Citations

BACKGROUND: The rate of stroke in patients with heart failure (HF) and preserved ejection fraction but without atrial fibrillation (AF), is uncertain as is whether it is possible to reliably predict the risk of stroke in these patients. METHODS: We validated a previously developed simple risk model for stroke among patients enrolled in the I-Preserve trial (Irbesartan in Heart Failure With Preserved Systolic Function) and PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction). The risk model consisted of 3 variables: history of previous stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level. RESULTS: Of the 8924 patients included in the pooled trial dataset, 5126 patients did not have AF at baseline. Among patients without AF, 190 (3.7%) experienced a stroke over a median follow-up of 3.6 years (rate 10.5 per 1000 patient-years). The risk for stroke increased with increasing risk score: second tertile hazard ratio, 1.78 (95% CI, 1.17–2.71); third tertile hazard ratio, 3.03 (95% CI, 2.06–4.47), with the first tertile as reference. For patients in the third tertile, the occurrence rate of stroke was 17.7 per 1000 patient-years, similar to that in patients with AF not receiving anticoagulation (20.7 per 1000 patient-years), and those with AF who were receiving anticoagulation (14.5 per 1000 patient-years). Model discrimination was good with a C index of 0.81 (0.68–0.91) and a simple score could be created from the model. CONCLUSIONS: A simple risk model can detect a subset of HF and preserved ejection fraction patients without AF who have a higher risk for stroke. The balance of risk-to-benefit in these individuals may justify the use of prophylactic anticoagulation, but this hypothesis needs to be prospectively evaluated. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT00095238 and NCT01920711.

Abstract Objective To conduct a scoping review of models of care for chronic disease management to identify potentially effective components for management of chronic traumatic brain injury (TBI). Methods Information sources : Systematic searches of three databases (Ovid MEDLINE, Embase, and Cochrane Database of Systematic Reviews) from January 2010 to May 2021. Eligibility criteria : Systematic reviews and meta‐analyses reporting on the effectiveness of the Chronic Care Model (CCM), collaborative/integrated care, and other chronic disease management models. Data : Target diseases, model components used ( n = 11), and six outcomes (disease‐specific, generic health‐related quality of life and functioning, adherence, health knowledge, patient satisfaction, and cost/health care use). Synthesis : Narrative synthesis, including proportion of reviews documenting outcome benefits. Results More than half (55%) of the 186 eligible reviews focused on collaborative/integrated care models, with 25% focusing on CCM and 20% focusing on other chronic disease management models. The most common health conditions were diabetes ( n = 22), depression ( n = 16), heart disease ( n = 12), aging ( n = 11), and kidney disease ( n = 8). Other single medical conditions were the focus of 22 reviews, multiple medical conditions of 59 reviews, and other or mixed mental health/behavioral conditions of 20 reviews. Some type of quality rating for individual studies was conducted in 126 (68%) of the reviews. Of reviews that assessed particular outcomes, 80% reported disease‐specific benefits, and 57% to 72% reported benefits for the other five types of outcomes. Outcomes did not differ by the model category, number or type of components, or target disease. Conclusions Although there is a paucity of evidence for TBI per se, care model components proven effective for other chronic diseases may be adaptable for chronic TBI care.

Abstract The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of VPS35L, VPS26C and VPS29, together with the CCC complex comprising CCDC22, CCDC93, and COMMD proteins, plays a crucial role in this process. The precise mechanisms underlying Retriever assembly and its interaction with CCC have remained elusive. Here, we present the first high-resolution structure of Retriever determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog, Retromer. By combining AlphaFold predictions and biochemical, cellular, and proteomic analyses, we further elucidate the structural organization of the entire Retriever-CCC complex and uncover how cancer-associated mutations disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with Retriever-CCC-mediated endosomal recycling.

Background: Vaccination in patients with multiple sclerosis (MS) treated with immunosuppressive drugs is highly recommended. Regarding COVID-19 vaccination, no specific concern has been raised. Objectives: We aimed to evaluate if COVID-19 vaccination or infection increased the risk of disease activity, either radiological or clinical, with conversion to MS in a cohort of people with a radiologically isolated syndrome (RIS). Methods: This multicentric observational study analyzed patients in the RIS Consortium cohort during the pandemic between January 2020 and December 2022. We compared the occurrence of disease activity in patients according to their vaccination status. The same analysis was conducted by comparing patients’ history of COVID-19 infection. Results: No difference was found concerning clinical conversion to MS in the vaccinated versus unvaccinated group (6.7% vs 8.5%, p > 0.9). The rate of disease activity was not statistically different (13.6% and 7.4%, respectively, p = 0.54). The clinical conversion rate to MS was not significantly different in patients with a documented COVID-19 infection versus non-infected patients. Conclusion: Our study suggests that COVID-19 infection or immunization in RIS individuals does not increase the risk of disease activity. Our results support that COVID-19 vaccination can be safely proposed and repeated for these subjects.

