The National Institutes of Health Lasker Clinical Research Scholars Program: A Decade of Launching Clinician-Scientist Careers.

PURPOSE: In response to the decades-long decrease in U.S. clinician-scientists, the National Institutes of Health (NIH) and the Albert and Mary Lasker Foundation launched the Lasker Clinical Research Scholars Program in academic year 2011 to 2012. The investigators examined the early outcomes of this program. METHOD: Thirty-nine scholars have matriculated into the program as of May 2023. Productivity was assessed for all scholars who joined the program before October 2020 (n = 31). Extramural early-stage investigators (ESIs) were used as a control group, and coarsened exact matching was used to compare the groups. The scholars were compared with the matched ESIs on 4 productivity metrics: publication count, weighted relative citation ratio, clinical impact, and approximate potential to translate. Publication records for both groups were compiled using the NIH Office of Portfolio Analysis' name disambiguation method and manually curated to ensure integrity of the data set. RESULTS: Of the 39 scholars, 29 were compared with 121 matched extramural ESIs. Five years before matriculation, the 2 groups had comparable numbers of publications, but scholars had a higher median weighted relative citation ratio, clinical impact, and approximate potential to translate score. Five years after matriculation, the scholars had a higher median number of publications than the ESIs, and the gap between scholars and ESIs, with scholars having higher scores, had widened for all metrics except approximate potential to translate scores. Of 10 of the 39 scholars at or approaching tenure eligibility, 6 have attained tenure (3 at NIH and 3 in academic institutions), and 4 are on track to attain tenure at NIH. CONCLUSIONS: All the Lasker clinical research scholars are substantially involved in clinical and translational research. Their productivity matches or exceeds that of a matched cohort of ESIs at U.S. academic institutions.

Localising culprit artery in inferior STEMI.

BACKGROUND: ST elevation myocardial infarction (STEMI) represents a cardiac emergency. Time to diagnosis, identification of culprit lesion, and intervention are important. Inferior STEMI represents a dilemma for cardiologists. The territory can be supplied by the right coronary artery (RCA) or the left circumflex coronary artery (LCx). Diagnostic algorithms have been proposed to predict the culprit artery. METHODS: We performed a single-centre retrospective cohort analysis of all patients admitted to our hospital from 2008 to 2020 with a diagnosis of inferior STEMI. We examined the diagnostic 12 lead ECG for quantification of ST elevation in leads II and III and compared this to culprit lesion found on angiography. RESULTS: There were 304 patients identified with STEMI in our database; 105 were found to have an inferior myocardial infarction by ECG criteria. Ninety-nine were included in our study with either RCA or LCx culprit lesions on angiography (82 males, 17 females). The average age of these patients was 64.9 years old. Sensitivity, specificity, positive predictive value and negative predictive value for ST elevation in lead II exceeding lead III predicting LCx culprit lesion was 0.32 (95% CI 0.13 to 0.57), 0.94 (95% CI 0.86 to 0.98), 0.55 (95% CI 0.29 to 0.78), 0.85 (95% CI 0.81 to 0.89), respectively. Sensitivity, specificity, positive predictive value and negative predictive value for ST elevation in lead III exceeding lead II predicting RCA culprit lesion was 0.94 (95% CI 0.86 to 0.98), 0.32 (95% CI 0.13 to 0.57), 0.85 (95% CI 0.81 to 0.89), 0.55 (95% CI 0.29 to 0.78), respectively. CONCLUSIONS: In inferior STEMI, comparison of ST elevation in leads II and III can reliably predict culprit lesion artery and guide intervention. SUBJECT INDEXING: Culprit artery localisation, inferior stemi, ECG.

Retrospective analysis of the impact of pre-transplant implantable cardioverter-defibrillator status on long-term prognosis in heart transplant patients.

