OmicNavigator: open-source software for the exploration, visualization, and archival of omic studies.

BACKGROUND: The results of high-throughput biology ('omic') experiments provide insight into biological mechanisms but can be challenging to explore, archive and share. The scale of these challenges continues to grow as omic research volume expands and multiple analytical technologies, bioinformatic pipelines, and visualization preferences have emerged. Multiple software applications exist that support omic study exploration and/or archival. However, an opportunity remains for open-source software that can archive and present the results of omic analyses with broad accommodation of study-specific analytical approaches and visualizations with useful exploration features. RESULTS: We present OmicNavigator, an R package for the archival, visualization and interactive exploration of omic studies. OmicNavigator enables bioinformaticians to create web applications that interactively display their custom visualizations and analysis results linked with app-derived analytical tools, graphics, and tables. Studies created with OmicNavigator can be viewed within an interactive R session or hosted on a server for shared access. CONCLUSIONS: OmicNavigator can be found at https://github.com/abbvie-external/OmicNavigator.

Genomic Characterization of Prostatic Basal Cell Carcinoma.

Basal cell carcinoma (BCC) of the prostate is a rare tumor. Compared with the more common acinar adenocarcinoma (AAC) of the prostate, BCCs show features of basal cell differentiation and are thought to be biologically distinct from AAC. The spectrum of molecular alterations of BCC has not been comprehensively described, and genomic studies are lacking. Herein, whole genome sequencing was performed on archival formalin-fixed, paraffin-embedded specimens of two cases with BCC. Prostatic BCCs were characterized by an overall low copy number and mutational burden. Recurrent copy number loss of chromosome 16 was observed. In addition, putative driver gene alterations in KIT, DENND3, PTPRU, MGA, and CYLD were identified. Mechanistically, depletion of the CYLD protein resulted in increased proliferation of prostatic basal cells in vitro. Collectively, these studies show that prostatic BCC displays distinct genomic alterations from AAC and highlight a potential role for loss of chromosome 16 in the pathogenesis of this rare tumor type.

The clinical utility of dual-energy CT in post-thrombectomy care: Part 2, the predictive value of contrast density and volume for delayed hemorrhagic transformation.

OBJECTIVES: Dual-energy CT allows differentiation between blood and iodinated contrast. This study aims to determine the predictive value of contrast density and volume on post-thrombectomy dual-energy CT for delayed hemorrhagic transformation and its impact on 90-day outcomes. MATERIALS AND METHODS: A retrospective analysis was performed on patients who underwent thrombectomy for anterior circulation large-vessel occlusion at a comprehensive stroke center from 2018-2021. Per institutional protocol, all patients underwent dual-energy CT immediately post-thrombectomy and MRI or CT 24 hours afterward. The presence of hemorrhage and contrast staining was evaluated by dual-energy CT. Delayed hemorrhagic transformation was determined by 24-hour imaging and classified into petechial hemorrhage or parenchymal hematoma using ECASS III criteria. Univariable and multivariable analyses were performed to determine predictors and outcomes of delayed hemorrhagic transformation. RESULTS: Of 97 patients with contrast staining and without hemorrhage on dual-energy CT, 30 and 18 patients developed delayed petechial hemorrhage and delayed parenchymal hematoma, respectively. On multivariable analysis, delayed petechial hemorrhage was predicted by anticoagulant use (OR,3.53;p=0.021;95%CI,1.19-10.48) and maximum contrast density (OR,1.21;p=0.004;95%CI,1.06-1.37;per 10 HU increase), while delayed parenchymal hematoma was predicted by contrast volume (OR,1.37;p=0.023;95%CI,1.04-1.82;per 10 mL increase) and low-density lipoprotein (OR,0.97;p=0.043;95%CI,0.94-1.00;per 1 mg/dL increase). After adjusting for potential confounders, delayed parenchymal hematoma was associated with worse functional outcomes (OR,0.07;p=0.013;95%CI,0.01-0.58) and mortality (OR,7.83;p=0.008;95%CI,1.66-37.07), while delayed petechial hemorrhage was associated with neither. CONCLUSION: Contrast volume predicted delayed parenchymal hematoma, which was associated with worse functional outcomes and mortality. Contrast volume can serve as a useful predictor of delayed parenchymal hematoma following thrombectomy and may have implications for patient management.

