Feasibility of aortic aneurysm sac embolization using a novel shape memory polymer embolic device.

BACKGROUND: We investigated the feasibility of aneurysm sac embolization using a novel self-expanding porous shape memory polymer (SMP) device during endovascular aortic abdominal or thoracic aneurysm repair (EVAR). METHODS: Retrospective analysis of consecutive patients treated at 2 centers in Germany. Patients were treated from January 2019 to July 2021 with follow-up at 7 days and 3, 6, and 12 months. Aneurysm sacs were implanted with SMP devices immediately following endograft placement during the same procedure. Primary endpoint was technically successful SMP-device deployment into the aneurysm sac outside the endograft. Secondary endpoints were changes in aneurysm volume and associated complications (e.g., endoleaks). RESULTS: We included 18 patients (16 males), aged 72 ± 9 years, achieving 100% technical success. Mean preprocedure aortic aneurysm sac volume was 195 ± 117 mL with a perfused aneurysm volume of 97 ± 60 mL. A mean of 24 ± 12 SMP devices per patient were used (range 5-45, corresponding to 6.25-56.25 mL expanded embolic material volume). All evaluable patients exhibited sac regression except 2 patients yet to reach 3-month follow-up. At mean 11 ± 7 months (range 3-24), change in aneurysm volume from baseline was -30 ± 21 mL (p < 0.001). In 8 patients, aneurysm regression was observed despite type 2 endoleaks in 6 and type 1A endoleaks in 2, none of them requiring further intervention to date. No morbidity or mortality related to this treatment occurred. CONCLUSIONS: SMP devices for aortic aneurysm sac embolization during endovascular repair appear feasible and safe in this small case series. Prospective studies are needed. KEY POINTS: • Shape memory polymer is a novel, self-expanding, porous, and radiolucent embolic device material. • Aortic aneurysm sacs were treated with polymer devices immediately following endograft placement. • Aortic aneurysm sac regression was observed in all patients with over 3-month follow-up. • Aortic aneurysm sac regression was observed even in the presence of endoleaks.

Management of pediatric appendicitis during the COVID-19 pandemic: A nationwide multicenter cohort study.

BACKGROUND: The COVID-19 pandemic has impacted timely access to care for children, including patients with appendicitis. This study aimed to evaluate the effect of the COVID-19 pandemic on management of appendicitis and patient outcomes. METHODS: A multicenter retrospective study was performed including 19 children's hospitals from April 2019-October 2020 of children (age≤18 years) diagnosed with appendicitis. Groups were defined by each hospital's city/state stay-at-home orders (SAHO), designating patients as Pre-COVID (Pre-SAHO) or COVID (Post-SAHO). Demographic, treatment, and outcome data were obtained, and univariate and multivariable analysis was performed. RESULTS: Of 6,014 patients, 2,413 (40.1%) presented during the COVID-19 pandemic. More patients were managed non-operatively during the COVID-19 pandemic compared to before the pandemic (147 (6.1%) vs 144 (4.0%), p < 0.001). Despite this change, there was no difference in the proportion of complicated appendicitis between groups (1,247 (34.6%) vs 849 (35.2%), p = 0.12). COVID era non-operative patients received fewer additional procedures, including interventional radiology (IR) drain placements, compared to pre-COVID non-operative patients (29 (19.7%) vs 69 (47.9%), p < 0.001). On adjusted analysis, factors associated with increased odds of receiving non-operative management included: increasing duration of symptoms (OR=1.01, 95% CI: 1.01-1.012), African American race (OR=2.4, 95% CI: 1.3-4.6), and testing positive for COVID-19 (OR=10.8, 95% CI: 5.4-21.6). CONCLUSION: Non-operative management of appendicitis increased during the COVID-19 pandemic. Additionally, fewer COVID era cases required IR procedures. These changes in the management of pediatric appendicitis during the COVID pandemic demonstrates the potential for future utilization of non-operative management.

Relative Source Power: A novel method for localizing epileptiform EEG discharges.

OBJECTIVE: To validate relative source power (RSP) imaging of extratemporal interictal epileptiform discharges (IEDs). METHODS: The accuracy of RSP was validated in a cohort of patients with extratemporal focal epilepsy and a confined epileptogenic lesion (<19 cm3) using distance to the lesion, concordance with resected area and postoperative outcome. Performance was compared with three conventional methods: voltage maps, equivalent current dipole and a distributed source model. RESULTS: Thirty-three of 41 consecutive patients (80%) had IED averages suitable for analysis. While the peak negativity in voltage maps localized above the epileptogenic lesion only in 18 cases, RSP-maps matched in 29 cases (88%, p < 0.0026). Source localization showed a median distance of 9.8 mm from the lesion. Source-regions with 20 mm radius included 98% of all source-to-lesion distances. In the 21 surgical cases, outcome showed a sensitivity of 82.35% and specificity of 50% without significant differences between the three source imaging methods. CONCLUSIONS: RSP-maps provide a rapid, intuitive and more accurate source estimation than voltage maps. At sublobar level, RSP localizes with an accuracy similar to conventional methods and results of previous studies. SIGNIFICANCE: The definition of a source region with 20 mm radius helps in guiding further exploration in extratemporal focal epilepsy.

