Search

Michael S Albosta,1 Jelani K Grant,2 Pam Taub,3 Roger S Blumenthal,2 Seth S Martin,2 Erin D Michos2 1Internal Medicine Department, University of Miami Miller School of Medicine/ Jackson Memorial Hospital, Miami, FL, USA; 2Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Division of Cardiology, University of California San Diego, San Diego, CA, USACorrespondence: Erin D Michos, Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Blalock 524-B, 600 N. Wolfe Street, Baltimore, MD, 21287, USA, Tel +1 410-502-6813, Email edonnell@jhmi.eduAbstract: Multiple lines of evidence confirm that the cumulative burden of low-density lipoprotein cholesterol (LDL-C) is causally related to the development of atherosclerotic cardiovascular disease (ASCVD). As such, lowering LDL-C is a central tenet in all ASCVD prevention guidelines, which recommend matching the intensity of LDL-C lowering with the absolute risk of the patient. Unfortunately, issues such as difficulty with long-term adherence to statin therapy and inability to achieve desired LDL-C thresholds with statins alone results in residual elevated ASCVD risk. Non-statin therapies generally provide similar risk reduction per mmol/L of LDL-C reduction and are included by major society guidelines as part of the treatment algorithm for managing LDL-C. Per the 2022 American College of Cardiology Expert Consensus Decision Pathway, patients with ASCVD are recommended to achieve both an LDL-C reduction ≥ 50% and an LDL-C threshold of < 55 mg/dL in patients at very high-risk and < 70 mg/dL in those not at very high risk. Patients with familial hypercholesterolemia (FH) but without ASCVD should lower LDL-C to < 100 mg/dL. For patients who remain above LDL-C thresholds with maximally tolerated statin therapy plus lifestyle changes, non-statin therapy warrants strong consideration. While several non-statin therapies have been granted FDA approval for managing hypercholesterolemia (eg, ezetimibe, Proprotein Convertase Subtilisin/Kexin 9 [PCSK9] monoclonal antibodies, and bempedoic acid), the focus of the current review is on inclisiran, a novel small interfering RNA therapy that inhibits the production of the PCSK9 protein. Inclisiran is currently FDA approved as an adjunct to statin therapy in patients with clinical ASCVD or heterozygous FH who require additional LDL-lowering. The drug is administered by subcutaneous injection twice a year, after an initial baseline and 3 month dose. In this review, we sought to provide an overview of the use of inclisiran, review current trial data, and outline an approach to potential patient selection.Keywords: inclisiran, lipids, cardiovascular disease prevention, LDL-cholesterol

The current study measures the extent to which students' self-regulated learning tactics and learning outcomes change as the result of a deliberate, data-driven improvement in the learning design of mastery-based online learning modules. In the original design, students were required to attempt the assessment once before being allowed to access the learning material. The improved design gave students the choice to skip the first attempt and access the learning material directly. Student learning tactics were measured using a multi-level clustering and process mining algorithm, and a quasi-experiment design was implemented to remove or reduce differences in extraneous factors, including content being covered, time of implementation, and naturally occurring fluctuations in student learning tactics. The analysis suggests that most students who chose to skip the first attempt were effectively self-regulating their learning and were thus successful in learning from the instructional materials. Students who would have failed the first attempt were much more likely to skip it than those who would have passed the first attempt. The new design also resulted in a small improvement in learning outcome and median learning time. The study demonstrates the creation of a closed loop between learning design and learning analytics: first, using learning analytics to inform improvements to the learning design, then assessing the effectiveness and impact of the improvements.

Integrating Artificial Intelligence-Powered Personalized Learning (AI-PPL) in special education teacher preparation represents a shift toward tailoring educational experiences to meet the unique needs of preservice teachers and students with disabilities. This article explores the implementation of AI-PPL tools in teacher preparation programs, highlighting their potential to customize learning experiences, provide adaptive feedback, and enhance engagement through interactive content. This review of current AI-PPL functionalities, such as adaptive learning environments and customized feedback mechanisms, demonstrates how AI-PPL can impact teaching practices and student learning outcomes. The article introduces critical attributes for successful AI-PPL integration, such as ensuring accessibility and inclusivity. It calls for further professional development to enhance educator competency and skills. By presenting real-world examples and guiding questions for special education faculty, the authors offer practical insights for educators and faculty members to effectively navigate the complexities of adopting AI technologies in teacher preparation programs.

