The molecular immune modulator adenosine deaminase-1 enhances HIV specific humoral and cellular responses to a native-like HIV envelope trimer DNA vaccine.

There is currently no prophylactic vaccine available for human immunodeficiency virus (HIV). Research efforts have resulted in improved immunogens that mimic the native envelope (Env) glycoprotein structure. Recently, a novel triple tandem trimer (TTT) platform has been used to generate a plasmid encoding Env immunogen (pBG505-TTT) that expresses only as trimers, making it more suitable for nucleic acid vaccines. We have previously demonstrated that adenosine deaminase-1 (ADA-1) is critical to the T follicular helper (TFH) function and improves vaccine immune responses in vivo. In this study, we demonstrate that co-delivery of plasmid-encoded adenosine deaminase 1 (pADA) with pBG505-TTT enhances the magnitude, durability, isotype switching and functionality of HIV-specific antibodies in a dose-sparing manner. Co-delivery of the molecular immune modulator ADA-1 also enhances HIV-specific T cell polyfunctionality, activation, and degranulation as well as memory B cell responses. These data demonstrate that pADA enhances HIV-specific cellular and humoral immunity, making ADA-1 a promising immune modulator for HIV-targeting vaccines.

Using the power of innate immunoprofiling to understand vaccine design, infection, and immunity.

In the field of immunology, a systems biology approach is crucial to understanding the immune response to infection and vaccination considering the complex interplay between genetic, epigenetic, and environmental factors. Significant progress has been made in understanding the innate immune response, including cell players and critical signaling pathways, but many questions remain unanswered, including how the innate immune response dictates host/pathogen responses and responses to vaccines. To complicate things further, it is becoming increasingly clear that the innate immune response is not a linear pathway but is formed from complex networks and interactions. To further our understanding of the crosstalk and complexities, systems-level analyses and expanded experimental technologies are now needed. In this review, we discuss the most recent immunoprofiling techniques and discuss systems approaches to studying the global innate immune landscape which will inform on the development of personalized medicine and innovative vaccine strategies.

Lipid nanoparticles (LNP) induce activation and maturation of antigen presenting cells in young and aged individuals.

Herein, we studied the impact of empty LNP (eLNP), component of mRNA-based vaccine, on anti-viral pathways and immune function of cells from young and aged individuals. eLNP induced maturation of monocyte derived dendritic cells (MDDCs). We further show that eLNP upregulated CD40 and induced cytokine production in multiple DC subsets and monocytes. This coincided with phosphorylation of TANK binding kinase 1 (pTBK1) and interferon response factor 7 (pIRF7). In response to eLNP, healthy older adults (>65 yrs) have decreased CD40 expression, and IFN-γ output compared to young adults (<65 yrs). Additionally, cells from older adults have a dysregulated anti-viral signaling response to eLNP stimulation, measured by the defect in type I IFN production, and phagocytosis. Overall, our data show function of eLNP in eliciting DC maturation and innate immune signaling pathways that is impaired in older adults resulting in lower immune responses to SARS-CoV-2 mRNA-based vaccines.

Imaging-based stratification of adult gliomas prognosticates survival and correlates with the 2021 WHO classification.

