Miracle-dz/UniFAR-FTUs huggingface dataset:
Long-term Outcomes Associated With Implantable Cardioverter Defibrillator in Adults With Chronic Kidney Disease

Importance Chronic kidney disease (CKD) is common in adults with heart failure and is associated with an increased risk of sudden cardiac death. Randomized trials of participants without CKD have demonstrated that implantable cardioverter defibrillators (ICDs) decrease the risk of arrhythmic death in selected patients with reduced left ventricular ejection fraction (LVEF) heart failure. However, whether ICDs improve clinical outcomes in patients with CKD is not well elucidated. Objective To examine the association of primary prevention ICDs with risk of death and hospitalization in a community-based population of potentially ICD-eligible patients who had heart failure with reduced LVEF and CKD. Design, Settings, and Participants This noninterventional cohort study included adults with heart failure and an LVEF of 40% or less and measures of serum creatinine levels available from January 1, 2005, through December 31, 2012, who were enrolled in 4 Kaiser Permanente health care delivery systems. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2. Patients who received and did not receive an ICD were matched (1:3) on CKD status, age, and high-dimensional propensity score to receive an ICD. Follow-up was completed on December 31, 2013. Data were analyzed from 2015 to 2017. Exposures Placement of an ICD. Main Outcomes and Measures All-cause death, hospitalizations due to heart failure, and any-cause hospitalizations. Results A total of 5877 matched eligible adults with CKD (1556 with an ICD and 4321 without an ICD) were identified (4049 men [68.9%] and 1828 women [31.1%]; mean [SD] age, 72.9 [8.2] years). In models adjusted for demographics, comorbidity, and cardiovascular medication use, no difference was found in all-cause mortality between patients with CKD in the ICD vs non-ICD groups (adjusted hazard ratio, 0.96; 95% CI, 0.87-1.06). However, ICD placement was associated with increased risk of subsequent hospitalization due to heart failure (adjusted relative risk, 1.49; 95% CI, 1.33-1.60) and any-cause hospitalization (adjusted relative risk, 1.25; 95% CI, 1.20-1.30) among patients with CKD. Conclusions and Relevance In a large, contemporary, noninterventional study of community-based patients with heart failure and CKD, ICD placement was not significantly associated with improved survival but was associated with increased risk for subsequent hospitalization due to heart failure and all-cause hospitalization. The potential risks and benefits of ICDs should be carefully considered in patients with heart failure and CKD.
Soft Tissue Deformations in Abusive Head Trauma

iii Acknowledgements . v Table of Figures . xiv Table of Tables . xxi Chapter 1: Introduction . 1 1.1 Motivation . 1 1.2 Aim of the Research . 3 1.2.1 Aims of the Thesis . 4 1.3 Thesis Overview . 4 1.4 Novel Contributions . 6 1.5 Publications list . 7 Chapter 2: Background . 9 2.1 Historical Background . 9 2.1.1 Development of the Concept of Shaken Baby Syndrome . 10 2.1.2 The Debate: Impact or No Impact . 11 2.2 The Prevalence of Abusive Head Trauma. 13 2.3 Anatomy . 14 2.3. 1 The Skull. 14 2.3. 2 The Brain . 16
Therapeutic advances in interventional neurology

SummaryRapid advances in the field of interventional neurology and the development of minimally invasive techniques have resulted in a great expansion of potential therapeutic applications. We discuss therapeutic interventional neurology as applied in clinical practice in one of the two possible ways: 1) embolization leading to occlusion of blood vessels; and 2) revascularization leading to reopening of blood vessels. These procedures can be applied to a broad range of cerebrovascular diseases. In the first section of this review, we will explore the evolution of these interventions to occlude aneurysms, arteriovenous malformations, neurovascular tumors, and injuries. In the second section, revascularization in acute ischemic stroke, stenosis, and dural venous thrombosis will be discussed.
Dendritic cells up‐regulate immunoproteasomes and the proteasome regulator PA28 during maturation

Dendritic cells (DC) are highly specialized professional antigen presenting cells which are pivotal for the initiation and control of the cytotoxic T cell response. Upon stimulation by cytokines, bacteria, or CD40L DC undergo a maturation process from an antigen‐receptive state to a state of optimal stimulation of T cells. We investigated the composition of proteasomes of DC derived from human peripheral blood monocytes before and after stimulation by CD40L, LPS, or proinflammatory cytokines (TNF‐α + IL‐6 + IL‐1β). Immunoprecipitation of proteasomes and analysis on two‐dimensional gels revealed that during maturation the inducible proteasome subunits LMP2, LMP7, and MECL‐1 are up‐regulated and that the neosynthesis of proteasomes is switched exclusively to the production of immunoproteasomes containing these subunits. The proteasome regulator PA28 is markedly up‐regulated in mature DC and in addition a so – far unidentified 21‐kDa protein co‐precipitates with the proteasome in LPS – stimulated DC. These changes in proteasome composition may be functionally linked to special properties of DC like MHC class I up‐regulation or cross‐priming. Our findings imply that the spectrum of class I‐bound peptides may change after DC maturation which could be relevant for the design of DC – based vaccines.
Oxidative DNA damage is epigenetic by regulating gene transcription via base excision repair

