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End-stage renal disease has traditionally been noted to disproportionately affect patients with fewer resources. Our goal was to assess practice patterns and outcomes in patients with unstable housing undergoing permanent hemodialysis access creation.A retrospective, single-center review of patients with unstable housing was conducted. Perioperative and long-term outcomes were assessed. Univariable and multivariable analysis as well as Kaplan-Meier analysis were performed.There were 144 patients (63% male) identified with a mean age of 57 years. Thirty-three percent of patients had no current permanent residence, and 81% had at least 3 addresses the year before operation. Access type included brachiocephalic (48%), brachiobasilic (19%), radiocephalic fistulas (11%), and prosthetic grafts (19%). Thirty-day readmission was seen in 27.8% of patients. Kaplan-Meier analysis showed that 1-year and 4-year patient survival were 94.4% and 80.6%, respectively. Multivariable analysis demonstrated that newly formed access (odds ratio [OR] 3.66, 95% CI 1.02 to 13.16, p = 0.05), absence of a permanent residence (OR 2.92, 95% CI 1.15 to 7.44, p = 0.03), and female gender (OR 2.86, 95% CI, 1.18 to 7.14, p = 0.02) were associated with 90-day readmission. Multivariable analysis of mortality revealed that previous stroke (hazard ratio [HR] 7.15, 95% CI 1.93 to 26.5, p = 0.003), history of alcohol use disorder (HR 4.55, 95% CI 1.22 to 16.99, p = 0.024), and age (HR 1.10, 95% CI, 1.02 to 1.18, p = 0.017) were associated with 4-year mortality; housing instability was not associated with decreased survival. Preoperative tunneled dialysis catheter (HR 1.63, 95% CI 1.02 to 2.61, p = 0.04) was associated with 4-year reintervention and frequent address change (HR 0.47, 95% CI 0.27 to 0.81, p = 0.01) was found to be a protective factor against long-term reintervention.Poor outcomes in patients with unstable housing were primarily driven by comorbidities. Lack of permanent residence was significantly associated with readmission.

Supplementary Methods and Figure legends

MetaCoreTM schematic of the TGF-β signaling pathway showing genes regulated by miR-17 TuD in Hep3B (1) and HepG2 (2).

The PI3K/AKT/mTOR pathway is often activated in lymphoma through alterations in PI3K, PTEN, and B-cell receptor signaling, leading to dysregulation of eIF4A (through its regulators, eIF4B, eIF4G, and PDCD4) and the eIF4F complex. Activation of eIF4F has a direct role in tumorigenesis due to increased synthesis of oncogenes that are dependent on enhanced eIF4A RNA helicase activity for translation. eFT226, which inhibits translation of specific mRNAs by promoting eIF4A1 binding to 5′-untranslated regions (UTR) containing polypurine and/or G-quadruplex recognition motifs, shows potent antiproliferative activity and significant in vivo efficacy against a panel of diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma models with ≤1 mg/kg/week intravenous administration. Evaluation of predictive markers of sensitivity or resistance has shown that activation of eIF4A, mediated by mTOR signaling, correlated with eFT226 sensitivity in in vivo xenograft models. Mutation of PTEN is associated with reduced apoptosis in vitro and diminished efficacy in vivo in response to eFT226. In models evaluated with PTEN loss, AKT was stimulated without a corresponding increase in mTOR activation. AKT activation leads to the degradation of PDCD4, which can alter eIF4F complex formation. The association of eFT226 activity with PTEN/PI3K/mTOR pathway regulation of mRNA translation provides a means to identify patient subsets during clinical development.

Expression levels of miR-17 TuD. The data are expressed as delta CT value normalized to GAPDH.

Inhibition of miR-17, 20a, 20b, 93 and 106b activity by miR-17 TuD in HeLa cells as determined by luciferase reporter assays.

Tables S1-S3, Figures S1-S5

Inhibition of miR-17 family by miR-17 TuD had no effect on caspase 3/7 activity. Caspase 3/7 activity was represented as relative activity compared to NC TuD expression cells.