BACKGROUND: Because of the lack of global accessibility, delay, and cost-effectiveness of genetic testing, there is a clinical need for an imaging-based stratification of gliomas that can prognosticate survival and correlate with the 2021-WHO classification. METHODS: In this retrospective study, adult primary glioma patients with pre-surgery/pre-treatment MRI brain images having T2, FLAIR, T1, T1 post-contrast, DWI sequences, and survival information were included in TCIA training-dataset (n = 275) and independent validation-dataset (n = 200). A flowchart for imaging-based stratification of adult gliomas(IBGS) was created in consensus by three authors to encompass all adult glioma types. Diagnostic features used were T2-FLAIR mismatch sign, central necrosis with peripheral enhancement, diffusion restriction, and continuous cortex sign. Roman numerals (I, II, and III) denote IBGS types. Two independent teams of three and two radiologists, blinded to genetic, histology, and survival information, manually read MRI into three types based on the flowchart. Overall survival-analysis was done using age-adjusted Cox-regression analysis, which provided both hazard-ratio (HR) and area-under-curve (AUC) for each stratification system(IBGS and 2021-WHO). The sensitivity and specificity of each IBSG type were analyzed with cross-table to identify the corresponding 2021-WHO genotype. RESULTS: Imaging-based stratification was statistically significant in predicting survival in both datasets with good inter-observer agreement (age-adjusted Cox-regression, AUC > 0.5, k > 0.6, p < 0.001). IBGS type-I, type-II, and type-III gliomas had good specificity in identifying IDHmut 1p19q-codel oligodendroglioma (training - 97%, validation - 85%); IDHmut 1p19q non-codel astrocytoma (training - 80%, validation - 85.9%); and IDHwt glioblastoma (training - 76.5%, validation- 87.3%) respectively (p-value < 0.01). CONCLUSIONS: Imaging-based stratification of adult diffuse gliomas predicted patient survival and correlated well with 2021-WHO glioma classification.

MRI features predict tumor grade in isocitrate dehydrogenase (IDH)-mutant astrocytoma and oligodendroglioma.

PURPOSE: Nearly all literature for predicting tumor grade in astrocytoma and oligodendroglioma pre-dates the molecular classification system. We investigated the association between contrast enhancement, ADC, and rCBV with tumor grade separately for IDH-mutant astrocytomas and molecularly-defined oligodendrogliomas. METHODS: For this retrospective study, 44 patients with IDH-mutant astrocytomas (WHO grades II, III, or IV) and 39 patients with oligodendrogliomas (IDH-mutant and 1p/19q codeleted) (WHO grade II or III) were enrolled. Two readers independently assessed preoperative MRI for contrast enhancement, ADC, and rCBV. Inter-reader agreement was calculated, and statistical associations between MRI metrics and WHO grade were determined per reader. RESULTS: For IDH-mutant astrocytomas, both readers found a stepwise positive association between contrast enhancement and WHO grade (Reader A: OR 7.79 [1.97, 30.80], p = 0.003; Reader B: OR 6.62 [1.70, 25.82], p = 0.006); both readers found that ADC was negatively associated with WHO grade (Reader A: OR 0.74 [0.61, 0.90], p = 0.002); Reader B: OR 0.80 [0.66, 0.96], p = 0.017), and both readers found that rCBV was positively associated with WHO grade (Reader A: OR 2.33 [1.35, 4.00], p = 0.002; Reader B: OR 2.13 [1.30, 3.57], p = 0.003). For oligodendrogliomas, both readers found a positive association between contrast enhancement and WHO grade (Reader A: OR 15.33 [2.56, 91.95], p = 0.003; Reader B: OR 20.00 [2.19, 182.45], p = 0.008), but neither reader found an association between ADC or rCBV and WHO grade. CONCLUSIONS: Contrast enhancement predicts WHO grade for IDH-mutant astrocytomas and oligodendrogliomas. ADC and rCBV predict WHO grade for IDH-mutant astrocytomas, but not for oligodendrogliomas.

Collateral status, hyperglycemia, and functional outcome after acute ischemic stroke.