PURPOSE OF REVIEW: Cardiovascular disease is a leading cause of death worldwide. Dyslipidemia is a critical modifiable risk factor for the prevention of cardiovascular disease. Dyslipidemia affects a large population of women and is especially pervasive within racial/ethnic minorities. RECENT FINDINGS: Dyslipidemia in pregnancy leads to worse outcomes for patients and creates increased cardiovascular risk for women at an older age. However, women remain underscreened and undertreated compared to men. Females also comprise a small portion of clinical trial participants for lipid lowering agents with increased disease prevalence compared to trial representation. However, recent lipid trials have shown different efficacies of therapies such as ezetimibe, inclisiran, and bempedoic acid with a greater relative benefit for women. SUMMARY: Pathophysiology of dyslipidemia varies between men and women and across a womans lifetime. While increased lipid levels or lipid imbalances are more common in postmenopausal women over age 50, conditions such as PCOS and FH produce higher cardiovascular risk for young women.Best practices for management of women with dyslipidemia include early screening with lifestyle intervention and pharmacotherapy with statin and non-statin agents to achieve guideline directed LDL-C thresholds.

Clinical risk scores based on traditional risk factors of atherosclerosis correlate imprecisely to an individuals complex pathophysiological predisposition to atherosclerosis and provide limited accuracy for predicting major adverse cardiovascular events (MACE). Over the past two decades, computed tomography scanners and techniques for coronary computed tomography angiography (CCTA) analysis have substantially improved, enabling more precise atherosclerotic plaque quantification and characterization. The accuracy of CCTA for quantifying stenosis and atherosclerosis has been validated in numerous multicentre studies and has shown consistent incremental prognostic value for MACE over the clinical risk spectrum in different populations. Serial CCTA studies have advanced our understanding of vascular biology and atherosclerotic disease progression. The direct disease visualization of CCTA has the potential to be used synergistically with indirect markers of risk to significantly improve prevention of MACE, pending large-scale randomized evaluation.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is characterized by asymptomatic stage B heart failure (SBHF) caused by diabetes-related metabolic alterations. DbCM is associated with an increased risk of progression to overt heart failure (HF). The prevalence of DbCM in patients with type 2 diabetes (T2D) is not well established. This study aims to determine prevalence of DbCM in adult T2D patients in real-world clinical practice. METHODS: Retrospective multi-step review of electronic medical records of patients with the diagnosis of T2D who had echocardiogram at UC San Diego Medical Center (UCSD) within 2010-2019 was conducted to identify T2D patients with SBHF. We defined pure DbCM when SBHF is associated solely with T2D and mixed SBHF when other medical conditions can contribute to SBHF. Pure DbCM was diagnosed in T2D patients with echocardiographic demonstration of SBHF defined as left atrial (LA) enlargement (LAE), as evidenced by LA volume index ≥ 34 mL/m2, in the presence of left ventricular ejection fraction (LVEF) ≥ 45%, while excluding overt HF and comorbidities that can contribute to SBHF. RESULTS: Of 778,314 UCSD patients in 2010-2019, 45,600 (5.9%) had T2D diagnosis. In this group, 15,182 T2D patients (33.3%) had echocardiogram and, among them, 13,680 (90.1%) had LVEF ≥ 45%. Out of 13,680 patients, 4,790 patients had LAE. Of them, 1,070 patients were excluded due to incomplete data and/or a lack of confirmed T2D according to the American Diabetes Association recommendations. Thus, 3,720 T2D patients with LVEF ≥ 45% and LAE were identified, regardless of HF symptoms. In this group, 1,604 patients (43.1%) had overt HF and were excluded. Thus, 2,116 T2D patients (56.9% of T2D patients with LVEF ≥ 45% and LAE) with asymptomatic SBHF were identified. Out of them, 1,773 patients (83.8%) were diagnosed with mixed SBHF due to comorbidities such as hypertension (58%), coronary artery disease (36%), and valvular heart disease (17%). Finally, 343 patients met the diagnostic criteria of pure DbCM, which represents 16.2% of T2D patients with SBHF, i.e., at least 2.9% of the entire T2D population in this study. CONCLUSIONS: Our findings provide insights into prevalence of DbCM in real-world clinical practice and indicate that DbCM affects a significant portion of T2D patients.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL-C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline-recommended LDL-C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes. With atherosclerotic cardiovascular disease-related mortality increasing globally, there remains a need for additional therapeutic options for lowering LDL-C as part of an atherosclerotic cardiovascular disease prevention strategy. Following the identification of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a promising therapeutic target, inclisiran was developed using the natural process of RNA interference for robust, sustained prevention of hepatic PCSK9 synthesis. Twice-yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL-C levels by ≈50% versus placebo when added to maximally tolerated statins. Long-term safety and tolerability of inclisiran have been assessed, with studies underway to evaluate the effects of inclisiran on cardiovascular outcomes and to provide additional safety and effectiveness data. In 2021,