The clinical utility of dual-energy CT in post-thrombectomy care: Part 1, predictors and outcomes of subarachnoid and intraparenchymal hemorrhage.

OBJECTIVES: Dual-energy CT allows differentiation between blood and iodinated contrast. We aimed to determine predictors of subarachnoid and intraparenchymal hemorrhage on dual-energy CT performed immediately post-thrombectomy and the impact of these hemorrhages on 90-day outcomes. MATERIALS AND METHODS: A retrospective analysis was performed on patients who underwent thrombectomy for anterior circulation large-vessel occlusion and subsequent dual-energy CT at a comprehensive stroke center from 2018-2021. The presence of contrast, subarachnoid hemorrhage, or intraparenchymal hemorrhage immediately post-thrombectomy was assessed by dual-energy CT. Univariable and multivariable analyses were performed to identify predictors of post-thrombectomy hemorrhages and 90-day outcomes. Patients with unknown 90-day mRS were excluded. RESULTS: Of 196 patients, subarachnoid hemorrhage was seen in 17, and intraparenchymal hemorrhage in 23 on dual-energy CT performed immediately post-thrombectomy. On multivariable analysis, subarachnoid hemorrhage was predicted by stent retriever use in the M2 segment of MCA (OR,4.64;p=0.017;95%CI,1.49-14.35) and the number of thrombectomy passes (OR,1.79;p=0.019;95%CI,1.09-2.94;per an additional pass), while intraparenchymal hemorrhage was predicted by preprocedural non-contrast CT-based ASPECTS (OR,8.66;p=0.049;95%CI,0.92-81.55;per 1 score decrease) and preprocedural systolic blood pressure (OR,5.10;p=0.037;95%CI,1.04-24.93;per 10 mmHg increase). After adjusting for potential confounders, intraparenchymal hemorrhage was associated with worse functional outcomes (OR,0.25;p=0.021;95%CI,0.07-0.82) and mortality (OR,4.30;p=0.023,95%CI,1.20-15.36), while subarachnoid hemorrhage was associated with neither. CONCLUSIONS: Intraparenchymal hemorrhage immediately post-thrombectomy was associated with worse functional outcomes and mortality and can be predicted by low ASPECTS and elevated preprocedural systolic blood pressure. Future studies focusing on management strategies for patients presenting with low ASPECTS or elevated blood pressure to prevent post-thrombectomy intraparenchymal hemorrhage are warranted.

Phenotypic characterization of two novel cell line models of castration-resistant prostate cancer.

BACKGROUND: Resistance to androgen deprivation therapies is a major driver of mortality in advanced prostate cancer. Therefore, there is a need to develop new preclinical models that allow the investigation of resistance mechanisms and the assessment of drugs for the treatment of castration-resistant prostate cancer. METHODS: We generated two novel cell line models (LAPC4-CR and VCaP-CR) which were derived by passaging LAPC4 and VCaP cells in vivo and in vitro under castrate conditions. We performed detailed transcriptomic (RNA-seq) and proteomic analyses (SWATH-MS) to delineate expression differences between castration-sensitive and castration-resistant cell lines. Furthermore, we characterized the in vivo and in vitro growth characteristics of these novel cell line models. RESULTS: The two cell line derivatives LAPC4-CR and VCaP-CR showed castration-resistant growth in vitro and in vivo which was only minimally inhibited by AR antagonists, enzalutamide, and bicalutamide. High-dose androgen treatment resulted in significant growth arrest of VCaP-CR but not in LAPC4-CR cells. Both cell lines maintained AR expression, but exhibited distinct expression changes on the mRNA and protein level. Integrated analyses including data from LNCaP and the previously described castration-resistant LNCaP-abl cells revealed an expression signature of castration resistance. CONCLUSIONS: The two novel cell line models LAPC4-CR and VCaP-CR and their comprehensive characterization on the RNA and protein level represent important resources to study the molecular mechanisms of castration resistance.

Predictors of acute post-thrombectomy intracranial hemorrhage expansion in anterior circulation infarcts.

