Miracle-dz/UniFAR-FTUs huggingface dataset:
The basolateral amygdala-medial prefrontal cortex circuitry regulates behavioral flexibility during appetitive reversal learning.

Environmental cues can become predictors of food availability through Pavlovian conditioning. Two forebrain regions important in this associative learning are the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). Recent work showed the BLA-mPFC pathway is activated when a cue reliably signals food, suggesting the BLA informs the mPFC of the cue's value. The current study tested this hypothesis by altering the value of 2 food cues using reversal learning and illness-induced devaluation paradigms. Rats that received unilateral excitotoxic lesions of the BLA and mPFC contralaterally placed, along with ipsilateral and sham controls, underwent discriminative conditioning, followed by reversal learning and then devaluation. All groups successfully discriminated between 2 auditory stimuli that were followed by food delivery (conditional stimulus [CS] +) or not rewarded (CS-), demonstrating this learning does not require BLA-mPFC communication. When the outcomes of the stimuli were reversed, the rats with disconnected BLA-mPFC (contralateral condition) showed increased responding to the CSs, especially to the rCS + (original CS-) during the first session, suggesting impaired cue memory recall and behavioral inhibition compared to the other groups. For devaluation, all groups successfully learned conditioned taste aversion; however, there was no evidence of cue devaluation or differences between groups. Interestingly, at the end of testing, the nondevalued contralateral group was still responding more to the original CS + (rCS-) compared to the devalued contralateral group. These results suggest a potential role for BLA-mPFC communication in guiding appropriate responding during periods of behavioral flexibility when the outcomes, and thus the values, of learned cues are altered. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Racial/ethnic disparities in the risk of intracerebral hemorrhage recurrence

Objective To estimate the risk of intracerebral hemorrhage (ICH) recurrence in a large, diverse, US-based population and to identify racial/ethnic and socioeconomic subgroups at higher risk. Methods We performed a longitudinal analysis of prospectively collected claims data from all hospitalizations in nonfederal California hospitals between 2005 and 2011. We used validated diagnosis codes to identify nontraumatic ICH and our primary outcome of recurrent ICH. California residents who survived to discharge were included. We used log-rank tests for unadjusted analyses of survival across racial/ethnic groups and multivariable Cox proportional hazards regression to determine factors associated with risk of recurrence after adjusting for potential confounders. Results We identified 31,355 California residents with first-recorded ICH who survived to discharge, of whom 15,548 (50%) were white, 6,174 (20%) were Hispanic, 4,205 (14%) were Asian, and 2,772 (9%) were black. There were 1,330 recurrences (4.1%) over a median follow-up of 2.9 years (interquartile range 3.8). The 1-year recurrence rate was 3.0% (95% confidence interval [CI] 2.8%–3.2%). In multivariable analysis, black participants (hazard ratio [HR] 1.22; 95% CI 1.01–1.48; p = 0.04) and Asian participants (HR 1.29; 95% CI 1.10–1.50; p = 0.001) had a higher risk of recurrence than white participants. Private insurance was associated with a significant reduction in risk compared to patients with Medicare (HR 0.60; 95% CI 0.50–0.73; p < 0.001), with consistent estimates across racial/ethnic groups. Conclusions Black and Asian patients had a higher risk of ICH recurrence than white patients, whereas private insurance was associated with reduced risk compared to those with Medicare. Further research is needed to determine the drivers of these disparities.
Local Proximity for Enhanced Visibility in Haze

Atmospheric medium often constrains the visibility of outdoor scenes due to scattering of light rays. This causes attenuation in the irradiance reaching the imaging device along with an additive component to render a hazy effect in the image. The visibility is further reduced for poorly illuminated scenes. The attenuation becomes wavelength dependent in underwater scenario, causing undesired color cast along with hazy effect. In order to suppress the effect of different atmospheric/underwater conditions such as haze and to enhance the contrast of such images, we reformulate local haziness in a generalized manner. The parameters are estimated by harnessing the similarity of patches within a local neighborhood. Unlike existing methods, our approach is developed based on the assumption that for outdoor scenes, the depth of patches changes gradually in a local neighborhood surrounding the patch. This change in depth can be approximated by patch similarity in that neighborhood. As the attenuation in irradiance of an image in presence of atmospheric medium relies on the depth of the scene, the coefficients related to the attenuation are estimated from the weights of patch similarity. The additive haze effect is deduced using non-local mean of the patch. Our experimental results demonstrate the effectiveness of our approach in reducing the haze component as well as in enhancing the image under different conditions of haze (daytime, nighttime, and underwater).
A novel multi-locus genetic risk score identifies patients with higher risk of generalized aggressive periodontitis.