BACKGROUND: Mixed data exist regarding the association between hyperglycemia and functional outcome after acute ischemic stroke when accounting for the impact of leptomeningeal collateral flow. We sought to determine whether collateral status modifies the association between treatment group and functional outcome in a subset of patients with large vessel occlusion enrolled in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial. METHODS: In this post-hoc analysis, we analyzed patients enrolled into the SHINE trial with anterior circulation large vessel occlusion who underwent imaging with CT angiography prior to glucose control treatment group assignment. The primary analysis assessed the degree to which collateral status modified the effect between treatment group and functional outcome as defined by the 90-day modified Rankin Scale score. Logistic regression was used to model the data, with adjustments made for thrombectomy status, age, post-perfusion thrombolysis in cerebral infarction (TICI) score, tissue plasminogen activator (tPA) use, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Five SHINE trial centers contributed data for this analysis. Statistical significance was defined as a p-value < 0.05. RESULTS: Among the 1151 patients in the SHINE trial, 57 with angiographic data were included in this sub-analysis, of whom 19 had poor collaterals and 38 had good collaterals. While collateral status had no effect (p = 0.855) on the association between glucose control treatment group and functional outcome, patients with good collaterals were more likely to have a favorable functional outcome (p = 0.001, OR 5.02; 95% CI 1.37-16.0). CONCLUSIONS: In a post-hoc analysis using a subset of patients with angiographic data enrolled in the SHINE trial, collateral status did not modify the association between glucose control treatment group and functional outcome. However, consistent with prior studies, there was a significant association between good collateral status and favorable outcome in patients with large vessel occlusion stroke. TRIAL REGISTRATION: ClinicalTrials.gov Identifier is NCT01369069. Registration date is June 8, 2011.

Lipid nanoparticles (LNP) induce activation and maturation of antigen presenting cells in young and aged individuals.

Despite the overwhelming success of mRNA-based vaccine in protecting against SARS-CoV-2 infection and reducing disease severity and hospitalization, little is known about the role lipid nanoparticles (LNP) play in initiating immune response. In this report we studied the adjuvantive impact of empty LNP with no mRNA cargo (eLNP) on anti-viral pathways and immune function of cells from young and aged individuals. We found that eLNP induced maturation of monocyte derived dendritic cells by measuring the expression of CD40, CD80, HLA-DR and production of cytokines including IFN-α,IL-6, IFN-γ, IL-12, and IL-21. Flow cytometry analysis of specific dendritic cell subsets showed that eLNP can induce CD40 expression and cytokine production in cDC1, cDC2 and monocytes. Empty LNP (eLNP) effects on dendritic cells and monocytes coincided with induction pIRF7 and pTBK1, which are both important in mitigating innate immune signaling. Interestingly our data show that in response to eLNP stimulus at 6 and 24 hrs, aged individuals have decreased CD40 expression and reduced IFN- γ output compared to young adults. Furthermore, we show that cDC1, cDC2, and CD14 dim CD16 + monocytes from healthy aged individuals have dysregulated anti-viral signaling response to eLNP stimulation as measured by the defect in type I IFN production, phosphorylation of IRF7, TBK-1, and immune function like phagocytosis. These data showed a novel function of eLNP in eliciting DC maturation and innate immune signaling pathways and that some of these functions are impaired in older individuals providing some suggestion of why older individuals (> 65 yrs of age) respond display lower immune responses and adverse events to SARS-CoV-2 mRNA-based vaccines.

Lymph Node Dissection: Principles and Postoperative Imaging.

The management of neck nodes in head and neck cancer is critical, given a markedly increased poor prognosis in patients with nodal metastasis. The surgical management of neck nodes has undergone radical changes secondary to a paradigm shift from curative surgery to nonsurgical organ and function-preserving options, such as radiation therapy. In the neck after treatment, radiologists should be familiar with imaging findings in various types of neck dissections and post-chemoradiation changes, along with signs of residual or recurrent disease. A multidisciplinary approach is essential with well-designed evidence-based surveillance imaging protocols and standardized reporting.

Prospective validation of a rapid CT-based bone mineral density screening method using colored spinal images.

