Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of ARKL1 as a Negative Regulator of Epstein-Barr Virus Reactivation

Epstein-Barr virus (EBV) maintains a life-long infection due to the ability to alternate between latent and lytic modes of replication and is associated with several types of cancer. We have identified a cellular protein (ARKL1) that acts to repress the reactivation of EBV from the latent to the lytic cycle. We show that ARKL1 acts to repress transcription of the EBV lytic switch protein by inhibiting the activity of the cellular transcription factor c-Jun. This not only provides a new mechanism of regulating EBV reactivation but also identifies a novel cellular function of ARKL1 as an inhibitor of Jun-mediated transcription. ABSTRACT Epstein-Barr virus (EBV) maintains a life-long infection due to the ability to alternate between latent and lytic modes of replication. Lytic reactivation starts with derepression of the Zp promoter controlling BZLF1 gene expression, which binds and is activated by the c-Jun transcriptional activator. Here, we identified the cellular Arkadia-like 1 (ARKL1) protein as a negative regulator of Zp and EBV reactivation. Silencing of ARKL1 in the context of EBV-positive gastric carcinoma (AGS) cells, nasopharyngeal carcinoma (NPC43) cells, and B (M81) cells led to increased lytic protein expression, whereas overexpression inhibited BZLF1 expression. Similar effects of ARKL1 modulation were seen on BZLF1 transcripts as well as on Zp activity in Zp reporter assays, showing that ARKL1 repressed Zp. Proteomic profiling of ARKL1-host interactions identified c-Jun as an ARKL1 interactor, and reporter assays for Jun transcriptional activity showed that ARKL1 inhibited Jun activity. The ARKL1-Jun interaction required ARKL1 sequences that we previously showed mediated binding to the CK2 kinase regulatory subunit CK2β, suggesting that CK2β might mediate the ARKL1-Jun interaction. This model was supported by the findings that silencing of CK2β, but not the CK2α catalytic subunit, abrogated the ARKL1-Jun interaction and phenocopied ARKL1 silencing in promoting EBV reactivation. Additionally, ARKL1 was associated with Zp in reporter assays and this was increased by additional CK2β. Together, the data indicate that ARKL1 is a negative regulator of Zp and EBV reactivation that acts by inhibiting Jun activity through a CK2β-mediated interaction. IMPORTANCE Epstein-Barr virus (EBV) maintains a life-long infection due to the ability to alternate between latent and lytic modes of replication and is associated with several types of cancer. We have identified a cellular protein (ARKL1) that acts to repress the reactivation of EBV from the latent to the lytic cycle. We show that ARKL1 acts to repress transcription of the EBV lytic switch protein by inhibiting the activity of the cellular transcription factor c-Jun. This not only provides a new mechanism of regulating EBV reactivation but also identifies a novel cellular function of ARKL1 as an inhibitor of Jun-mediated transcription.
Mineral-Vitamin Treatment Associated with Remission in Attention-Deficit/Hyperactivity Disorder Symptoms and Related Problems: 1-Year Naturalistic Outcomes of a 10-Week Randomized Placebo-Controlled Trial.

Objective: This article presents 1-year follow-up of a randomized placebo-controlled trial with open-label extension evaluating the efficacy of a broad-spectrum micronutrient (vitamins and minerals) intervention. The object was to determine if dominant treatment at follow-up was associated with differential psychological outcomes. Methods: Ninety percent of the original sample of 93 children with attention-deficit/hyperactivity disorder (ADHD) were followed 52 weeks postbaseline. Assessments included measures of ADHD, mood, anxiety, and general function based on parent/clinician report. Outcome was considered based on dominant therapy at 52 weeks (trial micronutrients [n = 19], medications [n = 21], and no treatment [n = 35]). Nine children were not categorized due to inconsistent therapies. Results: Based on dominant treatment, more of those who stayed on trial micronutrients (84%) were identified as "Much" or "Very Much" improved overall relative to baseline functioning, compared to 50% of those who switched to psychiatric medications and only 21% of those who discontinued treatment [χ2(2) = 19.476, p < 0.001]. Fifteen (79%) of those still taking micronutrients, 8 (42%) of those using medications, and 7 (23%) of those who discontinued treatment were considered remitters based on parent-reported ADHD [χ2(2) = 15.3, p < 0.001]. Those who stayed on micronutrients were more likely to have failed medication treatment in the past. The micronutrient group also displayed better outcomes on measures of parent-rated hyperactivity and anxiety, and clinician-rated general function and mood, with moderate to large between-group effect sizes (micronutrients vs. medication: ES = 0.73-1.01; micronutrients vs. no treatment: ES = 0.54-1.01). Most common reasons for stopping trial micronutrients were cost and number of pills to swallow. No continued side effects were associated with micronutrients. Conclusions: Children who benefitted from micronutrients in the short term maintained changes at follow-up, without side effects. While both those who continued micronutrients and those who switched to medication showed improved ADHD symptoms, psychiatric medication use was associated with deterioration in mood and anxiety. Inherent selection bias limits generalizability.
Selection and promotion processes are not associated by the relative age effect in an elite Spanish soccer academy

