Citations

Coronary artery disease (CAD) is the leading cause of death globally. Apolipoprotein A-1 (apoA-1), the primary protein component of high-density lipoprotein (HDL), facilitates reverse cholesterol transport and has emerged as a potential therapeutic target. While pharmacologic efforts to raise HDL-C levels have failed to reduce cardiovascular events, focus has shifted to HDL functionality, particularly cholesterol efflux capacity (CEC). ApoA-1 infusions have demonstrated antiatherogenic effects in preclinical models and early human trials by enhancing CEC and promoting cholesterol clearance. This review summarizes the rationale and evolving clinical trial landscape investigating apoA-1 infusions as a novel therapy for CAD prevention and treatment.

ABSTRACT Despite remarkable interest in the biomarker potential of urinary extracellular vesicles (uEVs) and the identification of numerous promising candidates, their clinical translation still presents multiple challenges. The opportunities for successful translation are obvious, yet the main roadblocks on the way have hardly been systematically considered and more coordinated approaches are needed to overcome them. In the present review article, we have identified the most relevant roadblocks of clinical translation of urinary EV‐based biomarkers and discuss possible solutions to overcome them. These roadblocks are categorized as fundamental and technical but also related to development of novel biomarker assays and clinical acceptance. In addition, hurdles within the regulatory approval process are discussed. It is clear that various roadblocks to clinical translation of urinary EV biomarkers exist; however, they are addressable by promoting rigor and reproducibility as well as collaboration between basic and clinical scientists, clinicians, industry and regulatory bodies. Moreover, knowledge of obstacles for assay development and regulatory requirements should already be considered when developing a new biomarker to maximize the chance of successful translation. This review presents not only a status quo, but also a roadmap for the further development of the field.

The increasing prevalence of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) has led to a growing demand for kidney transplantation (KTx). Identifying risk factors that enable improved allograft survival through novel therapeutic agents, advanced biomarkers, and artificial intelligence (AI)-driven data integration are critical to addressing this challenge. Drugs, such as SGLT2 inhibitors and finerenone, have demonstrated improved outcomes in patients but lack comprehensive long-term evidence in KTx patients. The use of biomarkers, including circulating cytokines and transcriptomics, coupled with AI, could enhance early detection and personalized treatment strategies. Addressing patient self-management and addressing health access disparities may be more achievable using technologies used at home rather than traditional models of healthcare and thus lead to increased transplant success, both in terms of transplantation rates and allograft longevity.

BACKGROUND AND OBJECTIVES: This study aimed to evaluate predictors of hypertrophic olivary degeneration (HOD) in patients with brainstem cerebral cavernous malformations (CCMs) and to examine its association with functional outcomes. METHODS: A cohort of 120 patients with brainstem CCM was analyzed using prospectively collected registry data and retrospective chart reviews. Demographic, clinical, radiological, and surgical data were evaluated. Predictors of HOD and poor functional outcomes were identified through univariate and multivariate analyses. RESULTS: The cohort included 54 females (45.0%), with a mean age at diagnosis of 43.8 years (SD = 16.5). Symptomatic hemorrhage was present in 70.8% of patients at diagnosis, and 28.3% underwent surgical intervention. Radiographic HOD was observed in 20% of patients (n = 24), with 87% of cases involving lesions within the Guillain–Mollaret triangle (GMT). Larger lesion size (odds ratio [OR] = 1.09, 95% CI: 1.01-1.19, P = .027), pontine location (OR = 19.81, P = .006), and GMT involvement (OR = 25.24, P < .001) were significantly associated with HOD. Repeated symptomatic hemorrhage and surgery, including the extent of resection, did not predict the development of HOD. Patients with HOD had worse functional outcomes at last follow-up ( P = .012), with GMT involvement remaining the sole independent predictor of mRS ≥3 (OR = 3.44, P = .040). CONCLUSION: HOD reflects trans-synaptic degeneration within the GMT and is strongly associated with lesion location and size. It serves as a radiological marker of cumulative damage to the brainstem. Preoperative imaging and risk stratification focusing on GMT involvement are critical for guiding management and counseling patients with brainstem CCM.

