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Optic Nerve Sheath Diameter: Which Axis Should Be Measured?
No full textBackground and purpose: Optic nerve sheath diameter (ONSD) measured by point-of-care ultrasound (POCUS) is a commonly used non-invasive estimate of intracranial pressure (ICP). However, methodological variations limit standardization of this promising technique. Different imaging axes are identified as one such source of ONSD POCUS methodological variation. This study aimed to evaluate the agreement and diagnostic accuracy for elevated ICP between transverse and sagittal ONSD measurements.
Methods: We conducted a post-hoc analysis of 213 intensive care patients from three prior studies. ONSD was measured in both transverse and sagittal planes, externally (ONSDext) and internally (ONSDint) of the dura mater. Agreement was assessed using Lin\u27s concordance correlation coefficient (CCC). Diagnostic accuracy for detecting ICP ≥20 mmHg was evaluated using area under the receiver operator characteristics curve (AUROC) analyses in a subset of 139 patients.
Results: Sagittal ONSD was significantly larger than transverse ONSD (median difference 0.2 mm, p\u3c 0.001). Agreement between transverse and sagittal ONSD was poor (CCC: 0.65 and 0.70 for right and left side ONSDext, and 0.43 and 0.51 for right and left side ONSDint). No significant differences in AUROC were found between transverse, sagittal, or averaged measurements.
Conclusions: Transverse and sagittal ONSD measurements are not interchangeable due to significant differences and poor agreement. Diagnostic accuracy was similar across methods. These findings support continued use of transverse measurement as the standard approach for ONSD POCUS in clinical practice
Pan-Cancer Copy Number Analysis Identifies Optimized Size Thresholds and Co-occurrence Models for Individualized Risk Stratification
No full textChromosome instability leading to aneuploidy and accumulation of copy number gains or losses is a hallmark of cancer. Copy number alteration (CNA) signatures are increasingly used for cancer risk stratification, but size thresholds for defining CNAs across cancers are variable and the biological and clinical implications of CNA size heterogeneity and co-occurrence are incompletely understood. Here we analyze CNA and clinical data from 691 meningiomas and 10,383 tumors from The Cancer Genome Atlas to develop cancer- and chromosome-specific size-dependent CNA and CNA co-occurrence models to predict tumor control and overall survival. Our results shed light on technical considerations for biomarker development and reveal prognostic CNAs with optimized size thresholds and co-occurrence patterns that refine risk stratification across a diversity of cancer types. These data suggest that consideration of CNA size, focality, number, and co-occurrence can be used to identify biomarkers of aggressive tumor behavior that may be useful for individualized risk stratification
Cognitive Reserve Predicts Baseline Tau Burden in the U.S. Pointer Trial Imaging Cohort
No full textIntroduction: Higher cognitive reserve (CR) is associated with reduced dementia risk. We hypothesized that higher CR is associated with less baseline Alzheimer\u27s disease (AD) pathology in the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort.
Methods: A subsample of participants underwent amyloid beta and tau positron emission tomography imaging. Regression analysis was used to model the association between educational attainment (EA) as a CR proxy measure, amyloid positivity, and entorhinal cortex (ERC) and meta-temporal region of interest (meta-ROI) tau standardized uptake value ratio (SUVR).
Results: In 911 participants with complete imaging data, higher CR was significantly associated with lower ERC tau SUVR. CR was not associated with amyloid status or meta-ROI tau.
Discussion: In the U.S. POINTER cohort, higher EA predicted lower tau burden in the ERC. Meta-ROI tau levels may be too low in this cognitively unimpaired sample to reveal associations. CR may have a role in promoting biological resistance to AD pathology.
Highlights: Higher cognitive reserve is associated with a lower dementia risk and better cognitive performance after a diagnosis of Alzheimer\u27s disease. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk trial imaging cohort was cognitively unimpaired at baseline and a subsample received amyloid and tau positron emission tomography scans. Higher educational attainment, a proxy measure of cognitive reserve, was significantly related to tau levels in the entorhinal cortex region of interest
Integrated Analysis of Molecular and Clinical Features in Melanoma Patients with Brain Metastases
No full textMelanoma brain metastases (MBMs) are diagnosed in up to 60% of metastatic melanoma patients. Previous studies have identified clinical factors that correlate with overall survival (OS) after MBM diagnosis. However, molecular and immune features associated with OS are poorly understood. An improved understanding of the molecular and immune correlates of OS could provide insights into MBM patient outcomes and guide therapeutic development. Thus, we analyzed clinical features and outcomes of 74 melanoma patients who underwent surgical resection (via craniotomy) between 1991 and 2015 at our institution with bulk RNA-seq data generated from their MBMs. On univariate analysis, the expression of multiple immune gene signatures was associated with improved OS. The gene expression signatures of several immune cell types positively correlated with OS, except for higher neutrophil gene expression which correlated with shorter OS. Univariate analysis of clinical features identified a low Karnofsky performance score (KPS), elevated serum lactate dehydrogenase (LDH), the presence of extracranial metastases (ECMs), and uncontrolled (versus controlled) ECMs as clinical predictors of shorter survival. Multivariate analyses were performed with significant clinical factors and immune features with no correlated variables in the model. After backward selection algorithm, the multivariable coxPH model identified low KPS, low T cell signature, and low monocytic lineage signature as independent predictors of shorter survival. Comparative analysis of MBMs from patients with MBMs-only showed that these tumors were characterized by decreased oxidative phosphorylation (OXPHOS) and increased immune infiltration signatures compared to MBMs from patients with concurrent ECMs. To further characterize the role of OXPHOS in MBM progression, intra-patient variation in OXPHOS gene expression was studied using bulk RNA-seq data on 24 samples from 10 patients, who had multiple distinct MBMs. The intra-tumor variation in OXPHOS in MBMs was defined at the transcriptomic level using single-cell RNA-seq, single-nuclei RNA-seq, and spatial transcriptomics (ST) technologies. Together these results support the clinical significance of specific molecular and immune features of MBMs and suggest their potential use for developing reliable biomarkers and rational therapeutic combinations to improve patient outcomes
Life-Threatening Bradycardia in Anti-NMDA-Receptor Encephalitis and a Novel Use for Permanent Pacing
No full textBackground: Pediatric anti-NMDA receptor encephalitis (pNMDARE) is an autoantibody-mediated disorder that can cause severe autonomic dysfunction, including symptomatic bradycardia and asystole. Dysautonomia can last for years, making it very challenging to manage.