Significance Damage to DNA bases due to oxidative stress is thought to be deleterious, leading to stalled replication forks and mutations. Similarly, folding of DNA strands into G-quadruplexes slows the progression of polymerases, requiring specialized helicases for unfolding before transcription. In the case of oxidative damage in a G-quadruplex–forming sequence of a promoter, we show that the presence of the DNA damage lesion 8-oxoguanine (OG) leads to an ∼300% increase in gene expression. This concept was demonstrated by chemical synthesis of a segment of the vascular endothelial growth factor (VEGF) or endonuclease III-like protein 1 (NTHL1) promoter with a site specifically incorporated lesion in a reporter plasmid. This observation is direct evidence that OG represents an epigenetic modification and G-quadruplex–forming sequences can serve as sensors of oxidative stress. Reactive oxygen species (ROS) have emerged as important cellular-signaling agents for cellular survival. Herein, we demonstrate that ROS-mediated oxidation of DNA to yield 8-oxo-7,8-dihydroguanine (OG) in gene promoters is a signaling agent for gene activation. Enhanced gene expression occurs when OG is formed in guanine-rich, potential G-quadruplex–forming sequences (PQS) in promoter-coding strands, initiating base excision repair (BER) by 8-oxoguanine DNA glycosylase (OGG1), yielding an abasic site (AP). The AP enables melting of the duplex to unmask the PQS, adopting a G-quadruplex fold in which apurinic/apyrimidinic endonuclease 1 (APE1) binds, but inefficiently cleaves, the AP for activation of vascular endothelial growth factor (VEGF) or endonuclease III-like protein 1 (NTHL1) genes. These details were mapped via synthesis of OG and AP analogs at single-nucleotide precision within the promoter of a luciferase reporter system. The reporters were analyzed in human and mouse cells while selectively knocking out or down critical BER proteins to identify the impact on luciferase expression. Identification of the oxidatively modified DNA base OG to guide BER activity in a gene promoter and impact cellular phenotype ascribes an epigenetic role to OG.
FAR-RED ELONGATED HYPOCOTYL3 promotes floral meristem determinacy in Arabidopsis

ABSTRACT The transposase-derived transcription factor genes FAR-RED ELONGATED HYPOCOTYL3 (FHY3) and FAR-RED IMPAIRED RESPONSE1 (FAR1) have redundant and multifaceted roles in plant growth and development during the vegetative stage, including phytochrome A-mediated far-red light (FR) signaling and circadian clock entrainment. Little is known about their functions in the reproductive stage. We recently demonstrated that FHY3 plays important roles in shoot apical meristem (SAM) maintenance and floral meristem (FM) determinacy through its target genes CLAVATA3 (CLV3), SEPALLATA1 (SEP1) and SEP2. Here we present data that FHY3 but not its homolog, FAR1, has a distinct role in FM determinacy in a manner independent of its light signaling and circadian pathway functions. Moreover, genome-wide gene expression profiling showed that the homeostasis of the FM is critical for the regulation of FM activity.
Symmetry of Charge Partitioning in Collisional and UV Photon-Induced Dissociation of Protein Assemblies

Tandem mass spectrometry can provide structural information on intact protein assemblies, generating mass fingerprints indicative of the stoichiometry and quaternary arrangement of the subunits. However, in such experiments, collision-induced dissociation yields restricted information due to simultaneous subunit unfolding, charge rearrangement, and subsequent ejection of a highly charged unfolded single subunit. Alternative fragmentation strategies can potentially overcome this and supply a deeper level of structural detail. Here, we implemented ultraviolet photodissociation (UVPD) on an Orbitrap mass spectrometer optimized for native MS and benchmark its performance to HCD fragmentation using various protein oligomers. We investigated dimeric β-lactoglobulin, dimeric superoxide dismutase, dimeric and tetrameric concanavalin A, and heptameric GroES and Gp31; ranging in molecular weight from 32 to 102 kDa. We find that, for the investigated systems, UVPD produces more symmetric charge partitioning than HCD. While HCD spectra show sporadic fragmentation over the full protein backbone sequence of the subunits with a bias toward fragmenting labile bonds, UVPD spectra provided higher sequence coverage. Taken together, we conclude that UVPD is a strong addition to the toolbox of fragmentation methods for top-down proteomics experiments, especially for native protein assemblies.
Nutrition in peri-operative esophageal cancer management