The aim of this study was to analyze the influence of the relative age effect (RAE) on the selection and promotion processes in an elite soccer academy. One hundred and eleven elite youth players who belonged to an elite soccer club from the Spanish “La Liga” participated in this study. Players were classified into three age-categories: under 14 years (U14), under 16 years (U16) and under 18 years (U18); and they were also classified in quartiles based on their date of birth (i.e., January-March, Q1; April-June, Q2; July-September, Q3; October-December, Q4). In addition, two further classification criteria were established based on the selection (i.e., selected and non-selected players) and promotion (i.e., promoted and non-promoted players) processes. The main results showed that in U14 and U16 age-categories, players born early in the year were over-represented compared to players born late in the year, although birth-distribution was not associated with the likelihood of a player to be selected or promoted. In addition, less fat in sum skinfolds, less percentage of fat, higher percentage of muscle and lower endomorphy and mesomorphy components were showed in U14 selected players, in comparison with non-selected players. Likewise, better sprint performance was found in U16 selected players versus non-selected ones. However, no significant differences on anthropometry, body composition, somatotype and physical performance were found between promoted and non-promoted players. Therefore, our results suggest there is need for coaches to reorient their talent identification programs in order to make sure that players selected to continue playing in the club have the potential to promote to the excellence in soccer.
Ready for Transfer to Adult Care? A Triadic Evaluation of Transition Readiness in Adolescents With Congenital Heart Disease and Their Parents

Transfer to adult care for adolescents with chronic conditions ought to be determined by transition readiness. The aims of this study were (a) to describe the level of readiness for transition in adolescents with congenital heart disease, (b) to compare adolescents’ assessment of transition readiness with their parents’ assessments, and (c) to study potential correlates of transition readiness. A total of 157 triads of adolescents aged 14 to 18 years and their parents completed the Readiness for Transition Questionnaire. Adolescents scored higher on overall readiness than their parents. Multivariable analyses revealed that higher levels of adolescents’ overall readiness were associated with a less threatening view of the illness, a higher level of empowerment, and with higher mothers’ and fathers’ overall readiness scores. Adolescents’ responsibility scores were positively associated with age and parental adolescent responsibility scores. Parental involvement scores were negatively associated with adolescents’ age and positively with the mothers’ parental involvement scores. By using a triadic evaluation, the results of the present study significantly extend what is currently known about this population.
Diagnostic value of the blood monocyte–lymphocyte ratio in knee osteoarthritis

Objective Knee osteoarthritis (KOA) is a chronic inflammatory disease. The monocyte–lymphocyte ratio (MLR) was reported to be a non-invasive, cost-effective marker in various systemic diseases, but it has not yet been investigated in KOA. This cross-sectional study evaluated the diagnostic value of MLR in KOA. Methods Two hundred and five KOA patients and 120 healthy control subjects were enrolled. Patient data, including age, sex, blood cell counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, red blood cell distribution width, and the Kellgren–Lawrence (KL) score were recorded. Results One hundred nineteen patients (55 men, 64 women) were included, with a mean age of 55.47 ± 9.23 years. KOA patients showed a significantly higher MLR, neutrophil–lymphocyte ratio (NLR), and platelet–lymphocyte ratio (PLR) than controls. The MLR area under the curve was 0.81, which was higher than that of NLR and PLR. Multiple logistic regression analysis revealed blood MLR as an independent predictor of KOA. Correlation analysis showed that MLR was positively correlated with ESR and CRP levels. MLR and NLR were significantly higher in KL4 patients than in KL1–3 patients. Conclusions MLR has a high diagnostic value for KOA, so could be a reliable disease marker.
Smoking Is Associated With Lower Dose-Corrected Serum Concentrations of Escitalopram.

