Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity.

Methionine aminopeptidase type 2 (METAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. METAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of METAP2-specific substrates whose biological activity may be altered following METAP2 inhibition, and additionally, that METAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of METAP2 using fumagillin analogues has established the anti-angiogenic and anti-tumor characteristics of these derivatives; however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting central nervous system (CNS) toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer-drug conjugate of the novel METAP2 inhibitor (METAP2i) SDX-7539. In vitro binding, enzyme, and cell-based assays demonstrated that SDX-7539 is a potent and selective METAP2 inhibitor. In utilizing a high molecular weight, water-soluble polymer to conjugate the novel fumagillol-derived, cathepsin-released, METAP2i SDX-7539, limitations observed with prior generation, small molecule fumagillol derivatives were ameliorated including reduced CNS exposure of the METAP2i, and prolonged half-life enabling convenient administration. Multiple xenograft and syngeneic cancer models were utilized to demonstrate the anti-tumor and anti-metastatic profile of SDX-7320. Unlike polymer-drug conjugates in general, reductions in small molecule-equivalent efficacious doses following polymer conjugation were observed. SDX-7320 has completed a phase I clinical safety study in patients with late-stage cancer and is currently being evaluated in multiple phase Ib/II clinical studies in patients with advanced solid tumors.

Racial Disparities in Outcomes of Delivery and Cardiac Complications Among Pregnant Women with Congenital Heart Disease.

Advances in cardiology have led to improved survival among patients with congenital heart disease (CHD). Racial disparities in cardiovascular and maternal outcomes are well known and are likely to be more profound among pregnant women with CHD. Using the 2001 to 2018 National Inpatient Sample, we identified all hospitalizations for delivery among women ≥ 18 years of age with CHD. Unadjusted and adjusted between-race differences in adverse maternal cardiovascular, obstetric, and fetal events were assessed using logistic regression models. During the study period, we identified 52,711 hospitalizations for delivery among women with concomitant CHD. Of these, 66%, 11%, and 16% were White, Black, and Hispanic, respectively. Obstetric complications and fetal adverse events were higher among Blacks compared to Whites and Hispanics (44% vs. 33% vs. 37%, p < .001; 36% vs. 28% vs. 30%, p < .001), respectively. No between-race differences were observed in overall cardiovascular adverse events (27% vs. 24% vs. 23%, p < .21). However, heart failure was significantly higher among Black women (3.6% vs. 1.7% vs. 2.2%, p = 0.001). While a lower income quartile was associated with higher rates of adverse outcomes, adjustment for income did not attenuate the adverse impact of race. Black females with CHD diagnoses were more likely to experience adverse obstetric, fetal events, and heart failure compared to White and Hispanic women irrespective of their income status. Further research is needed to identify causes and devise interventions to mitigate racial disparities in the care of pregnant women with CHD.

Continuing professional development (CPD) for anesthetists: A systematic review.

BACKGROUND: In accordance with the focus on patient safety and quality in healthcare, continuing professional development (CPD) has received increasing levels of attention as a means to ensure physicians maintain their clinical competencies and are fit to practice. There is some evidence of a beneficial effect of CPD, though few studies have evaluated its effect within anesthesia. The primary aim of this systematic review was to establish which CPD activities anesthetists are engaged in and their effectiveness. The secondary aim was to explore which methods are employed to evaluate anesthetists' clinical performance. METHODS: Databases searched: Medline, Embase and Web of Science, in May 2023. Additional papers were identified through searching the references of included studies. Eligible studies included anesthetists, either exclusively or combined with other healthcare professionals, who underwent a learning activity or assessment method as part of a formalized CPD program or a stand-alone activity. Non-English language studies, non-peer reviewed studies and studies published prior to 2000 were excluded. Eligible studies were quality assessed and narratively synthesized, with results presented as descriptive summaries. RESULTS: A total of 2112 studies were identified, of which 63 were eligible for inclusion, encompassing more than 137,518 participants. Studies were primarily of quantitative design and medium quality. Forty-one studies reported outcomes of single learning activities, whilst 12 studies investigated different roles of assessment methods in CPD and ten studies evaluated CPD programs or combined CPD activities. A 36 of the 41 studies reported positive effects of single learning activities. Investigations of assessment methods revealed evidence of inadequate performance amongst anesthetists and a mixed effect of feedback. Positive attitudes and high levels of engagement were identified for CPD programs, with some evidence of a positive impact on patient/organizational outcomes. DISCUSSION: Anesthetists are engaged in a variety of CPD activities, with evidence of high levels of satisfaction and a positive learning effect. However, the impact on clinical practice and patient outcomes remains unclear and the role of assessment is less well-defined. There is a need for further, high-quality studies, evaluating a broader range of outcomes, in order to identify which methods are most effective to train and assess specialists in anesthesia.

