Miracle-dz/UniFAR-FTUs huggingface dataset:
Natriuretic response to renal medullary endothelin B receptor activation is impaired in Dahl‐salt sensitive rats on a high‐caloric diet

Renal medullary endothelin B receptors (ETB) mediate sodium excretion and blood pressure (BP) control. Several animal models of hypertension including the Dahl salt sensitive (DS) rat on a high salt diet have impaired renal medullary endothelin system. Our lab has recently reported that the DS rat becomes hypertensive on a normal salt, high‐caloric diet. Thus we hypothesized that renal medullary ETB function is dysfunctional in DS rats fed a high‐caloric diet. The diuretic and natriuretic response to intramedullary infusion of ETB agonist sarafotoxin 6c (S6c) was determined in DS rats fed either a normal (14% fat; 3.93 kcal/g) or high‐caloric diet (59% fat; 5.45 kcal/g) for 4 weeks. We found that 4‐week high‐caloric diet elevated systolic BP in DS rats (126±2 vs. 143±3 mmHg, p<0.05). In DS rats fed a regular diet, intramedullary infusion of S6c (0.45 μg/kg/hr) increased urine flow (3.6±0.5 μl/min during baseline vs. 7.0±0.5 μl/min after S6c; p<0.05) and sodium excretion (0.42±0.09 vs. 0.97±0.08 μmol/min; p<0.05). However, DS rats fed a high‐caloric diet did not display an increase in urine flow (2.8±0.3 vs. 4.3±0.5 μl/min) or sodium excretion (0.35±0.07 vs. 0.48±0.12 μmol/min) upon S6c infusion. These data demonstrate that renal medullary ETB function is impaired in DS rats fed a high‐caloric diet, which may contribute to the elevation of blood pressure during high‐caloric feeding in this model.
Parental socioeconomic status and risk of cerebral palsy in the child: evidence from two Nordic population-based cohorts

Abstract Background We investigated whether the risk of cerebral palsy (CP) in the child varies by parents’ socioeconomic status, in Denmark and Norway. Methods We included almost 1.3 million children born in Demark during 1981–2007 and 2.4 million children born in Norway during 1967–2007, registered in the Medical Birth registries. Data on births were linked to Statistics Denmark and Norway to retrieve information on parents’ education and relationship status and, in Denmark, also income. CP diagnoses were obtained from linkage with national registries. We used multivariate log-binominal regression models to estimate relative risk (RR) of CP according to parental socioeconomic status. Results There was a strong trend of decreasing risk of CP with additional education of both the mother and the father. These trends were nearly identical for the two parents, with a one-third reduction in risk for those with the highest education compared with parents with the lowest education. When both parents had high education, risk of CP was further reduced (RR 0.58, 0.53–0.63). Women with partners had a reduction in risk (RR 0.79, 0.74–0.85) compared with single mothers overall. Risk patterns were stable over time, across countries and within spastic bilateral and unilateral CP. Household income was not associated with risk of CP. Conclusions Risk of CP in two Scandinavian countries was lower among educated parents and mothers with a partner, but unrelated to income. Factors underlying this stable association with education are unknown, but could include differences in potentially modifiable lifestyle factors and health behaviours.
Training Performed Above Lactate Threshold Decreases p53 and Shelterin Expression in Mice

Abstract Telomere shortening is associated to sarcopenia leading to functional impairment during aging. There are mechanisms associated with telomere attrition, as well to its protection and repair. Physical training is a factor that attenuates telomere shortening, but little is known about the effects of different exercise intensities on telomere biology. Thus, we evaluated the effects of exercise intensity (moderate vs. high-intensity domain) on gene expression of senescence markers Checkpoint kinase 2 and tumor suppressor (Chk2 and p53, respectively), shelterin telomere repeat binding 1 and 2 (Trf1/Trf2), DNA repair (Xrcc5), telomerase reverse transcriptase (mTERT) and telomere length in middle aged mice. Three groups were studied: a control group (CTL) and two groups submitted to swimming at intensities below the lactate threshold (LI group) and above the lactate threshold (HI group) for 40 and 20 min respectively, for 12 weeks. After training, the HI group showed reduction in p53 expression in the muscle, and decreased shelterin complex expression when compared to LI group. No differences were observed between groups for mTERT expression and telomere length. Thus, exercise training in high-intensity domain was more effective on reducing markers of senescence and apoptosis. The higher intensity exercise training also diminished shelterin expression, with no differences in telomere length and mTERT expression. Such results possibly indicate a more effective DNA protection for the higher-intensity exercise training.
Activating the pregnane X receptor by imperatorin attenuates dextran sulphate sodium‐induced colitis in mice

