Multicenter exploration of tenecteplase transition factors: A quantitative analysis.

BACKGROUND: Tenecteplase (TNK) is gaining recognition as a novel therapy for acute ischemic stroke (AIS). Despite TNK offering a longer half-life, time and cost saving benefits and comparable treatment and safety profiles to Alteplase (ALT), the adoption of TNK as a treatment for AIS presents challenges for hospital systems. OBJECTIVE: Identify barriers and facilitators of TNK implementation at acute care hospitals in Texas. METHODS: This prospective survey used open-ended questions and Likert statements generated from content experts and informed by qualitative research. Stroke clinicians and nurses working at 40 different hospitals in Texas were surveyed using a virtual platform. RESULTS: The 40 hospitals had a median of 34 (IQR 24.5-49) emergency department beds and 42.5 (IQR 23.5-64.5) inpatient stroke beds with 506.5 (IQR 350-797.5) annual stroke admissions. Fifty percent of the hospitals were Comprehensive Stroke Centers, and 18 (45 %) were solely using ALT for treatment of eligible AIS patients. Primary facilitators to TNK transition were team buy-in and a willingness of stroke physicians, nurses, and pharmacists to adopt TNK. Leading barriers were lack of clinical evidence supporting TNK safety profile inadequate evidence supporting TNK use and a lack of American Heart Association guidelines support for TNK administration in all AIS cases. CONCLUSION: Understanding common barriers and facilitators to TNK adoption can assist acute care hospitals deciding to implement TNK as a treatment for AIS. These findings will be used to design a TNK adoption Toolkit, utilizing implementation science techniques, to address identified obstacles and to leverage facilitators.

A qualitative study of barriers and facilitators to using tenecteplase to treat acute ischemic stroke.

BACKGROUND: Tenecteplase (TNK) is emerging as an alternative to alteplase (ALT) for thrombolytic treatment of acute ischemic stroke (AIS). Compared to ALT, TNK has a longer half-life, shorter administration time, lower cost, and similarly high efficacy in treating large vessel occlusion. Nevertheless, there are barriers to adopting TNK as a treatment for AIS. This study aimed to identify thematic barriers and facilitators to adopting TNK as an alternative to ALT as a thrombolytic for eligible AIS patients. METHODS: Qualitative research methodology using hermeneutic cycling and purposive sampling was used to interview four stroke clinicians in Texas. Interviews were recorded and transcribed verbatim. Enrollment was complete when saturation was reached. All members of the research team participated in content analysis during each cycle and in thematic analysis after saturation. RESULTS: Interviews were conducted between November 2022 and February 2023 with stroke center representatives from centers that either had successfully adopted TNK, or had not yet adopted TNK. Three themes and eight sub-themes were identified. The theme "Evidence" had three sub-themes: Pro-Con Balance, Fundamental Knowledge, and Pharmacotherapeutics. The theme "Process Flow" had four subthemes: Proactive, Reflective self-doubt, Change Process Barriers, and Parameter Barriers. The theme "Consensus" had one sub-theme: Getting Buy-In. CONCLUSION: Clinicians experience remarkably similar barriers and facilitators to adopting TNK. The results lead to a hypothesis that providing evidence to support a practice change, and identifying key change processes, will help clinicians achieve consensus across teams that need to 'buy in' to adopting TNK for AIS treatment.

Advances in biological and targeted therapies for systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is a severe, and often life-threatening, autoimmune disease, which causes inflammation and fibrosis of the skin and internal organs. There are currently limited effective therapeutic options for patients with SSc. There are recently completed and ongoing phase 2 and 3 studies looking at biologic therapies for SSc that target the underlying pathogenesis of the disease. AREAS COVERED: The purpose of this review is to describe completed and ongoing trials of different biologic therapies for the treatment of SSc. This review discusses biologic therapy directed at multiple pathways that are believed to contribute to inflammation and fibrosis in SSc including T cell, B cell, direct cytokines, and JAK signaling. Data presented is based on authors' expertise of completed and ongoing trials. EXPERT OPINION: Tocilizumab and rituximab have supporting data to advocate for use in early SSc. Data from tocilizumab showed preservation of forced vital capacity (FVC) and beneficial effects on global composite measure. Recent data from different trials with rituximab in SSc (with and without interstitial lung disease) show beneficial effects on skin and FVC with good tolerability. We highlight the molecular heterogeneity in early SSc phenotype and the need to account for this in future trials.

