Miracle-dz/UniFAR-FTUs huggingface dataset:
Precursor B-ALL Cell Lines Differentially Respond to SYK Inhibition by Entospletinib

Background: Impaired B-cell receptor (BCR) function has been associated with the progress of several B-cell malignancies. The spleen tyrosine kinase (SYK) represents a potential therapeutic target in a subset of B-cell neoplasias. In precursor B-acute lymphoblastic leukemia (B-ALL), the pathogenic role and therapeutic potential of SYK is still controversially discussed. We evaluate the application of the SYK inhibitor entospletinib (Ento) in pre- and pro-B-ALL cell lines, characterizing the biologic and molecular effects. Methods: SYK expression was characterized in pre-B-ALL (NALM-6) and pro-B-ALL cell lines (SEM and RS4;11). The cell lines were exposed to different Ento concentrations and the cell biological response analyzed by proliferation, metabolic activity, apoptosis induction, cell-cycle distribution and morphology. BCR pathway gene expression and protein modulations were further characterized. Results: Ento significantly induced anti-proliferative and pro-apoptotic effects in NALM-6 and SEM, while barely affecting RS4;11. Targeted RNAseq revealed pronounced gene expression modulation only in NALM-6, while Western Blot analyses demonstrated that vital downstream effector proteins, such as pAKT, pERK, pGSK3β, p53 and BCL-6, were affected by Ento exposure in the inhibitor-sensitive cell lines. Conclusion: Different acting modes of Ento, independent of pre-BCR dependency, were characterized, unexpected in SEM. Accordingly, SYK classifies as a potential target structure in a subset of pro-B-ALLs.
Gonadal and adrenal hormones interact with pubertal maturation to predict depressive symptoms in a group of high-school females

Abstract Adolescent females are at elevated risk for the development of depression. In this study, we addressed two questions: Are pubertal hormones associated with adolescent mental health? Might this association depend on pubertal development? We tested the hypothesis that estradiol, which has been associated with adolescent social sensitivity, might interact with pubertal stage to predict depression risk at three time points in ninth and tenth grade. Hormones and pubertal development were measured ninth-grade females. Linear regression analyses were used to predict fall ninth-grade (N = 79), spring ninth-grade (N = 76), and spring tenth-grade (N = 67) Children's Depression Inventory (CDI) scores. The hypothesized model was not statistically significant, but exploratory analyses revealed that two- and three-way interactions incorporating estradiol, puberty (stage and perceived onset), and cortisol predicted current and future CDI scores. Our exploratory model did not predict changes in CDI but did account for future (spring of ninth grade) CDI scores. Specifically, estradiol was positively correlated with fall and spring ninth-grade depressive symptoms in participants with high cortisol who also reported earlier stages and later perceived onset of pubertal development. These findings suggest that hormones associated with sensitivity to the social environment deserve consideration in models of adolescent depression risk.
Sleep apnoea is a risk factor for severe COVID-19

Background Obstructive sleep apnoea (OSA) is associated with higher body mass index (BMI), diabetes, older age and male gender, which are all risk factors for severe COVID-19. We aimed to study if OSA is an independent risk factor for COVID-19 infection or for severe COVID-19. Methods OSA diagnosis and COVID-19 infection were extracted from the hospital discharge, causes of death and infectious diseases registries in individuals who participated in the FinnGen study (n=260 405). Severe COVID-19 was defined as COVID-19 requiring hospitalisation. Multivariate logistic regression model was used to examine association. Comorbidities for either COVID-19 or OSA were selected as covariates. We performed a meta-analysis with previous studies. Results We identified 445 individuals with COVID-19, and 38 (8.5%) of them with OSA of whom 19 out of 91 (20.9%) were hospitalised. OSA associated with COVID-19 hospitalisation independent from age, sex, BMI and comorbidities (p-unadjusted=5.13×10−5, OR-adjusted=2.93 (95% CI 1.02 to 8.39), p-adjusted=0.045). OSA was not associated with the risk of contracting COVID-19 (p=0.25). A meta-analysis of OSA and severe COVID-19 showed association across 15 835 COVID-19 positive controls, and n=1294 patients with OSA with severe COVID-19 (OR=2.37 (95% 1.14 to 4.95), p=0.021). Conclusion Risk for contracting COVID-19 was the same for patients with OSA and those without OSA. In contrast, among COVID-19 positive patients, OSA was associated with higher risk for hospitalisation. Our findings are in line with earlier works and suggest OSA as an independent risk factor for severe COVID-19.
Prescribing errors and associated factors in discharge prescriptions in the emergency department: A prospective cross-sectional study