PURPOSE: To prospectively validate a method to accurately and rapidly differentiate normal from abnormal spinal bone mineral density (BMD) using colored abdominal CT images. METHODS: For this prospective observational study, 196 asymptomatic women ≥ 50 years of age presenting for screening mammograms underwent routine nonenhanced CT imaging of the abdomen. The CT images were processed with software designed to generate sagittal colored images with green vertebral trabecular bone indicating normal BMD and red indicating abnormal BMD (low BMD or osteoporosis). Four radiologists evaluated L1/L2 BMD on sagittal images using visual assessment of grayscale images, quantitative measurements of mean vertebral attenuation, and visual assessment of colored images. Mean BMD values at L1/L2 using quantitative CT with a phantom served as the reference standard. The average accuracy and time of interpretation were calculated. Inter-observer agreement was assessed using intraclass correlation coefficient (ICC). RESULTS: Mean attenuation at L1/L2 was highly correlated with mean BMD (r = 0.96/0.91, p < 0.001 for both). The average accuracy and mean time to assess BMD among four readers for differentiating normal from abnormal BMD was 66% and 6.0 s using visual assessment of grayscale images, 88% and 15.2 s using quantitative measurements of mean vertebral attenuation, and 92% and 2.1 s using visual assessment of colored images (p < 0.001 and p < 0.001, respectively). Inter-observer agreement was poor using visual assessment of grayscale images (ICC:0.31), good using quantitative measurements of mean vertebral attenuation (ICC:0.73), and excellent using visual assessment of colored images (ICC:0.90). CONCLUSION: Detection of abnormal BMD using colored abdominal CT images was highly accurate, rapid, and had excellent inter-observer agreement.

Magnetic Resonance Perfusion Changes of Arteriovenous Malformations Treated with Stereotactic Radiosurgery.

BACKGROUND: The latency period from stereotactic radiosurgery (SRS) to obliteration of arteriovenous malformations (AVM) requires continuous imaging surveillance. Magnetic resonance (MR) perfusion is promising for noninvasive monitoring of AVMs after SRS. We studied longitudinal MR perfusion changes of brain AVMs treated with SRS. METHODS: Consecutive patients treated for brain AVMs using SRS who had MR perfusion imaging studies performed before and at least once after SRS were studied. We estimated ipsilateral/contralateral brain hemisphere ratios of MR perfusion indexes, including regional cerebral blood flow (rCBF) and relative cerebral blood volume (rCBV), in the AVM nidus, perinidal region, and remote anterior and posterior brain regions. RESULTS: Eleven patients (6 women; median age, 21 years) underwent SRS (median prescription dose, 18 Gy; range, 12-20 Gy) for brain AVMs (median Spetzler-Martin grade 2 and median volume 4.6 mL). Before the SRS, rCBV and rCBF ratios were significantly higher in the AVM nidus compared with other investigated brain regions (P < 0.001). Median time from SRS to the first and last post-SRS MR perfusion studies was 8 and 35 months, respectively. There was a statically significant decrease of rCBV (P = 0.043) and rCBF (P = 0.036) ratios in the AVM nidus, but not other brain regions, during post-SRS follow-up. CONCLUSIONS: There is a gradual decrease of rCBV and rCBF in the AVM nidus after SRS. MR perfusion imaging is promising for monitoring of hemodynamic changes of AVMs after SRS. Larger studies investigating clinical value of MR perfusion imaging for AVMs after SRS are warranted.

Third-trimester in utero fetal brain diffusion tensor imaging fiber tractography: a prospective longitudinal characterization of normal white matter tract development.

BACKGROUND: White matter is responsible for inter-neuronal connections throughout the brain that are a driving force in cognitive development. Diffusion tensor imaging (DTI) fiber tractography has been used to evaluate white matter development in the fetal brain; however, longitudinal studies of DTI fiber tractography to assess white matter development in the third trimester are lacking. OBJECTIVE: To characterize in utero longitudinal changes in the fetal brain DTI fiber tracts of normal third-trimester fetuses. MATERIALS AND METHODS: For this single-center prospective longitudinal observational pilot study, we recruited 28 pregnant females with normal third-trimester pregnancies who had routine prenatal ultrasound. MRI of the in utero fetal brain was performed with a Siemens 1.5-tesla (T) Espree scanner at 31 weeks, 33 weeks and 36 weeks of gestation, with 14 DTI tractography parameters quantified in 7 brain regions using DTI-studio version 2.4 (Johns Hopkins University, Baltimore, MD; n=98 measurements). We used multilevel mixed models to examine the relationship between longitudinal changes in DTI measurements and between 98 DTI measurements at 31 weeks and 4 routine fetal brain anatomical biometrics (n=392 assessments). RESULTS: We observed statistically significant decreases in radial diffusivity and apparent diffusion coefficient in 13 of 14 brain regions from 31 weeks to 36 weeks of gestation (P<0.001 for all regions except the genu of the corpus callosum). Significant decreases in radial diffusivity from weeks 33 to 36 and weeks 31 to 36 were seen in the corticospinal tracts, centrum semiovale, posterior limb of the internal capsule, and crus cerebri (P<0.001 for all). When considering all possible combinations of DTI fiber tract measurements and the routine morphological fetal brain biometrics, only 6% (24/392) had a significant association (P<0.05), indicating relative independence of the DTI fiber tract measurements from anatomical biometrics. CONCLUSION: In utero longitudinal changes in fetal brain DTI fiber tractography are quantifiable in normal third-trimester fetuses and are largely independent of morphological brain changes.

