Citations

ABSTRACT Patients undergoing transcatheter aortic valve implantation (TAVI) often require long‐term oral anticoagulation (OAC), but it is unclear whether to continue or interrupt OAC during the procedure. This meta‐analysis compares clinical outcomes of continuing versus interrupting OAC during TAVI. PubMed, Embase, and Cochrane Central databases were searched from inception to September 2024 for studies comparing continuation versus interruption of OAC in patients undergoing TAVI with an indication for OAC, including vitamin K antagonists and direct oral anticoagulants. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a random‐effects model. Sensitivity analysis was performed using the Hartung‐Knapp‐Sidik‐Jonkman method. Three studies were included, one randomized controlled trial and two cohort studies, with 2773 patients, of whom 1314 (47.4%) continued OAC during TAVI. At a 30‐day follow‐up after TAVI, there were no significant differences between groups in all‐cause mortality (RR 0.74; 95% CI 0.45–1.20; p = 0.22), any bleeding (RR 1.08; 95% CI 0.81–1.43; p = 0.60), and major bleeding (RR 0.90; 95% CI 0.67–1.21; p = 0.48). However, the continued OAC group was associated with a lower stroke rate (RR 0.65; 95% CI 0.42–1.01; p = 0.053), also attested after a sensitivity analysis (RR 0.65; 95% CI 0.47–0.90; p < 0.03). In patients with an indication for OAC undergoing TAVI, uninterrupted anticoagulation is associated with similar thrombotic and hemorrhagic outcomes compared to interrupted OAC. Stroke risk was lower in the continued OAC group, with a significant reduction, as demonstrated in sensitivity analysis.

Hazardous alcohol use remains a major contributor to acute and chronic liver disease, while alcohol-associated liver disease (ALD) is a leading indication for liver transplantation. In recent years, embedded, interprofessional ALD clinics have improved access to alcohol use disorder care within hepatology and liver transplantation, but more work is needed to meet this challenge. The literature is lacking regarding scaling procedures to provide services for increasingly large ill patient populations. This article begins to fill this gap by describing “expanded ALD care”: broad, innovative, longitudinal, interprofessional care delivery strategies surpassing standalone clinics. Drawing from analogous patient populations served by collaborative models in primary care and comprehensive eating disorder treatment, the expanded ALD care framework proposes practical strategies toward specific innovations: equipoise between biomedical and psychosocial care elements, increased clinician number and reach, long-term patient relationships, harm reduction and palliative care, outreach to external agencies and clinicians, and enhanced support for patients and families. The article also defines attributes of innovative healthcare systems that support expanded ALD care.

Abstract An individual participant data (IPD) meta-analysis can assess the predictive value of data on outcomes at the individual level, offering a potential tool for developing personalized pain management. Pretreatment quantitative sensory testing (QST) may stratify patient groups, which are then linked to treatment outcomes. Our objective was to determine if measures of QST at baseline are related to treatment outcomes (at any time point) for pain and disability in lower-limb osteoarthritis. We performed a systematic review with an IPD meta-analysis. Searches were conducted in 9 databases until May 5, 2023 for intervention studies that measured baseline QST and longitudinal measures of participant-reported pain and disability. We performed a 2-stage approach to analyse longitudinal data. Individual models were fitted to each study and combined using random effects multivariate meta-analytic models. Study quality was assessed using the Joanna Briggs Institute checklist, and certainty of the evidence was assessed using GRADE. We identified 3082 records and included 1 hip and 28 knee datasets consisting of 2522 participants from 40 studies. Local warm detection thresholds (P = 0.024) predicted knee osteoarthritis pain outcomes (very-low certainty). Local warm detection thresholds (P = 0.030), remote cold detection thresholds (P = 0.05), and remote pressure tolerance thresholds (P = 0.007) predicted knee osteoarthritis disability outcomes (very-low certainty). Other QST variables were associated with hip and knee osteoarthritis pain and disability levels (eg, pressure pain thresholds), but this relationship did not change over time. This review finds that mechanism-based, QST methodologies do not consistently predict pain or disability on an individual level in hip or knee osteoarthritis.