Stemmed hemiarthroplasty with a suture collar and a common platform system for acute proximal humeral fractures.

Background: Hemiarthroplasty for acute proximal humeral fractures gives disappointing results, often due to rotator cuff insufficiency. Better tuberosity fixation might improve results. Therefore, the aim of this study was to: 1) report the outcome of a stemmed hemiarthroplasty with a common platform system and a modular suture collar; 2) compare the outcome with that of a standard stemmed hemiarthroplasty; 3) report the feasibility of revision arthroplasty with retention of the stem; and 4) to evaluate the association between tuberosity healing and functional outcome. Methods: Forty-four fractures that were deemed not suitable for nonsurgical treatment or open reduction and internal fixation were treated with the Global Unite fracture system between January 2017 and July 2019. The functional and radiographic results at 2 years were compared with the results of 44 Global Fx arthroplasties. The results of patients who had adequate healing of the greater tuberosity were compared with the results of patients who had severe malunion or nonunion (resorption). Results: Mean Oxford Shoulder Score, Constant-Murley Score, and Western Ontario Osteoarthritis of the Shoulder index was 33 (range: 10 to 48), 40 (range: 10 to 98), and 68 (range: 18 to 98) at 2 years. There were no differences in functional outcome scores or in the risk of inadequate healing of the greater tuberosity between the Global Unite and the Global Fx systems. Five (11%) patients underwent revision surgery with retention of the stem. Inadequate tuberosity healing was associated with an inferior Constant-Murley Score (mean difference: 6; 95% confidence interval: 1 to 10, P = .01) and an inferior Oxford Shoulder Score (mean difference: 9; 95% confidence interval: 1 to 16, P = .03). Conclusion: The use of stemmed hemiarthroplasty with a suture collar did not improve the healing of the greater tuberosity or the functional outcome. Five arthroplasties were revised with retention of the stem. This possibility could be arguments for using the Global Unite system when a stemmed hemiarthroplasty is used for acute proximal humeral fractures.

First-in-human study of a pharmacological duodenal exclusion therapy shows reduced postprandial glucose and insulin and increased bile acid and gut hormone concentrations.

AIMS: To address the need for noninvasive alternatives to metabolic surgery or duodenal exclusion devices for the management of type 2 diabetes (T2D) and obesity by developing an orally administered therapeutic polymer, GLY-200, designed to bind to and enhance the barrier function of mucus in the gastrointestinal tract to establish duodenal exclusion noninvasively. MATERIALS AND METHODS: A Phase 1, randomized, double-blind, placebo-controlled, single- (SAD) and multiple-ascending-dose (MAD) healthy volunteer study was conducted. In the SAD arm, four cohorts received a single dose of 0.5 g up to 6.0 g GLY-200 or placebo, while in the MAD arm, four cohorts received 5 days of twice-daily or three-times-daily dosing (total daily dose 2.0 g up to 6.0 g GLY-200 or placebo). Assessments included safety and tolerability (primary) and exploratory pharmacodynamics, including serum glucose, insulin, bile acids and gut hormones. RESULTS: No safety signals were observed; tolerability signals were limited to mild to moderate dose-dependent gastrointestinal events. In the MAD arm (Day 5), reductions in glucose and insulin and increases in bile acids, glucagon-like peptide-1, peptide YY and glicentin, were observed following a nonstandardized meal in subjects receiving twice-daily dosing of 2.0 g GLY-200 (N = 9) versus those receiving placebo (N = 8). CONCLUSIONS: GLY-200 is safe and generally well tolerated at doses of ≤2.0 g twice daily. Pharmacodynamic results mimic the biomarker signature observed after Roux-en-Y gastric bypass and duodenal exclusion devices, indicating a pharmacological effect in the proximal small intestine. This study represents the first clinical demonstration that duodenal exclusion can be achieved with an oral drug and supports further development of GLY-200 for the treatment of obesity and/or T2D.