Telehealth Trials to Address Health Equity in Stroke Survivors.

Telehealth has seen rapid expansion into chronic care management in the past 3 years because of the COVID-19 pandemic. Telehealth for acute care management has expanded access to equitable stroke care to many patients over the past two decades, but there is limited evidence for its benefit for addressing disparities in the chronic care of patients living with stroke. In this review, we discuss advantages and disadvantages of telehealth use for the outpatient management of stroke survivors. Further, we explore opportunities and potential barriers for telehealth in addressing disparities in stroke outcomes related to various social determinants of health. We discuss two ongoing large randomized trials that are utilizing telehealth and telemonitoring for management of blood pressure in diverse patient populations. Finally, we discuss strategies to address barriers to telehealth use in patients with stroke and in populations with adverse social determinants of health.

Sex differences in endovascular thrombectomy outcomes in large vessel occlusion: a propensity-matched analysis from the SELECT study.

BACKGROUND: Sex disparities in acute ischemic stroke outcomes are well reported with IV thrombolysis. Despite several studies, there is still a lack of consensus on whether endovascular thrombectomy (EVT) outcomes differ between men and women. OBJECTIVE: To compare sex differences in EVT outcomes at 90-day follow-up and assess whether progression in functional status from discharge to 90-day follow-up differs between men and women. METHODS: From the Selection for Endovascular Treatment in Acute Ischemic Stroke (SELECT) prospective cohort study (2016-2018), adult men and women (≥18 years) with anterior circulation large vessel occlusion (internal carotid artery, middle cerebral artery M1/M2) treated with EVT up to 24 hours from last known well were matched using propensity scores. Discharge and 90-day modified Rankin Scale (mRS) scores were compared between men and women. Furthermore, we evaluated the improvement in mRS scores from discharge to 90 days in men and women using a repeated-measures, mixed-effects regression model. RESULTS: Of 285 patients, 139 (48.8%) were women. Women were older with median (IQR) age 69 (57-81) years vs 64.5 (56-75), p=0.044, had smaller median perfusion deficits (Tmax >6 s) 109 vs 154 mL (p<0.001), and had better collaterals on CT angiography and CT perfusion but similar ischemic core size (relative cerebral blood flow <30%: 7.6 (0-25.2) vs 11.4 (0-38) mL, p=0.22). In 65 propensity-matched pairs, despite similar discharge functional independence rates (women: 42% vs men: 48%, aOR=0.55, 95% CI 0.18 to 1.69, p=0.30), women exhibited worse 90-day functional independence rates (women: 46% vs men: 60%, aOR=0.41, 95% CI 0.16 to 1.00, p=0.05). The reduction in mRS scores from discharge to 90 days also demonstrated a significantly larger improvement in men (discharge 2.49 and 90 days 1.88, improvement 0.61) than in women (discharge 2.52 and 90 days 2.44, improvement 0.08, p=0.036). CONCLUSION: In a propensity-matched cohort from the SELECT study, women had similar discharge outcomes as men following EVT, but the improvement from discharge to 90 days was significantly worse in women, suggesting the influence of post-discharge factors. Further exploration of this phenomenon to identify target interventions is warranted. TRIAL REGISTRATION NUMBER: NCT02446587.

Impact of a Musculoskeletal "Mini-Residency" Professional Development Program on Knee Magnetic Resonance Imaging Orders by Primary Care Providers.