BACKGROUND: Sudden cardiac death (SCD) post-heart transplantation affects 8%-35% of patients; however, the risk profile remains to be completely elucidated. While pre-transplant ICDs are typically removed during transplantation, no information exists to suggest if this pre-transplant risk stratification is also associated with post-transplant outcomes. The objective of this study was to assess the impact of pre-transplant ICD status on long-term prognosis post-heart transplant. METHODS: The United Network for Organ Sharing registry was queried for all adult heart transplant recipients from 2010 to 2018. Patients were categorized as with versus without ICD prior to heart transplantation. Survival was compared using Kaplan-Meier analysis. Proportional hazards regression analysis assessed the impact of ICDs adjusting for clinical and demographic covariates. RESULTS: Of 19 026 patients included, 78.6% (n = 14 960) had received an ICD at time of registration. Patients with an ICD were older [54.9 (±11.6) years vs. 48.6 (±15.3) years, p < .001], less likely to be female [25.7% (n = 3842) vs. 31.2% (n = 1269), p < .001], and more commonly diabetic [29.3% (n = 4376) vs 23.5% (n = 954), p < .001]. Kaplan-Meier analysis showed no difference in unadjusted survival trajectory by ICD status (chi-square = .48, p = .49). Survival was unrelated to ICD status in the multivariable model (HR = .98; 95% CI .90-1.07). CONCLUSIONS: Patients receiving an ICD pre-transplant had a higher prevalence of risk factors for SCD than non-ICD patients, yet ICD status prior to heart transplantation was not associated with a change in long-term prognosis post-heart transplantation.

Efficacy and Safety of the Non-Vitamin K Antagonist Oral Anticoagulant Among Patients With Nonvalvular Atrial Fibrillation and Cancer: A Systematic Review and Network Meta-analysis.

Patients with cancer are at higher risk of atrial fibrillation (AF). Currently there are no definitive data on clinical outcomes for nonvitamin K antagonist oral anticoagulant (NOACs) and warfarin in cancer patients with AF. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of NOACs compared with warfarin. A search through Pubmed/MEDLINE, Embase, and Cochrane library was done from the databases inception to March 2022. Studies that compared NOACs to warfarin in the setting of AF and cancer were included. The primary outcomes were the incidence of major bleeding and ischemic stroke/systemic embolism (SE). Secondary outcomes were major adverse cardiovascular event (MACE), intracranial bleeding, and Major gastrointestinal bleeding. Risk ratios (RRs) with 95% confidence intervals (CI) were used to report the outcomes. A total of 11 studies were included. We found that NOACs were associated with a lower incidence of major bleeding and combined ischemic stroke/SE in patients with AF and cancer compared with warfarin (RR 0.57; 95% CI 0.44-0.75, P < 0.0001 and RR 0.59; 95% CI 0.47-0.75, P < 0.0001, respectively). Also, there was lower incidence of Intracranial and major gastrointestinal bleeding in patients who received NOACs compared with warfarin (P < 0.0001). Network analyses revealed that apixaban and dabigatran were associated with reduction of major bleeding compared with warfarin. Among patients who diagnosed with AF and cancer, NOACs were associated with lower incidence of major bleeding ischemic stroke/SE compared with warfarin. Furthermore, NOACs were associated with lower gastrointestinal and intracranial bleeding.

Prevalence and Determinants of Atrial Fibrillation-Associated In-Hospital Ischemic Stroke in Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

Atrial fibrillation (AF) is an established risk factor ischemic stroke (IS) and is commonly encountered in patient hospitalized with acute myocardial infarction (AMI). Uncommonly, IS can occur as a complication resulting from percutaneous coronary intervention (PCI). There is limited real world data regarding AF-associated in-hospital IS (IH-IS) in patients admitted with AMI undergoing PCI. We queried the National Inpatient Sample database from January 2010 to December 2014 to identify patients admitted with AMI who underwent PCI. In this cohort, we determined the prevalence of AF associated IH-IS and compared risk factors for IH-IS between patients with AF and without AF using multivariable logistic regression models. IH-IS was present in 0.46% (n = 5,938) of the patients with AMI undergoing PCI (n = 1,282,829). Prevalence of IH-IS in patients with AF was higher compared with patients without AF (1.05% vs 0.4%; adjusted odds ratio: 1.634, 95% confidence interval: 1.527 to 1.748, p <0.001). Regardless of AF status, prevalence and risk of IH-IS was higher in females and increased with advancing age. There was significant overlap among risk-factors associated with increased risk of IH-IS in AF and non-AF cohorts, except for obesity in AF patients (adjusted odds ratio: 1.268, 95% confidence interval: 1.023 to 1.572, p = 0.03) in contrast to renal disease, malignancy, and peripheral vascular disease in non-AF patients. In conclusion, IH-IS is a rare complication affecting patients undergoing PCI for AMI and is more likely to occur in AF patients, females, and older adults, with heterogeneity among risk factors in patients with and without AF.