Objectives Evidence regarding the prevalence of medication prescribing errors (PEs) and potential factors that increase PEs among patients treated in the emergency department (ED) are limited. This study aimed to explore the prevalence and nature of PEs in discharge prescriptions in the ED and identify potential risk factors associated with PEs. Methods This was a prospective observational cross-sectional study in an ambulatory ED in a tertiary teaching hospital. Data were collected for six months using a customized reporting tool. All patients discharged from ED with a discharged prescription within the study period were enrolled in this study. Results About 13.5% (n = 68) of the 504 prescriptions reviewed (for 504 patients) had at least one error. Main PEs encountered were wrong dose (23.2%), wrong frequency (20.7%), and wrong strength errors (14.6%). About 36.8% of identified PEs were related to pediatric prescriptions, followed by the acute care emergency unit (26.5%) and the triage emergency unit (20.6%). The main leading human-related causes associated with PEs were lack of knowledge (40.9%) followed by an improper selection from a computer operator list (31.8%). The leading contributing systems related factors were pre-printed medication orders (50%), lack of training (31.5%), noise level (13.0%), and frequent interruption of prescriber and distraction (11.1%). Prescribers' involved with the identified errors were resident physicians (39.4%), specialists (30.3%), and (24.4%) were made by general practitioners. Physicians rejected around 12% of the pharmacist-raised recommendations related to the identified PEs as per their clinical judgment. Conclusion PEs in ED setting are common, and multiple human and systems-related factors may contribute to the development of PEs. Further training to residents and proper communication between the healthcare professionals may reduce the risk of PEs in ED.
Ontogenetic and in silico models of spatial‐packing in the hypermuscular mouse skull

Networks linking single genes to multiple phenotypic outcomes can be founded on local anatomical interactions as well as on systemic factors like biochemical products. Here we explore the effects of such interactions by investigating the competing spatial demands of brain and masticatory muscle growth within the hypermuscular myostatin‐deficient mouse model and in computational simulations. Mice that lacked both copies of the myostatin gene (‐/‐) and display gross hypermuscularity, and control mice that had both copies of the myostatin gene (+/+) were sampled at 1, 7, 14 and 28 postnatal days. A total of 48 mice were imaged with standard as well as contrast‐enhanced microCT. Size metrics and landmark configurations were collected from the image data and were analysed alongside in silico models of tissue expansion. Findings revealed that: masseter muscle volume was smaller in ‐/‐ mice at day 1 but became, and remained thereafter, larger by 7 days; ‐/‐ endocranial volumes begin and remained smaller; ‐/‐ enlargement of the masticatory muscles was associated with caudolateral displacement of the calvarium, lateral displacement of the zygomatic arches, and slight dorsal deflection of the face and basicranium. Simulations revealed basicranial retroflexion (flattening) and dorsal deflection of the face associated with muscle expansion and abrogative covariations of basicranial flexion and ventral facial deflection associated with endocranial expansion. Our findings support the spatial‐packing theory and highlight the importance of understanding the harmony of competing spatial demands that can shape and maintain mammalian skull architecture during ontogeny.
Design optimization of implant geometrical characteristics enhancing primary stability using FEA of stress distribution around dental prosthesis

Abstract The main objective of this study was to investigate the influence of implant geometrical characteristics: diameter, length and thread’s pitch, on stress distribution around dental prosthesis. A set of numerical simulations using FEM were conducted and responses surfaces were generated. With the aim of optimizing the equivalent stresses responses; desirability function approach was adopted to solve this multi-objective problem. Results showed that implant diameter had most significant influence on generated stresses and high concentration of stresses were identified in the lower part of the implant. This study is helpful in choosing the optimal dental implant for clinical application.
Testing risk and protective factor assumptions in the Icelandic model of adolescent substance use prevention.