Objective: To describe outcomes of 5 pNMDARE patients with life-threatening bradycardic and/or asystolic events who were managed with permanent or semi-permanent pacemaker implantation.
Methods: We performed a retrospective chart review of 5 patients from multiple institutions. We included patients with a diagnosis of pNMDARE (confirmed by positive cerebrospinal fluid and/or serum anti-NMDAR antibodies) who had a permanent or semi-permanent pacemaker placed due to symptomatic bradycardia, sinus pauses, and/or asystole. Assessed outcomes included mortality, the presence of additional bradycardic/asystolic events after pacemaker implantation, pacemaker complications (lead/device infection, device malfunction), and the ongoing need for ventricular pacing.
Results: Four patients had permanent pacing systems placed, and one patient had a semi-permanent pacemaker placed. Three patients required continued intermittent ventricular pacing months to years after disease onset. None of the patients had further episodes of symptomatic bradycardia or asystole after pacemaker implantation. One patient, who had a severe, intractable form of pNMDARE, died after discontinuing immunotherapies; she had multiple pacemaker interrogations that demonstrated no sign of pacemaker dysfunction.
Conclusion: Permanent and semi-permanent pacemakers are a safe, effective management strategy for cases of pNMDARE with prolonged courses of severe bradycardia and/or asystole
Global Trends and Forecast of Cardiovascular Diseases, Cancer, and Shared Risk Factors: Insights From the GBD 2021
No full textBackground: Cardiovascular disease (CVD) and cancer share multiple risk factors and are the leading causes of morbidity and death worldwide. This study aims to examine historical and projected trends of the combined CVD-cancer global estimates and their shared risk factors.
Methods: Death and disability-adjusted life years (DALYs) associated with CVDs, cancers, and their risk factors were obtained from the GBD (Global Burden of Disease) 2021 study. Historical estimates from 1990 to 2021 and forecast data from 2025 to 2050 were examined across age groups, regions, sociodemographic index, and sex.
Results: In 2021, CVD-cancer resulted in age-standardized DALY rates of 8009 per 100 000 population (63% contributed by CVD) and age-standardized mortality rates of 352 per 100 000 population (67% by CVD) globally. While age-standardized DALYs of the CVD-cancer burden declined by 30% (33% in CVD and 26% in cancer), crude DALYs increased by 46% from 1990 to 2021. CVD-cancer resulted in higher age-standardized DALY rates in men (9654 per 100 000 population) than women (6556 per 100 000 population). While low-middle sociodemographic index regions had the highest CVD-related age-standardized DALY rates (6744 per 100 000 population), high-middle sociodemographic index regions had the highest cancer-related rates (3388 per 100 000) in 2021. The top risk factors driving CVD-cancer morbidity burden in 2021 were high systolic blood pressure (largely CVD contribution), dietary risks (89% by CVD), and tobacco (60% by CVD), persisting to 2050.