Autoimmune rheumatic diseases in women with coronary microvascular dysfunction: a report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) project.

Background: While autoimmune rheumatic diseases (ARDs) have been linked with coronary microvascular dysfunction (CMD), the relationship between ARD and CMD in women with signs and symptoms of ischemia and no obstructive arteries (INOCA) are not well described. We hypothesized that among women with CMD, those with ARD history have greater angina, functional limitations, and myocardial perfusion compromise compared to those without ARD history. Methods: Women with INOCA and confirmed CMD by invasive coronary function testing were included from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) project (NCT00832702). Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI), and cardiac magnetic resonance myocardial perfusion reserve index (MPRI) were collected at baseline. Chart review was performed to confirm self-reported ARD diagnosis. Results: Of the 207 women with CMD, 19 (9%) had a confirmed history of ARD. Compared to those without ARD, women with ARD were younger (p = 0.04). In addition, they had lower DASI-estimated metabolic equivalents (p = 0.03) and lower MPRI (p = 0.008) but similar SAQ scores. There was a trend towards increased nocturnal angina and stress-induced angina in those with ARD (p = 0.05 for both). Invasive coronary function variables were not significantly different between groups. Conclusions: Among women with CMD, women with a history of ARD had lower functional status and worse myocardial perfusion reserve compared to women without ARD. Angina-related health status and invasive coronary function were not significantly different between groups. Further studies are warranted to understand mechanisms contributing to CMD among women with ARDs with INOCA.

Clinical assessment as a part of an early warning score-a Danish cluster-randomised, multicentre study of an individual early warning score.

BACKGROUND: The clinical benefit of Early Warning Scores (EWSs) is undocumented. Nursing staff's clinical assessment might improve the prediction of outcome and allow more efficient use of resources. We aimed to investigate whether the combination of clinical assessment and EWS would reduce the number of routine measurements without increasing mortality. METHODS: We did a cluster-randomised, crossover, non-inferiority study at eight hospitals in Denmark. Patients aged 18 years or older, admitted for more than 24 h were included. Admissions to paediatric or obstetric wards were excluded. The participating hospitals were randomly assigned 1:1 to start as either intervention or control with subsequent crossover. Primary outcomes were 30-day all-cause mortality (non-inferiority margin=0·5%) and average number of EWS per day per patient. The intervention was implementation of the Individual EWS (I-EWS), in which nursing staff can adjust the calculated score on the basis of their clinical assessment of the patient. I-EWS was compared with the National Early Warning Score (NEWS). The study is registered at ClinicalTrials.gov, NCT03690128 and is complete. FINDINGS: Unique admissions longer than 24 h were included from Oct 15, 2018 to Sept 30, 2019. Of 90 964 patients assessed, n=46 470 were assigned to the I-EWS group and n=44 494 to the NEWS group. Mortality within 30 days was 4·6% for the I-EWS group, and 4·3% for the NEWS group (adjusted odds ratio 1·05 [95% CI 0·99-1·12], p=0·12). In subgroup analyses I-EWS showed increased 30-day mortality for hospitals that did I-EWS in fall-winter, which was probably due to seasonality, and within patients admitted in a surgical specialty. Overall risk difference was 0·22% (95% CI -0·04 to 0·48) meaning that the non-inferiority criteria were met. The average number of scorings per patient per day was reduced from 3·14 to 3·10 (ie, a relative reduction of 0·64% [95% CI -0·16 to -1·11], p=0·0084) in the I-EWS group. INTERPRETATION: Including clinical assessment in I-EWS was feasible and overall non-inferior to the widely implemented NEWS in terms of all-cause mortality at 30 days, and the number of routine measurements was minimally reduced. However I-EWS should be used with caution in surgical patients. FUNDING: Capital Region Research Foundation, Gangsted Foundation, Candys Foundation, Herlev-Gentofte Hospital Research Foundation, Laerdal Foundation, and The Foundation of Director Boennelycke and wife.