ABSTRACT Introduction: Nutritional status and dietary intake are increasingly recognized as essential areas in esophageal cancer management. Nutritional management of esophageal cancer is a continuously evolving field and comprises an interesting area for scientific research. Areas covered: This review encompasses the current literature on nutrition in the pre-operative, peri-operative, and post-operative phases of esophageal cancer. Both established interventions and potential novel targets for nutritional management are discussed. Expert commentary: To ensure an optimal pre-operative status and to reduce peri-operative complications, it is key to assess nutritional status in all pre-operative esophageal cancer patients and to apply nutritional interventions accordingly. Since esophagectomy results in a permanent anatomical change, a special focus on nutritional strategies is needed in the post-operative phase, including early initiation of enteral feeding, nutritional interventions for post-operative complications, and attention to long-term nutritional intake and status. Nutritional aspects of pre-optimization and peri-operative management should be incorporated in novel Enhanced Recovery After Surgery programs for esophageal cancer.
The interplay between the duration of TCR and cytokine signaling determines T cell polarization

Development of Th1 and Th2 effector lymphocytes is driven primarily by IL‐12 or IL‐4, but is also influenced by the strength of antigenic stimulation. However, the mechanism by which TCR signaling contributes to T cell polarization remains elusive. We show that in the presence of IL‐12 a short TCR stimulation can lead to efficient Th1 polarization and IL‐12 exerts its effect when present during, as well as after, TCR signaling. In contrast, Th2 polarization requires a prolonged TCR stimulation and IL‐4 is effective only when present during the period of TCR triggering. The simultaneous stimulation by TCR and IL‐4 is required to induce demethylation of IL‐4 and IL‐13 genes that accompanies the stochastic generation of Th2 cells producing either or both cytokines. Thus, the duration of TCR stimulation represents a crucial parameter that influences the response to polarizing cytokines and the acquisition of T cell effector functions.
Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies

ABSTRACT ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1–8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.
Cross-View Retrieval via Probability-Based Semantics-Preserving Hashing

For efficiently retrieving nearest neighbors from large-scale multiview data, recently hashing methods are widely investigated, which can substantially improve query speeds. In this paper, we propose an effective probability-based semantics-preserving hashing (SePH) method to tackle the problem of cross-view retrieval. Considering the semantic consistency between views, SePH generates one unified hash code for all observed views of any instance. For training, SePH first transforms the given semantic affinities of training data into a probability distribution, and aims to approximate it with another one in Hamming space, via minimizing their Kullback–Leibler divergence. Specifically, the latter probability distribution is derived from all pair-wise Hamming distances between to-be-learnt hash codes of the training data. Then with learnt hash codes, any kind of predictive models like linear ridge regression, logistic regression, or kernel logistic regression, can be learnt as hash functions in each view for projecting the corresponding view-specific features into hash codes. As for out-of-sample extension, given any unseen instance, the learnt hash functions in its observed views can predict view-specific hash codes. Then by deriving or estimating the corresponding output probabilities with respect to the predicted view-specific hash codes, a novel probabilistic approach is further proposed to utilize them for determining a unified hash code. To evaluate the proposed SePH, we conduct extensive experiments on diverse benchmark datasets, and the experimental results demonstrate that SePH is reasonable and effective.
Multiuser SM-MIMO versus Massive MIMO: Uplink Performance Comparison

In this paper, we propose algorithms for signal detection in large-scale multiuser {\em spatial modulation multiple-input multiple-output (SM-MIMO)} systems. In large-scale SM-MIMO, each user is equipped with multiple transmit antennas (e.g., 2 or 4 antennas) but only one transmit RF chain, and the base station (BS) is equipped with tens to hundreds of (e.g., 128) receive antennas. In SM-MIMO, in a given channel use, each user activates any one of its multiple transmit antennas and the index of the activated antenna conveys information bits in addition to the information bits conveyed through conventional modulation symbols (e.g., QAM). We propose two different algorithms for detection of large-scale SM-MIMO signals at the BS; one is based on {\em message passing} and the other is based on {\em local search}. The proposed algorithms are shown to achieve very good performance and scale well. Also, for the same spectral efficiency, multiuser SM-MIMO outperforms conventional multiuser MIMO (recently being referred to as massive MIMO) by several dBs; for e.g., with 16 users, 128 antennas at the BS and 4 bpcu per user, SM-MIMO with 4 transmit antennas per user and 4-QAM outperforms massive MIMO with 1 transmit antenna per user and 16-QAM by about 4 to 5 dB at $10^{-3}$ uncoded BER. The SNR advantage of SM-MIMO over massive MIMO can be attributed to the following reasons: (i) because of the spatial index bits, SM-MIMO can use a lower-order QAM alphabet compared to that in massive MIMO to achieve the same spectral efficiency, and (ii) for the same spectral efficiency and QAM size, massive MIMO will need more spatial streams per user which leads to increased spatial interference.
A Novel Role-based Access Control Model in Cloud Environments

