Citations

Background Aneurysm treatments are crucial to minimize the rupture risk. The underlying molecular processes mediating cellular remodeling, endothelialization, and aneurysm healing following endovascular treatment are poorly understood. The current study aims to explore circulating miRNA as a treatment and outcome-associated biomarkers in patients undergoing endovascular treatment. Methods Patients undergoing endovascular interventions for unruptured intracranial aneurysms, using either flow diverter placement or coil embolization, were enrolled. Blood samples were collected before the intervention and during a follow-up period between 6 and 18 months. Total mRNA/miRNA was isolated from plasma, followed by RNA-seq analysis. Gene Ontology analysis was used to identify pathways linked to altered miRNA expression. Results Twenty-three patients participated, with 13 (56.5%) undergoing flow diversion and 10 (43.5%) coil embolization. The median follow-up sample collection time was 10.70 months (SEM ± 1.32). No significant differences in angiographic occlusion were noted between intervention groups. Differentially expressed miRNAs were not identified between groups at baseline. However, at follow-up, 39 miRNAs were upregulated and 41 were downregulated, independent of intervention. Notably, three miRNAs (miR-4746-5p, miR-4685-3p, and miR-490-3p) were downregulated in the flow diversion group compared to the coil embolization group. Bioinformatics analysis revealed associations with upregulated fluid shear stress, p53, adherens junction pathways, along with downregulated apoptosis pathways. Conclusions This study suggests that fluid shear stress and apoptosis may influence aneurysm healing or thromboembolic events in flow diverter-treated patients. Further research is warranted to elucidate the functional significance of these findings in treatment outcomes, providing valuable insights for improved patient care in intracranial aneurysm management.

SummaryTo assess the relevance of co‐occurring somatic mutations in TP53‐mutated myeloid neoplasms with ≥10% blasts, we pooled 325 individuals from 10 centres. We focused on comparing three published somatic co‐alteration signatures comprising (1) nine MDS‐related genes (‘ICC‐MDSR’), (2) ICC‐MDSR + additional secondary mutations‐related genes (‘Tazi signature’) and (3) EPI6 (comprising six genes). Outcomes examined were 24‐month overall survival (OS24) and front‐line complete response (CR1). The median age was 69 years with 77% receiving front‐line hypomethylating agents (HMA). All three signatures ICC‐MDSR (p = 0.009), Tazi signature (p = 0.001) and EPI6 (p = 0.025) predicted inferior CR1. In the low‐intensity (HMA) subgroup, only Tazi signature (p = 0.026) predicted inferior CR1. In OS24 analysis of the HMA‐treated subgroup (N = 200), only Tazi signature was adverse (hazard ratio, HR = 1.6 [1.1–2.2]; p = 0.011). However, a forward stepwise multivariable age‐adjusted Cox model including all three signatures picked EPI6 as the sole significant adverse predictor in the entire cohort (p = 0.0001) as well as within the HMA‐treated subgroup (p = 0.0071). These data confirm the value of testing co‐occurring somatic alterations even within a high‐grade TP53‐mutated myeloid neoplasm cohort.

Background African Americans have a higher prevalence of cardiovascular risk factors, leading to higher cardiovascular disease mortality than White adults. Our culturally tailored mobile health (mHealth) lifestyle intervention ( FAITH! App) has previously demonstrated efficacy in promoting ideal cardiovascular health in African Americans. Methods We conducted a secondary analysis from a cluster randomized controlled trial among African-Americans from 16 churches in Minnesota that compared the FAITH! App to a delayed intervention control group. A subgroup of participants with ≥ 1 diagnosis of overweight/obesity, hyperlipidemia, hypertension, or diabetes was examined. The primary outcome was a change in LS7 score—a measure of cardiovascular health ranging from poor to ideal (range 0–14 points)—at 6-months post-intervention. Results The analysis included 49 participants (intervention group: n = 20; mean age 58.8 years, 75% female; control group: n = 29, mean age 52.5 years, 76% female) with no significant baseline differences in cardiovascular risk factors. Compared to the control group, the intervention group showed a greater increase in LS7 score across all cardiovascular risk factors at 6-months post-intervention, with statistically significant differences among those with overweight/obesity (intervention effect 1.77, p < 0.0001) and 2+ or 3+ cardiovascular risk factors (1.00, p = 0.03; 1.09, p = 0.04). The intervention group demonstrated a higher increase in the percentage of participants with intermediate or ideal LS7 scores than the control group, although these differences were not statistically significant. Conclusions Our culturally tailored mHealth lifestyle intervention was associated with significant increases in LS7 scores among African Americans with preexisting cardiovascular risk factors, suggesting its efficacy in improving cardiovascular health among this population.