Elucidating complex triplet-state dynamics in the model system isopropylthioxanthone.

We introduce techniques for probing the dynamics of triplet states. We employ these tools, along with conventional techniques, to develop a detailed understanding of a complex chemical system: a negative-tone, radical photoresist for multiphoton absorption polymerization in which isopropylthioxanthone (ITX) is the photoinitiator. This work reveals that the same color of light used for the 2-photon excitation of ITX, leading to population of the triplet manifold through intersystem crossing, also depletes this triplet population via linear absorption followed by reverse intersystem crossing (RISC). Using spectroscopic tools and kinetic modeling, we identify the reactive triplet state and a non-reactive reservoir triplet state. We present compelling evidence that the deactivation channel involves RISC from an excited triplet state to a highly vibrationally excited level of the electronic ground state. The work described here offers the enticing possibility of understanding, and ultimately controlling, the photochemistry and photophysics of a broad range of triplet processes.

Continuing professional development for anesthesiologists: A systematic review protocol.

BACKGROUND: Regulators increasingly use formalized programs that are based on continuing professional development (CPD) activities to ensure that physicians are fit to practice. There is convincing evidence regarding the positive effects of CPD activities on performance and patient outcomes. However, there is limited available studies, investigating its effect in anesthesia, specifically. Moreover, although there exists considerable evidence linking specific CPD activities to improved performance, only few studies have investigated the effect of combinations of activities, or formalized systems, as a whole. Consequently, to address this uncertainty regarding the impact of CPD activities, within anesthesiology, this systematic review aims to establish which activities anesthesiologists are engaged in and their impact on clinical competence and subsequent patient outcomes. METHODS: A systematic review of the current literature regarding CPD for fully qualified anesthesiologists will be undertaken. Characteristics of the included studies will be summarized descriptively, and the screening process will be outlined using the preferred reporting items for systematic reviews and meta-analysis flow diagram. Given the diverse methods adopted within medical education research, it is anticipated that there will be significant heterogeneity between the included studies and therefore, a meta-analysis will not be possible and a narrative synthesis approach will be usd. The outcomes of interest include type of CPD learning activity and/or assessment method anesthesiologists are engaged in; and their effectiveness, either as standalone activities or as part of formalized systems. CONCLUSION: The aim of the study was to give an overview of the breadth and nature of CPD activities, and their effects on fully qualified anesthesiologists' clinical competences and patient outcomes.

Association of coronary microvascular dysfunction and cardiac bridge integrator 1, a cardiomyocyte dysfunction biomarker.