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

BackgroundNon-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) associated with steatosis, hepatocellular injury, inflammation and fibrosis. In a Phase 2 trial in adults with NASH (NCT02912260), resmetirom, an orally administered, liver-targeted thyroid hormone receptor-β selective agonist, significantly reduced hepatic fat (via imaging) and resolved NASH without worsening fibrosis (via liver biopsy) in a significant number of patients compared with placebo.AimsTo present the design of the Phase 3 MAESTRO clinical programme evaluating resmetirom for treatment of NASH (MAESTRO-NAFLD-1 [NCT04197479], MAESTRO-NAFLD-OLE [NCT04951219], MAESTRO-NASH [NCT03900429], MAESTRO-NASH-OUTCOMES [NCT05500222]).MethodsMAESTRO-NASH is a pivotal serial biopsy trial in up to 2000 adults with biopsy-confirmed at-risk NASH. Patients are randomised to a once-daily oral placebo, 80 mg resmetirom, or 100 mg resmetirom. Liver biopsies are conducted at screening, week 52 and month 54. MAESTRO-NAFLD-1 is a 52-week safety trial in ~1400 adults with NAFLD/presumed NASH (based on non-invasive testing); ~700 patients from MAESTRO-NAFLD-1 are enrolled in MAESTRO-NAFLD-OLE, a 52-week active treatment extension to further evaluate safety. MAESTRO-NASH-OUTCOMES is enrolling 700 adults with well-compensated NASH cirrhosis to evaluate the potential for resmetirom to slow progression to hepatic decompensation events. Non-invasive tests (biomarkers, imaging) are assessed longitudinally throughout, in addition to validated patient-reported outcomes.ConclusionThe MAESTRO clinical programme was designed in conjunction with regulatory authorities to support approval of resmetirom for treatment of NASH. The surrogate endpoints, based on week 52 liver biopsy, serum biomarkers and imaging, are confirmed by long-term clinical liver-related outcomes in MAESTRO-NASH (month 54) and MAESTRO-NASH-OUTCOMES (time to event).

With unprecedented and growing interest in data science education, there are limited educator materials that provide meaningful opportunities for learners to practice "statistical thinking," as defined by Wild and Pfannkuch, with messy data addressing real-world challenges. As a solution, Nolan and Speed advocated for bringing applications to the forefront in undergraduate statistics curriculum with the use of in-depth "case studies" to encourage and develop statistical thinking in the classroom. Limitations to this approach include the significant time investment required to develop a case study--namely, to select a motivating question and to create an illustrative data analysis--and the domain expertise needed. As a result, case studies based on realistic challenges, not toy examples, are scarce. To address this, we developed the Open Case Studies ("opencasestudies.org") project, which offers a new statistical and data science education case study model. This educational resource provides self-contained, multimodal, peer-reviewed, and open-source guides (or case studies) from real-world examples for active experiences of complete data analyses. We developed an educator's guide describing how to most effectively use the case studies, how to modify and adapt components of the case studies in the classroom, and how to contribute new case studies ("opencasestudies.org/OCS_Guide").

