipeptidyl peptidase 4 inhibitor sitagliptin. Treatment with drug was double blind and placebo controlled. Measurements were made at baseline, after 2 weeks of treatment prior to significant anticipated weight loss, and after 14 weeks of treatment. The primary outcomes were measures of endothelial function: flow-mediated vasodilation (FMD), plasminogen activator inhibitor-1 (PAI-1), and urine albumin-to-creatinine ratio (UACR).ResultsNinety-three obese pre-diabetic individuals were randomized, and data from 88 individuals who completed at least a single study day are included in the analysis (liraglutide N=44, diet N=22, sitagliptin N=22). Liraglutide and diet reduced weight and insulin resistance, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function as measured by FMD (Liraglutide: 2 weeks: difference from baseline +0.70%, 95% CI [-0.71, 2.11], P=0.33, 14 weeks: +1.38% [-0.01, 2.78], P=0.05; Sitagliptin: 2 weeks: +1.92% [-0.05, 3.88], P=0.06, 14 weeks: +1.59% [-0.30, 3.48], P=0.10; Diet: 2 weeks: +1.24% [-0.69, 3.18], P=0.21, 14 weeks: +1.20% [-0.97, 3.38], P=0.28). As baseline endothelial function was normal in the overall cohort, post hoc subgroup analyses were conducted in participants stratified by FMD below or above the median. Individuals with baseline FMD below the median, indicative of endothelial dysfunction, had higher BMI, waist circumference and insulin resistance as compared to those with baseline FMD above the median. All three treatments improved FMD at 2 and 14 weeks in individuals with baseline FMD below the median (PConclusionsLiraglutide and diet cause weight loss, improve insulin resistance and reduce PAI-1 concentrations. Liraglutide, sitagliptin and diet do not change FMD in obese pre-diabetic individuals with normal endothelial function after 14 weeks of treatment. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1 at 2 and 14 weeks, indicating that this beneficial cardiovascular effect is independent of weight loss.Clinicaltrials.gov IdentifierNCT03101930Research in contextWhat is already known about this subject?GLP-1 receptor agonists reduce cardiovascular events in patients with type 2 diabetes through unknown mechanism(s).GLP-1 receptor agonists cause weight loss in obese individuals with and without diabetes.What is the key question?Are vascular effects of GLP-1 receptor agonists mediated by weight loss or GLP-1 receptor activation?What are the new findings?The GLP-1 receptor agonist liraglutide and diet-induced weight loss reduce circulating PAI-1, a measure of fibrinolytic balance and inflammation, while the DPP-4 inhibitor sitagliptin does not.Liraglutide reduces the circulating pro-inflammatory chemokine MCP-1, while sitagliptin and diet-induced weight loss do not.Liraglutide, sitagliptin and diet-induced weight loss do not improve flow-mediated dilation, a measure of endothelial vasodilator function, in obese pre-diabetic individuals after 14 weeks of treatment.How might this impact on clinical practice in the foreseeable future?Understanding the mechanisms by which GLP-1 receptor agonists exert vascular effects is critical in improving patient selection and future drug development.

In the Florida Keys, queen conchs (Lobatus gigas) occur in two spatially distinct regions: nearshore in habitats immediately adjacent to the shoreline and offshore in habitats along the ree...

Background: Medication nonadherence presents one of the greatest challenges to hypertension management. Previous studies from our group have shown therapeutic drug monitoring (TDM), biochemical monitoring of drug levels, is more accurate than self-report, detailed questionnaires, or prescription fill rate in detecting nonadherence. Prior studies have also shown a prevalence of nonadherence from 45% to 80% among insured patients with uncontrolled hypertension despite having been prescribed a multi-drug regimen. Previous studies have not assessed adherence to antihypertensive drugs in a safety net population by TDM. Methods: We performed a cross-sectional study in patients with uncontrolled hypertension in the primary care Internal Medicine and Cardiology Clinics at Parkland Health& Hospital System (PHHS). Patients with BP of 130/80 mmHg, prescribed ≥2 antihypertensive medications, and self-reporting medication adherence were enrolled after informed consent. Plasma samples were obtained for measurement of 44 cardiovascular drugs using liquid chromatography mass spectrometry. Results: Among 77 patients with uncontrolled hypertension (57% female, 65% Black, 12% Hispanic), 13 (17%) were nonadherent to at least one anti-hypertensive drug by TDM. There was no difference in baseline characteristics between the two groups. The adherent and nonadherent groups had similar systolic (146±13 vs 148±18, p=0.67) and diastolic (83±9 vs 88±10 mmHg, p=0.13) BP. All patients had either medical insurance or some form of prescription financial assistance. 15 patients had prescription financial assistance, while 62 patients had medical insurance. Nonadherence rates for patients on financial assistance programs did not significantly differ from patients with medical insurance (13% vs 18%, p>0.999). Conclusions: We found a surprisingly low prevalence of anti-hypertensive medication nonadherence in this uncontrolled hypertension population despite many barriers to treatment. Our study suggests a lesser role of medication nonadherence in uncontrolled hypertension in the safety net population.