BACKGROUND: Coronary microvascular dysfunction (CMD) is associated with heart failure with preserved ejection fraction (HFpEF); however, pathophysiology is not well described. HYPOTHESIS: We hypothesized that CMD in women with suspected ischemia with no obstructive coronary artery disease (INOCA) is associated with cardiomyocyte dysfunction reflected by plasma levels of a cardiomyocyte calcium handling protein, cardiac bridge integrator 1 (cBIN1). METHODS: Women with suspected INOCA undergoing coronary function testing were included. Coronary flow reserve, vasodilation to nitroglycerin, change in coronary blood flow (ΔCBF), and vasodilation to acetylcholine (ΔAch) were evaluated. cBIN1 score (CS) levels in these women (n = 39) were compared to women with HFpEF (n = 20), heart failure with reduced ejection fraction (HFrEF) (n = 36), and reference controls (RC) (n = 50). Higher CS indicates cardiomyocyte tubule dysfunction. RESULTS: INOCA, HFpEF, and HFrEF women were older than RC (p < .05). Higher CS was associated with vasoconstriction to acetylcholine (r = -0.43, p = .011) with a trend towards lower ΔCBF (r = 0.30, p = .086). Higher CS was specific for ΔAch and ΔCBF but had limited sensitivity. INOCA women had higher CS than RC, but lower CS than HFpEF/HFrEF groups (p < .001). CONCLUSIONS: CS, a plasma biomarker indicating poor cardiomyocyte health, was higher in women with suspected INOCA as compared to RC, but lower than in women with HFpEF. Elevated CS in suspected INOCA patients represents an intermediate group between health and disease, supporting the hypothesis that CMD may progress to HFpEF. Larger prospective cohort studies are needed to confirm the pathophysiological relationship between cBIN1, CMD, and HFpEF.

Novel approach to delivering pro-environmental messages significantly shifts norms and motivation, but children are not more effective spokespeople than adults.

Three studies provided initial laboratory tests of the effectiveness of a novel form of community-based environmental messaging intended to be deployed on public digital signs. In all studies, adult participants watched a slideshow of "Community Voices," a display that combines community images and quotes to celebrate and empower pro-environmental and pro-community thought and action. In addition to assessing the general efficacy of the approach, a central goal was to assess the impact of alternative messengers by comparing identical text associated with either adult or child messengers (Studies 1, 2, and 3). We also assessed the impact of alternative framing of the message itself by comparing: injunctive vs non-injunctive wording (Study 1), political vs non-political content (Study 1), and future vs. present-oriented framing (Study 2). Studies 1 and 2 were conducted on a national sample. In addition, to assess the impact of local vs. non-local messengers, Study 3 compared the response of a non-local sample to a local population in which subjects had personal connections with the people and places featured in the message content. Exposure to Community Voices messages resulted in significant increases in social norm perception, concern about environmental issues, commitment to action, and optimism, suggesting that this approach to messaging is potentially valuable for stimulating cultural change. However, messages attributed to child messengers were generally not more effective, and in some cases were less effective than the same message attributed to adults. We also found no significant difference in the impact of the alternative message frames studied.

Myocarditis following mRNA vaccination against SARS-CoV-2, a case series.

INTRODUCTION: mRNA COVID-19 vaccines have emerged as a new form of vaccination that has proven to be highly safe and effective against COVID-19 vaccination. Rare adverse events including myocarditis have been reported in the literature. METHODS: Data were gathered from the electronic medical record of four patients personally treated by the authors. RESULTS: Four patients, ages 20 to 30, presented with myocarditis characterized by chest pain, elevations in troponin-I and C-reactive protein, and negative viral serologies two to four days following mRNA vaccine administration. One had a cardiac MRI showing delayed gadolinium enhancement in a subpericardial pattern. All experienced symptom resolution by the following day, and the two who have returned for follow-up had normal troponin-I and CRP values. DISCUSSION: Along with previously reported instances, these cases raise suspicion for a possible link between mRNA vaccines and myocarditis.

Transcatheter mitral valve-in-valve and valve-in-ring replacement: Lessons learned from bioprosthetic surgical valve failures.