The absence of evidence is not the evidence of absence: A case report on the challenges in diagnosing ostial left main stenosis.

Because left main (LM) coronary artery stenosis is known to have higher mortality and morbidity compared to lesions in other territories, an early diagnosis and management are crucial to prevent worse outcomes. Due to limitations of coronary angiography (CA), the diagnosis of ostial LM stenosis solely based on CA may result in underdiagnosis of such lesions. Therefore, additional testing is often needed either by pressure wire or intravascular ultrasound (IVUS) to make appropriate diagnosis. We, hereby, present a case of left main ostial stenosis in a 56-year-old male that was missed on multiple coronary angiograms, and highlights many of the considerations in the diagnosis of LM disease.

Assessment of Semi-automated Computed Tomographic Measures of Segmental Perfusion Defects in a Swine Model (Sus scrofa) of Intermediate Coronary Lesions.

Computed tomographic myocardial perfusion (CTP) imaging is a tool that shows promise in emergent settings for defining the hemodynamic significance of coronary artery disease. In this study, we examined the accuracy with which the transmural perfusion ratio (TPR) derived through semiautomated CTP analysis reflected segmental perfusion defects associated with intermediate coronary artery lesions in swine. Lesions (diameter stenosis, 65% ± 11%) of the left anterior descending coronary artery (LAD) were created in 10 anesthetized female swine (weight, 47.5 ± 1.9 kg) by using a pneumatic occlusion device implanted on the LAD. Occluder inflation pressures were adjusted to maintain fractional flow reserve (FFR, 74.3 ± 1.7) during adenosine infusion (140ug/kg/min). Static CTP imaging using a stress-rest protocol and segmental TPR derived from semiautomated CT perfusion software was compared with microsphere-derived TPR (mTPR) by using a 16-segment model and polar mapping. Intermediate LAD stenosis was verified through multiplanar coronary CT angiography. Receiver operating characteristic analysis identified an optimal threshold for segmental perfusion defects for intermediate lesions (TPR threshold, ≤0.80); however, the area under the receiver operating characteristic curve was 0.58, and the overall accuracy was 63%. At this threshold, the sensitivity and specificity were 65% and 61%, and the positive and negative predictive values were 61% and 65%, respectively. Although CTP-TPR illustrated segmental perfusion defects with intermediate lesions, the disparity between CTP-TPR and mTPR measures of segmental perfusion suggests that further advances in analysis software may be necessary to improve the localization of segmental defects for intermediated lesions.

Right Ventricular Failure Following Patent Foramen Ovale Closure on Venovenous-Extracorporeal Membrane Oxygenation.

We present a patient with pulmonary arterial hypertension requiring venovenous-extracorporeal membrane oxygenation for acute respiratory distress syndrome. Refractory hypoxemia secondary to right-to-left interatrial shunting via a patent foramen ovale was discovered. Right heart catheterization with invasive occlusion test heralded worsening right heart failure so closure was aborted. (Level of Difficulty: Intermediate.).

The increasing importance of fellowships and career development awards in the careers of early-stage biomedical academic researchers.