PURPOSE: Patients with cancer often experience elevated levels of distress. This double-blind, randomized controlled trial compared the impact of an app-based version of cognitive behavioral stress management (CBSM) versus a health education sham app on anxiety and depression symptoms. METHODS: Patients with nonmetastatic (stage I-III) cancer who were receiving or recently completed (≤6 months) systemic treatment were recruited nationwide. The primary outcome of change in anxiety symptoms (PROMIS-Anxiety) over 12 weeks and the top secondary outcome of change in depression symptoms (PROMIS-Depression) over 12 weeks were analyzed using mixed-effects modeling with repeated measures (weeks 0, 4, 8, 12). Patient global impressions of change in anxiety and depression were reported at weeks 4, 8, and 12. In addition, self-reported adverse events were collected throughout the study and adjudicated by the site principal investigator. RESULTS: Four hundred forty-nine patients were enrolled in the trial (age M [standard deviation] = 52.44 [11.46]; 81% female; 76% White; 53% breast cancer). Patients randomly assigned to digitized CBSM showed significantly greater reductions in anxiety (B = -0.03; P = .019) and depression (B = -0.02; P = .042) symptoms over 12 weeks. Patients who received digitized CBSM were also significantly more likely to perceive much or very much improvement (v no/minimal change or much/very much worse) in their symptoms of anxiety (χ2 = 31.76; P < .001) and depression (χ2 = 19.70; P < .001) compared with the control. CONCLUSION: The use of digitized CBSM led to significant improvements in anxiety and depression outcomes compared with the sham app.

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

High density lipoprotein cholesterol (HDL-C) is a known contributor to atherosclerotic cardiovascular disease (ASCVD) risk when HDL-C 90 mg/dL and >70 mg/dL in women and men, respectively. The ability for the HDL particle to effectively transport cholesterol from the periphery for excretion in bile is more complex than illustrated on a standard cholesterol panel. There is variability in its function, size, density, subclass, reverse cholesterol transport, and cholesterol efflux capacity, which impact the particles ability to effectively reduce cardiovascular disease (CVD) risk. Research has shown that HDL particles are prone to have a reduction in its efficacy in response to infection, auto-immune disease, menopause and cardiometabolic conditions during pregnancy. Additionally, recent studies have shown that low HDL-C may not adequately influence ASCVD risk in Black adults. The purpose of this contemporary review is to highlight the utility of using HDL-C in assessing CVD risk.

BackgroundNonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are independent risk factors for cardiovascular disease (CVD).AimsTo examine the clinical utility of liver fat quantification for determining CVD risk among a well-phenotyped cohort of patients with T2DM.MethodsThis was a cross-sectional analysis of a prospective cohort of adults aged ≥50 with T2DM. Liver fat was quantified with magnetic resonance imaging proton-density-fat-fraction (MRI-PDFF), an advanced imaging-based biomarker. Patients were stratified into a higher liver fat group (MRI-PDFF ≥ 14.6%), and a lower liver fat group (MRI-PDFF

BACKGROUND: Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease. METHODS: Participants from the UK Biobank and Womens Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause and LTL with incident coronary artery disease. RESULTS: This study included 130 254 postmenopausal women (UK Biobank: n=122 224; Womens Health Initiative: n=8030), of whom 4809 (3.7%) had experienced menopause before age 40. Earlier menopause was associated with shorter LTL (meta-analyzed ß=-0.02 SD/5 years of earlier menopause [95% CI, -0.02 to -0.01]; P=7.2×10-12). This association was stronger and significant in both cohorts for women with natural/spontaneous menopause (meta-analyzed ß=-0.04 SD/5 years of earlier menopause [95% CI, -0.04 to -0.03]; P

PurposeCardiac rehabilitation (CR) improves clinical outcomes in patients with cardiovascular disease (CDV). Patients with CVD often have multiple comorbidities, including obstructive sleep apnea (OSA), potentially affecting their ability to participate and achieve functional improvement during CR. We aimed to test the hypothesis that OSA reduces peak exercise capacity (EC) in patients undergoing CR and to explore if OSA treatment modifies this relationship.MethodsData from a retrospective cohort of CR patients was analyzed. OSA was defined as a respiratory event index > 5/h or physician diagnosis. Patients with OSA were considered "treated" if using continuous positive airway pressure regularly during the CR period. Change in METs was the primary study outcome.ResultsAmong 312 CR patients, median age of 67 years, 103 (33%) had known OSA (30 treated, 73 untreated). Patients with OSA vs. those with no OSA were more likely to be obese and male; otherwise, groups were similar. Compared with the no OSA group, patients with OSA had lower pre-CR METs (3.3 [2.9-4.5] vs. 3.9 [3.1-5], P = .01) and lower post-CR METs (5.3 [4-7] vs. 6 [4.6-7.6], P = .04), but achieved a similar increase in METs post-CR (1.8 [0.6-2.6] vs. 2.0 [0.9-3], P = .22). Furthermore, compared to no OSA, pre-CR and post-CR METs tended to be similar in patients with treated OSA, but lower in untreated patients, with similar increases in METs across all groups, even when adjusting for covariates via multivariable regression.ConclusionOSA is prevalent in patients with CVD undergoing CR. CR substantially improves exercise capacity independent of OSA status, but screening for-and treatment of-OSA may improve the absolute exercise capacity achieved through CR.