BACKGROUND Each genetic variant individually explains only a tiny proportion of the genetic variation with insignificant predictive power. The tool of multi-locus genetic risk score (GRS), which aggregates information from multiple genetic variants, has been widely utilized in many complex diseases but not applied to generalized aggressive periodontitis (GAgP) yet. OBJECTIVE To examine the joint genetic effects of significant risk variants based on a candidate gene study and their combination effects with conventional risk factors on risk of GAgP. METHODS 335 GAgP patients and 114 healthy controls were enrolled in the case-control study. The unweighted GRS (uGRS) and weighted GRS (wGRS) were calculated based on significant variants. Logistic regression models were conducted for the GRS-based association analyses on the risk of GAgP. Receiver operating characteristic (ROC) analysis was performed to compare the discriminatory ability of predictors of GAgP risk. RESULTS Four loci were found to be significantly associated with GAgP. They were MMP8 rs11225395 (OR = 1.40, 95%CI: 1.03, 1.91), EGF rs2237051 (OR = 1.41, 95%CI: 1.03, 1.93), PPAR-a rs4253623 (OR = 1.53, 95%CI: 1.03, 2.26) and APOE rs429358 (OR = 1.79, 95%CI: 1.08, 2.97). Each additional point of the uGRS/wGRS was associated with a 50%/31% increased risk of developing GAgP (OR = 1.50, 95% CI: 1.21-1.85 or OR = 1.31, 95% CI: 1.14-1.51, respectively) after adjusting for age, gender and BMI. Participants in the high group of uGRS/wGRS (OR = 2.87, 95%CI: 1.59-5.17 or OR = 2.67, 95%CI: 1.46-4.88, respectively) and the middle group of uGRS/wGRS (OR = 2.21, 95%CI: 1.29-3.78 or OR = 1.88, 95%CI: 1.09-3.08, respectively) had an increased risk of GAgP comparing with those in the low group of score after adjustment for age, gender and BMI. The addition of GRS to a model of conventional risk factors improved discrimination by 4.5% (from 0.695 to 0.740, P = 0.048). CONCLUSION We demonstrated that the multi-locus GRS based on 4 significant SNPs might be useful for assessing genetic predisposition to GAgP. The GRS in combination with conventional risk factors significantly improved the power of identifying subgroups of Chinese population with a particularly high risk for GAgP. This article is protected by copyright. All rights reserved.
Adding value to core outcome set development using multimethod systematic reviews

Trials evaluating the same interventions rarely measure or report identical outcomes. This limits the possibility of aggregating effect sizes across studies to generate high‐quality evidence through systematic reviews and meta‐analyses. To address this problem, core outcome sets (COS) establish agreed sets of outcomes to be used in all future trials. When developing COS, potential outcome domains are identified by systematically reviewing the outcomes of trials, and increasingly, through primary qualitative research exploring the experiences of key stakeholders, with relevant outcome domains subsequently determined through transdisciplinary consensus development. However, the primary qualitative component can be time consuming with unclear impact. We aimed to examine the potential added value of a qualitative systematic review alongside a quantitative systematic review of trial outcomes to inform COS development in neonatal care using case analysis methods. We compared the methods and findings of a scoping review of neonatal trial outcomes and a scoping review of qualitative research on parents', patients', and professional caregivers' perspectives of neonatal care. Together, these identified a wider range and greater depth of health and social outcome domains, some unique to each review, which were incorporated into the subsequent Delphi process and informed the final set of core outcome domains. Qualitative scoping reviews of participant perspectives research, used in conjunction with quantitative scoping reviews of trials, could identify more outcome domains for consideration and could provide greater depth of understanding to inform stakeholder group discussion in COS development. This is an innovation in the application of research synthesis methods.
Regulatory T-cell subset distribution in children with primary hypertension is associated with hypertension severity and hypertensive target organ damage.