BACKGROUND: Post-mechanical thrombectomy (MT) intracranial hemorrhage (ICH) is a major source of morbidity in treated acute ischemic stroke patients with large vessel occlusion. ICH expansion may further contribute to morbidity. We sought to identify factors associated with ICH expansion on imaging evaluation post-MT. METHODS: We performed a retrospective cohort study of patients undergoing MT at a single comprehensive stroke center. Per protocol, patients underwent dual-energy head CT (DEHCT) post-MT followed by a 24-h interval non-contrast enhanced MRI. ICH expansion was defined as any increase in blood volume between the two studies if identified on the DEHCT. Univariate and multivariable analyses were performed to identify risk factors for ICH expansion. RESULTS: ICH was identified on DEHCT in 13% of patients (n = 35/262), with 20% (7/35) demonstrating expansion on interval MRI. The average increase in blood volume was 11.4 ml (SD 6.9). Univariate analysis identified anticoagulant usage (57% vs 14%, p = 0.03), petechial hemorrhage inside the infarct margins or intraparenchymal hematoma on DEHCT (ECASS-II HI2/PH1/PH2) (71% vs 14%, p < 0.01), basal ganglia hemorrhage (71% vs 21%, p = 0.02), and basal ganglia infarction (86% vs 32%, p = 0.03) as factors associated with ICH expansion. Multivariate regression demonstrated that anticoagulant usage (OR 20.3, 95% C.I. 2.43-446, p < 0.05) and ECASS II scores of HI2/PH1/PH2 (OR 11.7, 95% C.I. 1.24-264, p < 0.05) were significantly predictive of ICH expansion. CONCLUSION: Expansion of post-MT ICH on 24-h interval MRI relative to immediate post-thrombectomy DEHCT is significantly associated with baseline anticoagulant usage and petechial hemorrhage inside the infarct margins or presence of intraparenchymal hematoma (ECASS-II HI2/PH1/PH2).

Assessing Clinical Outcome Measures in Chiari I Malformation.

The purpose of this article was to consider, evaluate, and compare the clinical outcomes measurement tools that are used to assess patients with Chiari I malformation. This article highlights the variety of general and disease-specific outcome measures used in both the pediatric and adult Chiari I malformation patient populations. Although general measures can be associated with clinical outcomes and quality of life, that association is not often found to be statistically significant, and they do not often have the capabilities to assess and measure factors that directly impact the Chiari patient population. However, limitations exist when considering the disease-specific outcome measures, as these tools most often have not been rigorously evaluated externally from the initial validation or have been externally validated but results cannot be replicated. Identifying an outcomes measurement tool for both adults and patients will contribute to the clinical tools available to providers for decision-making and management.

Flat-panel dual-energy head computed tomography in the angiography suite after thrombectomy for acute stroke: A clinical feasibility study.

BACKGROUND: Management of large vessel occlusion (LVO) patients after thrombectomy is affected by the presence of intracranial hemorrhage (ICH) on post-procedure imaging. Differentiating contrast staining from hemorrhage on post-procedural imaging has been facilitated by dual-energy computed tomography (DECT), traditionally performed in dedicated computed tomography (CT) scanners with subsequent delays in treatment. We employed a novel method of DECT using the Siemens cone beam CT (DE-CBCT) in the angiography suite to evaluate for post-procedure ICH and contrast extravasation. METHODS: After endovascular treatment for LVO was performed and before the patient was removed from the operating table, DE-CBCT was performed using the Siemens Q-biplane system, with two separate 20-second CBCT scans at two energy levels: 70 keV (standard) and 125 keV with tin filtration (nonstandard). Post-procedurally, patients also underwent a standard DECT using Siemens SOMATOM Force CT scanner. Two independent reviewers blindly evaluated the DE-CBCT and DECT for hemorrhage and contrast extravasation. RESULTS: We successfully performed intra-procedural DE-CBCT in 10 subjects with no technical failure. The images were high-quality and subjectively useful to differentiate contrast from hemorrhage. The one hemorrhage seen on standard DECT was very small and clinically silent. The interrater reliability was 100% for both contrast and hemorrhage detection. CONCLUSION: We demonstrate that intra-procedural DE-CBCT after thrombectomy is feasible and provides clinically meaningful images. There was close agreement between findings on DE-CBCT and standard DECT. Our findings suggest that DE-CBCT could be used in the future to improve stroke thrombectomy patient workflow and to more efficiently guide the postoperative management of these patients.