AbstractIn Cloud environments, the relationship between resources and users is more ad hoc and dynamic. The role-based access control (RBAC) model is an appropriate access control model for Cloud environments. When using the RBAC model in Cloud environments, some new elements should be considered. This pa- per proposes a SAT-RBAC model (security and availability based trust relationship in RBAC) and adopts the following elements as the main factors of a trust relationship: the security state and network avail- ability of the host used by a user, the protection state of the service providers that are related to the role. A security-based scheduling model for Cloud environments is presented. Because of the uncertainty of Cloud environments, the trust relationship is divided into three zones: the unbelievable zone, the prob- able believable zone and the believable zone. Bayesian method is used to estimate the trust probability distribution in the probable believable zone. This paper also provides algorithms .
Screening interval recommendations following a normal colonoscopy in individuals with a familial risk of colorectal cancer

Abstract Background In view of the increased risk of developing colorectal cancer (CRC) in individuals with affected first-degree relatives (FDRs), the German evidence-based S3 guideline recommends having the first screening colonoscopy early and then, following a normal examination, repeating it at least every 10 years. The aim of this analysis was to explore colonoscopy interval recommendations in clinical practice among individuals aged < 55 years with a familial risk of CRC. Methods We analyzed data from the FRIDA.Frankfurt study. Patients aged 40 – 54 years with at least 1 reported FDR with CRC (excluding suspected/known hereditary cancer syndromes) and a normal colonoscopy result (no findings) were included. Data on colonoscopist recommendations for intervals between subsequent colonoscopies were extracted from colonoscopy reports. Results Of 63 reports of normal colonoscopies, 20 (32 %) did not include a recommendation on when to undergo a further colonoscopy. Of 43 reports with recommendations, 40 (93 %) suggested an interval that was shorter than the recommended maximum interval in the guideline: 1 (2 %) was for a 3-year interval, 37 (86 %) were for 5-year intervals, and 2 (5 %) were for 8-year intervals. Conclusions Although the low number of cases limits generalizability, the results indicate that recommended intervals in clinical practice are considerably shorter than the recommended maximum interval in the guideline.
Clinical Utility of Fecal Calprotectin Monitoring in Asymptomatic Patients with Inflammatory Bowel Disease: A Systematic Review and Practical Guide

Background: In asymptomatic patients with inflammatory bowel disease (IBD), “monitoring” involves repeated testing aimed at early recognition of disease exacerbation. We aimed to determine the usefulness of repeated fecal calprotectin (FC) measurements to predict IBD relapses by a systematic literature review. Methods: An electronic search was performed in Medline, Embase, and Cochrane from inception to April 2016. Inclusion criteria were prospective studies that followed patients with IBD in remission at baseline and had at least 2 consecutive FC measurements with a test interval of 2 weeks to 6 months. Methodological assessment was based on the second Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist. Results: A total of 1719 articles were identified; 193 were retrieved for full text review. Six studies met eligibility for inclusion. The time interval between FC tests varied between 1 and 3 months. Asymptomatic patients with IBD who had repeated FC measurements above the study's cutoff level had a 53% to 83% probability of developing disease relapse within the next 2 to 3 months. Patients with repeated normal FC values had a 67% to 94% probability to remain in remission in the next 2 to 3 months. The ideal FC cutoff for monitoring could not be identified because of the limited number studies meeting inclusion criteria and heterogeneity between selected studies. Conclusions: Two consecutively elevated FC values are highly associated with disease relapse, indicating a consideration to proactively optimize IBD therapy plans. More prospective data are necessary to assess whether FC monitoring improves health outcomes.
Biomarkers of Alzheimer disease in plasma

SummaryPlasma and serum biochemical markers proposed for Alzheimer disease (AD) are based on pathophysiologic processes such as amyloid plaque formation [amyloid β-protein (Aβ), Aβ autoantibodies, platelet amyloid precursor protein (APP) isoforms], inflammation (cytokines), oxidative stress (vitamin E, isoprostanes), lipid metabolism (apolipoprotein E, 24S-hydroxycholesterol), and vascular disease [homocysteine, lipoprotein (a)]. Most proteins or metabolites evaluated in plasma or serum thus far are, at best, biological correlates of AD: levels are statistically different in AD versus controls in some cohorts, but they lack sensitivity or specificity for diagnosis or for tracking response to therapy. Approaches combining panels of existing biomarkers or surveying the range of proteins in plasma (proteomics) show promise for discovering biomarker profiles that are characteristic of AD, yet distinct from nondemented patients or patients with other forms of dementia.