BACKGROUND Snapping triceps is a dynamic condition in which a portion of the medial head of the triceps dislocates over the medial epicondyle during flexion or extension. Pushed by the triceps, the ulnar nerve typically also dislocates over the medial epicondyle, causing neuropathy. Posttraumatic cubitus varus deformities resulting from pediatric supracondylar fractures have been associated with snapping triceps. This is the first case of snapping triceps associated with cubitus varus due to distal humeral malunion, which occurred in an adult. OBSERVATIONS A 23-year-old man sustained a left distal humeral fracture from arm wrestling, which was treated nonoperatively, healing in a varus malunion. Within several months, he developed ulnar neuropathy and snapping at the medial elbow, which was diagnosed as a dislocating ulnar nerve and was treated with ulnar nerve transposition. He presented 8 years later with continued ulnar neuritis symptoms and snapping and was found to have snapping medial triceps. He chose nonoperative treatment. LESSONS Snapping triceps, presenting as snapping at the elbow with ulnar nerve symptoms, can be incorrectly diagnosed as isolated ulnar nerve dislocation. Unrecognized snapping triceps leads to persistent symptoms after ulnar nerve transposition. The patient in this case demonstrated that an altered triceps line of pull can cause snapping triceps regardless of how the cubitus varus originated. https://thejns.org/doi/10.3171/CASE24596

Background MEDI5395 is a recombinant attenuated Newcastle disease virus engineered to express a human granulocyte-macrophage colony-stimulating factor transgene. Preclinically, MEDI5395 demonstrated broad oncolytic activity, augmented by concomitant programmed cell death-1/programmed cell death ligand-1 (PD-L1) axis blockade. Durvalumab is an anti-PD-L1 immune checkpoint inhibitor approved for the treatment of various solid tumors. We describe the results of the first-in-human study combining intravenous MEDI5395 with durvalumab in patients with advanced solid tumors. Methods This phase I, open-label, multicenter, dose-escalation, dose-expansion study recruited adult patients with advanced solid tumors, who had relapsed or were refractory or intolerant to ≥1 prior line of standard treatment. MEDI5395 was administered intravenously as six doses over 15–18 days. The dose-escalation phase assessed four-dose levels (108, 109, 1010, 1011 focus forming units (FFU)) of MEDI5395, with sequential or delayed durvalumab. Durvalumab 1500 mg was administered intravenously every 4 weeks up to 2 years. The dose-expansion phase was not initiated. The primary objectives were to evaluate safety and tolerability, dose-limiting toxicities (DLTs) and the dose and schedule of MEDI5395 plus durvalumab administration. Secondary objectives included the assessment of the efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI5395. Results 39 patients were treated with MEDI5395; 36 patients also received durvalumab. All 39 patients experienced ≥1 treatment-emergent adverse event (TEAE), most commonly fatigue (61.5%), nausea (53.8%) and chills (51.3%). Grade 3–4 TEAEs occurred in 27 (69.2%) patients; these were deemed MEDI5395-related in 12 (30.8%) patients. Two patients experienced a DLT, and the maximum tolerated dose of MEDI5395 with sequential and delayed durvalumab at study termination was 1011 and 1010 FFU, respectively. Four patients (10.3%) achieved a partial response (PR). Patients with PR or stable disease tended to have higher baseline PD-L1 and CD8+ levels in their tumor tissue. A tendency to dose-dependent pharmacokinetics of the viral genome was observed in whole blood and a tendency to dose-dependent viral shedding was observed in saliva and urine. Neutralizing antibodies were observed in all patients but did not appear to impact efficacy negatively. Conclusion This study demonstrates the feasibility, safety and preliminary efficacy of MEDI5395 with durvalumab in patients with advanced solid tumors. Trial registration number NCT03889275