BACKGROUND The relationship between circulating regulatory T-cell (Tregs) subset distribution and hypertension severity in children with primary hypertension is not known. We aimed to find out if target organ damage (TOD) in children with primary hypertension is related to defects in Tregs distribution reflected by their phenotype characteristics. METHODS The study constituted 33 nontreated hypertensive children and 35 sex-matched and age-matched controls. Using multicolor flow cytometry technique, we assessed a distribution of the total Tregs (CD4CD25CD127) and their subsets (CD45RA-naive Tregs, CD45RA memory/activated Tregs, CD45RACD31 recent thymic emigrants Tregs and mature naive CD45RACD31 Tregs) in the whole blood. RESULTS Hypertensive children showed decreased percentage of the total Tregs, the CD45RA-naive Tregs, the total CD31 Tregs and the recent thymic emigrants Tregs but elevation of the CD45RA memory/activated Treg and mature naive CD45RACD31 Tregs. Decreased frequency of the total Tregs, naive Tregs and CD31-bearing Treg cell subsets (CD31 total Tregs, CD45RACD31 recent thymic emigrants Tregs) negatively correlated to TOD markers, arterial stiffness and blood pressure elevation. In contrast, increased percentage of memory Tregs and CD31 Tregs subsets positively correlated to organ damage markers, arterial stiffness and blood pressure values. These changes were independent of BMI, age, sex and hsCRP. CONCLUSION Both diagnosis of hypertension, TOD and arterial stiffness in hypertensive children were associated with decreased population of total CD4 Tregs, limited output of recent thymic emigrants Tregs, and increased pool of activated/memory Tregs. Hypertension was an independent predictor of the circulating Treg subsets distribution irrespective of hsCRP.
The Epidemiology of Herpes Zoster in Immunocompetent, Unvaccinated Adults ≥50 Years Old: Incidence, Complications, Hospitalization, Mortality, and Recurrence

Abstract Background Data on the epidemiology of herpes zoster (HZ), particularly in the unvaccinated immunocompetent population, are needed to assess disease burden and the potential impact of vaccination. Methods The study at a large health care organization comprised: (1) incidence estimated from immunocompetent adults aged ≥50 years unvaccinated with zoster vaccine live who had incident HZ in 2011–2015; (2) proportion of HZ-related nonpain complications assessed by double abstraction of electronic health records (EHRs) of 600 incident patients 2011–2015; (3) HZ-related hospitalizations among HZ patients diagnosed in 2015; (4) HZ-related death determined from automated data and EHRs; and (5) recurrent HZ identified from a cohort initially diagnosed with HZ in 2007–2008 and followed through 2016. Results HZ incidence rate was 9.92/1000 person-years (95% confidence interval [CI], 9.82–10.01). Proportions of cutaneous, neurologic, and other complications were 6.40% (95% CI,1.73%–11.07%), 0.77% (95% CI, .00%–2.36%), and 1.01% (95% CI, .00%–2.93%), respectively. Only 0.86% of patients had an HZ-related hospitalization. The case-fatality rate was 0.04%. Recurrence rate was 10.96/1000 person-years (95% CI, 10.18–11.79) with 10-year recurrence risk of 10.26% (95% CI, 9.36%–11.23%). Conclusions These recent HZ epidemiology data among an immunocompetent, unvaccinated population measure real-world disease burden.
The cardiac sympathetic co-transmitter neuropeptide Y is pro-arrhythmic following ST-elevation myocardial infarction despite beta-blockade

Abstract Aims ST-elevation myocardial infarction is associated with high levels of cardiac sympathetic drive and release of the co-transmitter neuropeptide Y (NPY). We hypothesized that despite beta-blockade, NPY promotes arrhythmogenesis via ventricular myocyte receptors. Methods and results In 78 patients treated with primary percutaneous coronary intervention, sustained ventricular tachycardia (VT) or fibrillation (VF) occurred in 6 (7.7%) within 48 h. These patients had significantly (P < 0.05) higher venous NPY levels despite the absence of classical risk factors including late presentation, larger infarct size, and beta-blocker usage. Receiver operating curve identified an NPY threshold of 27.3 pg/mL with a sensitivity of 0.83 and a specificity of 0.71. RT-qPCR demonstrated the presence of NPY mRNA in both human and rat stellate ganglia. In the isolated Langendorff perfused rat heart, prolonged (10 Hz, 2 min) stimulation of the stellate ganglia caused significant NPY release. Despite maximal beta-blockade with metoprolol (10 μmol/L), optical mapping of ventricular voltage and calcium (using RH237 and Rhod2) demonstrated an increase in magnitude and shortening in duration of the calcium transient and a significant lowering of ventricular fibrillation threshold. These effects were prevented by the Y1 receptor antagonist BIBO3304 (1 μmol/L). Neuropeptide Y (250 nmol/L) significantly increased the incidence of VT/VF (60% vs. 10%) during experimental ST-elevation ischaemia and reperfusion compared to control, and this could also be prevented by BIBO3304. Conclusions The co-transmitter NPY is released during sympathetic stimulation and acts as a novel arrhythmic trigger. Drugs inhibiting the Y1 receptor work synergistically with beta-blockade as a new anti-arrhythmic therapy.
EVALUATION OF IN VITRO ANTI-INFLAMMATORY ACTIVITY OF HARPAGOPHYTUM PROCUMBENS AND URTICA DIOICA AGAINST THE DENATURATION OF PROTEIN