BACKGROUND: The US Department of Veterans Affairs has created a portfolio of educational programs to train primary care providers (PCPs) in the evaluation and management of common musculoskeletal (MSK) conditions. Appropriate resource utilization for evaluation of knee pain, including limiting unnecessary magnetic resonance imaging (MRI) studies, is an important theme of these initiatives. The objective of this study was to report the utilization of knee MRI by PCP providers before and after the MSK education program and to determine the appropriateness of these MRI orders. METHODS: Twenty-six PCPs participated in the MSK Mini-Residency educational program held in Salt Lake City between April 2012 and October 2014. Knee MRI orders submitted by these providers 12 months before and 12 months after their participation were reviewed. Magnetic resonance imaging orders were categorized as "inappropriate," "probably inappropriate," or "possibly appropriate," based on accepted guidelines for knee MRI utilization. Differences in the numbers of precourse and postcourse MRI orders for each of these categories were compared using Student t test. RESULTS: Following our program, MRI orders decreased from 130 (precourse) to 93 (postcourse), a reduction of 28% ( p = 0.04). This reduction was observed entirely within the "inappropriate" and "probably inappropriate" categories; the number of orders categorized as "possibly appropriate" increased, but not significantly. CONCLUSIONS: The MSK Mini-Residency training program was a successful educational intervention and was associated with a reduction in inappropriate knee MRI utilization for some participants, while keeping appropriate MRI utilization stable.

Sphingosine 1-phosphate receptor 5 (S1PR5) regulates the peripheral retention of tissue-resident lymphocytes.

Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-ß signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet-ZEB2-S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes.

Racial and Ethnic Disparities in Functional Outcome after Thrombectomy: A Cohort Study of an Integrated Stroke Network.

OBJECTIVES: Previous studies have shown racial disparities in access to treatment and outcomes in ischemic stroke patients. We sought to define racial disparities in functional outcomes among ischemic stroke patients receiving endovascular thrombectomy (EVT). MATERIALS AND METHODS: We performed a retrospective review of patients in our institution's prospectively collected stroke patient registry from 08/2015 to 06/2019 at 1 comprehensive and 2 thrombectomy-ready stroke centers. We reviewed patients aged ≥ 18 who received mechanical thrombectomy including only patients with race/ethnicity data belonging to the 3 largest race/ethnic groups: Non-Hispanic White (NHW), Non-Hispanic Black (NHB), and Hispanic (HIS). We compared baseline characteristics and performed multivariable logistic regression to evaluate differences in good functional outcome defined as 90-day modified Rankin score (90 day mRS 0-2) as the primary outcome. Secondary outcomes were discharge disposition, length of stay, and excellent functional outcome (90 day mRS 0-1). Results are given as OR [95% CI]. RESULTS: Among 666 patients that met inclusion criteria, 45% were NHW, 30% were NHB, and 19% were HIS. NHB and HIS patients were younger than NHW (average age NHB 62; HIS 64; and NHW 70; p < 0.001). Diabetes was more prevalent in NHB (32%, p = 0.02) and HIS (47%, p < 0.001) compared to NHW (23%). There were no significant racial differences in pre-morbid mRS, arrival NIHSS, tPA treatment rates. There was no difference in primary outcome by race comparing NHW to the other racial groups (OR 1.08 [0.68-1.72]) but compared to HIS patients, NHW had a higher likelihood of the secondary outcome of excellent functional outcome (aOR 2.23 [1.01-4.93]) defined as mRS 0-1. CONCLUSIONS: In this study of over 600 patients treated with EVT, we did not find significant racial disparities in functional outcome except for less excellent functional outcome in HIS compared to NHW. Further study on disparities in post-acute stroke care is needed.

Decade-Long Nationwide Trends and Disparities in Use of Comfort Care Interventions for Patients With Ischemic Stroke.