BACKGROUND Tobacco smoking rates in depressive patients are higher compared with the general population. Smoking was demonstrated to accelerate the metabolism of different drugs metabolized by CYP1A2, but possibly also by CYP2C19 and CYP3A4. The principle aim of the present investigation from 2015 to 2018 was to determine the differences in the pharmacokinetics of escitalopram between smokers and nonsmokers. METHODS A group of nonsmokers (n = 88) was compared with smokers (n = 36), both receiving escitalopram, using the Mann-Whitney U test. Linear regression analysis was used to account for the impact of escitalopram dose, age, and sex in addition to smoking on the steady-state serum concentration of escitalopram. RESULTS Smokers received by mean 17.6% higher doses of escitalopram (P = 0.026) but showed 31.9% lower serum concentrations (P = 0.031). To control for confounders, linear regression analysis showed that dose (P < 0.001), sex (P = 0.03), and smoking tobacco (P = 0.027) did significantly influence serum concentrations of escitalopram with higher levels in women and nonsmokers. CONCLUSIONS Notwithstanding higher daily doses, smokers had significantly lower serum concentrations of escitalopram. In concordance with previous results, besides CYP1A2, a possible induction of CYP2C19 and CYP3A4 by tobacco smoke, resulting in lower serum concentrations of escitalopram in smokers than in nonsmokers, is suggested. Therefore, to provide personalized therapy, clinicians should consider smoking status and inform patients on the interactions of smoking and escitalopram metabolism.
Unsupervised online learning of temporal information in spiking neural network using thin-film transistor-type NOR flash memory devices

Brain-inspired analog neuromorphic systems based on the synaptic arrays have attracted large attention due to low-power computing. Spike-timing-dependent plasticity (STDP) algorithm is considered as one of the appropriate neuro-inspired techniques to be applied for on-chip learning. The aim of this study is to investigate the methodology of unsupervised STDP based learning in temporal encoding systems. The system-level simulation was performed based on the measurement results of thin-film transistor-type asymmetric floating-gate NOR flash memory. With proposed learning methods, 91.53% of recognition accuracy is obtained in inferencing MNIST standard dataset with 200 output neurons. Moreover, temporal encoding rules showed that the number of input pulses and the computing power can be compressed without significant loss of recognition accuracy compared to the conventional rate encoding scheme. In addition, temporal computing in a multi-layer network is suitable for learning data sequences, suggesting the possibility of applying to real-world tasks such as classifying direction of moving objects.
The African strain of Zika virus causes more severe in utero infection than Asian strain in a porcine fetal transmission model

ABSTRACT Studies in mice showed that African Zika virus (ZIKV) strains cause more damage in embryos. These studies, however, were limited to the mouse-adapted African MR766 strain or infection at early gestation. Here, we compared infection of Asian and African strains in the fetal pig model at midgestation. Both strains caused fetal infection. ZIKV was detected in placenta, amniotic membrane, amniotic fluid, fetal blood, and brain. The African strain produced more vigorous in utero infection as represented by more efficient virus transmission between siblings, and higher viral loads in fetal organs and membranes. Infection with both strains was associated with reduced fetal brain weight and increased number of placental CD163-positive cells, as well as elevated in utero interferon alpha and cortisol levels. This is the first large animal model study which demonstrated that African strain of ZIKV, with no passage history in experimental animals, can cause persistent infection in fetuses and fetal membranes at midgestation. Our studies also suggest that similar to Asian strains, ZIKV of African lineage might cause silent pathology which is difficult to identify in deceptively healthy fetuses. The findings emphasize the need for further studies to highlight the impact of ZIKV heterogeneity on infection outcomes during pregnancy.
Sexual orientation and substance use treatment outcomes across five clinical trials of contingency management.