INTRODUCTION: Limited data are available about the outcomes of transcatheter mitral valve replacement (TMVR) using transseptal approach in patients with prior mitral valve repair (valve-in-ring) or replacement (valve-in-valve) (TMViVR) and on modes of the prior surgical valve failures. We report our tertiary center TMVR experience in high surgical risk patients with prior mitral valve repair or replacement. METHODS: From December 2016 to January 2020, patients with symptomatic severe mitral valve stenosis and/or insufficiency at increased redo surgical risk were included. TMViVR was performed off-label with Sapien S3 valve (Edwards Lifesciences). Patients were followed within 30-days and 1-year from the procedure. RESULTS: Twenty-seven patients underwent transcatheter mitral valve-in-valve (n = 21) or valve-in-ring (n = 6) replacement. Mean ± SD age was 71.8 ± 11 years with Society of Thoracic Surgeons' calculated mortality 7.1 ± 4.6%. The etiology of valve failure was stenosis in 17 (63%) patients, insufficiency in 4 (14.8%) patients, and both in 6 (22.2%) patients. TMViVR technical success was 100% in all patients. Left ventricular outflow track (LVOT) obstruction was observed in only one (3.7%) patient. Zero patients had moderate or severe central mitral valve regurgitation or paravalvular leak. All patients had symptomatic improvement at 30 days. The mean transmitral diastolic pressure gradient decreased from 14.1 ± 4.6 to 6.9 ± 4.6 mm Hg (p < .001) at 30 days. The one patient with LOVT obstruction required readmission at 5-months. One-year survival was 95%. At 1-year mean gradients remained lower than the baseline (7.0 ± 3.0 vs. 12.4 ± 4.0, p = .002). CONCLUSIONS: Transcatheter mitral valve-in-valve and valve-in-ring replacement is feasible and safe. The improvement in mitral valve hemodynamics appears to be durable.

Angina relates to coronary flow in women with ischemia and no obstructive coronary artery disease.

BACKGROUND: Women with suspected ischemia and no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD) as measured by impaired coronary flow reserve (CFR), which is associated with angina and adverse cardiovascular events. CFR is a ratio of hyperemic to baseline average peak velocity (bAPV), and the relation of baseline flow to angina is not understood. METHODS: We evaluated 259 women enrolled in the WISE-Coronary Vascular Dysfunction (WISE-CVD) project with suspected CMD who underwent invasive coronary functional testing. We analyzed variables stratified by high (e.g. ≥22 cm/s) vs low (<22 cm/s) bAPV, using t-test or Wilcoxon rank; linear and multivariable regression was used with bAPV as a continuous variable. RESULTS: Women with high bAPV had worse Seattle Angina Questionnaire (SAQ) angina frequency (58 ± 26 vs 67 ± 25, p = 0.005) and SAQ-7 scores (57 ± 22 vs 62 ± 21, p = 0.03), with higher nitrate (p = 0.02) and ranolazine use (p = 0.03). The high bAPV subgroup also had lower CFR (p < 0.001)). Linear regression related higher bAPV with lower SAQ-7 (p = 0.01) and lower angina frequency scores (p = 0.001). These results remained significant in multivariable modelling adjusting for baseline differences (p < 0.04). SAQ-7 was significantly predicted by bAPV. CONCLUSIONS: Among women with suspected INOCA, angina relates to high bAPV, a result supported by the concomitant greater use of anti-anginal drugs. These results suggest that high bAPV contributes to impaired CFR and may represent a specific pathophysiologic contributor to CMD and may be a treatment target in INOCA subjects.

Relationship between coronary function testing and migraine: results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction project.

Aim: To determine the relationship between coronary vascular dysfunction and history of migraines in women with suspected ischemia and no obstructive coronary arteries (INOCA). Methods: In the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study, 402 women with suspected INOCA answered baseline angina questionnaires, including the Seattle Angina Questionnaire (SAQ). Coronary function testing (CFT) performed in a subgroup of 252 women evaluated for nonendothelial and endothelial-dependent coronary vascular function. Wilcoxon rank sum test, t-test, and linear regression models were performed. Results: Of the 252 women who underwent CFT, 126 (50%) women reported migraine history. Compared to women who reported no migraines, women with migraines were younger and more were premenopausal. They had more angina at rest, with strong emotions, and hot/cold temperatures, as well as angina that wakes them from sleep (P < 0.05 for all). Women with migraines also scored worse on SAQ angina frequency and quality of life P < 0.01 for both). There was no difference in prevalence of coronary vascular dysfunction in the two groups. In addition, linear regression models demonstrated no significant age-adjusted differences in absolute CFT variables. Conclusion: Among women with suspected INOCA, migraine history is prevalent and women with migraines have worse angina compared to those without migraines. Coronary vascular dysfunction diagnosed by CFT does not appear to relate to migraine history.