Neurological Examination Frequency and Time-to-Delirium After Traumatic Brain Injury.

BACKGROUND: Frequent neurological examinations in patients with traumatic brain injury (TBI) disrupt sleep-wake cycles and potentially contribute to the development of delirium. OBJECTIVE: To evaluate the risk of delirium among patients with TBI with respect to their neuro-check frequencies. METHODS: A retrospective study of patients presenting with TBI at a single level I trauma center between January 2018 and December 2019. The primary exposure was the frequency of neurological examinations (neuro-checks) assigned at the time of admission. Patients admitted with hourly (Q1) neuro-check frequencies were compared with those who received examinations every 2 (Q2) or 4 (Q4) hours. The primary outcomes were delirium and time-to-delirium. The onset of delirium was defined as the first documented positive Confusion Assessment Method for the Intensive Care Unit score. RESULTS: Of 1552 patients with TBI, 458 (29.5%) patients experienced delirium during their hospital stay. The median time-to-delirium was 1.8 days (IQR: 1.1, 2.9). Kaplan-Meier analysis demonstrated that patients assigned Q1 neuro-checks had the greatest rate of delirium compared with the patients with Q2 and Q4 neuro-checks ( P < .001). Multivariable Cox regression modeling demonstrated that Q2 neuro-checks (hazard ratio: 0.439, 95% CI: 0.33-0.58) and Q4 neuro-checks (hazard ratio: 0.48, 95% CI: 0.34-0.68) were protective against the development of delirium compared with Q1. Other risk factors for developing delirium included pre-existing dementia, tobacco use, lower Glasgow Coma Scale score, higher injury severity score, and certain hemorrhage patterns. CONCLUSION: Patients with more frequent neuro-checks had a higher risk of developing delirium compared with those with less frequent neuro-checks.

Assessment of safety and effectiveness of non-neurosurgical management for minimal traumatic brain injury (TBI).

BACKGROUND: Patients with mild traumatic brain injury (TBI) and intracranial hemorrhage often receive neurosurgical consultation. However, only a small proportion of patients require intervention. Our hypothesis is that low-risk minimal TBI patients managed without immediate neurosurgical consultation will have a reasonable safety and effectiveness outcome profile. METHODS: A non-neurosurgical management protocol for adult minimal TBI was implemented at a level I trauma center as an interdisciplinary quality-improvement initiative in November 2018. Minimal TBI was defined as Glasgow Coma Scale (GCS) of 15 secondary to blunt mechanism, without anticoagulant or antiplatelet therapy, and isolated pneumocephalus and/or traumatic subarachnoid hemorrhage on head CT imaging. Safety was assessed by in-hospital mortality, neurosurgical interventions, and ED revisits within two weeks of discharge. Effectiveness was assessed by neurosurgical consult rate and length of stay. Outcomes were compared 8-months pre- and post-protocol implementation. RESULTS: A total of 97 patients were included, of which 49 were pre-protocol and 48 were post-protocol There was no difference in rates of in-hospital mortality [0 (0%) vs 0 (0%)], neurosurgical procedure [1 (2.1%) vs 0 (0%)], operations [0 (0%) vs 0 (0%)], and ED revisits [1 (2.0%) vs 2 (4.2%), p = 0.985] between the periods. There was a significant reduction in neurosurgical consults post-protocol implementation (92% vs 29%, p<0.001). CONCLUSION: A protocol for minimal TBI patients effectively reduced neurosurgical consultation without changes in safety profile. Such an interdisciplinary management protocol for low-risk neurotrauma can effectively utilize the neurosurgery consult services by stratifying neurologically stable TBI patient.

A Comprehensive Overview of Antibiotic Selection and the Factors Affecting It.