Anti-denaturation effects of plant extracts in heat treated Bovine Serum Albumin (BSA), are potential therapeutic parameters for finding anti-inflammatory compounds without the use of animal for preliminary pharmacological screening. Harpagophytum procumbens and Urtica Dioica can bring natural compounds with significant anti-inflammatory effects. The anti-denaturation effects of H. procumbens and U. Dioica ethanol extracts and their combinations were evaluated using albumin denaturation assay at different concentrations. Aspirin was used as standard drug. The present finding exhibited a concentration dependent inhibition of protein (albumin) denaturation by H. procumbens and U. Dioica extracts. The effect of Aspirin was found to be less than extracts. In conclusion it can be concluded that H. procumbens and U. Dioica extracts possessed in vitro antiinflammatory effect against the denaturation of protein and H. procumbens was stronger than U. Dioica. Also combination of H. procumbens and U. Dioica extracts hadn’t good effect on inhibition of protein (albumin) denaturation. Further investigations are required to isolate the active component responsible for their anti inflammatory effects.
TFE3‐associated neurodevelopmental disorder: A distinct recognizable syndrome

The transcription factor for immunoglobulin heavy‐chain enhancer 3 (TFE3) gene encodes a transcription factor that regulates embryonic stem cell (ESC) differentiation. Its phosphorylation by the lysosomal Rag GTPase signaling pathway leads to cytoplasmic sequestration and inactivation promoting ESC differentiation and exit from pluripotency. Somatic translocations of this X‐linked gene cause papillary renal cell carcinoma in which nuclear accumulation of the TFE3 oncoprotein is one of the most significant histopathologic characteristics. Early this year, Villegas et al. identified missense mutations in a TFE3 domain required for cytoplasmic inactivation as potentially causal for a mosaic human developmental disorder. They published five patients with de novo TFE3 nonsynonymous missense variants, four females and one male, with severe intellectual disability (5/5), coarse facial features (4/5), and Blaschkoid pigmentary mosaicism (4/5). The only male described has somatic mosaicism. All patients had normal brain Magnetic Resonance Imagings (MRIs). We present two unrelated females with this distinctive phenotype including the above triad along with other features not previously well described. Both were found to have de novo heterozygous variants in TFE3 on whole exome sequencing, one nonsynonymous missense, and one canonical splice site variant, thereby expanding the phenotypic and mutational spectrum for this disorder. Interestingly, due to significant coarsening of the facial features, both patients were initially thought to have a lysosomal storage disorder but enzyme screening and brain MRIs were negative.
Association of visit-to-visit variability in blood pressure and first stroke risk in hypertensive patients with chronic kidney disease.

OBJECTIVE Data on the association between visit-to-visit variability (VVV) in blood pressure (BP) and the risk of stroke among hypertensive patients with chronic kidney disease (CKD) is limited. We aimed to evaluate the relation of VVV in BP with the risk of stroke, and examine any possible effect modifiers in hypertensive patients with mild-to-moderate CKD. METHODS This is a post-hoc analysis of the China Stroke Primary Prevention Trial. A total of 3091 patients with estimated glomerular filtration rate 30-60 ml/min per 1.73 m and/or proteinuria at baseline, without occurring stroke and with BP measurements of at least two visits from randomization to the 12-month visit were included. The main VVV in BP was expressed as SD. The primary outcome was first stroke. RESULTS The median subsequent treatment duration was 3.7 years. After multivariable adjustment, including baseline SBP and mean SBP during the first 12-month follow-up, there was a significantly positive relationship of SD SBP with the risk of subsequent first stroke (per SD increment; odds ratio, 1.41; 95% confidence interval: 1.17-1.69) and first ischemic stroke (odds ratio, 1.55; 95% confidence interval: 1.26-1.90). Results were consistent across various subgroups, including age, sex, baseline SBP, treatment compliance, and mean SBP, concomitant usage of calcium channel blocker during the first 12-month follow-up period. Similar trends were also found for coefficient of variation SBP, and SD or coefficient of variation DBP. However, there was no significant association between BP variability and first hemorrhagic stroke. CONCLUSION In hypertensive adults with mild-to-moderate CKD, visit-to-visit variability in BP was significantly associated with the risk of subsequent first stroke.
Epstein-Barr virus NK and T cell lymphoproliferative disease: report of a 2018 international meeting