Background Left ventricular (LV) end‐systolic enlargement in severe degenerative mitral‐regurgitation (MR) is a class I surgical trigger. Whether it occurs disproportionately to less‐than‐severe MR due to mitral valve prolapse and is associated with mortality are unknown. We aimed to analyze prevalence and association with survival of disproportionate LV enlargement in less‐than‐severe MR. Methods A multicenter cohort international study enrolled 2848 consecutive patients (52% women, 69±16 years) with degenerative MR prospectively quantified and graded mild or moderate. Primary end point was survival under medical management. Secondary outcome was survival throughout follow‐up stratified by performance of early mitral surgery within 3 months postdiagnosis. Results Among LV remodeling parameters (abnormal end‐diastolic diameter, LV end‐systolic diameter [LVESD] absolute and indexed), LVESD ≥40 mm (present in 12.4%) was the sole independent associate of reduced survival (5‐year 70±3 versus 76±9%; P =0.009). LVESD ≥40 mm was independently linked to larger body surface area, effective regurgitant orifice, and left atrium, and to male sex and diabetes. With multivariable comprehensive adjustment, LVESD ≥40 mm (adjusted hazard ratio [aHR], 1.25 [95% CI, 1.005–1.53]; P =0.04) remained associated with excess mortality under medical management, even after adjustment for lowered ejection fraction (aHR, 1.49 [95% CI, 1.13–1.95]; P =0.004) and in all patient subsets. Among patients with moderate degenerative MR and LVESD ≥40 mm, 22% underwent mitral surgery within 3 months, which was associated with superior survival, even after comprehensive adjustment (aHR, 0.11 [95% CI, 0.005–0.51]; P =0.002). Conclusions Disproportionate LV enlargement in patients with less‐than‐severe degenerative MR is common, particularly with larger bodies, regurgitation, and overall cardiac remodeling. LVESD ≥40 mm is associated with worse survival independent of all baseline characteristics, even lowered ejection fraction, and represents a marker for risk stratification of patients who are generally not yet considered for medical or surgical/interventional treatment.

Background We aimed to assess the longitudinal changes of glycocalyx, a proteoglycan/glycoprotein layer that lines and protects endothelial cells in normotensive pregnancies (NPs); to correlate glycocalyx parameters with kidney injury markers (podocin‐positive to nephrin‐positive [P/N] ratio); and to explore changes in P/N ratio in preeclampsia. Methods Plasma and urine samples and glycocalyx measurements using side‐stream darkfield imaging were collected at each trimester from pregnant women (n=31). Plasma glycocalyx components were measured by ELISA, and urinary P/N‐positive extracellular vesicles by flow cytometry. Results In NPs (n=26), glycocalyx degradation increased from the first to the second trimester ( P =0.008) and returned to first‐trimester values in the third trimester ( P =0.008). Microvascular perfusion decreased from the first to the second trimester ( P =0.006) and increased back to first‐trimester values by the third trimester ( P =0.039). Plasma syndecan 1 level showed a steady increase from the first to the second trimester ( P <0.001) and further in the third trimester ( P <0.001); hyaluronic acid increased from the first to the second trimester ( P =0.016) without further changes. Glycocalyx degradation was associated with an increase in P/N ratio from the first to the second trimester of NPs and remained stable through the third trimester. P/N ratio strongly correlated with elevated syndecan 1 and hyaluronic acid levels in the third trimester. Comparison of P/N ratios between NP and preeclampsia (n=5) showed higher values in preeclampsia across all trimesters ( P =0.028). Conclusions Glycocalyx changes during NPs are associated with elevated urinary podocyte markers. Increase in P/N ratio across NPs, and further in preeclampsia, suggests that podocyte injury in preeclampsia is extension of physiological changes in pregnancy, which may predate its clinical presentation.

Empirical evidence suggests direct thrombin inhibitors (DTIs) produce more favorable hemostatic outcomes than heparin in patients supported by extracorporeal membrane oxygenation (ECMO), yet the exact mechanisms responsible are unknown. We systematically searched databases and registers for studies comparing DTIs to heparin in humans receiving ECMO. A total of 28 studies were identified, most of which (n = 25) used bivalirudin, while the rest (n = 3) used argatroban. In random-effects meta-analysis, DTIs achieved the therapeutic anticoagulation range faster (mean difference = −6.96 hours, 95% confidence interval [CI] = −11.98 to −1.95, p = 0.006) and maintained the therapeutic range for a greater proportion of time (mean difference = 18.6%, 95% CI = 8.78–28.42, p < 0.001) than heparin. Subgroup analysis revealed these effects were similarly significant in adult patients and when bivalirudin was the DTI; however, they were not significant in pediatric patients or when argatroban was the DTI. Sensitivity analysis confirmed robustness of the primary findings in only low-risk of bias studies and in only studies published as full papers. In summary, DTIs—specifically bivalirudin—were associated with faster time to therapeutic anticoagulation and maintained the goal range for a greater percentage of time than heparin during ECMO support.

