Citations

Objective Cognitive impairment is increasingly recognized in patients with cerebral venous congestion (CVC), yet the cognitive tools used are largely adapted from stroke and dementia research. This review examines current literature on cognitive function in CVC, including conditions such as cerebral venous sinus thrombosis (CVST), idiopathic intracranial hypertension (IIH), and dural arteriovenous fistulas (dAVFs). Special emphasis is placed on the limitations of common screening tools like the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). Cognitive dysfunction—primarily affecting executive function, processing speed, and attention—is reported in up to 86% of CVC cases, yet only about 20% of studies use validated cognitive testing tools, most of which may lack sensitivity for CVC-specific deficits. Emerging techniques such as ocular motor testing and physiological markers show promise but require further validation. There is an urgent need for standardized, CVC-specific cognitive assessment protocols that reflect the unique pathophysiology of venous disorders. Future research should prioritize the development of targeted cognitive batteries and integrate objective physiological measures to enhance diagnostic accuracy.

Abstract Front-line pharmaceutical interventions for treating acute graft-versus-host disease (GVHD) are not uniformly effective and have toxic side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with potent in vitro and in vivo immunosuppressive functions. Clinical translation of in vitro–generated MDSCs has been limited because of requirements for multiple, high infusion doses, the relatively low yield from peripheral blood–sourced MDSCs (PB-MDSCs), and inconsistent product quality. To circumvent these obstacles, we developed a methodology to generate MDSCs using human induced pluripotent stem cell (iPSC)–derived CD34+ cells. Compared with PB-MDSCs, iPSC-derived MDSCs (iMDSCs) shared similar morphology, phenotype, and suppressive function. We found that the CD14+ iMDSC subset possessed the highest suppressor function. In previous studies, we reported that MDSCs transferred into mice with GVHD lost suppressor function because of inflammasome activation and immature myeloid cell maturation. In striking contrast to human PB-MDSCs, we show herein that iMDSCs retained 95% of suppressor function in vitro despite exposure to lipopolysaccharide (LPS) plus adenosine triphosphate (ATP), which are stimuli that activate the inflammasome via danger-associated molecular patterns released during early posttransplant conditioning and GVHD-induced injury. In an in vivo xenogenic GVHD model with PB mononuclear cells, iMDSCs significantly increased recipient survival without loss of antileukemia effects. iMDSC RNA sequencing and gene knockdown studies revealed that the maintenance of the purine metabolizing enzyme, phosphoglycerate dehydrogenase, during LPS plus ATP treatment, was linked to iMDSC inflammasome resistance. Taken together, these findings provide a platform for translating in vitro–generated, off-the-shelf iMDSCs into the clinic for suppressing a spectrum of adverse immune responses, including GVHD.

Abstract Background Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.

Abstract Craniopharyngiomas are rare parasellar tumors, and papillary craniopharyngiomas (PCPs) represent 8 to 20% of cases. Interim analysis of retrospective data collected from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). Fourteen U.S.-based academic skull base centers between 2011 and 2023. Patients with PCPs. Demographic, imaging, surgical, and outcome variables. Ninety-nine patients with PCPs were included. The mean age was 51.8 ± 14.7, and 57.6% were male. Most tumors showed mixed cystic/solid components (67.5%), were transinfundibular (50.0%), and were treated with an endoscopic endonasal approach (74.5%), with 51.1% demonstrating gross total resection (GTR). Pituitary stalk was preserved in 51.9%. Permanent arginine vasopressin deficiency was seen in 67.1% and was associated with pituitary stalk sacrifice (p = 0.003). Cerebrospinal fluid leak was the most common nonendocrine postsurgical, 30-day complication (9.1%), reason for return to the operating room (3.1%), and reason for 90-day readmission (8.1%). Most patients (63.9%) received no adjuvant therapy; GTR was associated with decreased radiotherapy use (p = 0.0001). BRAFV600E mutation was detected in 64/69 tumors tested, although only one patient was treated with a BRAF inhibitor. A mean follow-up of 12.3 ± 14.6 months was seen for the group. RAPID consortium enabled the largest real-world clinical information dataset for PCPs. Early findings support that GTR and stalk preservation are important to outcomes. Iterative analysis and discussion of data led to the generation of a framework for future studies to fully leverage the capabilities of multicenter registries.