Activation of the human pregnane X receptor (PXR; NR1I2) has potential therapeutic uses for inflammatory bowel disease (IBD). Imperatorin (IMP), a naturally occurring coumarin, is the main bioactive ingredient of Angelica dahurica Radix, which is regularly used to treat the common cold and intestinal disorders. However, there are no data on the protective effects of IMP against IBD.
A data-driven method for identifying shorter symptom criteria sets: the case for DSM-5 alcohol use disorder

Abstract Background Although the DSM is a widely used diagnostic guide, lengthy criteria sets can be problematic and provide the primary motivation to identify short-forms. Using the 11 diagnostic criteria provided by the DSM-5 for alcohol use disorder (AUD), the present study develops a data-driven method to systematically identify subsets and associated cut-offs that yield diagnoses as similar as possible to use all 11 criteria. Method Relying on data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III), our methodology identifies diagnostic short-forms for AUD by: (1) maximizing the association between the sum scores of all 11 criteria with newly constructed subscales from subsets of criteria; (2) optimizing the similarity of AUD prevalence between the current DSM-5 rule and newly constructed diagnostic short-forms; (3) maximizing sensitivity and specificity of the short-forms against the current DSM-5 rule; and (4) minimizing differences in the accuracy of the short-form across chosen covariates. Replication is shown using NESARC-Wave 2. Results More than 11 000 diagnostic short-forms for DSM-5 AUD can be created and our method narrows down the optimal choices to eight. Results found that ‘Neglecting major roles’ and ‘Activities given up’ could be dropped with practically no change in who is diagnosed (specificity = 100%, sensitivity ⩾ 99.6%) or the severity of those diagnosed (κ = 0.97). Conclusions With a continuous improvement model adopted by the APA for DSM revisions, we offer a data-driven tool (a SAS Macro) that identifies diagnostic short-forms in a systematic and reproducible way to help advance potential improvements in future DSM revisions.
Molecular Analyses Support the Safety and Activity of Retroviral Replicating Vector Toca 511 in Patients

Purpose: Toca 511 is a gammaretroviral replicating vector encoding cytosine deaminase that selectively infects tumor cells and converts the antifungal drug 5-fluorocytosine into the antineoplastic drug 5-fluorouracil, which directly kills tumor cells and stimulates antitumor immune responses. As part of clinical monitoring of phase I clinical trials in recurrent high-grade glioma, we have performed extensive molecular analyses of patient specimens to track vector fate. Patients and Methods: Toca 511 and Toca FC (extended-release 5-fluorocytosine) have been administered to 127 high-grade glioma patients across three phase I studies. We measured Toca 511 RNA and DNA levels in available body fluids and tumor samples from patients to assess tumor specificity. We mapped Toca 511 integration sites and sequenced integrated Toca 511 genomes from patient samples with detectable virus. We measured Toca 511 levels in a diverse set of tissue samples from one patient. Results: Integrated Toca 511 is commonly detected in tumor samples and is only transiently detected in blood in a small fraction of patients. There was no believable evidence for clonal expansion of cells with integrated Toca 511 DNA, or preferential retrieval of integration sites near oncogenes. Toca 511 sequence profiles suggest most mutations are caused by APOBEC cytidine deaminases acting during reverse transcription. Tissue samples from a single whole-body autopsy affirm Toca 511 tumor selectivity. Conclusions: Toca 511 and Toca FC treatment was not associated with inappropriate integration sites and clonal expansion. The vector is tumor-selective and persistent in patients who received Toca 511 injections. Clin Cancer Res; 24(19); 4680–93. ©2018 AACR.
Socioeconomic influences on brain function: implications for health