Epoxyeicosatrienoic acids (EETs) reduce blood pressure by acting in the vasculature and kidney, and interventions to increase circulating EETs improve insulin sensitivity and prevent diabetes in animal models. Inhibition of EET hydrolysis with a sEH (soluble epoxide hydrolase) inhibitor is an attractive approach for hypertension and diabetes. We tested the hypothesis that sEH inhibition increases circulating EETs, reduces blood pressure, and improves insulin sensitivity, blood flow, and inflammation in a randomized, double-blind, placebo-controlled crossover study. Sixteen participants with obesity and prediabetes were randomized to GSK2256294 10 mg QD or placebo for 7 days, insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and adipose and muscle tissues biopsies were performed to assess insulin-stimulated Akt phosphorylation. We assessed tissue and plasma EETs and their respective diol concentrations and sEH activity within plasma, muscle, and adipose tissues. GSK2256294 reduced circulating and adipose tissue sEH activity, but blood pressure, circulating EET, and tissue EETs were unchanged. Plasma sEH activity correlated with muscle and adipose tissue sEH activity. Insulin sensitivity assessed during hyperinsulinemic clamps, as well as adipose and muscle phosphorylated-Akt/Akt expression were similar during GSK2256294 and placebo. sEH inhibition with GSK2256294 reduced plasma F2-isoprostanes (50.7±15.8 versus 37.2±17.3 pg/mL; P =0.03) but not IL (interleukin)-6. Resting blood pressure, forearm blood flow, and renal plasma flow were similar during GSK2256294 and placebo. We demonstrate that GSK2256294 administration for 7 days effectively inhibits sEH activity in plasma, muscle, and adipose tissue and reduces F2-isoprostanes—a marker of oxidative stress—but does not improve insulin sensitivity or blood pressure.

Adipose tissue contains a complex immune environment and is a central contributor to heightened systemic inflammation in obese persons. Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules that decrease inflammation in obese animals, but their effect on inflammation in humans is unknown. The enzyme soluble epoxide hydrolase (sEH) hydrolyzes EETs to less active diols, and we hypothesized that pharmacologic sEH inhibition would decrease adipose inflammation in obese individuals. We treated obese prediabetic adults with the sEH inhibitor GSK2256294 versus placebo in a crossover design, collected subcutaneous abdominal adipose tissue via lipoaspiration and characterized the tissue T cell profile. Treatment with GSK2256294 decreased the percentage of pro-inflammatory T cells producing interferon-gamma (IFNγ), but not interleukin (IL)-17A, and decreased the amount of secreted tumor necrosis factor-alpha (TNFα). Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate adipose and systemic inflammation.

Apparent treatment-resistant hypertension (ATRH) has been linked to end-stage kidney disease (ESKD) and cardiovascular disease. We tested the hypothesis that the effect of ATRH on ESKD is greater in Black patients than in White patients and investigated the effect of ATRH on ESKD independent of APOL1 genotype. In a retrospective cohort of 139 685 hypertensive veterans (22% Black, 5% women) in the Million Veteran Program, ATRH was defined as failure to achieve outpatient blood pressure P -interactionAPOL1 genotype. Patients with ATRH experienced excess ESKD and cardiovascular disease risk. This excess ATRH-related ESKD risk was magnified among Black patients independently of APOL1 genotype. Targeted treatment of ATRH could curtail ESKD and cardiovascular disease incidence.