Excessive competition for biomedical faculty positions has ratcheted up the need to accumulate some mix of high-quality publications and prestigious grants to move from a training position to university faculty. How universities value each of these attributes when considering faculty candidates is critical for understanding what is needed to succeed as academic faculty. In this study, I analyzed publicly available NIH grant information to determine the grants first-time R01 (FTR01) awardees held during their training period. Increases in the percentage of the FTR01 population that held a training award demonstrate these awards are becoming a more common component of a faculty candidate's resume. The increase was largely due to an expansion of NIH K-series career development awards between 2000 and 2017. FTR01 awardees with a K01, K08, K23, or K99 award were overrepresented in a subset of institutions, whereas FTR01 awardees with F32 fellowships and those with no training award were evenly distributed across institutions. Finally, training awardees from the largest institutions were overrepresented in the faculty of the majority of institutions, echoing data from other fields where a select few institutions supply an overwhelming majority of the faculty for the rest of the field. These data give important insight into how trainees compete for NIH funding and faculty positions and how institutions prefer those with or without training awards.

Cost effectiveness and clinical efficacy of patent foramen ovale closure as compared to medical therapy in cryptogenic stroke patients: A detailed cost analysis and meta-analysis of randomized controlled trials.

BACKGROUND: Up to half the patients with cryptogenic stroke under the age of 55 years have been found to have a PFO. Observational studies have demonstrated a benefit from closure of PFO and several RCTs have shown a trend toward benefit. The cost and clinical effectiveness of PFO closure is unclear. METHODS AND RESULTS: We searched for RCTs of PFO closure in patients with cryptogenic stroke and performed a detailed cost analysis and meta-analysis of treatment outcomes based on the results of the meta-analysis. Five RCTs containing 3404 patients with cryptogenic stroke were included. Of these 1829 underwent PFO closure and 1611 received medical therapy. Mean follow-up was 4.0 years. PFO closure achieved cost effectiveness (<$50,000/Quality-adjusted life-year gained) 2.7 years (95% Confidence Interval (CI) 2.2-3.4) after closure. The incremental cost to prevent one combined end point (CEP, combined transient ischemic attack (TIA), stroke, and death) by PFO closure was $535,655(95% CI $458,329-$642,674). After 55.4 years (95%CI 51.1-60.5) of follow-up, the per patient total cost of medical therapy exceeded that of PFO closure. PFO closure demonstrated clinical efficacy with a decreased risk of CEP (pooled hazard ratio (HR = 0.43(95%CI 0.27-0.59))) and a decreased risk of stroke (HR = 0.29(95%CI 0.02-0.57)). CONCLUSIONS: In comparison to medical therapy alone, PFO closure appears to be cost-effective and clinically efficacious.

The future of graduate and postdoctoral training in the biosciences.

This article summarizes the outcomes of the second national conference on the Future of Bioscience Graduate and Postdoctoral Training. Five topics were addressed during the conference: diversity in leadership positions; mentoring; modernizing the curriculum; experiential learning; and the need for better data on trainees. The goal of the conference was to develop a consensus around these five topics and to recommend policies that can be implemented by academic and research institutions and federal funding agencies in the United States.

A new test for diagnosing vasovagal syncope: Standing after treadmill test with sublingual nitrate administration.

INTRODUCTION: Increased adrenergic tone might be an additional trigger of orthostatic stress of vasovagal syncope (VVS). Exercise before standing might provide increased sensitivity compared to standing using a sublingual nitroglycerines protocol during tilt table testing. The aim of this study was to evaluate the diagnostic value of treadmill testing before standing with nitroglycerin administration. METHODS AND RESULTS: A total of 36 patients with syncope or presyncope were enrolled for the test. VVS was confirmed in 29 patients according to the Calgary Score (≥ -2), including 20 patients who were likely to have typical (classical) VVS. All 36 subjects were subjected to a novel provocation test consisting of treadmill test using the Bruce protocol followed by standing with administration of 300 µg sublingual nitroglycerin. Consequently, syncope or presyncope occurred in 22 patients of the 36 patients. The sensitivity and a specificity of the test for Calgary score based VVS was 82.7% and 85.75%, respectively. Reproducibility rate for typical VVS was 90% (18 of 20). In all symptomatic patients, systolic blood pressure dropped to < 90 mmHg and symptom occurred a mean of 6.7 ± 2.3 minutes after the nitroglycerine administration. No patient required anticholinergics injection to restore vital signs. CONCLUSIONS: Treadmill test with administration of sublingual nitroglycerines might be safely used to reproduce syncope in patients with VVS. More clinical experience and confirmation are needed to validate this protocol.