Socioeconomic‐based disparities in physical health outcomes are well established, with individuals from lower socioeconomic status (SES) backgrounds being more likely to experience chronic disease morbidity and early mortality compared to those from higher SES strata. While numerous studies in recent decades have focused on understanding the contextual, psychosocial, and biological mechanisms linking SES and health, the neural pathways that contribute to this relationship are currently underinvestigated. The present paper reviews and synthesizes the small number of published studies that have explored links between SES and health‐relevant neural functioning. Specifically, current knowledge of the relationship between socioeconomic factors and neural systems that may be affected by low SES contexts, including those related to processing threat and stress, responding to reward, and engaging in emotion regulation, is reviewed. Gaps in our knowledge that could be filled by health neuroscience research are emphasized, in an effort to catalyze future studies in this area. Understanding the neural mechanisms linking SES and health is crucial for building comprehensive models of the pathways by which social inequalities become health inequalities and may help identify novel targets for intervention to prevent health disparities. Health neuroscience research has a critical role to play in this important area of research.
Type 2 diabetes mellitus and thyroid disease: a two-sided analysis.

AIM OF THE STUDY To assess the prevalence of thyroid diseases in patients with type 2 diabetes mellitus (T2DM) in comparison with normal population; to determine prevalence of T2DM in patients with thyroid diseases. MATERIALS AND METHODS First group consisted of 60 patients with T2DM without previous history of thyroid disease. Second group consisted of 60 patients with thyroid disease without any previously known impairment of glucose metabolism. Control group (CG) included 100 subjects who had no previous history of thyroid disease or glucose metabolism impairment. Blood tests were performed to evaluate thyroid and glucose metabolism parameters. RESULTS We found a significantly higher prevalence of thyroid diseases in patients with T2DM when compared to CG. Patients with T2DM showed to have higher serum levels of free triiodothyronine (fT3), thyroid‑stimulating hormone (TSH) and anti-thyroid peroxidase (anti-TPO) autoantibodies. We found no statistical significance in prevalence of T2DM in patients with thyroid diseases and CG. Among parameters of glucose metabolism, there were only higher fasting glucose levels in patients with hyperthyroidism and autoimmune thyroid disease (AITD). CONCLUSIONS Patients with T2DM showed to have higher prevalence of AITD and primary hypothyroidism. We did not find higher prevalence of T2DM in patients with thyroid diseases (Tab. 3, Ref. 29).
An Algorithm Based on Deep Learning for Predicting In‐Hospital Cardiac Arrest

Background In‐hospital cardiac arrest is a major burden to public health, which affects patient safety. Although traditional track‐and‐trigger systems are used to predict cardiac arrest early, they have limitations, with low sensitivity and high false‐alarm rates. We propose a deep learning–based early warning system that shows higher performance than the existing track‐and‐trigger systems. Methods and Results This retrospective cohort study reviewed patients who were admitted to 2 hospitals from June 2010 to July 2017. A total of 52 131 patients were included. Specifically, a recurrent neural network was trained using data from June 2010 to January 2017. The result was tested using the data from February to July 2017. The primary outcome was cardiac arrest, and the secondary outcome was death without attempted resuscitation. As comparative measures, we used the area under the receiver operating characteristic curve (AUROC), the area under the precision–recall curve (AUPRC), and the net reclassification index. Furthermore, we evaluated sensitivity while varying the number of alarms. The deep learning–based early warning system (AUROC: 0.850; AUPRC: 0.044) significantly outperformed a modified early warning score (AUROC: 0.603; AUPRC: 0.003), a random forest algorithm (AUROC: 0.780; AUPRC: 0.014), and logistic regression (AUROC: 0.613; AUPRC: 0.007). Furthermore, the deep learning–based early warning system reduced the number of alarms by 82.2%, 13.5%, and 42.1% compared with the modified early warning system, random forest, and logistic regression, respectively, at the same sensitivity. Conclusions An algorithm based on deep learning had high sensitivity and a low false‐alarm rate for detection of patients with cardiac arrest in the multicenter study.
Hepatocellular Carcinoma: Diagnosis, Treatment Algorithms, and Imaging Appearance after Transarterial Chemoembolization