Taking the EEG Back Into the Brain: The Power of Multiple Discrete Sources.

Background: In contrast to many neuroimaging modalities, clinical interpretation of EEG does not take advantage of post-processing and digital signal analysis. In most centers, EEG is still interpreted at sensor level, exactly as half a century ago. A major task in clinical EEG interpretation is the identification of interictal epileptiform discharges (IEDs). However, due to the overlap of background activity, IEDs can be hard to detect in the scalp EEG. Since traditional montages, like bipolar and average reference, are linear transformations of the recorded channels, the question is whether we can provide linear transformations of the digital EEG to take it back into the brain, at least on a macroscopic level. The goal is to improve visibility of epileptiform activities and to separate out most of the overlap. Methods: Multiple discrete sources provide a stable linear inverse to transform the EEG into source space with little cross-talk between source regions. The model can be based on a few dipoles or regional sources, adapted to the individual EEG and MRI data, or on selected standard sources evenly distributed throughout the brain, e.g. below the 25 EEG standard electrodes. Results: Auditory and somatosensory evoked potentials serve as teaching examples to show how various source spaces can reveal the underlying source components including their loss or alteration due to lesions. Source spaces were able to reveal the propagation of source activities in frontal IEDs and the sequential activation of the major nodes of the underlying epileptic network in myoclonic epilepsy. The power of multiple discrete sources in separating the activities of different brain regions was also evident in the ongoing EEG of cases with frontal cortical dysplasia and bitemporal lobe epilepsy. The new source space 25 made IEDs more clearly visible over the EEG background signals. The more focal nature of source vs. scalp space was quantitatively confirmed using a new measurement of focality. Conclusion: Multiple discrete sources have the power to transform the EEG back into the brain by defining new EEG traces in source space. Using standard source space 25, these can provide for improved clinical interpretation of EEG.

Preliminary outcome of Nellix-in-Nellix extensions in patients treated with failed endovascular aneurysm sealing.

BACKGROUND: The 1-year results of the use of the Nellix (Endologix Inc, Irvine, Calif) endovascular aneurysm sealing (EVAS) device were initially promising. However, midterm complications including migration and aneurysm growth occurred more frequently than expected, which provided an incentive to refine the instructions for use. Strategies for the management of complications arising after endovascular aneurysm repair are often not applicable for EVAS, given the unique configuration of the Nellix device, and new techniques are needed. This study analyzes the clinical outcomes of both elective and emergency deployment of a new Nellix device within a primarily placed device, for failure of EVAS, which we refer to as a Nellix-in-Nellix application (NINA). METHODS: This is a global, retrospective, observational cohort study focusing on the early outcome of NINA for failed EVAS, including data from 11 European institutions and 1 hospital in New Zealand. RESULTS: A total of 41 patients were identified who underwent a NINA procedure. Of these, 32 (78%) were placed electively and 9 (22%) were placed on an emergency basis. Seven patients were initially treated with chimney EVAS (n = 5 in the elective NINA group and n = 2 in the emergency NINA group). The average time between the primary EVAS procedure and NINA was 573 days (interquartile range, [IQR] 397-1078 days) and 478 days (IQR, 120-806) for the elective and emergency groups, respectively. The indication for elective NINA was endoleak with migration (50%), endoleak without migration (25%), migration without endoleak (16%), and other (9%). Chimney grafts were used in 21 of 32 patients in the elective group and 3 of 9 patients in the emergency group. Technical success was achieved in 94% of patients in the elective group and 100% of patients in the emergency group. At latest follow-up (median, 104 days; IQR, 49-328 days), there were three aneurysm-related deaths (9%), no ruptures, and five device-related reinterventions (16%) within the elective group. In the emergency group (median follow-up, 23 days; IQR, 7-61 days), there were four aneurysm-related deaths and three aneurysm-related reinterventions. CONCLUSIONS: In conclusion, a NINA can be used to treat late failures of EVAS with an acceptable technical success rate and can be used when more established treatment options are unfeasible or contraindicated. The durability of this technique needs to be further reviewed.

The miR-96 and RARγ signaling axis governs androgen signaling and prostate cancer progression.

Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RARγ) are commonly reduced in prostate cancer (PCa). Therefore, we sought to establish the cellular and gene regulatory consequences of reduced RARγ expression, and determine RARγ regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RARγ levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RARγ cistrome, which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RARγ to regulate androgen signaling, RARγ knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RARγ downregulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RARγ expression and function. Capture of the miR-96 targetome by biotin-miR-96 identified that RARγ and a number of RARγ interacting co-factors including TACC1 were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels of RARG and TACC1 and upper quartile miR-96, compared to the reverse, identified a gene network including several RARγ target genes (e.g., SOX15) that significantly associated with worse disease-free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p = 0.015). In summary, miR-96 targets a RARγ network to govern AR signaling, PCa progression and disease outcome.