Iceland has witnessed a dramatic decline in adolescent substance use that may be partly the result of efforts related to the Icelandic prevention model (IPM). We sought to test risk and protective factor assumptions of the IPM using a prospective cohort study with 12 months separating baseline from follow-up. Participants were students in grades 8 and 9 in the national Icelandic school system enrolled in the spring of 2018 and 2019 (N=2165). Participants self-reported their experiences of cigarette smoking, alcohol consumption, and cannabis use and seven risk and protective factors. Analyses were conducted with generalized linear modeling with extension to general estimating equations with correlated outcomes data. Both individual main-effects models and collective models including all main-effects were tested. Out of 28 individual main-effects models, 23 produced findings consistent with study premises (P<0.05). Multiple main-effects models largely sustained the findings of the individual main-effects models. Findings support the assumption that the risk and protective factors commonly emphasized in the IPM are associated with the four different substance use outcomes in the hypothesized direction. Communities that plan to implement the IPM among adolescents might consider these factors in their work.
Biphasic Postnatal Umbilical Cord Shortening

Introduction Variations in postnatal length of refrigerated, unfixed umbilical cords were studied over time to elucidate natural changes and times of stability. Methods Length was measured in 132 cords following severance, repeated at varying timed intervals and studied by analysis of variance and regression analysis. Results Data show immediate rapid initial phase shortening (mean 4.2+/-3.9 cm SD); an interval of lengthening; stable length at hours 3-4 following severance, a slower second phase shortening (mean 1.5+/-0.7 cm SD) beginning at 5 hours and peaking at 12 hours; and gradual lengthening to stable length after 23 hours. Overall, there was a significant net mean decrease of 3.49+/-2.29 cm SD. Shortening was greatest for intact long cord segments (p=0.0001), as much as 11 cm. Two highly significant models for predicting umbilical cord length at delivery (OL) were determined using the post-delivery lengths (Length) measured at different times following delivery (Hours), as follows: At ≤ 3 hours following delivery: OL=1.02xLength cm+1.11xHours At >3 hours following delivery: OL=1.07xLength+0.44xHours-0.01x(Hours)2 Conclusion Cord lengths stabilized between hours 3-4 and after 23 hours following severance. Phase one shortening resembles vasoconstriction; phase two resembles rigor mortis. The models allow prediction of the original umbilical cord length at delivery, regardless of the time of measurement.
Using Accelerometer Data to Tune the Parameters of an Extended Kalman Filter for Optical Motion Capture: Preliminary Application to Gait Analysis

Optical motion capture is currently the most popular method for acquiring motion data in biomechanical applications. However, it presents a number of problems that make the process difficult and inefficient, such as marker occlusions and unwanted reflections. In addition, the obtained trajectories must be numerically differentiated twice in time in order to get the accelerations. Since the trajectories are normally noisy, they need to be filtered first, and the selection of the optimal amount of filtering is not trivial. In this work, an extended Kalman filter (EKF) that manages marker occlusions and undesired reflections in a robust way is presented. A preliminary test with inertial measurement units (IMUs) is carried out to determine their local reference frames. Then, the gait analysis of a healthy subject is performed using optical markers and IMUs simultaneously. The filtering parameters used in the optical motion capture process are tuned in order to achieve good correlation between the obtained accelerations and those measured by the IMUs. The results show that the EKF provides a robust and efficient method for optical system-based motion analysis, and that the availability of accelerations measured by inertial sensors can be very helpful for the adjustment of the filters.
Liver Fibrosis Biomarkers Accurately Exclude Advanced Fibrosis and Are Associated with Higher Cardiovascular Risk Scores in Patients with NAFLD or Viral Chronic Liver Disease