Teaching and learning fraction concepts continues to be increasingly challenging, especially for elementary and middle school mathematics teachers and students in intervention settings. It is critical for educators to implement instruction that proactively considers engagement, access, and conceptual growth for all students. Dream 2B, a web-based universally designed fraction game, has the potential to significantly impact engagement and conceptual understanding of fractions. In addition, it introduces students to Science, Technology, Engineering and Mathematics (STEM) and Information Communication Technology (ICT) careers. This manuscript provides guidance for utilizing Dream 2B as supplemental mathematics instruction. Components of Universal Design for Learning, as well as gameplay Concept/Skill connections, are provided. Guidance for expanding Dream2B into virtual learning environments is also discussed.

BackgroundThe MUC5B promoter variant (rs35705950) and telomere length are linked to pulmonary fibrosis and CT-based qualitative assessments of interstitial abnormalities, but their associations with longitudinal quantitative changes of the lung interstitium among community-dwelling adults are unknown.MethodsWe used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1-6 (2000-2018)) and MUC5B genotype (n=4552) and telomere length (n=4488) assessments. HAA was defined as the per cent of imaged lung with attenuation of -600 to -250 Hounsfield units. We used linear mixed-effects models to examine associations of MUC5B risk allele (T) and telomere length with longitudinal changes in HAAs. Joint models were used to examine associations of longitudinal changes in HAAs with death and interstitial lung disease (ILD).ResultsThe MUC5B risk allele (T) was associated with an absolute change in HAAs of 2.60% (95% CI 0.36% to 4.86%) per 10 years overall. This association was stronger among those with a telomere length below an age-adjusted percentile of 5% (p value for interaction=0.008). A 1% increase in HAAs per year was associated with 7% increase in mortality risk (rate ratio (RR)=1.07, 95% CI 1.02 to 1.12) for overall death and 34% increase in ILD (RR=1.34, 95% CI 1.20 to 1.50). Longer baseline telomere length was cross-sectionally associated with less HAAs from baseline scans, but not with longitudinal changes in HAAs.ConclusionsLongitudinal increases in HAAs were associated with the MUC5B risk allele and a higher risk of death and ILD.

PurposeObstructive sleep apnea (OSA)-related pulmonary hypertension (PH) can often be reversed with treatment of OSA via continuous positive airway pressure. We hypothesized that treatment of OSA would be associated with a greater improvement in exercise capacity (EC) with cardiac rehabilitation (CR), especially in patients with PH as compared with those who are untreated.MethodsWe reviewed medical records of 315 consecutive patients who participated in CR. Pulmonary hypertension status was assessed on the basis of peak tricuspid regurgitant velocity (>2.8 m/sec) on pre-CR echocardiograms. The OSA status (no, untreated, or treated OSA) was determined on the basis of results from sleep studies, continuous positive airway pressure device data, and physician notes. Exercise capacity was assessed by measuring metabolic equivalents (METs) using a treadmill stress test before and after CR.ResultsWe included 290 patients who participated in CR with available echocardiographic data: 44 (15%) had PH, and 102 (35%) had known OSA (30 treated and 72 untreated). Patients with OSA versus those with no OSA were more likely to have PH ( P = .06). Patients with PH versus no-PH were associated with significantly lower baseline METs in crude and adjusted analyses ( P ≤. 004). The PH and OSA status in isolation were not associated with changes in METs ( P > .2) with CR. There was a significant interaction between OSA treatment and PH in crude and adjusted analyses ( P ≤.01): treatment vs no treatment of OSA was associated with a clinically and statistically greater improvement in METs in patients who participated in CR with but not without PH.ConclusionBaseline PH was associated with decreased baseline EC but did not attenuate CR-related improvements in METs. However, in the subset of OSA patients with PH, OSA therapy was associated with improved EC after CR.