Abstract Hepatocellular carcinoma (HCC) is a common cause of cancer-related death, with incidence increasing worldwide. Unfortunately, the overall prognosis for patients with HCC is poor and many patients present with advanced stages of disease that preclude curative therapies. Diagnostic and interventional radiologists play a key role in the management of patients with HCC. Diagnostic radiologists can use contrast-enhanced computed tomography (CT), magnetic resonance imaging, and ultrasound to diagnose and stage HCC, without the need for pathologic confirmation, by following established criteria. Once staged, the interventional radiologist can treat the appropriate patients with percutaneous ablation, transarterial chemoembolization, or radioembolization. Follow-up imaging after these liver-directed therapies for HCC can be characterized according to various radiologic response criteria; although, enhancement-based criteria, such as European Association for the Study of the Liver and modified Response Evaluation Criteria in Solid Tumors, are more reflective of treatment effect in HCC. Newer imaging technologies like volumetric analysis, dual-energy CT, cone beam CT and perfusion CT may provide additional benefits for patients with HCC.
Patient Perceptions and Quality of Life After Colon and Rectal Surgery: What Do Patients Really Want?

BACKGROUND: Colorectal surgery outcomes must be accurately assessed and aligned with patient priorities. No study to date has investigated the patient’s subjective assessment of outcomes most important to them during and following their surgical recovery. Although surgeons greatly value the benefits of laparoscopy, patient priorities remain understudied. OBJECTIVE: This study aimed to assess what aspects of patients’ perioperative care and recovery they value most when queried in the postoperative period. DESIGN: This study is an exploratory cross-sectional investigation of a defined retrospective patient population. Enrollees were stratified into subcategories and analyzed, with statistical analysis performed via &khgr;2 test and unpaired t test. SETTINGS: This study was conducted at a single academic medical center in New England. PATIENTS: Patients who underwent a colorectal surgical resection between 2009 and 2015 were selected. INTERVENTIONS: Patients within a preidentified population were asked to voluntarily complete a 32-item questionnaire regarding their surgical care. MAIN OUTCOME MEASURES: The primary outcomes measured were patient perioperative and postoperative quality of life and satisfaction on selected areas of functioning. RESULTS: Of 167 queried respondents, 92.2% were satisfied with their recovery. Factors considered most important included being cured of colorectal cancer (76%), not having a permanent stoma (78%), and avoiding complications (74%). Least important included length of stay (13%), utilization of laparoscopy (14%), and incision appearance and length (2%, 4%). LIMITATIONS: The study had a relatively low response rate, the study is susceptible to responder’s bias, and there is temporal variability from surgery to questionnaire within the patient population. CONCLUSIONS: Overall, patients reported high satisfaction with their care. Most important priorities included being free of cancer, stoma, and surgical complications. In contrast, outcomes traditionally important to surgeons such as laparoscopy, incision appearance, and length of stay were deemed less important. This research helps elucidate the outcomes patients truly consider valuable, and surgeons should focus on these outcomes when making surgical decisions. See Video Abstract at http://links.lww. com/DCR/A596. See Visual Abstract at https://tinyurl.com/yb25xl66.
Mitochondrial Dysfunction and Infection Generate Immunity–Fecundity Tradeoffs in Drosophila

Abstract Physiological responses to short-term environmental stressors, such as infection, can have long-term consequences for fitness, particularly if the responses are inappropriate or nutrient resources are limited. Genetic variation affecting energy acquisition, storage, and usage can limit cellular energy availability and may influence resource-allocation tradeoffs even when environmental nutrients are plentiful. Here, we utilized Drosophila mitochondrial–nuclear genotypes to test whether disrupted mitochondrial function interferes with nutrient-sensing pathways, and whether this disruption has consequences for tradeoffs between immunity and fecundity. We found that an energetically-compromised genotype was relatively resistant to rapamycin—a drug that targets nutrient-sensing pathways and mimics resource limitation. Dietary resource limitation decreased survival of energetically-compromised flies. Furthermore, survival of infection with a natural pathogen was decreased in this genotype, and females of this genotype experienced immunity–fecundity tradeoffs that were not evident in genotypic controls with normal energy metabolism. Together, these results suggest that this genotype may have little excess energetic capacity and fewer cellular nutrients, even when environmental nutrients are not limiting. Genetic variation in energy metabolism may therefore act to limit the resources available for allocation to life-history traits in ways that generate tradeoffs even when environmental resources are not limiting.
Molecular model of human tropoelastin and implications of associated mutations