Liver fibrosis predicts liver-related and cardiovascular outcomes in chronic liver disease patients. We compared the diagnostic performance of various liver fibrosis biomarkers for identifying histological significant/advanced fibrosis. Additionally, the correlations of such liver fibrosis biomarkers with cardiovascular risk (CVR) scores were evaluated. 173 patients with viral hepatitis (157 HCV and 16 HBV) and 107 with a non-alcoholic fatty liver disease (NAFLD) were consecutively enrolled. Various liver fibrosis biomarkers: aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (ARR), AST to Platelet Ratio Index (APRI), Fibrosis-4 (FiB-4), Forns index, NAFLD fibrosis score (NFS), BARD (body mass index (BMI), AAR, Diabetes) score, and Hepamet fibrosis score (HFS), were used to identify significant/advanced fibrosis. CVR was assessed by using the SCORE, the Progetto CUORE, or the Framingham risk scoring systems. Liver fibrosis biomarkers performed better in predicting advanced rather than significant liver fibrosis in all patients, regardless of chronic liver disease aetiology. Forns index and HFS performed best in predicting advanced fibrosis in patients with viral chronic liver disease and NAFLD. Lower cut-offs of these liver fibrosis biomarkers had high negative predictive values for advanced fibrosis overall, as well as in patients with NAFLD or viral chronic liver disease. FIB-4, Forns index, NFS, and HFS were positively correlated with SCORE and Framingham risk scores. In conclusion, liver fibrosis biomarkers accurately exclude advanced fibrosis and positively correlate with CVR scores in patients with chronic liver disease.
Pentapeptide repeat protein QnrB1 requires ATP hydrolysis to rejuvenate poisoned gyrase complexes

Abstract DNA gyrase, a type II topoisomerase found predominantly in bacteria, is the target for a variety of ‘poisons’, namely natural product toxins (e.g. albicidin, microcin B17) and clinically important synthetic molecules (e.g. fluoroquinolones). Resistance to both groups can be mediated by pentapeptide repeat proteins (PRPs). Despite long-term studies, the mechanism of action of these protective PRPs is not known. We show that a PRP, QnrB1 provides specific protection against fluoroquinolones, which strictly requires ATP hydrolysis by gyrase. QnrB1 binds to the GyrB protein and stimulates ATPase activity of the isolated N-terminal ATPase domain of GyrB (GyrB43). We probed the QnrB1 binding site using site-specific incorporation of a photoreactive amino acid and mapped the crosslinks to the GyrB43 protein. We propose a model in which QnrB1 binding allosterically promotes dissociation of the fluoroquinolone molecule from the cleavage complex.
Selenium attenuates bisphenol A incurred damage and apoptosis in mice testes by regulating mitogen‐activated protein kinase signalling

Being a vital micronutrient, along with a trace element, selenium (Se) protects the cells from oxidative stress (OS) in the form of selenoproteins. Bisphenol A (BPA) is a xeno‐oestrogenic compound that adversely affects the spermatogenesis process by inducing oxidative stress, which ultimately leads to male infertility. Therefore, it is hypothesised that Se could protect against BPA‐induced OS, and further germ cell death by modifying mitogen‐activated protein kinase (MAPK) signalling. Male Balb/c mice were divided into four groups: Group I (C) (0.2 ppm Se), Group II (Se) (0.5 ppm Se), Group III (BPA) (0.2 ppm Se, and BPA = 1 mg/kg orally) and Group IV (Se + BPA) (0.5 ppm Se, and BPA = 1 mg/kg bodyweight orally). Results indicated that BPA‐treated animals demonstrated a marked decrease in antioxidant enzyme activities (superoxide dismutase, catalase, redox ratio), a marked elevation in the expressions of stress‐activated kinases (c‐Jun NH2‐terminal kinase (JNK), extracellular signal‐regulated kinase (ERK) and p38) and the expressions of pro‐apoptotic markers (caspase‐9, caspase‐8 and caspase‐3). However, Se supplementation considerably restored the antioxidant enzyme activities and lowered the expressions of stress‐activated kinases, which further down‐regulated the apoptosis. Thus, Se supplementation demonstrated to be effective against BPA provoked testicular damage.
Role of BRCA Mutation and HE4 in Predicting Chemotherapy Response in Ovarian Cancer: A Retrospective Pilot Study