BACKGROUND: Galectin-3, a biomarker of inflammation and fibrosis, can be associated with renal and myocardial damage and dysfunction in patients with acute heart failure (AHF). METHODS AND RESULTS: We retrospectively analyzed 790 patients with AHF who were enrolled in the AKINESIS study. During hospitalization, patients with galectin-3 elevation (> 25.9 ng/mL) on admission more commonly had acute kidney injury (assessed by KDIGO criteria), renal tubular damage (peak urine neutrophil gelatinase-associated lipocalin [uNGAL] > 150 ng/dL) and myocardial injury (≥ 20% increase in the peak high-sensitivity cardiac troponin I [hs-cTnI] values compared to admission). They less commonly had ≥ 30% reduction in B-type natriuretic peptide from admission to last measured value. In multivariable linear regression analysis, galectin-3 was negatively associated with estimated glomerular filtration rate and positively associated with uNGAL and hs-cTnI. Higher galectin-3 was associated with renal replacement therapy, inotrope use and mortality during hospitalization. In univariable Cox regression analysis, higher galectin-3 was associated with increased risk for the composite of death or rehospitalization due to HF and death alone at 1 year. After multivariable adjustment, higher galectin-3 levels were associated only with death. CONCLUSIONS: In patients with AHF, higher galectin-3 values were associated with renal dysfunction, renal tubular damage and myocardial injury, and they predicted worse outcomes.

BackgroundWe sought to determine whether management of LDL-C following invasive angiography and assessment by fractional flow reserve (FFR) differs between those with obstructive vs non-obstructive CAD.MethodsRetrospective study of 721 patients undergoing coronary angiography involving assessment by FFR between 2013 and 2020 at a single academic center. Groups with obstructive vs non-obstructive CAD by index angiographic and FFR findings were compared over 1 year of follow-up.ResultsBased on index angiographic and FFR findings, 421 (58%) patients had obstructive CAD vs 300 (42%) with non-obstructive CAD, mean (±SD) age 66±11 years, 217 (30%) women, and 594 (82%) white. There was no difference in baseline LDL-C. At 3-months follow-up, LDL-C was lower than baseline in both groups, with no between group difference. In contrast, at 6-months, median (Q1, Q3) LDL-C was significantly higher in non-obstructive vs obstructive CAD (LDL-C 73 (60, 93) vs 63 (48, 77) mg/dL, respectively (p = 0.003), (p = 0.001 in multivariable linear regression)). At 12-months, LDL-C remained higher in non-obstructive vs obstructive CAD (LDL-C 73 (49, 86) vs 64 (48, 79) mg/dL, respectively, although not statistically significant (p = 0.104)). The rate of high-intensity statin use was lower among those with non-obstructive CAD vs obstructive CAD at all time points (p

AimsKidney function changes dynamically during AHF treatment, but risk factors for and consequences of worsening renal function (WRF) at hospital admission are uncertain. We aimed to determine the significance of WRF at admission for acute heart failure (AHF).Methods and resultsWe evaluated a subgroup of 406 patients from The Acute Kidney Injury Neutrophil gelatinase-associated lipocalin Evaluation of Symptomatic heart failure Study (AKINESIS) who had serum creatinine measurements available within 3 months before and at the time of admission. Admission WRF was primarily defined as a 0.3 mg/dL or 50% creatinine increase from preadmission. Alternative definitions evaluated were a ≥0.5 mg/dL creatinine increase, ≥25% glomerular filtration rate decrease, and an overall change in creatinine. Predictors of admission WRF were evaluated. Outcomes evaluated were length of hospitalization, a composite of adverse in-hospital events, and the composite of death or HF readmission at 30, 90, and 365 days. Biomarkers' prognostic ability for these outcomes were evaluated in patients with admission WRF. One-hundred six patients (26%) had admission WRF. These patients had features of more severe AHF with lower blood pressure, higher BUN, and lower serum sodium concentrations at admission. Higher BNP (odds ratio [OR] per doubling 1.16-1.28, 95% confidence interval [CI] 1.00-1.55) and lower diastolic blood pressure (OR 0.97-0.98, 95% CI 0.96-0.99) were associated with a higher odds for the three definitions of admission WRF. The primary WRF definition was not associated with a longer hospitalization, but alternative WRF definitions were (1.3 to 1.6 days longer, 95% CI 1.0-2.2). WRF across definitions was not associated with a higher odds of adverse in-hospital events or a higher risk of death or HF readmission. In the subset of patients with WRF, biomarkers were not prognostic for any outcome.ConclusionsAdmission WRF is common in AHF patients and is associated with an increased length of hospitalization, but not adverse in-hospital events, death, or HF readmission. Among those with admission WRF, biomarkers did not risk stratify for adverse events.

