Citations

Abstract Frailty predicts adverse outcomes in multiple myeloma (MM), yet an objective frailty biomarker is lacking. Circulating senescence-associated secretory phenotype (SASP) factors correlate with frailty and adverse outcomes in chronic diseases, but their relevance in MM is unclear. In this study, we investigated the relationship between 36 plasma SASP factors, frailty, and clinical outcomes in: (1) a historical cohort using stored specimens from 59 patients with newly diagnosed MM, and (2) a prospective cohort of 36 patients initiating new MM treatment. Several SASP factors were significantly associated with frailty after adjusting for age, sex, and body mass index; GDF-15, TNF-RI, IL-6, and IL-8 showed positive correlations with both cumulative-deficit based and physical frailty indices. Additionally, significant age-adjusted associations were observed between SASP factors and treatment outcomes, including overall survival (OS), high-grade toxicity, and healthcare utilization. We developed a 5-factor SASP model that demonstrated superior predictive performance for OS compared to chronological age, R-ISS stage, and clinical frailty, and TNF-RI alone (5-year OS AUC: 0.90). These findings highlight the association between senescence biomarkers and frailty and OS, and support further investigation of SASP factors as objective frailty biomarkers in MM.

ABSTRACT Objective To describe the practice patterns of point‐of‐care ultrasound (POCUS) and compare its usage across subgroups (adult vs. paediatric practitioners, physicians vs. nurse practitioners [NPs], high income [HI] vs. low and middle ‐income [LMI] countries). Methods Survey distributed via the Society of Critical Care Medicine in May–June 2024. Respondents reported the percentage of eligible patients in the past year for whom POCUS was used for vascular access and diagnostic purposes. Responses (0%, < 25%, 25%–50%, 50%–75%, > 75%) were converted into binary categories (> 50% use) and compared across subgroups using logistic regression. Results The survey was completed by 503 respondents from 39 countries (6% response rate): 77.7% from HI countries, 20.9% paediatric practitioners and 18.3% Nurse Practitioner (NPs)/Physician assistants (PAs). POCUS was commonly used for vascular access, and similar usage was found among NP/PAs, physicians, and adult and paediatric practitioners. Practitioners from LMI countries were less likely to use POCUS for vascular access. Basic diagnostic applications, such as assessing pleural effusion (72.5%) and left ventricular function (69.2%), were more commonly used than advanced applications like pulmonary artery pressure measurement (22%). Physicians were more likely than NPs (for some indications), and adult practitioners were more likely than paediatric practitioners (for most indications) to use POCUS for diagnostic purposes. Practitioners in LMI countries reported higher use of diagnostic applications than practitioners in HI countries. Conclusions POCUS is widely adopted in critical care but is less accepted for diagnostic use among paediatric practitioners and NP/PAs. Diagnostic utilisation is higher in LMI countries, while procedural use is lower. Impact Statement Point‐of‐care ultrasound (POCUS) is increasingly used in intensive care units to guide diagnosis and procedures. Despite its importance, little is known about how consistently it is used by different types of clinicians around the world. This international survey of critical care practitioners from 39 countries shows that POCUS is widely used, particularly for procedures, but diagnostic use remains uneven. Paediatric clinicians and advanced practice providers report lower diagnostic use, while clinicians in low‐ and middle‐income countries report higher diagnostic adoption. These findings highlight opportunities to improve access to training and support broader, more equitable use of POCUS in critical care.

ABSTRACT 162 patients with relapsed secondary central nervous system lymphoma (R‐SCNSL) (median age, 65 years; male, 59.9%) including central nervous system (CNS)‐only ( n = 120) and concomitant CNS/systemic relapse ( n = 42) were retrospectively analyzed. Overall, 21.9% of patients were classified as high risk according to the CNS International Prognostic Index (CNS‐IPI). Several biological and clinical features were significantly associated with leptomeningeal involvement, including double‐ or triple‐hit (DHL/THL) status, MYC rearrangement, negative BCL6 expression by IHC, bone marrow involvement, and concomitant R‐SCNSL. Multivariable analysis showed that leptomeningeal involvement independently predicted inferior OS and was associated with a 98% increase in the hazard of death compared with parenchymal relapse (HR = 1.98, 95% CI: 1.20–3.26, p = 0.008). Based on anatomical localization, R‐SCNSL was classified into four subtypes: parenchymal‐only involvement (parenchymal‐CNS [P‐CNS], 68/42%) and parenchymal involvement plus systemic relapse (parenchymal‐concomitant [P‐concomitant], 17/10.5%); and leptomeningeal with or without parenchymal involvement (leptomeningeal‐CNS [LM‐CNS], 52/32.1%) and leptomeningeal with systemic relapse (leptomeningeal‐concomitant [LM‐concomitant], 25/15.4%). This anatomical classification significantly impacted OS and PFS ( p < 0.001). Two‐year OS and PFS were 58.2% and 29.1% for P‐CNS, 32.4% and 17.7% for P‐concomitant, 22% and 13.9% for LM‐CNS, and 7.1% and 0% for LM‐concomitant, respectively. ASCT showed a trend toward improved survival among patients with a response (CR/PR) in a 4‐month landmark analysis. These findings support the clinical application of the anatomical classification in the management of R‐SCNSL.