Abstract Background: Replication checkpoint modulators (RCMs), including inhibitors of CHK1, ATR, and WEE1, have been widely studied for their ability to inhibit cell cycle checkpoints and enhance the toxicity of agents that stall replication forks. In preclinical studies each of these inhibitors also demonstrates notable activity as a single agent against relapsed/refractory acute myeloid leukemia (R/R AML). In particular, our prior study (PMID: 33414171) demonstrated that several myeloid cell lines underwent cell death at nanomolar concentrations, with a median IC50 of 9 nM irrespective of the TP53 status. Examination of pathways involved in RCM-induced leukemia cell killing demonstrated that CHK1 inhibition induces CDC25A upregulation accompanied by activation of a death program that involves a CDK2-initiated 10- to 50-fold upregulation of TNFα and downstream engagement of the extrinsic apoptotic pathway. Here we have comprehensively characterized the processes that occur between the interruption of replication checkpoints and leukemic cell death in these sensitive cells versus cells selected for RCM resistance. Methods: Using the CHK1 inhibitors MK8776 and prexasertib, ATR inhibitors berzosertib and ceralasertib, and WEE1 inhibitor adavosertib as paradigm drugs, we examined signaling in two AML cell lines, U937 and THP.1, that were selected for CHK1 inhibitor resistance, examined cross-resistance patterns, and assessed the biochemical basis for leukemic cell death. Changes in gene expression and signaling induced by RCMs were analyzed in isogenic pairs using RNA sequencing, flow cytometry and immunoblotting. Results: In contrast to parental U937 and THP.1 cells, CHK1 inhibitor-selected U937 and THP.1 cell exhibited a lack of TNFα mRNA induction and did not undergo cell death in response to multiple CHK1 inhibitors. RNA sequencing of CHK1 inhibitor-selected AML lines revealed an almost complete absence of induction of CDK2-activated genes following prexasertib treatment. Interestingly, unlike solid tumors, AML cell lines that were resistant to CHK1 inhibitors exhibited hypersensitivity to WEE1 or ATR inhibition. Further studies demonstrated that CHK1 inhibitor response was varied in primary AML samples, with 50% of primary AML specimens resistant to CHK1i monotherapy, again without any relationship to TP53 status. The common features among sensitive vs. resistant leukemias was the successful inhibition of CDK2 phosphorylation and the associated induction of TNFα. Conclusions: Our findings reveals critical new insights into the factors that influence the response to CHK1 inhibitors in AML. Importantly, we found no evidence of cross-resistance to inhibitors of other replication checkpoint proteins, enabling alternative options. Citation Format: Annapoorna Venkatachalam, Husheng Ding, Nicole Vincelette, Cordelia McGehee, Kevin Peterson, Paula Schneider, Cristina Correia, Hu Li, Scott Kaufmann. CDK2 activation mediates response of acute myeloid leukemia to CHK1, ATR and WEE1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 423.

Abstract Background: Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are the most common lung cancer subtypes. SCC is traditionally resistant to anti-angiogenic therapies, though the mechanisms remain unclear. Nintedanib, a multi-angiokinase receptor inhibitor, is approved for treating ADC in combination with docetaxel, based on selective efficacy in the LUME-1 trial. It is also FDA-approved for idiopathic pulmonary fibrosis due to its antifibrotic properties. Both ADC and SCC feature fibrotic stroma rich in activated tumor-associated fibroblasts (TAFs). Our prior work showed Nintedanib has stronger antifibrotic effects on ADC-TAFs than SCC-TAFs. However, its impact on TAF-driven angiogenesis and the role of TAFs in SCC resistance to multi-angiokinase inhibitors remain unexplored. Methods: The pro-angiogenic activity of TAFs secretome from ADC and SCC patients was assessed. TAFs were stimulated with TGF-β1 to mimic their activated phenotype, then treated with Nintedanib. Conditioned media from treated TAFs was used to assess endothelial cell migration and vascular network formation. Pro-angiogenic factor secretion was analyzed using antibody arrays, and functional roles of selected proteins were validated in vitro and in vivo using genetic approaches. Results: Nintedanib inhibited the pro-angiogenic effects of ADC-TAF secretome but paradoxically enhanced angiogenesis in SCC-TAFs, increasing endothelial cell migration in vitro and in vivo. Notably, Nintedanib selectively upregulated CXCL-1 secretion in SCC-TAFs. Silencing CXCL-1 using siRNA in SCC-TAFs abrogated the Nintedanib-induced angiogenesis. Similar findings with other multi-angiokinase inhibitors suggest aberrant CXCL-1 production in SCC-TAFs may drive universal resistance to these therapies. Conclusion: SCC-TAFs are resistant to the anti-angiogenic effects of Nintedanib, which paradoxically promotes angiogenesis via CXCL-1 upregulation. This study provides the first mechanistic insight into SCC resistance to anti-angiogenic therapies and underscores the critical role of TAFs in modulating therapeutic responses. Targeting CXCL-1 or TAF-mediated pathways may inform alternative anti-angiogenic strategies in SCC, potentially in combination with immune checkpoint inhibitors. Citation Format: Natalia Isabel Diaz Valdivia, Paula Duch, Alejandro Bernardo, Marselina Arshakyan, Noemi Reguart, Derek Radisky, Oriol Casanovas, Jordi Alcaraz. Intrinsic resistance mechanism of squamous cell lung carcinomas to the multiangiokinase receptor inhibitor Nintedanib through CXCL-1 upregulation in tumor associated fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5554.