Lesbian, gay, and bisexual (LGB) individuals have elevated rates of substance use disorders and present to treatment with more severe substance use problems. Despite this health disparity, recent reviews highlight the paucity of studies reporting sexual orientation in substance use research (e.g., Flentje, Bacca, & Cochran, 2015). Using data from 5 clinical trials of contingency management (CM), the current study investigated the impact of sexual orientation on 3 substance use outcomes: treatment retention, longest duration of abstinence, and percent negative samples submitted. Participants (N = 912; mean age = 36.6 years; 51.1% female; 45% African American, 42.2% Caucasian) were randomized to standard care in community-based intensive outpatient treatment (IOP) or the same plus CM. Patients identifying as LGB made up 10.6% of the sample. A significant proportion identified as bisexual (8.2% of the total sample). Regardless of sexual orientation, participants receiving CM achieved better treatment outcomes than those receiving IOP alone. There were no statistically significant differences between LGB and heterosexual participants in their response to IOP in general, and CM specifically, across all 3 treatment outcomes (ps > .05). However, equivalence testing revealed that outcomes were not statistically equivalent for LGB and heterosexual participants, with the exception of percentage of negative samples, which was equivalent within the CM group only. Differences in treatment response to CM and standard community-based IOP do not reach the level of statistical significance; however, in most cases, we cannot conclude that treatment response is equivalent for LGB and heterosexual individuals. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Estimating Sedentary Time from a Hip- and Wrist-worn Accelerometer.

PURPOSE Determine the validity of existing methods to estimate sedentary behavior (SB) under free-living conditions using ActiGraph GT3X+ accelerometers (AG). METHODS Forty-eight young (18-25 yr) adults wore an AG on the right hip and non-dominant wrist and were video recorded during four 1-hour sessions in free-living settings (home, community, school, exercise). Direct observation videos were coded for postural orientation, activity type (e.g. walking), and METs derived from the Compendium of Physical Activities, which served as the criterion measure of SB (sitting or lying posture, METs < 1.5). Thirteen methods using cut-points from vertical counts/minute (CPM), counts/15-s (CP15s), and vector magnitude counts (vm) (e.g., CPM1853vm), raw acceleration and arm-angle (Sedentary Sphere), Euclidean norm corrected for gravity (ENMO, mg) thresholds, uni- or tri-axial Sojourn hybrid-machine learning models (Soj1x and Soj3x), random forest (RF) and decision tree (TR) models were used to estimate SB minutes from AG data. Method bias, mean absolute percent error (MAPE), and their 95% confidence-intervals were estimated using repeated measures linear mixed models. RESULTS On average, participants spent 34.1 minutes/session in SB. CPM100, CPM150, Soj1x, and Soj3x were the only methods to accurately estimate SB from the hip. Sedentary Sphere and ENMO44.8 over-estimated SB by 3.9 and 6.1 minutes, respectively, while the remaining wrist methods underestimated SB (range: 9.5-2.5 minutes). In general, MAPE was lower using hip methods compared to wrist methods. CONCLUSION Accurate group-level estimates of SB from a hip-worn AG can be achieved using either simpler count-based approaches (CPM100, CPM150) or machine learning models (Soj1x, Soj3x). Wrist-methods did not provide accurate or precise estimates of SB. Development of large open source free-living calibration datasets may lead to improvements in SB estimates.
Development of the

This is a public deliverable of One Health EJP Joint Research Project, Integrative Action-2.2, OH-Harmony-Cap: One Health Harmonisation of Protocols for the Detection of Foodborne Pathogens and AMR Determinants OH-Harmony-CAP is a 2.5 year project, which aims to collect information on current capabilities, capacities and interoperability at both the National Reference Laboratory (NRL) and the primary diagnostic level. The quantitative description of current and best practices and the development of harmonised protocols will identify and possibly close the gaps and suggest future studies of how best to detect and characterise food borne pathogens across the One Health sectors.
Addition of 100 mg of Tramadol to 40 mL of 0.5% Ropivacaine for Interscalene Brachial Plexus Block Improves Postoperative Analgesia in Patients Undergoing Shoulder Surgeries as Compared to Ropivacaine Alone—A Randomized Controlled Study