Background Stroke remains one of the leading causes of disability and death in the United States. We characterized 10-year nationwide trends in use of comfort care interventions (CCIs) among patients with ischemic stroke, particularly pertaining to acute thrombolytic therapy with intravenous tissue-type plasminogen activator and endovascular thrombectomy, and describe in-hospital outcomes and costs. Methods and Results We analyzed the National Inpatient Sample from 2006 to 2015 and identified adult patients with ischemic stroke with or without thrombolytic therapy and CCIs using validated International Classification of Diseases, Ninth Revision (ICD-9) codes. We report adjusted odds ratios (ORs) and 95% CI of CCI usage across five 2-year periods. Of 4 249 201 ischemic stroke encounters, 3.8% had CCI use. CCI use increased over time (adjusted OR, 4.80; 95% CI, 4.15-5.55) regardless of acute treatment type. Advanced age, female sex, White race, non-Medicare insurance, higher income, disease severity, comorbidity burden, and discharge from non-northeastern teaching hospitals were independently associated with receiving CCIs. In the fully adjusted model, thrombolytic therapy and endovascular thrombectomy, respectively, conferred a 6% and 10% greater likelihood of receiving CCIs. Among CCI users, there was a significant decline in in-hospital mortality compared with all other dispositions over time (adjusted OR, 0.46; 95% CI, 0.38-0.56). Despite longer length of stay, CCI hospitalizations incurred 16% lower adjusted costs. Conclusions CCI use among patients with ischemic stroke has increased regardless of acute treatment type. Nonetheless, considerable disparities persist. Closing the disparities gap and optimizing access, outcomes, and costs for CCIs among patients with stroke are important avenues for further research.

Group 1 innate lymphoid-cell-derived interferon-γ maintains anti-viral vigilance in the mucosal epithelium.

The oropharyngeal mucosa serves as a perpetual pathogen entry point and a critical site for viral replication and spread. Here, we demonstrate that type 1 innate lymphoid cells (ILC1s) were the major immune force providing early protection during acute oral mucosal viral infection. Using intravital microscopy, we show that ILC1s populated and patrolled the uninfected labial mucosa. ILC1s produced interferon-γ (IFN-γ) in the absence of infection, leading to the upregulation of key antiviral genes, which were downregulated in uninfected animals upon genetic ablation of ILC1s or antibody-based neutralization of IFN-γ. Thus, tonic IFN-γ production generates increased oral mucosal viral resistance even before infection. Our results demonstrate barrier-tissue protection through tissue surveillance in the absence of rearranged-antigen receptors and the induction of an antiviral state during homeostasis. This aspect of ILC1 biology raises the possibility that these cells do not share true functional redundancy with other tissue-resident lymphocytes.

Lack of Racial, Ethnic, and Sex Disparities in Ischemic Stroke Care Metrics within a Tele-Stroke Network.

INTRODUCTION: Differences in access to stroke care and compliance with standard of care stroke management among patients of varying racial and ethnic backgrounds and sex are well-characterized. However, little is known on the impact of telestroke in addressing disparities in acute ischemic stroke care. METHODS: We conducted a retrospective review of acute ischemic stroke patients evaluated over our 17-hospital telestroke network in Texas from 2015-2018. Patients were described as Non-Hispanic White (NHW) male or female, Non-Hispanic Black (NHB) male or female, or Hispanic (HIS) male or female. We compared frequency of tPA and mechanical thrombectomy (MT) utilization, door-to-consultation times, door-to-tPA times, and time-to-transfer for patients who went on to MT evaluation at the hub after having been screened for suspected large vessel occlusion at the spoke. RESULTS: Among 3873 patients (including 1146 NHW male (30%) and 1134 NHW female (29%), 405 NHB male (10%) and 491 NHB female (13%), and 358 HIS male (9%) and 339 HIS female (9%) patients), we did not find any differences in door-to consultation time, door-to-tPA time, time-to-transfer, frequency of tPA administration, or incidence of MT utilization. CONCLUSION: We did not find racial, ethnic, and sex disparities in ischemic stroke care metrics within our telestroke network. In order to fully understand how telestroke alleviates disparities in stroke care, collaboration among networks is needed to formulate a multicenter telestroke database similar to the Get-With-The Guidelines.