Introduction: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is associated with increased risk of periprocedural complications. Estimating the risk of complications facilitates risk-benefit assessment and procedural planning. Methods: We analyzed the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS-CTO, NCT02061436) and created a risk score for in-hospital all-cause mortality. Logistic regression prediction modeling was used to identify independently associated variables and the model was internally validated with bootstrapping. Results: Of the 10,480 CTO PCI cases performed between 2012-2022 at 40 US and non-US centers, in-hospital mortality occurred in 47 (0.45%). The final prediction model identified 4 independent predictors of mortality: Age ≥65 years, Odds Ratio [OR]: 2.83 (95% confidence interval [CI], 1.30-6.16), 1-point; Left ventricular ejection fraction ≤45%, OR: 2.13 (95% CI, 1.14-3.98), 1-point; Moderate-severe calcification, OR: 2.45 (95% CI, 1.18-5.08), 1-point; and Antegrade dissection re-entry, OR: 2.81 (95% CI, 1.06-7.43), 1-point; or Retrograde strategy, OR: 3.51 (95% CI, 1.67-7.37), 1-point; with a bootstrap corrected c-statistics of 0.71 (95% confidence interval: 0.63-0.81). The calculated risk percentages for mortality based on the PROGRESS-CTO mortality score ranged from 0.05-2.42% for mortality, and 63% of patients in the PROGRESS-CTO cohort had PROGRESS-CTO mortality score of 1 or 2, corresponding to a mortality risk of 0.1-0.5% (Figure 1). Conclusions: The PROGRESS-CTO in-hospital mortality risk score can facilitate risk-benefit assessment and procedural planning in patients undergoing CTO PCI.

Background & Aims: Early-stage HCC can be treated with thermal ablation or stereotactic body radiation therapy (SBRT). We retrospectively compared local progression, mortality, and toxicity among patients with HCC treated with ablation or SBRT in a multicenter, US cohort. Approach & Results: We included adult patients with treatment-naïve HCC lesions without vascular invasion treated with thermal ablation or SBRT per individual physician or institutional preference from January 2012 to December 2018. Outcomes included local progression after a 3-month landmark period assessed at the lesion level and overall survival at the patient level. Inverse probability of treatment weighting was used to account for imbalances in treatment groups. The Cox proportional hazard modeling was used to compare progression and overall survival, and logistic regression was used for toxicity. There were 642 patients with 786 lesions (median size: 2.1 cm) treated with ablation or SBRT. In adjusted analyses, SBRT was associated with a reduced risk of local progression compared to ablation (aHR 0.30, 95% CI: 0.15–0.60). However, SBRT-treated patients had an increased risk of liver dysfunction at 3 months (absolute difference 5.5%, aOR 2.31, 95% CI: 1.13–4.73) and death (aHR 2.04, 95% CI: 1.44–2.88, p < 0.0001). Conclusions: In this multicenter study of patients with HCC, SBRT was associated with a lower risk of local progression compared to thermal ablation but higher all-cause mortality. Survival differences may be attributable to residual confounding, patient selection, or downstream treatments. These retrospective real-world data help guide treatment decisions while demonstrating the need for a prospective clinical trial.

Abstract Metastatic pancreatic cancer patients who previously progressed on nab-paclitaxel/gemcitabine (average of 3 previous lines if treatment) were treated with elraglusib in combination with a rechallenge of this combination. The majority of patients demonstrated a prolonged progression free survival. While this early clinical evidence is highly encouraging, the biological determinants of elraglusib response are unknown. In vitro screens of elraglusib on pancreatic PDX cell lines showed that some tumor cells possess modest intrinsic resistance to elraglusib as measured by LD50 which ranged from 316.9 nM to 1080 nM in a screen of 10 cell lines. To explore this phenomena further, we induced resistance in three cell line models by growing cells in the presence of increasing concentrations of elraglusib. We then sequenced the transcriptome of the parental and resistant lines to identify potential mechanisms of elraglusib resistance. Comparison of RNA sequencing profiles identified upregulation of the Aldo-keto reductase (AKR) family of genes. This upregulation was confirmed by qRT-PCR and by immunoblot demonstrating that AKRs were upregulated at both the transcriptomic and protein level. We further quantified the AKR levels in the remainder of the 10 cell lines and found that many of the more resistant lines had high expression of AKR1C2. However, not all of the resistant lines had high expression which could be because they have a separate mechanism of resistance to elraglusib. A large body of literature has found that AKR genes provide resistance to many other small molecule inhibitors either by direct metabolism or by indirectly relieving oxidative stress. Given these results, we identify aldo-keto reductases as potentially associated with elraglusib resistance, but further investigation is warranted to establish a causal link between AKR and the resistant phenotype. Citation Format: Taylor Weiskittel, Ding Li, Lingling Han, Joseph McDermott, Benedito Caneiro, Hu Li, Daniel Billadeau, Andrew Mazar. Exploring mechanisms of resistance to elraglusib in pancreatic cancer PDX models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3857.