NEVBD Pesticide Resistance Monitoring Network: Establishing a Centralized Network to Increase Regional Capacity for Pesticide Resistance Detection and Monitoring.

Pesticide resistance in arthropod vectors of disease agents is a growing issue globally. Despite the importance of resistance monitoring to inform mosquito control programs, no regional monitoring programs exist in the United States. The Northeastern Regional Center for Excellence in Vector-Borne Diseases (NEVBD) is a consortium of researchers and public health practitioners with a primary goal of supporting regional vector control activities. NEVBD initiated a pesticide resistance monitoring program to detect resistant mosquito populations throughout the northeastern United States. A regionwide survey was distributed to vector control agencies to determine needs and refine program development and in response, a specimen submission system was established, allowing agencies to submit Culex pipiens (L.) (Diptera:Culicidae) and Aedes albopictus (Skuse) (Diptera: Culicidae) for pesticide resistance testing. NEVBD also established larvicide resistance diagnostics for Bacillus thuringiensis israelensis (Bti) and methoprene. Additional diagnostics were developed for Cx. pipiens resistance to Lysinibacillus sphaericus. We received 58 survey responses, representing at least one agency from each of the 13 northeastern U.S. states. Results indicated that larvicides were deployed more frequently than adulticides, but rarely paired with resistance monitoring. Over 18,000 mosquitoes were tested from six states. Widespread low-level (1 × LC-99) methoprene resistance was detected in Cx. pipiens, but not in Ae. albopictus. No resistance to Bti or L. sphaericus was detected. Resistance to pyrethroids was detected in many locations for both species. Our results highlight the need for increased pesticide resistance testing in the United States and we provide guidance for building a centralized pesticide resistance testing program.

Left ventricular circumferential strain and coronary microvascular dysfunction: A report from the Women's Ischemia Syndrome Evaluation Coronary Vascular Dysfunction (WISE-CVD) Project.

AIMS: Women with ischemia but no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD). Left ventricular (LV) circumferential strain (CS) is often lower in INOCA compared to healthy controls; however, it remains unclear whether CS differs between INOCA women with and without CMD. We hypothesized that CS would be lower in women with CMD, consistent with CMD-induced LV mechanical dysfunction. METHODS AND RESULTS: Cardiac magnetic resonance (cMR) images were examined from women enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project. CS by feature tracking in INOCA women with CMD, defined as myocardial perfusion reserve index (MPRI) <1.84 during adenosine-stress perfusion cMR, was compared with CS in women without CMD. In a subset who had invasive coronary function testing (CFT), the relationship between CS and CFT metrics, LV ejection fraction (LVEF) and cardiovascular risk factors was investigated. Among 317 women with INOCA, 174 (55%) had CMD measured by MPRI. CS was greater in women with CMD compared to those without CMD (23.2 ± 2.5% vs. 22.1 ± 3.0%, respectively, P = 0.001). In the subset with CFT (n = 153), greater CS was associated with increased likelihood of reduced vasodilator capacity (OR = 1.33, 95%CI = 1.02-1.72, p = 0.03) and discriminated abnormal vs. normal coronary vascular function compared to CAD risk factors, LVEF and LV concentricity (AUC: 0.82 [0.73-0.96 95%CI] vs. 0.65 [0.60-0.71 95%CI], respectively, P = 0.007). CONCLUSION: The data indicate that LV circumferential strain is related to and predicts CMD, although in a direction contrary with our hypothesis, which may represent an early sign of LV mechanical dysfunction in CMD.