Background: Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) are leading causes of transfusion-related morbidity and mortality. Soluble factors in erythrocyte supernatant may increase risk for these complications. The authors hypothesized that point-of-care allogeneic erythrocyte washing may be an effective intervention to mitigate elevations in soluble factors as well as physiologic responses associated with transfusion-associated respiratory complications in the setting of cardiac surgery. Methods: This is a two-center, nonblinded, randomized clinical trial evaluating point-of-care washed versus standard issue allogeneic erythrocyte transfusions administered during or on the day of cardiac surgery. The primary analysis was performed via modified intention to treat. The primary outcomes assessed were changes in intermediate markers of lung injury as well as cardiopulmonary physiologic responses to erythrocyte transfusion. Secondary outcomes included the duration of intensive care unit and hospital stay, durations of mechanical ventilation and oxygen supplementation, presence of TRALI or TACO, and mortality. Results: Among 154 analyzed patients (81 washed, 73 standard issue), the median age was 66 yr, and 77 (50.0%) were women. The median (interquartile range) number of allogeneic erythrocyte units transfused on the day of surgery was 3.0 (2.0 to 5.0) in the washed erythrocyte group and 3.0 (2.0 to 4.0) in the standard issue group (P = 0.13). No between-group differences were identified in any of the assessed recipient lung injury biomarkers (all P values > adjusted alpha). Durations of intensive care unit stay (median [interquartile range], 3.0 [2.0 to 5.0] vs. 3.0 [2.0 to 4.0] days; P = 0.117) and hospital length of stay (12.0 [9.0 to 17.0] vs. 12.0 [9.0 to 17.0] days; P = 0.801) were similar, as were the number of ventilator-free days at day 28 (27.0 [27.0 to 27.0] vs. 27.0 [26.0 to 27.0]; P = 0.699) and oxygen-free days at day 28 (24.0 [19.0 to 26.0] vs. 24.0 [22.0 to 26.0]; P = 0.400). No significant differences were noted in mortality rate or in incidence rates for TRALI, TACO, and acute kidney injury. Conclusions: Among patients undergoing cardiovascular surgery with high risk of erythrocyte transfusion, point-of-care washing of allogeneic erythrocyte transfusions did not mitigate changes in intermediate markers of lung injury or cardiopulmonary physiologic responses to erythrocyte transfusion and was not associated with improved clinical outcomes.

Abstract Aims To investigate the cost‐effectiveness of early initiation of metformin and usual care for gestational diabetes mellitus (GDM). Methods Economic evaluation from a healthcare perspective, based on the EMERGE randomised controlled trial. In total, 535 women with GDM were randomised to placebo in addition to usual care or metformin in addition to usual care. Economic outcomes included incremental healthcare costs and quality adjusted life years ( QALYs ) and expected cost‐effectiveness at cost‐effectiveness threshold values of €20,000, €45,000 and €100,000 per QALY gained. Uncertainty was explored using parametric, non‐parametric, deterministic and probabilistic methods and heterogeneity using subgroup analysis. Results On average, relative to the placebo arm, the early metformin arm was associated with non‐statistically significant mean increases of €193.07 (95% CI : −€789.88, €1176.01; p = 0.700) and 0.002 QALYs (95% CI : −0.009, 0.013; p = 0.771). In terms of expected cost‐effectiveness at threshold values of €20,000, €45,000 and €100,000 per QALY gained, the probability of the early metformin arm being more cost‐effective was estimated at 0.423, 0.452 and 0.524. Exploratory subgroup analyses provided more favourable but not definitive evidence in favour of the early metformin arm for cohorts with previous GDM and previous caesarean section. Conclusions We do not find definitive evidence that early initiation of metformin in addition to usual care for GDM was more cost‐effective than usual care alone. The clinical and economic evidence may be considered equivocal, but worthy of further examination.

Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy. Diagnosis is clinical, but ~90% of patients have pathogenic variants in SCN1A . ATP6V0C has recently been proposed as a novel candidate gene for epilepsy, with or without developmental delay. Here we describe two adult patients with a clinical diagnosis of DS associated with ATP6V0C variants. Methods Patients with developmental and epileptic encephalopathies were evaluated by physicians who are experts in DS, and their clinical diagnosis was correlated with genetic findings. A subgroup of those patients with DS but without known genetic causes were evaluated through gene panels, whole exome sequencing, and chromosome microarray. Phenotype was determined by pediatric and adult chart reviews, interviews, and physical examinations. Results Of 753 patients with DS, two unrelated individuals with classic features of DS during childhood and adulthood were identified with heterozygous de novo missense variants in ATP6V0C (c.319G > C, p.(Gly107Arg) and c.284C > T, p.(Ala95Val), respectively). Both variants were absent in normal populations and computational prediction algorithms suggested deleterious effects on protein structure and/or function. No disease‐causing variants in other genes previously associated with DS were found. Significance Here we describe two adult patients with Dravet‐like syndrome and pathogenic/likely pathogenic variants in ATP6V0C . We propose that abnormal ATP6V0C function can, at the severe end of the clinical spectrum, be associated with Dravet‐like phenotype. This is relevant, as these patients would not qualify for disease‐modifying antisense nucleotide or gene therapies targeting SCN1A .

This article highlights the important role of speech-language pathologists (SLPs) in palliative care (PC), emphasizing their contribution to supporting people with eating, drinking, and swallowing difficulties during serious illnesses and at the end of life. The recommendations underscore the necessity of interdisciplinary collaboration among SLPs and other PC team members, the importance of patient and caregiver education, and the application of patient-centered, comfort-focused approaches to dysphagia intervention. Drawing on current research and expert insights, this article explores the use of SLP services in PC, as well as the challenges in supporting people with eating and drinking difficulties in advanced stages of illness, embedded with practical tips for clinicians.