Integration of VDR genome wide binding and GWAS genetic variation data reveals co-occurrence of VDR and NF-κB binding that is linked to immune phenotypes.

BACKGROUND: The nuclear hormone receptor superfamily acts as a genomic sensor of diverse signals. Their actions are often intertwined with other transcription factors. Nuclear hormone receptors are targets for many therapeutic drugs, and include the vitamin D receptor (VDR). VDR signaling is pleotropic, being implicated in calcaemic function, antibacterial actions, growth control, immunomodulation and anti-cancer actions. Specifically, we hypothesized that the biologically significant relationships between the VDR transcriptome and phenotype-associated biology could be discovered by integrating the known VDR transcription factor binding sites and all published trait- and disease-associated SNPs. By integrating VDR genome-wide binding data (ChIP-seq) with the National Human Genome Research Institute (NHGRI) GWAS catalog of SNPs we would see where and which target gene interactions and pathways are impacted by inherited genetic variation in VDR binding sites, indicating which of VDR's multiple functions are most biologically significant. RESULTS: To examine how genetic variation impacts VDR function we overlapped 23,409 VDR genomic binding peaks from six VDR ChIP-seq datasets with 191,482 SNPs, derived from GWAS-significant SNPs (Lead SNPs) and their correlated variants (r 2 > 0.8) from HapMap3 and the 1000 genomes project. In total, 574 SNPs (71 Lead and 503 SNPs in linkage disequilibrium with Lead SNPs) were present at VDR binding loci and associated with 211 phenotypes. For each phenotype a hypergeometric test was used to determine if SNPs were enriched at VDR binding sites. Bonferroni correction for multiple testing across the 211 phenotypes yielded 42 SNPs that were either disease- or phenotype-associated with seven predominately immune related including self-reported allergy; esophageal cancer was the only cancer phenotype. Motif analyses revealed that only two of these 42 SNPs reside within a canonical VDR binding site (DR3 motif), and that 1/3 of the 42 SNPs significantly impacted binding and gene regulation by other transcription factors, including NF-κB. This suggests a plausible link for the potential cross-talk between VDR and NF-κB. CONCLUSIONS: These analyses showed that VDR peaks are enriched for SNPs associated with immune phenotypes suggesting that VDR immunomodulatory functions are amongst its most important actions. The enrichment of genetic variation in non-DR3 motifs suggests a significant role for the VDR to bind in multimeric complexes containing other transcription factors that are the primary DNA binding component. Our work provides a framework for the combination of ChIP-seq and GWAS findings to provide insight into the underlying phenotype-associated biology of a given transcription factor.

Dumping Syndrome: A Review of the Current Concepts of Pathophysiology, Diagnosis, and Treatment.

Gastric surgery has long been known to be a cause of dumping syndrome (DS). However, the increasing incidence of gastric bypass surgery, as well as reports of DS unrelated to previous gastric surgeries, has increased the importance of understanding DS in recent years. DS is due to the gastrointestinal response to voluminous and hyperosmolar chyme that is rapidly expelled from the stomach into the small intestine. This response involves neural and hormonal mechanisms. This review encompasses the symptoms, diagnosis, and treatment approaches of DS and also focuses on the current research status of the pathophysiology of DS.

Integrative genomic analysis in K562 chronic myelogenous leukemia cells reveals that proximal NCOR1 binding positively regulates genes that govern erythroid differentiation and Imatinib sensitivity.

To define the functions of NCOR1 we developed an integrative analysis that combined ENCODE and NCI-60 data, followed by in vitro validation. NCOR1 and H3K9me3 ChIP-Seq, FAIRE-seq and DNA CpG methylation interactions were related to gene expression using bootstrapping approaches. Most NCOR1 combinations (24/44) were associated with significantly elevated level expression of protein coding genes and only very few combinations related to gene repression. DAVID's biological process annotation revealed that elevated gene expression was uniquely associated with acetylation and ETS binding. A matrix of gene and drug interactions built on NCI-60 data identified that Imatinib significantly targeted the NCOR1 governed transcriptome. Stable knockdown of NCOR1 in K562 cells slowed growth and significantly repressed genes associated with NCOR1 cistrome, again, with the GO terms acetylation and ETS binding, and significantly dampened sensitivity to Imatinib-induced erythroid differentiation. Mining public microarray data revealed that NCOR1-targeted genes were significantly enriched in Imatinib response gene signatures in cell lines and chronic myelogenous leukemia (CML) patients. These approaches integrated cistrome, transcriptome and drug sensitivity relationships to reveal that NCOR1 function is surprisingly most associated with elevated gene expression, and that these targets, both in CML cell lines and patients, associate with sensitivity to Imatinib.