Neurotrauma, especially repetitive neurotrauma, is associated with the development of progressive neurodegeneration leading to chronic traumatic encephalopathy (CTE). Exposure to neurotrauma regularly occurs during sports and military service, often not requiring medical care. However, exposure to severe and/or repeated sub-clinical neurotrauma has been shown cause physical and psychological disability, leading to reduce life expectancy. Misfolding of proteins, or proteinopathy, is a pathological hallmark of CTE, in which chronic injury leads to local and diffuse protein aggregates. These aggregates are an overlapping feature of many neurodegenerative diseases such as CTE, Alzheimer’s Disease, Parkinsons disease. Neurotrauma is also a significant risk factor for the development of these diseases, however the mechanism’s underlying this association are not well understood. While phosphorylated tau aggregates are the primary feature of CTE, amyloid-beta, Transactive response DNA-binding protein 43 (TDP-43), and alpha-synuclein (αSyn) are also well documented. Aberrant misfolding of these proteins has been shown to disrupt brain homeostasis leading to neurodegeneration in a disease dependent manor. In CTE, the interaction between proteinopathies and their associated neurodegeneration is a current area of study. Here we provide an update on current literature surrounding the prevalence, characteristics, and pathogenesis of proteinopathies in CTE.

Ovarian cancer is one of the leading causes of cancer-related deaths among women in the United States. Metastasis to the central nervous system has become more frequent in the previous decades, however, treatment options remain limited. In this review, we discuss the pathophysiology of ovarian cancer and how metastasis to the central nervous system typically occurs. We then discuss cases of metastasis presented in the literature to evaluate current treatment regimens and protocols. Finally, we highlight emerging treatment options that are being utilized in clinics to provide personalized treatment therapy for a patient’s unique diagnosis. This review aims to further the understanding of pathophysiology, stimulate further innovative treatments, and present accessible resources through tables and figures.

Gray zone, a measure of tissue heterogeneity on late gadolinium enhanced-cardiac magnetic resonance (LGE-CMR) imaging, has been shown to predict ventricular arrhythmias (VAs) in ischemic cardiomyopathy (ICM) patients. However, no studies have described whether left ventricular (LV) tissue heterogeneity and intramyocardial fat mass on contrast-enhanced computed tomography (CE-CT), which provides greater spatial resolution, is useful for assessing the risk of VAs in ICM patients with LV systolic dysfunction and no previous VAs.The purpose of this proof-of-concept study was to determine the feasibility of measuring global LV tissue heterogeneity and intramyocardial fat mass by CE-CT for predicting the risk of VAs in ICM patients with LV systolic dysfunction and no previous history of VAs.Patients with left ventricular ejection fraction ≤35% and no previous VAs were enrolled in a prospective, observational registry and underwent LGE-CMR. From this cohort, patients with ICM who additionally received CE-CT were included in the present analysis. Gray zone on LGE-CMR was defined as myocardium with signal intensity (SI)peak SI of healthy myocardium but50% maximal SI. Tissue heterogeneity on CE-CT was defined as the standard deviation of the Hounsfield unit image gradients (HU/mm) within the myocardium. Intramyocardial fat on CE-CT was identified as regions of image pixels between -180 and -5 HU. The primary outcome was VAs, defined as appropriate implantable cardioverter-defibrillator shock or sudden arrhythmic death.The study consisted of 47 ICM patients, 13 (27.7%) of whom experienced VA events during mean follow-up of 5.6 ± 3.4 years. Increasing tissue heterogeneity (per HU/mm) was significantly associated with VAs after multivariable adjustment, including for gray zone (odds ratio [OR] 1.22;In ICM patients, CE-CT-derived LV tissue heterogeneity was independently associated with VAs and may represent a novel marker useful for risk stratification.