Even though 80% of patients with High-Grade Serous Ovarian Cancer respond to standard first-line chemotherapy, a majority of them could relapse in the following five years due to a resistance to platinum. Human Epididymis protein 4 (HE4) is one of the most promising markers in predicting platinum therapy response. This pilot study aims to evaluate the potential role of HE4 value in predicting chemotherapy response in BRCA mutated patients and in BRCA wild-type (non-mutated) ones. We selected 69 patients, affected by High-Grade Serous Ovarian Cancer, and optimally debulked and submitted to standard chemotherapy protocols. HE4 was dosed during every chemotherapy course. Patients were classified as platinum-resistant and platinum-sensitive. According to BRCA mutation test, patients were further divided into BRCA wild-type (53 patients), and BRCA mutated (16 patients). 35 patients out of 69 (52%) were platinum-sensitive (recurrence > 12 months), while 33 patients (48%) were platinum-resistant (recurrence < 12 months). Thus, in the total population, HE4 performed as a marker of chemosensitivity with a sensibility of 79% and a specificity of 97%. In the BRCA WT group, 23 patients out of 53 (43%) were platinum-sensitive, while 30 patients out of 53 (57%) were platinum-resistant. In the BRCA WT group, HE4 performed as a predictive marker of chemosensitivity with a sensibility of 80% and a specificity of 100%. In the BRCA mutated group, 13 patients out of 16 (82%) were platinum-sensitive, while 3 patients (18%) were platinum-resistant. In the BRCA mutated group, HE4 performed as a predictive marker of chemosensitivity in all patients. The ability to detect platinum-resistant patients before tumor relapse probably could open new therapeutic scenarios.
Detection of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) in outpatients: A multicenter comparison of self-collected saline gargle, oral swab, and combined oral–anterior nasal swab to a provider collected nasopharyngeal swab

Abstract Background: Widespread testing for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) is necessary to curb the spread of coronavirus disease 2019 (COVID-19), but testing is undermined when the only option is a nasopharyngeal swab. Self-collected swab techniques can overcome many of the disadvantages of a nasopharyngeal swab, but they require evaluation. Methods: Three self-collected non-nasopharyngeal swab techniques (saline gargle, oral swab and combined oral-anterior nasal swab) were compared to a nasopharyngeal swab for SARS-CoV-2 detection at multiple COVID-19 assessment centers in Toronto, Canada. The performance characteristics of each test were assessed. Results: The adjusted sensitivity of the saline gargle was 0.90 (95% CI 0.86-0.94), the oral swab was 0.82 (95% CI, 0.72–0.89) and the combined oral–anterior nasal swab was 0.87 (95% CI, 0.77–0.93) compared to a nasopharyngeal swab, which demonstrated a sensitivity of ˜90% when all positive tests were the reference standard. The median cycle threshold values for the SARS-CoV-2 E-gene for concordant and discordant saline gargle specimens were 17 and 31 (P < .001), for the oral swabs these values were 17 and 28 (P < .001), and for oral–anterior nasal swabs these values were 18 and 31 (P = .007). Conclusions: Self-collected saline gargle and an oral–anterior nasal swab have a similar sensitivity to a nasopharyngeal swab for the detection of SARS-CoV-2. These alternative collection techniques are cheap and can eliminate barriers to testing, particularly in underserved populations.
CHD2-Related CNS Pathologies

Epileptic encephalopathies (EE) are severe epilepsy syndromes characterized by multiple seizure types, developmental delay and even regression. This class of disorders are increasingly being identified as resulting from de novo genetic mutations including many identified mutations in the family of chromodomain helicase DNA binding (CHD) proteins. In particular, several de novo pathogenic mutations have been identified in the gene encoding chromodomain helicase DNA binding protein 2 (CHD2), a member of the sucrose nonfermenting (SNF-2) protein family of epigenetic regulators. These mutations in the CHD2 gene are causative of early onset epileptic encephalopathy, abnormal brain function, and intellectual disability. Our understanding of the mechanisms by which modification or loss of CHD2 cause this condition remains poorly understood. Here, we review what is known and still to be elucidated as regards the structure and function of CHD2 and how its dysregulation leads to a highly variable range of phenotypic presentations.
Persistent median artery may explain the transition from 11 to 12 meridians in ancient Chinese medicine

Persistent median artery (PMA) has been recognized as a major arterial variant of the forearm in about 30% adults and it also shows a continuously increasing trend in the last two hundred years. This may explain well the mystery why a "new meridian" was added to the older 11-meridian system over two thousand years ago in Chinese medicine. The 12th meridian, Hand Jue Yin Meridian, happens to run along the same pathway as PMA.