AbstractDocumentation burden contributes to health professional burnout and negatively impacts health professional well-being and patient care quality. Yet, there is a gap in the literature regarding an effective measure to assess the perceived documentation burden of health professionals in a wide range of care settings over time.We developed and administered a pulse survey to trend, with subsequent administrations, the perceived documentation burden of health professionals in all care settings in the United States over time.A multimethods approach was used which included conducting a scoping review of the literature to identify and then curate a set of potential survey items based on scoping review results. Next, a modified Delphi approach was used with clinical informatics experts for consensus-driven item selection and pulse survey development. Finally, we administered the pulse survey nationally using snowball sampling through professional listservs and networks of organizations.The scoping review helped to identify constructs and items to include on the pulse survey. After four iterations of the modified Delphi approach, consensus was reached on five final items for the pulse survey, labeled “TrendBurden.” The first administration of “TrendBurden” was completed by 1,253 healthcare professionals in April 2024. Most respondents (73.26%) disagreed that the time and effort spent documenting patient care is appropriate, with 77.42% reporting finishing work later or needing to work from home due to excessive documentation tasks. Seventy-four point three-eight percent agreed that the effort or time required to complete documentation tasks impedes patient care, and less than one-third (31.76%) agreed that the EHR is easy to use.The “TrendBurden” Pulse Survey was developed through a scoping review of the literature and expert consensus. The resulting five-question pulse survey was administered nationally and provided insight into current perceptions of documentation burden among healthcare professionals.

ABSTRACT Recent decades have seen a rise in the incidence of tick-borne diseases in the US, along with an increased number of pathogens transmitted by ticks, and geographic expansion of tick populations. A variety of laboratory testing methodologies are available for the diagnosis of tick-borne diseases, including serology, microscopy, and molecular-based methods. The preferred approach varies by the specific disease, locally available test options, and the stage of illness at patient presentation. This mini-review focuses on updates in our understanding of the epidemiology of tick-borne diseases in the US and advances in the field of laboratory diagnostics.

Background: Cell-penetrating peptides cross cell membrane barriers while carrying cargoes in a functional form. Our work identified two novel lung-targeting peptides, S7A and R11A. Here, we present studies on biodistribution, the cell types targeted, and an in vitro proof of application. Methods: Studies were performed in human bronchial epithelial cells (HBECs) with and without various endocytic inhibitors, and coincubation with fluorescently labeled transferrin or endocytic markers. Cyclic R11A (cR11A) was conjugated to siRNA duplexes and anti-viral activity against SARS-CoV-2 was tested. Biodistribution studies were performed by injecting wild-type mice with fluorescently labeled peptides, and various circulation times were allowed for, as well as cross-staining of lung sections or isolated single cells with various cellular markers, followed by fluorescence-activated cell sorting or confocal microscopy. Results: cR11A showed peak uptake in 15 min, with the highest uptake in airway epithelial type II (ATII) cells, followed by p63+ basal cells and ionocytes. Cyclization increased transduction efficiencies ~100-fold. Endocytosis studies showed a decrease in peptide uptake by pre-treatment with Pitstop2 but not Amiloride or Nystatin. Endocytic marker Lamp1 showed colocalization at the earliest time point, with the escape of the peptide from endocytic vesicles later. cR11A conjugated to ant-spike and anti-envelop proteins showed anti-viral effects with an EC90 of 0.6 μM and 1.0 µM, respectively. Conclusions: We have identified a novel peptide, cR11A, that targets ATII, basal cells, and ionocytes, the cyclization of which increased transduction efficiency in vitro and in vivo. The uptake mechanism appears to be via clathrin-mediated endocytosis with escape from endocytic vesicles. cR11A can act as a vector to deliver anti-viral siRNA to epithelial cells.