The transition to academic leadership entails learning to utilize an enormous new collection of skills. Executive leadership coaching is a personalized training approach that is being increasingly used to accelerate the onboarding of effective leaders. Vanderbilt University Medical Center has invested in a robust coaching strategy that is offered broadly to institutional leaders. This case study details the early transformational learning of leadership skills by one new institutional leader in the first two years in an academic leadership role, telling the first-person account of the experience of being coached while independently leading a division of hematology and oncology at a highly ranked medical center. Over two years’ time, assessed in 6-month intervals, the academician transitions into the role, and using scenarios from regular practice in this position, learns to incorporate core leadership principles into the daily activities of running a division. The transition to academic leadership involves a transformation; a conversion that can be accelerated, guided, and applied with a greater deal of sophistication through intentional coaching, and the application of principles of behavioral science and psychology. Much like the process of coaching a high performing athlete, an elite academician can be trained in skills that enhance their game and succeed in creating a winning team. The academic medical center (AMC) is an interesting social organization, made up of highly accomplished and well-educated people, brought together around a variety of missions and motivations: education, patient service, research, community building, financial margins, and citizenship to name a few. Moreover, the leadership of AMCs almost entirely comes from within this community, drawing people with talents in science, teaching, clinical research, and service into roles that industries reserve usually for MBAs, lawyers, and other professionals who undergo rigorous guided training. Fortunately, academics are well-equipped with skills in lifelong learning, focused curiosity, and tend to be ambitious to a fault. Thus, there is a steady pipeline of budding leaders in AMC’s eager to tackle new challenges that will further their missions. Like major industries in the public and private sectors, the demands of leadership are significant. How to navigate the transitions from physician, teacher, or scientist to academic leader is not covered easily in any text. Vanderbilt University Medical Center has adopted a model of Leadership Coaching, akin to the Trusted Leadership Advisor model (Wasylyshyn, 2017). This case study details the experience of one new leader (first author), freshly plucked from the medical science proving ground. Accounts and description of the experiences and intentions of the leadership coach, Dick Kilburg, provide insight into the processes applied in facilitating this transition. Finally, observations of the transition from the vantage point of the primary supervisor (Department Chair, Nancy Brown) provide a further description of the coaching effect on the early development of an AMC leader. The experience of the client, Kimryn Rathmell (Kim), is told in first person narrative format—fitting for the intense and personal experience that accompanies the transition to a leadership role.

Reducing ambient formaldehyde concentrations is a complex task because formaldehyde is both a primary and a secondary air pollutant, with significant anthropogenic and biogenic sources of volatile organic compound (VOC) precursor emissions. This work uses adjoint sensitivity analysis in a chemical transport model to identify emission sources and chemical reactions that influence formaldehyde mixing ratios in the San Francisco Bay Area and within three urbanized sub-areas. For each of these receptors, the use of the adjoint technique allows for efficient calculation of the sensitivity of formaldehyde to emissions of NOx, formaldehyde, and VOC precursors occurring at any location and time. Formaldehyde mixing ratios are found to be generally higher in summer than in winter. The opposite seasonal trend is observed for the sensitivities of these mixing ratios to formaldehyde emissions. In other words, even though formaldehyde is higher in summer, reducing formaldehyde emissions has a greater impact in winter. In winter, 85 %–90 % of the sensitivity to emissions is attributed to direct formaldehyde emissions. In summer, this contribution is smaller and more variable, ranging from 27 % to 75 % among the receptor areas investigated in this study. Higher relative contributions of secondary formation versus direct emissions are associated with receptors located farther away from heavily urbanized and emission-rich areas. In particular, the relative contribution of biogenic VOC emissions (15 %–43 % in summer) is largest for these receptors. Ethene and other alkenes are the most influential anthropogenic precursors to secondary formaldehyde. Isoprene is the most influential biogenic precursor. Sensitivities of formaldehyde to NOx emissions are generally negative but relatively small in magnitude compared to sensitivities to VOC emissions. The magnitude of anthropogenic emissions of organic compounds other than formaldehyde is found to correlate reasonably well with their influence on population-weighted formaldehyde mixing ratios at the air-basin scale. This correlation does not hold for ambient formaldehyde in smaller urbanized sub-areas. The magnitude of biogenic emissions does not correlate with their influence in either case.