Background Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium–glucose cotransporter‐2 inhibitors (SGLT2is) have favorable cardiovascular outcomes compared with dipeptidyl peptidase‐4 inhibitors (DPP4is) and sulfonylureas in adults with type 2 diabetes and high cardiovascular risk. How these benefits vary across lower levels of cardiovascular risk is unknown. Methods We used nationwide claims data to emulate a comparative effectiveness trial and examine the heterogeneity of treatment effects of GLP‐1RAs, SGLT2is, DPP4is, and sulfonylureas on major adverse cardiovascular events (MACEs) among adults with type 2 diabetes and moderate cardiovascular risk (annualized MACE risk 1%–5%, estimated using the annualized claims‐based MACE estimator). Results Among 386 276 included adults with type 2 diabetes, 25.2% had baseline ACME–predicted MACE risk >1% to ≤2% (lower‐risk patients) and 13.3% had ACME–predicted risk >4% to ≤5% (higher‐risk patients). By year 3 of treatment, higher‐risk patients derived greater absolute benefit than lower‐risk patients when treated with GLP‐1RAs versus sulfonylureas (absolute reduction in the estimated rate of MACE of 3.1% in higher‐risk patients and 1.6% in lower‐risk patients), SGLT2is versus sulfonylureas (absolute reduction, 3.9% in higher‐risk patients and 1.3% in lower‐risk patients), and GLP‐1RAs versus DPP4is (absolute reduction, 1.6% in higher‐risk patients and 0.5% in lower‐risk patients). The relative benefits for MACE were also greater in higher‐risk than lower‐risk patients with SGLT2is versus DPP4is (hazard ratio [HR], 0.78 [95% CI, 0.70–0.87] in higher‐risk patients; HR, 0.99 [95% CI, 0.88–1.12] in lower‐risk patients). Conversely, the relative benefits of DPP4is and GLP‐1RAs versus sulfonylureas were greater in lower‐risk patients: HR 0.76 (95% CI, 0.71–0.81) in lower‐risk and HR 0.91 (95% CI, 0.97–0.96) in higher‐risk patients for DPP4is versus sulfonylureas; HR 0.67 (95% CI, 0.58–0.78) in lower‐risk and HR 0.80 (95% CI, 0.70–0.93) in higher‐risk patients for GLP‐1RAs versus sulfonylurea. Benefits of SGLT2is and GLP‐1RAs were comparable across all risk levels. Conclusions Cardiovascular benefits of SGLT2is and GLP‐1RAs exist across all levels of moderate cardiovascular risk, reinforcing the importance of choosing glucose‐lowering therapies that can prevent MACE in all people with type 2 diabetes.

Hematopoietic stem cell transplantation (HSCT) is a lifesaving intervention for various hematologic and oncologic diseases that presents significant psychological risks for pediatric patients and their caregivers. Implementation of a longitudinal screening pathway for associated symptoms of post-traumatic stress disorder (PTSD) has been recommended; however, feasibility and utility in directing behavioral health needs remains unclear. Patients’ eligibility for enrollment included scheduled allogeneic or autologous HSCT through our institution’s Center for Cancer and Blood Disorders. Eligible caregivers and patients completed psychometrically validated self-report instruments assessing PTSD symptoms via REDCap pre-transplant, at 30 days, 100 days, 180 days, and 365 days following transplant. Individuals who reported experiencing clinically significant trauma symptoms at any timepoint were referred to a mental health clinician for treatment. If already involved in therapy, session frequency was recommended to increase and trauma-focused interventions were prioritized. Between April 2022 and April 2024, approximately 90% of eligible patients and caregivers consented for study participation ( N = 62). Preliminary findings suggest excellent retention and participants represented a diverse sample. Additionally, based on screening results at each timepoint, approximately 70% of our sample was connected to mental health services or offered increased session frequency if already engaged in treatment based on screening results. HSCT reflects a stressful experience for both patients and their caregivers. Systematically screening for PTSD among this population at the time of transplant and throughout the subsequent year was feasible and enabled targeted provision of behavioral health services.