Impact of a preventive cardiology clinic focusing on lifestyle and nutrition counseling: A pilot analysis.

Standard cardiology practice often defers preventive strategies to primary care providers. We aimed to evaluate the effectiveness of a preventive cardiology clinic focused on lifestyle and nutrition counseling combined with guideline-directed medical therapy on reducing cardiovascular disease (CVD) risk. We queried the University of Florida-Health database for patients enrolled in the preventive cardiology clinic, and a general and interventional cardiology clinic from January 2016 to October 2019. Mean change in weight and blood cholesterol including LDL cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG) were compared in the three clinics in the initial cohort and stratified into primary and secondary prevention. A propensity score-matched analysis was done to adjust for CVD risk factors and statin use. Among a cohort of 239 patients, enrollment in the preventive clinic (n = 99) was associated with greater weight loss at 6 months compared to other clinics (n = 140) (mean -1.7 vs +0.1 kg, p 0.007). Preventive clinic was also associated with greater mean reduction in LDL-C (-24.8 vs -7.1 mg/dl, p 0.021), TC (-29.3 vs -2.0, p 0.003) and TG (-19.7 vs +13.3, p 0.002) at both initial and last follow-up (median time 6 and 16 months). The association with reduction in TG was observed in both primary and secondary prevention, but reduction in LDL-C and TC was only significant in secondary prevention. In a propensity-matched linear regression analysis, preventive clinic was independently associated with LDL-C reduction (b -14.7, r -0.3, p 0.038). A preventive cardiology clinic focused on patient education can be effective in reducing CVD risk.

Coronary Vascular Function and Cardiomyocyte Injury: A Report From the WISE-CVD.

OBJECTIVE: Women with symptoms or signs of myocardial ischemia but no obstructive coronary artery disease (INOCA) often have coronary vascular dysfunction and elevated risk for adverse cardiovascular events. We hypothesized that u-hscTnI (ultra-high-sensitivity cardiac troponin I), a sensitive indicator of ischemic cardiomyocyte injury, is associated with coronary vascular dysfunction in women with INOCA. Approach and Results: Women (N=263) with INOCA enrolled in the WISE-CVD study (Women's Ischemic Syndrome Evaluation-Coronary Vascular Dysfunction) underwent invasive coronary vascular function testing and u-hscTnI measurements (Simoa HD-1 Analyzer; Quanterix Corporation, Lexington, MA). Logistic regression models, adjusted for traditional cardiovascular risk factors were used to evaluate associations between u-hscTnI and coronary vascular function. Women with coronary vascular dysfunction (microvascular constriction and limited coronary epicardial dilation) had higher plasma u-hscTnI levels (both P=0.001). u-hscTnI levels were associated with microvascular constriction (odds ratio, 1.38 per doubling of u-hscTnI [95% CI, 1.03-1.84]; P=0.033) and limited coronary epicardial dilation (odds ratio, 1.37 per doubling of u-hscTnI [95% CI, 1.04-1.81]; P=0.026). u-hscTnI levels were not associated with microvascular dilation or coronary epicardial constriction. CONCLUSIONS: Our findings indicate that higher u-hscTnI is associated with coronary vascular dysfunction in women with INOCA. This suggests that ischemic cardiomyocyte injury in the setting of coronary vascular dysfunction has the potential to contribute to adverse cardiovascular outcomes observed in these women. Additional studies are needed to confirm and investigate mechanisms underlying these findings in INOCA. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00832702.

Paravalvular leak closure with real time transesophageal echocardiography and fluoroscopy fusion.

Transcatheter technology has been increasingly used for paravalvular leak closure. We report the use of "Fusion Technology" (EchoNaviagator, Phillips, Tustin, CA) that combines real-time 2 and 3 dimensional trans-esophageal echocardiography with fluoroscopy imaging to facilitate paravalvular leak closure. This could help to identify the exact site, size, depth and shape of the paravalvular leak for proper positioning of the occluder device, which may result in saving time and effort.