Publisher Correction: Metabolic characteristics of CD8+ T cell subsets in young and aged individuals are not predictive of functionality.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Racial disparities in post-stroke functional outcomes in young patients with ischemic stroke.

BACKGROUND AND PURPOSE: Recent studies show rising incidence of stroke in the young, for which risk factors are not well characterized. There is evidence of increased risk in certain racial and ethnic groups. We assessed racial differences in risk factors, stroke etiology, and outcomes among young stroke patients. METHODS: Using data from our inpatient registry for ischemic stroke, we reviewed patients aged 18-50 who were admitted 01/2013 to 04/2018. Race/ethnicity were characterized as non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic (HIS). For univariate comparisons Chi-square and Kruskal-Wallis tests were performed as appropriate. Multivariable logistic regression was used to assess impact of race on day seven modified Rankin score (mRS). RESULTS: Among 810 patients with race and outcome data who were admitted in the study period, median age was 43, 57.1% were male, and 36.5% NHW, 43.2% NHB, 20.2% HIS. History of hypertension (HTN), type II diabetes (DM II), smoking, heart failure (CHF), prior stroke, and end-stage renal disease varied significantly by race. Compared to NHW, NHB had higher odds of HTN (OR 2.28, 1.65-3.15), CHF (OR 2.17, 1.06-4.46), and DM II 1.92 (1.25-2.94) while HIS had higher odds of DM II (OR 2.52, 1.55-4.10) and lower odds of smoking (OR 0.56, 0.35-0.90). Arrival NIHSS was higher in NHB, but etiology and rates of tpA treatment and thrombectomy did not vary by race. Compared to NHW patients, NHB (OR 0.50 CI (0.31-0.78)) and HIS (OR 0.37 CI (0.21-0.67)) were less likely to have good functional outcome (mRS <2) at day 7 in adjusted analyses. CONCLUSIONS: In this study, there was a higher prevalence of several modifiable risk factors in NHB and HIS young stroke patients and early functional outcome was worse in these groups. Our study suggests a need for targeted prevention efforts for younger populations at highest risk for stroke.

Metabolic characteristics of CD8+ T cell subsets in young and aged individuals are not predictive of functionality.

Virtual memory T (TVM) cells are antigen-naïve CD8+ T cells that exist in a semi-differentiated state and exhibit marked proliferative dysfunction in advanced age. High spare respiratory capacity (SRC) has been proposed as a defining metabolic characteristic of antigen-experienced memory T (TMEM) cells, facilitating rapid functionality and survival. Given the semi-differentiated state of TVM cells and their altered functionality with age, here we investigate TVM cell metabolism and its association with longevity and functionality. Elevated SRC is a feature of TVM, but not TMEM, cells and it increases with age in both subsets. The elevated SRC observed in aged mouse TVM cells and human CD8+ T cells from older individuals is associated with a heightened sensitivity to IL-15. We conclude that elevated SRC is a feature of TVM, but not TMEM, cells, is driven by physiological levels of IL-15, and is not indicative of enhanced functionality in CD8+ T cells.

Endovascular Thrombectomy for Acute Ischemic Strokes: Current US Access Paradigms and Optimization Methodology.