Alternative to General Anesthesia for a Stat Cesarean Delivery in a Patient with a Large Arteriovenous Malformation Involving the Cervicomedullary Junction in Active Labor.

A 20-year-old G1P0 patient at 38 weeks and 1 day of gestation was admitted for emergency cesarean delivery. Her past medical history was positive for cervicomedullary arteriovenous malformation (AVM) that ruptured three years before. Spontaneous vaginal delivery was contraindicated by neurosurgery. Aiming for cardiovascular stability and immediate reduction of sympathetic activity, a combined spinal epidural was successfully placed. An uneventful cesarean section was performed. The patient was transferred to the intensive care unit neurologically intact and discharged home after 8 days. This report describes an unusual anesthetic management of a patient with a large AVM in active labor.

Atrial Fibrillation, Brain Volumes, and Subclinical Cerebrovascular Disease (from the Atherosclerosis Risk in Communities Neurocognitive Study [ARIC-NCS]).

The aim of the present study was to investigate the association between atrial fibrillation (AF) and total and regional brain volumes among participants in the community-based Atherosclerosis Risk in Communities Neurocognitive study (ARIC-NCS). A total of 1,930 participants (130 with AF) with a mean age of 76.3 ± 5.2, who underwent 3T brain MRI scans in 2011 to 2013 were included. Prevalent AF was ascertained from study ECGs and hospital discharge codes. Brain volumes were measured using FreeSurfer image analysis software. Markers of subclinical cerebrovascular disease included lobar microhemorrhages, subcortical microhemorrhages, cortical infarcts, subcortical infarcts, lacunar infarcts, and volume of white matter hyperintensities. Linear regression models were used to assess the associations between AF status and brain volumes. In adjusted analyses, AF was not associated with markers of subclinical cerebrovascular disease. However, AF was associated with smaller regional brain volumes (including temporal, occipital, and parietal lobes; deep gray matter; Alzheimer disease signature region; and hippocampus [all p <0.05]) after controlling for demographics, cardiovascular risk factors, prevalent cardiovascular disease, and markers of subclinical cerebrovascular disease. Subgroup analysis revealed a significant interaction between AF and total brain volume with respect to age (p = 0.02), with associations between AF and smaller brain volumes being stronger for older individuals. In conclusion, AF was associated with smaller brain volumes, and the association was stronger among older individuals. This finding may be related to the longer exposure period of the older population to AF or the possibility that older people are more susceptible to the effects of AF on brain volume.

Atypical Teratoid Rhabdoid Tumor of the Cauda Equina in a Child: Report of a Very Unusual Case.

Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive malignant primitive neoplasms that commonly occur in children younger than 2 years of age. The prognosis is generally dismal with a median survival time of <1 year. The majority of AT/RT occur in the posterior fossa and less frequently the supratentorium. Primary pediatric spinal AT/RT are exceedingly rare and only 15 cases have been reported to date. Here we report a very unusual case of primary spinal AT/RT extensively involving the spinal cord from T11 down to the cauda equina. In this patient, the tumor was highly aggressive and resulted in extensive dissemination into the nerve roots and paraspinal soft tissue rapidly resulting in the patient's death 1 month after diagnosis. to the best of our knowledge, this degree of involvement of the spine by a primary AT/RT has not been described before.