Aims Direct remuscularization with pluripotent stem cell-derived cardiomyocytes (PSC-CMs) seeks to address the onset of heart failure post-myocardial infarction (MI) by treating the persistent muscle deficiency that underlies it. However, direct remuscularization with PSC-CMs could potentially be arrhythmogenic. We investigated two possible mechanisms of arrhythmogenesis-focal vs reentrant-arising from direct remuscularization with PSC-CM patches in two personalized, human ventricular computer models of post-MI. Moreover, we developed a principled approach for evaluating arrhythmogenicity of direct remuscularization that factors in the VT propensity of the patient-specific post-MI fibrotic substrate and use it to investigate different conditions of patch remuscularization. Methods & results Two personalized, human ventricular models of post-MI (P1 & P2) were constructed from late gadolinium enhanced (LGE)-magnetic resonance images (MRI). In each model, remuscularization with PSC-CM patches were simulated under different treatment conditions that included patch engraftment, patch myofibril orientation, remuscularization site, patch size (thickness and diameter), and patch maturation. To determine arrhythmogenicity of treatment conditions, VT burden of heart models was quantified prior to and after simulated remuscularization and compared. VT burden was quantified based on inducibility (i.e., weighted sum of pacing sites that induced) and severity (i.e., the number of distinct VT morphologies induced). Prior to remuscularization, VT burden was significant in P1 (0.275) and not in P2 (0.0, not VT inducible). We highlight that reentrant VT mechanisms would dominate over focal mechanisms; spontaneous beats emerging from PSC-CM grafts were always a fraction of resting sinus rate. Moreover, incomplete patch engraftment can be particularly arrhythmogenic, giving rise to particularly aberrant electrical activation and conduction slowing across the PSC-CM patches along with elevated VT burden when compared to complete engraftment. Under conditions of complete patch engraftment, remuscularization was almost always arrhythmogenic in P2 but certain treatment conditions could be anti-arrhythmogenic in P1. Moreover, the remuscularization site was the most important factor affecting VT burden in both P1 and P2. Complete maturation of PSC-CM patches, both ionically and electrotonically, at the appropriate site could completely alleviate VT burden. Conclusion We identified that reentrant VT would be the primary VT mechanism in patch remuscularization. To evaluate the arrhythmogenicity of remuscularization, we developed a principled approach that factors in the propensity of the patient-specific fibrotic substrate for VT. We showed that arrhythmogenicity is sensitive to the patient-specific fibrotic substrate and remuscularization site. We demonstrate that targeted remuscularization can be safe in the appropriate individual and holds the potential to nondestructively eliminate VT post-MI in addition to addressing muscle deficiency underlying heart failure progression. Translational perspective If safety from ventricular arrhythmias can be addressed, direct remuscularization with PSC-CMs-achieved either through engineered myocardial patches or intramyocardial injections-holds the potential to halt heart failure progression post-MI. Using personalized 3 D models of the post-MI ventricles derived from LGE-MRI, we provide evidence that arrhythmogenesis following remuscularization with PSC-CM patches is driven by a reentrant as opposed to focal VT mechanism. Moreover, the existing patient-specific fibrotic substrate together with the remuscularization site were primary determinants of arrhythmogenesis. These results suggest that the clinical safety of remuscularization can be achieved through patient-specific optimization guided in-part by computational modeling.

In the transmit signal path of a cellular terminal that supports the Long-Term Evolution (LTE) standard, the third-order counter-intermodulation (CIM3) product can be a significant contributor to spurious emissions in protected bands, primarily in cases where all the transmit power is concentrated in one resource block at the edge of the allocated bandwidth. This problem can be addressed with a harmonic rejection architecture for the up-conversion mixer in the transceiver. Prior work in this area retains the four-phase baseband inputs of a conventional quadrature mixer, utilizes various techniques in the local oscillator (LO) path involving overlapping LO waveforms to suppress harmonics and requires the digitally-controlled oscillator (DCO) to be operated at two or more times the LO frequency. The harmonic rejection architecture presented in this paper has six baseband phases and six non-overlapping LO phases and, for higher-frequency bands, allows the DCO to run at 1.5 times the LO frequency. It also provides an inherently higher uncalibrated image rejection than architectures with quadrature baseband inputs, which is advantageous for any wireless communication standard that supports higher-order quadrature amplitude modulation (QAM) schemes such as 1024-QAM and 4096-QAM.

Introduction We recently developed two noninvasive methodologies to help guide VT ablation: population-derived automated VT exit localization (PAVEL) and virtual-heart arrhythmia ablation targeting (VAAT). We hypothesized that while very different in their nature, limitations, and type of ablation targets (substrate-based vs. clinical VT), the image-based VAAT and the ECG-based PAVEL technologies would be spatially concordant in their predictions. Objective The objective is to test this hypothesis in ischemic cardiomyopathy patients in a retrospective feasibility study. Methods Four post-infarct patients who underwent LV VT ablation and had pre-procedural LGE-CMRs were enrolled. Virtual hearts with patient-specific scar and border zone identified potential VTs and ablation targets. Patient-specific PAVEL based on a population-derived statistical method localized VT exit sites onto a patient-specific 238-triangle LV endocardial surface. Results Ten induced VTs were analyzed and 9-exit sites were localized by PAVEL onto the patient-specific LV endocardial surface. All nine predicted VT exit sites were in the scar border zone defined by voltage mapping and spatially correlated with successful clinical lesions. There were 2.3 ± 1.9 VTs per patient in the models. All five VAAT lesions fell within regions ablated clinically. VAAT targets correlated well with 6 PAVEL-predicted VT exit sites. The distance between the center of the predicted VT-exit-site triangle and nearest corresponding VAAT ablation lesion was 10.7 ± 7.3 mm. Conclusions VAAT targets are concordant with the patient-specific PAVEL-predicted VT exit sites. These findings support investigation into combining these two complementary technologies as a noninvasive, clinical tool for targeting clinically induced VTs and regions likely to harbor potential VTs.