Background and Purpose- Timely access to endovascular thrombectomy (EVT) centers is vital for best acute ischemic stroke outcomes. Methods- US stroke-treating centers were mapped utilizing geo-mapping and stratified into non-EVT or EVT if they reported ≥1 acute ischemic stroke thrombectomy code in 2017 to Center for Medicare and Medicaid Services. Direct EVT-access, defined as the population with the closest facility being an EVT-center, was calculated from validated trauma-models adapted for stroke. Current 15- and 30-minute access were described nationwide and at state-level with emphasis on 4 states (TX, NY, CA, IL). Two optimization models were utilized. Model-A used a greedy algorithm to capture the largest population with direct access when flipping 10% and 20% non-EVT to EVT-centers to maximize access. Model-B used bypassing methodology to directly transport patients to the nearest EVT centers if the drive-time difference from the geo-centroid to hospital was within 15 minutes from the geo-centroid to the closest non-EVT center. Results- Of 1941 stroke-centers, 713 (37%) were EVT. Approximately 61 million (19.8%) Americans have direct EVT access within 15 minutes while 95 million (30.9%) within 30 minutes. There were 65 (43%) EVT centers in TX with 22% of the population currently within 15-minute access. Flipping 10% hospitals with top population density improved access to 30.8%, while bypassing resulted in 45.5% having direct access to EVT centers. Similar results were found in NY (current, 20.9%; flipping, 34.7%; bypassing, 50.4%), CA (current, 25.5%; flipping, 37.3%; bypassing, 53.9%), and IL (current, 15.3%; flipping, 21.9%; bypassing, 34.6%). Nationwide, the current direct access within 15 minutes of 19.8% increased by 7.5% by flipping the top 10% non-EVT to EVT-capable in all states. Bypassing non-EVT centers by 15 minutes resulted in a 16.7% gain in coverage. Conclusions- EVT-access within 15 minutes is limited to less than one-fifth of the US population. Optimization methodologies that increase EVT centers or bypass non-EVT to the closest EVT center both showed enhanced access. Results varied by states based on the population size and density. However, bypass showed more potential for maximizing direct EVT-access. National and state efforts should focus on identifying gaps and tailoring solutions to improve EVT-access.

Increased long-term mortality in women with high left ventricular ejection fraction: data from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) long-term registry.

AIMS: There are significant sex-specific differences in left ventricular ejection fraction (LVEF), with a higher LVEF being observed in women. We sought to assess the clinical relevance of an increased LVEF in women and men. METHODS AND RESULTS: A total of 4632 patients from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry (44.8% women; mean age 58.7 ± 13.2 years in men and 59.5 ± 13.3 years in women, P = 0.05), in whom LVEF was measured by cardiac computed tomography, were categorized according to LVEF (low <55%, normal 55-65%, and high >65%). The prevalence of high LVEF was similar in both sexes (33.5% in women and 32.5% in men, P = 0.46). After 6 years of follow-up, no difference in mortality was observed in patients with high LVEF in the overall cohort (P = 0.41). When data were stratified by sex, women with high LVEF died more often from any cause as compared to women with normal LVEF (8.6% vs. 7.1%, log rank P = 0.032), while an opposite trend was observed in men (5.8% vs. 6.8% in normal LVEF, log rank P = 0.89). Accordingly, a first order interaction term of male sex and high LVEF was significant (hazard ratios 0.63, 95% confidence intervals 0.41-0.98, P = 0.043) in a Cox regression model of all-cause mortality adjusted for age, cardiovascular risk factors, and severity of coronary artery disease (CAD). CONCLUSION: Increased LVEF is highly prevalent in patients referred for evaluation of CAD and is associated with an increased risk of death in women, but not in men. Differentiating between normal and hyperdynamic left ventricles might improve risk stratification in women with CAD. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01443637.

Machine learning of clinical variables and coronary artery calcium scoring for the prediction of obstructive coronary artery disease on coronary computed tomography angiography: analysis from the CONFIRM registry.

AIMS: Symptom-based pretest probability scores that estimate the likelihood of obstructive coronary artery disease (CAD) in stable chest pain have moderate accuracy. We sought to develop a machine learning (ML) model, utilizing clinical factors and the coronary artery calcium score (CACS), to predict the presence of obstructive CAD on coronary computed tomography angiography (CCTA). METHODS AND RESULTS: The study screened 35 281 participants enrolled in the CONFIRM registry, who underwent ≥64 detector row CCTA evaluation because of either suspected or previously established CAD. A boosted ensemble algorithm (XGBoost) was used, with data split into a training set (80%) on which 10-fold cross-validation was done and a test set (20%). Performance was assessed of the (1) ML model (using 25 clinical and demographic features), (2) ML + CACS, (3) CAD consortium clinical score, (4) CAD consortium clinical score + CACS, and (5) updated Diamond-Forrester (UDF) score. The study population comprised of 13 054 patients, of whom 2380 (18.2%) had obstructive CAD (≥50% stenosis). Machine learning with CACS produced the best performance [area under the curve (AUC) of 0.881] compared with ML alone (AUC of 0.773), CAD consortium clinical score (AUC of 0.734), and with CACS (AUC of 0.866) and UDF (AUC of 0.682), P < 0.05 for all comparisons. CACS, age, and gender were the highest ranking features. CONCLUSION: A ML model incorporating clinical features in addition to CACS can accurately estimate the pretest likelihood of obstructive CAD on CCTA. In clinical practice, the utilization of such an approach could improve risk stratification and help guide downstream management.