Conclusions: Global improvements in CVD-cancer age-standardized morbidity will be offset by the ever-rising crude CVD-cancer morbidity burden. Preventive efforts should prioritize key shared risk factors of hypertension, dietary risks, and tobacco
Identifying Compounds to Treat Opiate Use Disorder by Leveraging Multi-Omic Data Integration and Multiple Drug Repurposing Databases
No full textGenes influencing opioid use disorder (OUD) biology have been identified via genome-wide association studies (GWAS), gene expression, and network analyses. These discoveries provide opportunities to identifying existing compounds targeting these genes for drug repurposing studies. However, systematically integrating discovery results and identifying relevant available pharmacotherapies for OUD repurposing studies is challenging. To address this, we\u27ve constructed a framework that uses existing results and drug databases to identify candidate pharmacotherapies. For this study, two independent OUD related meta-analyses were used including a GWAS and a differential gene expression (DGE) study of post-mortem human brain. Protein-Protein Interaction (PPI) sub-networks enriched for GWAS risk loci were identified via network analyses. Drug databases Pharos, Open Targets, Therapeutic Target Database (TTD), and DrugBank were queried for clinical status and target selectivity. Cross-omic and drug query results were then integrated to identify candidate compounds. GWAS and DGE analyses revealed 3 and 335 target genes (FDR q \u3c 0.05), respectively, while network analysis detected 70 genes in 22 enriched PPI networks. Four selection strategies were implemented, which yielded between 72 and 676 genes with statistically significant support and 110 to 683 drugs targeting these genes, respectively. After filtering out less specific compounds or those targeting well-established psychiatric-related receptors (OPRM1 and DRD2), between 2 and 329 approved drugs remained across the four strategies. By leveraging multiple lines of biological evidence and resources, we identified many FDA approved drugs that target genes associated with OUD. This approach a) allows high-throughput querying of OUD-related genes, b) detects OUD-related genes and compounds not identified using a single domain or resource, and c) produces a succinct summary of FDA approved compounds eligible for efficient expert review. Identifying larger pools of candidate pharmacotherapies and summarizing the supporting evidence bridges the gap between discovery and drug repurposing studies
Protocol for a Multisite, Observational Clinical Study of the Association Between Skin Colour and Pulse Oximeter Accuracy in Children Undergoing Cardiac Catheterisation (Pach Study)
No full textIntroduction: Prospective, real-world clinical studies of the association between skin color and pulse oximeter (SpO2) accuracy in children are needed to address the limitations of previous research. Such studies are essential for generating evidence for clinicians, regulators and industry. This is the protocol for a multisite study funded by the National Heart, Lung, and Blood Institute (R01HL171313; 1 January 2024-31 December 2028).
Methods and analysis: In this pragmatic, observational study conducted in three large paediatric cardiac catheterisation centres in the USA, children undergoing cardiac catheterisation with directly measured arterial oxygen saturation will be prospectively enrolled. The outcome variable (SpO2 bias) is the difference between contemporaneous paired measurements of pulse oximetry (SpO2) and the standard reference comparator, arterial blood sample oxygen saturation (SaO2), obtained during the catheterisation procedure. The independent variable is an objective measure of skin colour obtained via spectrophotometry. Our primary analysis is a multivariable regression model testing the relationship between skin colour and SpO2 bias, after adjusting for covariates. We will also conduct a moderator analysis to identify factors that may affect the magnitude of the association. The target sample size is 584 participants.
Ethics and dissemination: This study was approved by the University of Pennsylvania Institutional Review Board (#854895) under expedited review. Study risks are minimal. Parental permission, and child assent when applicable, are obtained prior to enrolment. In accordance with the NIH Public Access Policy, publications associated with the study will be made publicly available through PubMed Central. The analytic dataset will be contributed to a repository for future use. In collaboration with a children\u27s hospital-based research family advisory council, interpretation and dissemination of the results for lay, clinical and scientific audiences will be considered
Cervical Cancer Outcomes in Women With HIV in the Age of Antiretroviral Therapy
No full textThis cross-sectional study investigates the outcomes for women living with HIV and cervical cancer in the US after the emergence of antiretroviral therapy
Implementing the NYU Electronic Patient Visit Assessment (ePVA)
No full textBackground: Aggressive treatment with multimodal therapies such as surgery, chemotherapy, and radiation therapy has improved survival in head and neck cancer (HNC) but at a human cost of a substantial symptom burden and impact on quality of life. We developed the NYU Electronic Patient Visit Assessment (ePVA)© for HNC as a digital patient-reported symptom monitoring system that enables early symptom detection and real-time interventions at the point of care. With this study protocol, we aim to test the effectiveness of the ePVA in improving HNC outcomes in real-world settings and to identify implementation strategies optimizing its effectiveness.
Methods: We will conduct a longitudinal mixed-methods hybrid type I study at four National Cancer Institute-designated Comprehensive Cancer Centers serving diverse populations in rural and urban settings (New York University, the University of Kansas Cancer Center, Fox Chase Cancer Center, and Baylor College of Medicine) guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Patient eligibility criteria include having histologically diagnosed HNC and undergoing radiation therapy with or without chemotherapy for curative intent. We will also interview clinicians caring for patients with HNC at the participating institutions regarding facilitators and barriers to implementing the ePVA. The accrual goal is 270 patients. Aim 1 is to determine the effect of the ePVA on HNC symptoms in a two-arm (usual care vs. ePVA + usual care) trial. The study\u27s primary outcomes are patients\u27 self-reported social function, senses of taste and smell, and swallowing, measured by the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-H&N35. For Aim 2, we will interview patients (n = 40) as well as clinicians (n = 30) caring for patients with HNC at the participating institutions regarding facilitators and barriers to implementing the ePVA. In Aim 3, we will integrate Aims 1 and 2 data to identify strategies that optimize the use of the ePVA.
Discussion: The overarching goal of this research is to advance cancer care by identifying implementation standards for effective, widespread use of the ePVA that apply to all patient-reported outcomes in cancer care