Context Dipeptidyl peptidase 4 (DPP4) inhibitors may increase the risk of heart failure. Decreased degradation of vasoactive peptides like substance P [also degraded by angiotensin-converting enzyme (ACE)] and Y1 agonists peptide YY (PYY 1-36) and neuropeptide Y (NPY 1-36) could contribute. Objective This study tested the hypothesis that there is an interactive effect of DPP4 inhibition and ACE inhibition (vs antihypertensive control subjects) on vasoactive peptides after a mixed meal. Participants and Design Fifty-three patients with type 2 diabetes and hypertension were randomized to double-blind treatment with ramipril, valsartan, or amlodipine for 15 weeks in parallel groups. During the 5th, 10th, and 15th weeks, participants also received placebo + placebo, sitagliptin 100 mg/d + placebo, and sitagliptin + aprepitant 80 mg/d in random order. On the last day of each crossover treatment, participants underwent a mixed-meal study. Results Sitagliptin increased postprandial glucagon-like peptide-1 and decreased glucose in all antihypertensive groups. Sitagliptin increased NPY 1-36 and decreased Y2 agonists NPY 3-36 and PYY 3-36 in all groups. During ramipril or valsartan, but not amlodipine, sitagliptin increased postprandial norepinephrine; substance P receptor blockade with aprepitant prevented this effect. Despite increased norepinephrine, sitagliptin decreased postprandial blood pressure during ACE inhibition. Conclusion DPP4 inhibition increases postprandial concentrations of the Y1 agonist NPY 1-36. During treatment with an ACE inhibitor or angiotensin receptor blocker, DPP4 inhibition increased postprandial norepinephrine through a substance P receptor–dependent mechanism. Increased NPY 1-36 and norepinephrine could increase risk of heart failure but did not result in higher postprandial blood pressure.

There are conflicting data on whether variations of physiologic cortisol levels associated with cardiovascular risk. We hypothesize that prior discordant findings are related to problems associated with varying sample size, techniques for assessing cardiovascular risk and failure to adequately account for environmental factors. To address these issues, we utilized a large sample size, selected the Framingham risk score to compute cardiovascular risk and performed the study in a highly controlled setting. We had two main objectives: determine whether higher, yet physiologic, cortisol levels associated with increased cardiovascular risk and determine whether caveolin-1 (rs926198) risk allele carriers associated with increased cardiovascular risk. This was a cross-sectional study of 574 non-diabetic individuals who completed a common protocol. Data collection included fasting blood samples, blood pressure measurements and a 24-h urine-free cortisol collection. Five hundred seventeen of these participants also completed caveolin-1 genotyping. Subjects were classified as belonging to either the low-mode or high-mode urine-free cortisol groups, based on the bimodal distribution of urine-free cortisol. In multivariate analysis, Framingham risk score was statistically higher in the high-mode cortisol group (10.22 (mean) ± 0.43 (s.e.m.)) compared to the low-mode cortisol group (7.73 ± 0.34), P P = 0.034. Overall, the estimated effect on Framingham risk score of carrying the caveolin-1 risk allele was 1.33 ± 0.61, P = 0.029. Both urinary cortisol and caveolin-1 risk allele status are independent predictors of Framingham risk score.

Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules formed from arachidonic acid by the action of CYP450s. EETs cause vasodilation, exert anti-inflammatory effects, and enhance insulin secretion and sensitivity in rodents. EETs are metabolized to less active dihydroxyeicosatrienoic acids (DHETs) by sEH (soluble epoxide hydrolase), and 14,15-DHET has been reported to be increased in patients with primary aldosteronism, but the effects of aldosterone on EET concentrations and sEH activity are unknown. We tested the hypothesis that treatment of primary aldosteronism would alter EET concentrations in humans. We studied 9 patients with primary aldosteronism before and at least 3 months after unilateral adrenalectomy (6) or treatment with a mineralocorticoid antagonist (3). Circulating total EET concentrations increased to 18.5±12.6 from 11.9±5.9 nmol/L with treatment of primary aldosteronism ( P =0.027). Among the regioisomers of EETs, 14,15-EET significantly increased after treatment, whereas 11,12-EET and 8,9 EET were unaltered. Total DHET concentrations and specific regioisomers of DHET did not change significantly. Circulating total EETs (ρ=−0.52, P =0.026), 14,15-EET ( ρ =−0.56, P =0.015), and 11,12-EET ( ρ =−0.48, P =0.042) correlated inversely with aldosterone. We also assessed EETs after a 12-hour aldosterone or vehicle infusion in a randomized cross-over study in healthy volunteers. Plasma EETs were similar after 12-hour aldosterone or vehicle infusion. Lastly, 3-day infusion of aldosterone in mice decreased EET concentrations in adipose and muscle and increased sEH expression as determined by molar ratio of DHETs to EETs and soluble epoxide hydrolase ( Ephx2 ) mRNA expression in adipose tissue. These studies suggest that prolonged exposure to increased aldosterone decreases EET concentrations.