Diagnostic yield of device interrogation in the evaluation of syncope in an elderly population.

BACKGROUND: Device interrogation has become a standard part of the syncope evaluation for patients admitted with permanent pacemakers (PPM) or implantable cardiac defibrillators (ICD), although few studies have shown interrogation yields clinically useful data. The purpose of this study is to determine the diagnostic yield of device interrogation as well as other commonly performed tests in the workup of unexplained syncope in patients with previously implanted PPMs or ICDs. METHODS: We retrospectively reviewed records of 88 patients admitted to our medical center for syncope with previously implanted pacemakers between January 1, 2005 and January 1, 2015 using ICD-9 billing data. RESULTS: Pacemaker interrogation demonstrated an arrhythmia as the cause for syncope in 4 patients (4%) and evidence of device failure secondary to perforation in 1 patient (1%). The cause of syncope was unknown in 34 patients (39%). Orthostatic hypotension was the most commonly identified cause of syncope (26%), followed by vasovagal syncope (13%), autonomic dysfunction (5%), ventricular arrhythmia (3%), atrial arrhythmia (2%), congestive heart failure (2%), stroke (2%), and other less common causes (8%). History was the most important determinant of syncope (36%), followed by orthostatic vital signs (14%), device interrogations (4%), head CT (2%), and transthoracic echocardiogram (1%). CONCLUSIONS: Device interrogation is rarely useful for elucidating a cause of syncope without concerning physical exam, telemetry, or EKG findings. Interrogation may occasionally yield paroxysmal arrhythmias responsible for syncopal episode, but these rarely alter clinical outcomes. Interrogation appears to be more useful in patients with syncope after recent device placement.

Muonium Chemistry at Diiron Subsite Analogues of [FeFe]-Hydrogenase.

The chemistry of metal hydrides is implicated in a range of catalytic processes at metal centers. Gaining insight into the formation of such sites by protonation and/or electronation is therefore of significant value in fully exploiting the potential of such systems. Here, we show that the muonium radical (Mu. ), used as a low isotopic mass analogue of hydrogen, can be exploited to probe the early stages of hydride formation at metal centers. Mu. undergoes the same chemical reactions as H. and can be directly observed due to its short lifetime (in the microseconds) and unique breakdown signature. By implanting Mu. into three models of the [FeFe]-hydrogenase active site we have been able to detect key muoniated intermediates of direct relevance to the hydride chemistry of these systems.

Encapsulating Subsite Analogues of the [FeFe]-Hydrogenases in Micelles Enables Direct Water Interactions.

Encapsulation of subsite analogues of the [FeFe]-hydrogenase enzymes in supramolecular structures has been shown to dramatically increase their catalytic ability, but the molecular basis for this enhancement remains unclear. We report the results of experiments employing infrared absorption, ultrafast infrared pump-probe, and 2D-IR spectroscopy to investigate the molecular environment of Fe2(pdt)(CO)6 (pdt: propanedithiolate) [1] encapsulated in the dispersed alkane phase of a heptane-dodecyltrimethylammonium bromide-water microemulsion. It is demonstrated that 1 is partitioned between two molecular environments, one that closely resembles bulk heptane solution and a second that features direct hydrogen-bonding interactions with water molecules that penetrate the surfactant shell. Our results demonstrate that the extent of water access to the normally water-insoluble subsite analogue 1 can be tuned with micelle size, while IR spectroscopy provides a straightforward tool that can be used to measure and fine-tune the chemical environment of catalyst species in self-assembled structures.