Abstract Epstein-Barr virus (EBV) normally infects B cells, but in some persons the virus infects T or NK cells. Infection of B cells can result in infectious mononucleosis, and the virus is associated with several B cell malignancies including Hodgkin lymphoma, Burkitt lymphoma, and diffuse large B cell lymphoma. Infection of T or NK cells with EBV is associated with extranodal NK/T cell lymphoma, aggressive NK-cell leukemia, systemic EBV-associated T-cell lymphoma, and chronic active EBV disease, which in some cases can include hydroa vacciniforme-like lymphoproliferative disease and severe mosquito bite allergy. While NK and T cell lymphoproliferative disease is more common in Asia and Latin America, increasing numbers of cases are being reported from the United States and Europe. This review focuses on classification, clinical findings, pathogenesis, and recent genetic advances in NK and T cell lymphoproliferative diseases associated with EBV.
GABA and glycine neurons from the ventral medullary region inhibit hypoglossal motoneurons.

Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive sleep related losses of upper airway patency that occur most frequently during rapid eye movement (REM) sleep. Hypoglossal motoneurons play a key role in regulating upper airway muscle tone and patency during sleep. REM sleep actives GABA and glycine neurons in the ventral medulla (VM) to induce cortical desynchronization and skeletal muscle atonia during REM sleep; however, the role of this brain region in modulating hypoglossal motor activity is unknown. We combined optogenetic and chemogenetic approaches with in-vitro and in-vivo electrophysiology, respectfully, in GAD2-Cre mice of both sexes to test the hypothesis that VM GABA/glycine neurons control the activity of hypoglossal motoneurons and tongue muscles. Here we show there is a pathway originating from GABA/glycine neurons in the VM that monosynaptically inhibits brainstem hypoglossal motoneurons innervating both tongue protruder genioglossus (GMNs) and retractor (RMNs) muscles. Optogenetic activation of ChR2-expressing fibers induced a greater postsynaptic inhibition in RMNs than in GMNs. In-vivo chemogenetic activation of VM GABA/glycine neurons produced an inhibitory effect on tongue electromyographic (EMG) activity, decreasing both the amplitude and duration of inspiratory-related EMG bursts without any change in respiratory rate. These results indicate that activation of GABA/glycine neurons from the VM inhibits tongue muscles via a direct pathway to both GMNs and RMNs. This inhibition may play a role in REM sleep associated upper airway obstructions that occur in patients with OSA.
Molecular and physiological consequences of faulty eukaryotic ribonucleotide excision repair

The duplication of the eukaryotic genome is an intricate process that has to be tightly safe‐guarded. One of the most frequently occurring errors during DNA synthesis is the mis‐insertion of a ribonucleotide instead of a deoxyribonucleotide. Ribonucleotide excision repair (RER) is initiated by RNase H2 and results in error‐free removal of such mis‐incorporated ribonucleotides. If left unrepaired, DNA‐embedded ribonucleotides result in a variety of alterations within chromosomal DNA, which ultimately lead to genome instability. Here, we review how genomic ribonucleotides lead to chromosomal aberrations and discuss how the tight regulation of RER timing may be important for preventing unwanted DNA damage. We describe the structural impact of unrepaired ribonucleotides on DNA and chromatin and comment on the potential consequences for cellular fitness. In the context of the molecular mechanisms associated with faulty RER, we have placed an emphasis on how and why increased levels of genomic ribonucleotides are associated with severe autoimmune syndromes, neuropathology, and cancer. In addition, we discuss therapeutic directions that could be followed for pathologies associated with defective removal of ribonucleotides from double‐stranded DNA.