Background and objectives: Brachial plexus block is commonly used in shoulder surgery, as it provides satisfactory surgical conditions and adequate postoperative pain control. However, there are contradictory reports regarding the addition of tramadol to the injected regional anesthetic solution. We performed a prospective randomized study to evaluate the effectiveness of tramadol as an adjuvant to ropivacaine during interscalene brachial plexus block and assess its impact on the opioid consumption and the early postoperative pain in patients that underwent shoulder surgery. Materials and Methods: Eighty patients scheduled for elective shoulder surgery and anesthesia via interscalene brachial plexus block were randomly divided into two groups. In group A (n = 40), a solution of 40 mL of ropivacaine 0.5% and 2 mL (100 mg) of tramadol was administered during the brachial plexus block, while in group B (n = 40), a solution of 40 mL of ropivacaine 0.5% and 2 mL NaCl 0.9% (placebo) was administered. The effectiveness and duration of sensory and motor blocks were recorded in both groups. The sensory block was assessed recording the loss of sensation to pin prick test over the skin distribution of the axillary, radial, and musculocutaneous nerves. The motor block was assessed using the modified 3-point Bromage score (0–2 points). Cumulative morphine consumption and pain, using the Visual Analog Scale (VAS), were evaluated in both groups at 2, 4, 8, and 24 h after surgery. Results: Sensory block onset was achieved earlier in group A than in group B (5.21 ± 3.15 minutes (min) vs. 7.1 ± 4.51 min, p = 0.029). The motor block onset was similar between the two groups (13.08 ± 6.23 min vs. 13.28 ± 6.59 min; p = 0.932). The duration of the sensory block was longer in group A as compared to group B (13 ± 2.3 h vs. 12 ± 2.8 h; p = 0.013). The duration of the motor block did not present any difference between the groups (10 ± 2.2 h vs. 10 ± 2.8 h; p = 0.308). Differences in morphine administration were not significant at 2, 4, and 8 h, however, morphine consumption was found to be decreased in group A 24 h postoperatively A (p = 0.04). The values of VAS were similar at 2, 4, and 8 h, however, they were lower in group A at 24 h (p < 0.013). Conclusions: Combined regional administration of tramadol and ropivacaine during interscalene brachial plexus block improves the time of onset and the duration of the sensory block, while it is associated with reduced morphine consumption during the first 24 h after shoulder surgery.
Long-term efficacy and cost-effectiveness of infliximab as first-line treatment in rheumatoid arthritis: systematic review and meta-analysis

ABSTRACT Introduction: Early biological treatment of rheumatoid arthritis (RA) may reverse the autoimmune response in some patients resulting in favorable long-term outcomes. Although the cost-effectiveness of this strategy has been questioned, biosimilar entries warrant the revision of clinical and pharmaco-economic evidence. Areas covered: We conducted a systematic review of randomized controlled trials (RCTs) published up to 24 May 2018 in Pubmed, EMBASE and Cochrane CENTRAL, comparing infliximab with non-biological therapy in patients with RA naïve to methotrexate. We performed meta-analyses for efficacy outcomes at month 6 and years 1 and 2. Six RCTs were identified, involving 1832 patients. At month 6 ACR70 response and remission, and at year 1 ACR20/ACR70 responses and remission were improved significantly with first-line infliximab versus control. The differences were not significant at year 2. We reviewed cost-utility studies, up to 31 October 2018 in PubMed, Cochrane CENTRAL and the CRD HTA databases. Four studies indicated that first-line use of originator infliximab calculated at 2005–2008 prices was not cost-effective. Expert opinion: We demonstrated the efficacy benefits of first-line infliximab therapy up to 1 year in methotrexate-naïve RA. We highlighted the need for standardized reporting of outcomes and conducting cost-effectiveness analyses of first-line biosimilar therapy in RA.