In order to prescribe an antibiotic, a physician must go through a series of decision-making processes that involve both the drug and the host. In this review article, we outline exactly what those decision-making processes are and some of their limitations. Before a medication can be prescribed, a physician has to determine if the antibiotic works against the host pathogen. To do this, basic science techniques are employed including phenotypic methods such as broth dilution methods, Kirby-Bauer susceptibility testing, Epsilometer test (E-test), and genotypic methods such as the new and upcoming automated tests. After determining if a drug has potential to work, the physician must consider the drug's mechanism of action in order to determine a dosing regimen. Some groups of drugs should be administered at high concentrations infrequently, others should be given more frequently in smaller doses, and others lie somewhere between this spectrum. Finally, external factors such as the patient's age, especially for pediatrics and geriatrics patients, need to be considered, as these groups have the highest health care burden but are among the most vulnerable when it comes to the side effects of drugs.

A high-throughput screen of pharmacologically active compounds for inhibitors of UHRF1 reveals epigenetic activity of anthracycline derivative chemotherapeutic drugs.

DNA methylation can mediate epigenetic silencing of tumor suppressor and cancer protective genes. The protein ubiquitin-like containing PHD and ring finger domains 1 (UHRF1) is an essential component in cells for DNA methylation maintenance. The SET- and RING-associated (SRA) domain of UHRF1 can bind hemimethylated DNA, and mediate recruitment of DNA methyltransferases to copy the methylation pattern to the newly synthesized daughter strand. Loss of UHRF1 function can lead to demethylation and re-expression of epigenetically silenced tumor suppressor genes and can reduce cancer cell growth and survival. We created a high-throughput time-resolved fluorescence resonance energy transfer (TR-FRET) assay to screen for inhibitors capable of disrupting the interaction between the UHRF1-SRA domain and hemimethylated DNA. Using this assay (Z' factor of 0.74 in 384-well format) we screened the Library of Pharmacologically Active Compounds (LOPAC) for UHRF1-SRA inhibitors, and validated 7 hit compounds. These compounds included the anthracycline derivatives idarubicin and mitoxantrone, which are commonly used chemotherapeutic drugs known to mediate cytotoxicity by acting as class II topoisomerase (TOP2) poisons. In a panel of additional known topoisomerase poisons, only the anthracycline derivatives showed dose responsive inhibition of UHRF1-SRA. Additionally, mitoxantrone and doxorubicin showed dose-responsive global DNA demethylation and demonstrated a synergistic growth inhibition of multiple cancer cell lines when combined with the DNA methyltransferase (DNMT) inhibitor decitabine. These data validate a novel TR-FRET assay for identification of UHRF1 inhibitors, and revealed unexpected epigenetic properties of commonly used chemotherapeutic drugs that showed synergistic cytotoxicity of cancer cells when combined with a demethylating agent.

Integrating Advance Care Planning Videos into Surgical Oncologic Care: A Randomized Clinical Trial.

Background: Preoperative advance care planning (ACP) may benefit patients undergoing major surgery. Objective: To evaluate feasibility, safety, and early effectiveness of video-based ACP in a surgical population. Design: Randomized controlled trial with two study arms. Setting: Single, academic, inner-city tertiary care hospital. Subjects: Patients undergoing major cancer surgery were recruited from nine surgical clinics. Of 106 consecutive potential participants, 103 were eligible and 92 enrolled. Interventions: In the intervention arm, patients viewed an ACP video developed by patients, surgeons, palliative care clinicians, and other stakeholders. In the control arm, patients viewed an informational video about the hospital's surgical program. Measurements: Primary Outcomes-ACP content and patient-centeredness in patient-surgeon preoperative conversation. Secondary outcomes-patient Hospital Anxiety and Depression Scale (HADS) score; patient goals of care; patient and surgeon satisfaction; video helpfulness; and medical decision maker designation. Results: Ninety-two patients (target enrollment: 90) were enrolled. The ACP video was successfully integrated with no harm noted. Patient-centeredness was unchanged (incidence rate ratio [IRR] = 1.06, confidence interval [0.87-1.3], p = 0.545), although there were more ACP discussions in the intervention arm (23% intervention vs. 10% control, p = 0.18). While slightly underpowered, study results did not signal that further enrollment would have yielded statistical significance. There were no differences in secondary outcomes other than the intervention video was more helpful (p = 0.007). Conclusions: The ACP video was successfully integrated into surgical care without harm and was thought to be helpful, although video content did not significantly change the ACP content or patient-surgeon communication. Future studies could increase the ACP dose through modifying video content and/or who presents ACP. Trial Registration: clinicaltrials.gov Identifier NCT02489799.