Abstract Introduction Left atrial-to-coronary sinus (LA-to-CS) shunting through the APTURE transcatheter shunt system aims to unload the LA while preserving the interatrial septum. This article aims to examine the 3-year health status, functional capacity, and clinical outcomes of the ALT-FLOW Early Feasibility Study (EFS). Methods Device safety, patency, and echocardiographic parameters, but also symptoms, health status, and exercise capacity were assessed in patients with left ventricular ejection fraction (LVEF) &gt; 40% (n & 95). Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score predicted 3-year all-cause mortality was compared with observed mortality assessed by Kaplan–Meier analysis using adjudicated events. Predicted and observed HF hospitalization (HFH)-free survival rates were also compared. Results At 3 years, the safety profile remained stable with no new safety signals, and all implanted shunts remained patent. 76.3% of patients improved by at least one NYHA class, and mean KCCQ Overall Summary Scores increased by 25 points from baseline (P &lt; .0001). The 6-min walk distance improved by an average of 39 m (P & .002). These benefits were consistent regardless of baseline pulmonary vascular resistance (PVR). Right heart echocardiographic parameters after 3 years were stable, though a reduction in TAPSE was observed, primarily in the high PVR subgroup. The observed 3-year survival was significantly higher than the MAGGIC-predicted survival (84.4% vs 70.2, respectively; P & .009), as well as the HFH-free survival (68.0% vs 24.0%, respectively; P &lt; 0001). Conclusion In patients with HF and LVEF &gt;40%, the APTURE LA-to-CS shunting confirmed an acceptable safety profile with stable right heart parameters and sustained improvements in symptoms, quality of life, and functional capacity at 3 years. Observed survival and HFH were superior to MAGGIC predictions.

Abstract Cellular senescence has been implicated in the pathophysiology of radiotherapy-related bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of mouse femurs. In a proof-of-concept study, following two preclinical radiotherapy regimens of cumulative doses of 30Gy (5 x 6Gy) and 60Gy (5 x 12Gy), a senomorphic approach of JAKi treatment was more effective in alleviating radiation-related bone loss compared to the senolytic cocktail of D+Q. Early and intermittent suppression of SASP using JAK inhibitors alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression, reduced bone-marrow adiposity, and mitigated radiation related lymphatic impairment. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures. Lay Summary Radiotherapy as part of cancer treatment is correlated with an acute increase in senescent cells. Here we show that the pro-inflammatory senescence associated secretory phenotype (SASP) becomes much more prominent soon after radiotherapy in both patients and mice. Suppression of the SASP using a Janus kinase inhibitor, ruxolitinib, reduced the overall senescent cell burden, improved bone architecture by promoting bone formation, reduced bone marrow adiposity, and mitigated radiation-induced lymphatic impairment. Overall, these findings suggest that early inhibition of the SASP may help mitigate several bone anomalies and prevent long-term bone loss and fractures after radiotherapy. Graphical Abstract

BACKGROUND: While health systems have implemented resources to improve lipid management in people with atherosclerotic cardiovascular disease, the population-level effectiveness is unclear. METHODS: Electronic health record data from patients with atherosclerotic cardiovascular disease between January 1, 2021, and December 31, 2023, across 16 US academic health systems were analyzed. Atherosclerotic cardiovascular disease (defined by diagnosis and procedure codes) was established on or before the index date defined as the date of the most recent LDL-C (low-density lipoprotein-cholesterol) or the last day of the study period for those without an LDL-C available. Systems were surveyed to identify lipid management programs (eg, prevention/lipid clinic, electronic health record–based tools, and lipid management algorithms). Sequential multilevel multivariable logistic regression modeling was used to (1) assess the system-level association between an LDL-C <70 mg/dL and the presence of lipid management programs, adjusting for patient-level demographic and clinical characteristics, and (2) whether system-level uptake of statin or nonstatin lipid-lowering therapy was associated with an LDL-C <70 mg/dL. RESULTS: We included 1 738 042 patients with atherosclerotic cardiovascular disease (median, 88 365 per system; range, 17 086–2 48 371). About 81% of the health systems had prevention or lipid clinics. The proportion of those on statins ranged from 31.0% to 60.4% across health systems (median, 46.3%). Lower proportions were observed in the use of high-intensity statins (16.2%–33.1%), nonstatins (2.6%–8.1%), and combination lipid-lowering therapy (1.7%–6.3%). Among those with an LDL-C level available (n=890 521), 42.5% had an LDL-C <70 mg/dL, ranging 35.8% to 49.4% across systems. There was no association between the odds of achieving LDL-C <70 mg/dL and health system lipid management algorithm, prevention clinics/lipid clinics, or electronic health record–based tools. Neither system-level high-intensity statin utilization nor nonstatin use was associated with an LDL-C <70 mg/dL. CONCLUSIONS: Despite variability in lipid management resources and lipid-lowering therapy use across systems, many did not reach an LDL-C <70 mg/dL, and there was low uptake of lipid-lowering therapy. Innovative implementation strategies are needed for system-level lipid management.