Construction of a Machine Learning Dataset through Collaboration: The RSNA 2019 Brain CT Hemorrhage Challenge.

This dataset is composed of annotations of the five hemorrhage subtypes (subarachnoid, intraventricular, subdural, epidural, and intraparenchymal hemorrhage) typically encountered at brain CT.

Erratum: Construction of a Machine Learning Dataset through Collaboration: The RSNA 2019 Brain CT Hemorrhage Challenge.

[This corrects the article DOI: 10.1148/ryai.2020190211.].

Opportunistic bone density screening for the abdominal radiologist using colored CT images: a pilot retrospective study.

PURPOSE: The purpose of the study was to develop an accurate and reproducible method for detecting low spinal bone density on abdominal CT images. METHODS: For this IRB-approved HIPAA-compliant single-center retrospective study, nonenhanced CT images of the lower abdomen were obtained in 631 African-American participants. Mean attenuation of L3/L4 was associated with quantitative CT bone density (QCT) in a randomly selected training cohort (N = 511), and receiver operating characteristics analysis was used to identify the optimal mean attenuation threshold for differentiating normal from low bone density. Custom image processing software was used to generate grayscale and colored CT images of the midline spine, with green for normal and red for low bone density. Five radiologists independently assessed bone density at L3/L4 in a validation cohort (N = 120) using various methods: QCT, visual assessment of sagittal grayscale images (Grayscale), quantitative measurement of mean attenuation on a midline sagittal image (Attenuation), and visual assessment of a midline sagittal colored image (Color). Accuracy was calculated using the average QCT bone density as a reference standard. Inter-observer agreement was assessed using intraclass correlation coefficient (ICC). RESULTS: The optimal mean attenuation threshold for differentiating normal from low bone density at L3/L4 was 145 Hounsfield Units. The average accuracy of Grayscale, Attenuation, and Color methods was 58, 87, and 91% (p < 0.001), respectively. Inter-observer agreement was poor for Grayscale (ICC: 0.20; 95% CI 0.12, 0.28) and excellent for both Attenuation (ICC: 0.85; 95% CI 0.73, 0.91) and Color methods (ICC: 0.87; 95% CI 0.83, 0.90). CONCLUSION: Detection of low spinal bone density using colored abdominal CT images was highly accurate and reproducible.

Liposarcoma of the glottis: A report of an unusual diagnosis in an unusual location.

Liposarcoma of the larynx is a rare entity, typically well differentiated with a good prognosis. We present a patient who presented to ENT clinic with a 3-month history of hoarseness. Contrast-enhanced computed tomography of the neck demonstrated a 2.5-cm mass of the true vocal cord, which biopsy demonstrated to be dedifferentiated liposarcoma of the larynx. The patient went on to total laryngectomy with planned adjuvant radiation therapy. The presentation and imaging findings of laryngeal liposarcoma are nonspecific, but this neoplasm should be considered in the differential of masses in the head and neck.

Lethal disseminated dysembryoplastic neuroepithelial tumor following West Nile virus: Report of a very unusual combination.

Dysembryoplastic neuroepithelial tumors (DNETs) are typically benign World Health Organization (WHO) grade I tumors of the cortical or deep gray matter with a favorable prognosis. We encountered a patient with DNET who has been evaluated and treated for West Nile encephalitis 7 months before presentation. Over the course of 2 years, the patient developed diffuse leptomeningeal carcinomatosis. As the disease burden increased, the patient eventually became quadriparetic. The patient elected for hospice care and expired shortly thereafter. Autopsy revealed DNET (WHO grade I) with extensive involvement of the cervical, thoracic, and lumbar spinal cord, bilateral cerebellar hemispheres, brainstem, the cortex of the right frontal and temporal lobes, and meningeal carcinomatosis of the brain and spinal cord. Mortality from DNET is rare, and as per our extensive literature search, there has been only 1 case reported of death attributed to seizures from this diagnosis. To the best of our knowledge, this is the only case of disseminated DNET with meningeal infiltration or carcinomatosis resulting in mortality.