Significance Tropoelastin, the precursor molecule to elastic fibers, is a large, flexible elastic protein whose structure has been the subject of investigation and debate over several decades. Here, we present the fully atomistic structure of human tropoelastin, based on molecular dynamics simulations, and validate it with experiments. We explore the functional role of two key residues by inserting alanine substitutions and explain conformational changes and variations in hierarchical assembly. We also predict essential dynamics of the molecule by building elastin network models, to explain experimentally observed differences in assembly. Finally, we study the structural and dynamic molecular changes associated with the acquired cutis laxa disorder. The approach developed here is applicable for studying structure and function of other highly disordered proteins. Protein folding poses unique challenges for large, disordered proteins due to the low resolution of structural data accessible in experiment and on the basis of short time scales and limited sampling attainable in computation. Such molecules are uniquely suited to accelerated-sampling molecular dynamics algorithms due to a flat-energy landscape. We apply these methods to report here the folded structure in water from a fully extended chain of tropoelastin, a 698-amino acid molecular precursor to elastic fibers that confer elasticity and recoil to tissues, finding good agreement with experimental data. We then study a series of artificial and disease-related mutations, yielding molecular mechanisms to explain structural differences and variation in hierarchical assembly observed in experiment. The present model builds a framework for studying assembly and disease and yields critical insight into molecular mechanisms behind these processes. These results suggest that proteins with disordered regions are suitable candidates for characterization by this approach.
The Association Between Cannabis Use and Aberrant Behaviors During Chronic Opioid Therapy for Chronic Pain

Objective Health care providers are likely to see an increase in the concomitant use of cannabis and opioids, particularly with the increased liberalization and ongoing research into the possible role of medical marijuana for chronic pain. Recent literature reports a prevalence of concurrent use ranging from 8.9% to 31.8%. The primary aim of this study was to determine the relationship between cannabis use and aberrant drug behaviors in noncancer pain patients receiving chronic opioid therapy. Design Retrospective chart review. Setting Community-based, interdisciplinary pain management center. Subjects Data from 209 patients who were evaluated for a medication management program between October 1, 2011, and January 1, 2014, and met inclusion criteria. Forty-four were positive for cannabis in their initial random urine drug toxicology. Methods Data from electronic health records, including demographics, urine drug toxicology, disability, opioid dose, opioid risk assessment data, and pain severity were analyzed to examine differences among cannabis users and noncannabis users. Results Subjects with cannabis in their initial urine drug toxicology were more likely to have a future occurrence of an opioid-related aberrancy (P < 0.001), be male (P = 0.047), have a history of substance abuse (P = 0.013), and be enrolled into a higher level of clinical monitoring of opioid medication use (P = 0.008). No other associations with demographic and clinical variables reached statistical significance. Conclusions Concurrent use of cannabis and opioids by patients with chronic pain appears to indicate higher risk for opioid misuse. Closer monitoring for opioid-related aberrancy is indicated for this group of patients.
Conditioning Deep Generative Raw Audio Models for Structured Automatic Music

Existing automatic music generation approaches that feature deep learning can be broadly classified into two types: raw audio models and symbolic models. Symbolic models, which train and generate at the note level, are currently the more prevalent approach; these models can capture long-range dependencies of melodic structure, but fail to grasp the nuances and richness of raw audio generations. Raw audio models, such as DeepMind's WaveNet, train directly on sampled audio waveforms, allowing them to produce realistic-sounding, albeit unstructured music. In this paper, we propose an automatic music generation methodology combining both of these approaches to create structured, realistic-sounding compositions. We consider a Long Short Term Memory network to learn the melodic structure of different styles of music, and then use the unique symbolic generations from this model as a conditioning input to a WaveNet-based raw audio generator, creating a model for automatic, novel music. We then evaluate this approach by showcasing results of this work.