Abstract Background Pneumocystis jirovecii pneumonia (PCP) is increasingly seen in patients who are non-HIV immunocompromised hosts, yet modern risk factors and outcomes are poorly recognized and defined. Methods A retrospective review was conducted of adult patients who met criteria for proven or probable PCP from 2017 to 2024 across a large academic multicenter health system. The primary outcome was mortality among cohorts, defined by etiology of immunosuppression through univariate and age-adjusted logistic regression. Secondary analyses included trends in annual diagnoses and testing patterns. Results A total of 701 patients met criteria for inclusion, representing one of the largest clinically characterized cohorts of PCP to date. The median age was 65 years (IQR, 54–73) and 62% were male. The most common risk groups were hematologic malignancy (32.2%), solid tumor cancers receiving chemotherapy (22.4%), and autoimmune disease with immunosuppression (17.7%). Annual PCP diagnoses increased at a rate of 15.8% (95% CI, 8.9%–23.2%) in parallel with increased testing. Only 5.4% of patients were receiving prophylaxis at the time of diagnosis. Overall mortality was 20% (95% CI, 17%–23%) and highest in cirrhosis (adjusted odds ratio, 6.24; 95% CI, 2.84–13.69; P < .001). Conclusions PCP in the current era affects a broad range of patients who are immunocompromised, with high associated mortality and low rates of prophylaxis. Patients with solid tumors and those with cirrhosis are at particularly high risk of mortality. These findings highlight the need to reassess and redefine PCP prophylaxis guidelines in specific populations and our understanding of who is at risk.

Context.— Complexity of ordering and transfusing blood is particularly evident in the pediatric population. Simplification, clarification, and standardization of blood orders can decrease complexity and improve patient safety. Objective.— To improve patient safety by optimizing electronic ordering of blood components in pediatrics through a collaborative process improvement initiative. Design.— A multidisciplinary working group, formed as part of a value stream analysis to improve transfusion safety at Children’s Healthcare of Atlanta (Atlanta, Georgia), focused on decreasing variability and providing clarity when ordering, preparing, and transfusing blood using the electronic health record. Through benchmarking with other pediatric institutions and a collaborative design process with multiple local stakeholders, an extensive redesign in the existing orders and order sets occurred. Metrics were collected to determine if a change was an improvement. Results.— Nurse and laboratory informaticists, a pathology informaticist, and a transfusion medicine specialist built the new orders based on the design. The new orders focused on the following changes: standardization, introduction of logic, naming conventions, clarifying definitions, adding calculations, improving transparency of history and laboratory data, removing aliquots, clarifying communication, and implementing additional modules to inform the provider of necessary information about the patient. Metrics included a decrease in the number of orders changed within an hour, decreased calls from the blood bank to the provider to clarify the order, and an absence of overtransfusions and transfusion-related serious safety events for a year following implementation. Conclusions.— This collaborative initiative, using standard process improvement tools, resulted in standardized blood orders improving transfusion safety.

AbstractThe Enhanced EHR-facilitated Cancer Symptom Control (E2C2) Trial is a pragmatic trial testing a collaborative care approach for managing common cancer symptoms. There were challenges in identifying cancer site and metastatic status.This study compares three different approaches to determine cancer site and six strategies for identifying the presence of metastasis using EHR and cancer registry data.The E2C2 cohort included 50,559 patients seen in the medical oncology clinics of a large health system. SPPADE symptoms were assessed with 0 to 10 numeric rating scales (NRS). A multistep process was used to develop three approaches for representing cancer site: the single most prevalent International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) code, the two most prevalent codes, and any diagnostic code. Six approaches for identifying metastatic disease were compared: ICD-10 codes, natural language processing (NLP), cancer registry, medications typically prescribed for incurable disease, treatment plan, and evaluation for phase 1 trials.The approach counting the two most prevalent ICD-10 cancer site diagnoses per patient detected a median of 92% of the cases identified by counting all cancer site diagnoses, whereas the approach counting only the single most prevalent cancer site diagnosis identified a median of 65%. However, agreement among the three approaches was very good (kappa > 0.80) for most cancer sites. ICD and NLP methods could be applied to the entire cohort and had the highest agreement (kappa = 0.53) for identifying metastasis. Cancer registry data was available for less than half of the patients.Identification of cancer site and metastatic disease using EHR data was feasible in this large and diverse cohort of patients with common cancer symptoms. The methods were pragmatic and may be acceptable for covariates, but likely require refinement for key dependent and independent variables.