Abstract Despite progress in screening and treatment, lung cancer remains the leading cause of cancer- related deaths worldwide. An overarching issue is the complexity and heterogeneous nature of the tumor microenvironment and eventual tumor spread. While aging is a key determinant, the relationship between aging and cancer is multi-faceted and extends beyond the accumulation of mutations. Therefore, a much-needed framework integrating the mechanistic principles that change with aging to drive neoplastic transformation beyond genetics will help us uncover predictive biomarkers that inform treatment decision-making and how we may use them to prevent, postpone, suppress tumor growth, and limit spread. Here, we investigate the role of age-related senescent cell accumulation in lung tumorigenesis and propose a potential strategy to delay tumor progression and spread by selectively targeting tumor-promoting senescent cells that arise with increasing age to sustain protective antitumor immunity. Citation Format: Luis Prieto. Effects of senescence on the lung tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A014.

Abstract Purpose Pharmacogenomics is the study of how individual responses to medication are influenced by genetics. As medication experts, pharmacists are uniquely suited to practicing this application of precision medicine. Fundamental operational aspects of developing a pharmacy clinical pharmacogenomics practice are described, and the specific experience of a multisite health system in developing a pharmacogenomics service is discussed. Summary Considerations for the development of a clinical pharmacy–driven pharmacogenomics service include understanding testing selection, targeting the appropriate patient population, exploration of reimbursement, design of the practice, and education of the pharmacogenomics workforce. Testing can be preemptive or reactive, can occur in house or as a send-out service, and can be panel based or specific to a single gene. Pharmacogenomics is applicable to many medicine specialties, making deployment of services to strategic groups essential. Reimbursement for pharmacogenomics is variable and may pose a barrier to implementation. The demand for pharmacogenomics education for pharmacy students and as a formal postgraduate career path is growing. Pharmacogenomics service planning and implementation details for a multisite health system are described. Conclusion The practice of pharmacogenomics presents a remarkable opportunity for clinical pharmacists and health systems to improve patient care outcomes and experiences.

In this case series study, pulmonary artery systolic, diastolic, and mean pressures of 2 participants with obesity and heart failure with preserved ejection fraction were measured at zero gravity during parabolic flight to assess the effect of external constraint on left ventricular filling pressures.

ABSTRACTBackgroundAdenovirus (ADV) infection can lead to significant morbidity and mortality in immunocompromised patients, particularly in those with hematopoietic stem cells or solid organ transplants. The incidence of ADV infection in kidney transplant (KT) is not well‐defined as ADV is often asymptomatic and not routinely checked.MethodsThis retrospective case‐series study included KT and simultaneous pancreas‐KT (SPKT) recipients from January 1, 2008, to January 31, 2024, across three Mayo Clinic sites (Arizona, Florida, and Minnesota) with symptomatic adenovirus polymerase chain reaction cases. The primary outcomes were allograft function at various intervals post‐ADV infection, allograft, and patient survival.ResultsWe report one of the largest multi‐site case series regarding outcomes of ADV in KT with 17 patients. The median time to ADV infection was 30 weeks (5–74). Five patients (29%) developed disseminated infection. Nine patients (53%) of the entire cohort experienced graft loss within a median of 35 (4–168) weeks, with four (44%) of graft loss attributed to ADV. Nine patients (53%) developed rejections post‐ADV infection with a median of 4 (2–8) weeks after resolution. One patient died from acute hypoxic respiratory failure from ADV infection.ConclusionADV should be considered in KT/SPKT patients with renal dysfunction, hematuria, and with or without fever. Despite the low mortality rate, there is a significant risk of graft loss and rejection after ADV infection. It is crucial to screen for ADV and develop intervention strategies for treatment. Further multicenter studies are needed to better define, stage, and manage ADV infection. image

The neuromotor control of the diaphragm muscle (DIAm) in response to hypercapnia is not well understood. We show that both the number of motor units recruited and their discharge rates increase with hypercapnia, consistent with increased respiratory drive during hypercapnia. Potentially in response to this increased drive, the greatest effect of hypercapnia is on during the postinspiratory (descending) ramp of DIAm EMG activity, which shortens to facilitate higher respiratory rates.