Multiple lines of evidence confirm that the cumulative burden of low-density lipoprotein cholesterol (LDL-C) is causally related to the development of atherosclerotic cardiovascular disease (ASCVD). As such, lowering LDL-C is a central tenet in all ASCVD prevention guidelines, which recommend matching the intensity of LDL-C lowering with the absolute risk of the patient. Unfortunately, issues such as difficulty with long-term adherence to statin therapy and inability to achieve desired LDL-C thresholds with statins alone results in residual elevated ASCVD risk. Non-statin therapies generally provide similar risk reduction per mmol/L of LDL-C reduction and are included by major society guidelines as part of the treatment algorithm for managing LDL-C. Per the 2022 American College of Cardiology Expert Consensus Decision Pathway, patients with ASCVD are recommended to achieve both an LDL-C reduction ≥50% and an LDL-C threshold of

Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI). We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample. Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not. Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function-but not peripheral inflammation-predicts greater GWI symptoms and severity.

Research into extracellular vesicles (EVs) has grown significantly over the last few decades with EVs being widely regarded as a source of biomarkers for human health and disease with massive clinical potential. Secreted by every cell type in the body, EVs report on the internal cellular conditions across all tissue types. Their presence in readily accessible biofluids makes the potential of EV biosensing highly attractive as a noninvasive diagnostic platform via liquid biopsies. However, their small size (50-250 nm), inherent heterogeneity, and the complexity of the native biofluids introduce challenges for effective characterization, thus, limiting their clinical utility. This has led to a surge in the development of various novel EV biosensing techniques, with capabilities beyond those of conventional methods that have been directly transferred from cell biology. In this review, key detection principles used for EV biosensing are summarized, with a focus on some of the most recent and fundamental developments in the field over the last 5 years. This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > In Vitro Nanoparticle-Based Sensing.

Finding pathways to success for students with disabilities is important to the work of administrators and educators who wish to support this population. Guided by an anti-deficit framework and the minority group model, data from the 2015 and 2016 administration of the National Survey of Student Engagement were examined to learn how Engagement Indicators related to outcomes (GPA, satisfaction, and self-reported learning) for over fifteen thousand first-year students with disabilities. To avoid deficit framing, structural equation modeling was employed to measure the mediation effects of four Engagement Indicators for students with learning disabilities compared to other students with disabilities. Results from this study indicate that most Engagement Indicators are significantly, and in some cases strongly, related to outcomes for students with disabilities; however, only Student-Faculty Interaction was a significant, positive mediator for students with learning disabilities whereas the significant negative mediators indicate that engagement has divergent effects for students with disabilities.

Background Higher cardiac troponin is associated with worse outcomes in patients with acute heart failure. The significance of repeat measurements over hours remains unclear. We assessed whether a repeat measurement and the Δ between measurements of high‐sensitivity cardiac troponin I (hs‐cTnI) were associated with outcomes in hypervolemic patients with acute heart failure without acute coronary syndrome. Methods and Results We analyzed 582 individuals from AKINESIS (Acute Kidney Injury Neutrophil Gelatinase‐Associated Lipocalin Evaluation of Symptomatic Heart Failure Study) with hs‐cTnI measured ≤12 hours from admission and repeated ≤6 hours thereafter. Associations between hs‐cTnI levels and their Δ with short‐term (death, intensive care unit admission, receipt of inotropes, or positive pressure ventilation during hospitalization) and long‐term (death or heart failure readmission within 1 year) outcomes were assessed. The average age was 69±13 years, 62% were men, 65% were White, 46% had coronary artery disease, and 22% had chest pain. Median hs‐cTnI levels were 27 (interquartile range [IQR], 13–62) ng/L initially and 28 (IQR, 14–68) ng/L subsequently, with a Δ of 0 [IQR, −2 to 4] ng/L over 3.4±1 hours. Only the second measurement was associated with short‐term outcomes (odds ratio, 1.14 per 2‐fold higher [95% CI, 1.02–1.28]). Both individual measurements and the Δ were associated with long‐term outcomes (hazard ratios, 1.09, 1.12, and 1.16 for first, second, and Δ, respectively). Associated risk for the first and second measurements were not constant over the year but highest early after being measured and decreased over 1 year. Conclusions Repeat measurements of hs‐cTnI over hours can identify individuals with acute heart failure without acute coronary syndrome at risk for short‐ and long‐term outcomes.