Coronary atherosclerosis scoring with semiquantitative CCTA risk scores for prediction of major adverse cardiac events: Propensity score-based analysis of diabetic and non-diabetic patients.

AIMS: We aimed to compare semiquantitative coronary computed tomography angiography (CCTA) risk scores - which score presence, extent, composition, stenosis and/or location of coronary artery disease (CAD) - and their prognostic value between patients with and without diabetes mellitus (DM). Risk scores derived from general chest-pain populations are often challenging to apply in DM patients, because of numerous confounders. METHODS: Out of a combined cohort from the Leiden University Medical Center and the CONFIRM registry with 5-year follow-up data, we performed a secondary analysis in diabetic patients with suspected CAD who were clinically referred for CCTA. A total of 732 DM patients was 1:1 propensity-matched with 732 non-DM patients by age, sex and cardiovascular risk factors. A subset of 7 semiquantitative CCTA risk scores was compared between groups: 1) any stenosis ≥50%, 2) any stenosis ≥70%, 3) stenosis-severity component of the coronary artery disease-reporting and data system (CAD-RADS), 4) segment involvement score (SIS), 5) segment stenosis score (SSS), 6) CT-adapted Leaman score (CT-LeSc), and 7) Leiden CCTA risk score. Cox-regression analysis was performed to assess the association between the scores and the primary endpoint of all-cause death and non-fatal myocardial infarction. Also, area under the receiver-operating characteristics curves were compared to evaluate discriminatory ability. RESULTS: A total of 1,464 DM and non-DM patients (mean age 58 ± 12 years, 40% women) underwent CCTA and 155 (11%) events were documented after median follow-up of 5.1 years. In DM patients, the 7 semiquantitative CCTA risk scores were significantly more prevalent or higher as compared to non-DM patients (p ≤ 0.022). All scores were independently associated with the primary endpoint in both patients with and without DM (p ≤ 0.020), with non-significant interaction between the scores and diabetes (interaction p ≥ 0.109). Discriminatory ability of the Leiden CCTA risk score in DM patients was significantly better than any stenosis ≥50% and ≥70% (p = 0.003 and p = 0.007, respectively), but comparable to the CAD-RADS, SIS, SSS and CT-LeSc that also focus on the extent of CAD (p ≥ 0.265). CONCLUSION: Coronary atherosclerosis scoring with semiquantitative CCTA risk scores incorporating the total extent of CAD discriminate major adverse cardiac events well, and might be useful for risk stratification of patients with DM beyond the binary evaluation of obstructive stenosis alone.

Association of ß-Amyloid Burden With Sleep Dysfunction and Cognitive Impairment in Elderly Individuals With Cognitive Disorders.

Importance: Evidence shows that sleep dysfunction and ß-amyloid (Aß) deposition work synergistically to impair brain function in individuals with normal cognition, increasing the risk of developing dementia later in life. However, whether Aß continues to play an integral role in sleep dysfunction after the onset of cognitive decline in individuals with dementia is unclear. Objective: To determine whether Aß deposition in the brain is associated with subjective measures of sleep quality and cognition in elderly individuals with cognitive disorders. Design, Setting, and Participants: A nested survey study was conducted at the Cognitive Disorders and Comprehensive Alzheimer Disease Center of Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. Participants included patients aged 65 years and older with cognitive disorders verified by neuropsychological testing. Eligible participants were identified from a referral center-based sample of patients who underwent fluorine 18-labeled florbetaben positron emission tomography imaging at Thomas Jefferson University Hospital as part of the multicenter Imaging Dementia-Evidence for Amyloid Scanning study. Data collection and analysis occurred between November 2018 and March 2019. Main Outcomes and Measures: Sleep quality was measured via responses to sleep questionnaires, Aß deposition was measured via fluorine 18-labeled florbetaben positron emission tomography, and cognition was measured via Mini-Mental State Examination (MMSE) performance. Results: Of the 67 eligible participants, 52 (77.6%) gave informed consent to participate in the study. Of the 52 enrolled participants (mean [SD] age, 76.6 [7.4] years), 27 (51.9%) were women. Daytime sleepiness was associated with Aß deposition in the brainstem (B = 0.0063; 95% CI, 0.001 to 0.012; P = .02), but not MMSE performance (B = -0.01; 95% CI, -0.39 to 0.37; P = .96). The number of nocturnal awakenings was associated with Aß deposition in the precuneus (B = 0.11; 95% CI, 0.06 to 0.17; P < .001) and poor MMSE performance (B = -2.13; 95% CI, -3.13 to -1.13; P < .001). Mediation analysis demonstrated an indirect association between Aß deposition and poor MMSE performance that relied on nocturnal awakenings as an intermediary (B = -3.99; 95% CI, -7.88 to -0.83; P = .01). Conclusions and Relevance: Nighttime sleep disruption may mediate the association between Aß and cognitive impairment, suggesting that there is an underlying sleep-dependent mechanism that links Aß burden in the brain to cognitive decline. Further elucidation of this mechanism may improve understanding of disease processes associated with Aß accumulation.

Long-term prognostic utility of computed tomography coronary angiography in older populations.

AIMS: The long-term prognostic value of coronary computed tomography angiography (CCTA)-identified coronary artery disease (CAD) has not been evaluated in elderly patients (≥70 years). We compared the ability of coronary CCTA to predict 5-year mortality in older vs. younger populations. METHODS AND RESULTS: From the prospective CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry, we analysed CCTA results according to age <70 years (n = 7198) vs. ≥70 years (n = 1786). The severity of CAD was classified according to: (i) maximal stenosis degree per vessel: none, non-obstructive (1-49%), or obstructive (>50%); (ii) segment involvement score (SIS): number of segments with plaque. Cox-proportional hazard models assessed the relationship between CCTA findings and time to mortality. At a mean 5.6 ± 1.1 year follow-up, CCTA-identified CAD predicted increased mortality compared with patients with a normal CCTA in both <70 years [non-obstructive hazard ratio (HR) confidence interval (CI): 1.70 (1.19-2.41); one-vessel: 1.65 (1.03-2.67); two-vessel: 2.24 (1.21-4.15); three-vessel/left main: 4.12 (2.27-7.46), P < 0.001] and ≥70 years [non-obstructive: 1.84 (1.15-2.95); one-vessel: HR (CI): 2.28 (1.37-3.81); two-vessel: 2.36 (1.33-4.19); three-vessel/left main: 2.41 (1.33-4.36), P = 0.014]. Similarly, SIS was predictive of mortality in both <70 years [SIS 1-3: 1.57 (1.10-2.24); SIS ≥4: 2.42 (1.65-3.57), P < 0.001] and ≥70 years [SIS 1-3: 1.73 (1.07-2.79); SIS ≥4: 2.45 (1.52-3.93), P < 0.001]. CCTA findings similarly predicted long-term major adverse cardiovascular outcomes (MACE) (all-cause mortality, myocardial infarction, and late revascularization) in both groups compared with patients with no CAD. CONCLUSION: The presence and extent of CAD is a meaningful stratifier of long-term mortality and MACE in patients aged <70 years and ≥70 years old. The presence of obstructive and non-obstructive disease and the burden of atherosclerosis determined by SIS remain important predictors of prognosis in older populations.