Miracle-dz/UniFAR-FTUs huggingface dataset:
Cellular gp96 upregulates AFP expression by blocking NR5A2 SUMOylation and ubiquitination in hepatocellular carcinoma

Abstract Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, a substantial proportion of HCC patients have either normal or marginally increased AFP levels in serum, and the underlying mechanisms are not fully understood. In the present study, we provided in vitro and in vivo evidence that heat shock protein gp96 promoted AFP expression at the transcriptional level in HCC. NR5A2 was identified as a key transcription factor for the AFP gene, and its stability was enhanced by gp96. A further mechanistic study by co-immunoprecipitation, GST pull-down, and molecular docking showed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539. The binding of gp96 inhibited SUMOylation, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCC patients indicated that gp96 expression in tumors was positively correlated with serum AFP levels. Therefore, our study uncovered a novel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and ubiquitination. These findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.
Qualitative Assessment of Implementation of a Discharge Prediction Tool Using RE-AIM Framework

The implementation process in the routine clinical care of a new predictive tool based on machine learning algorithms has been investigated using the RE-AIM framework. Semi-structured qualitative interviews have been conducted with a broad range of clinicians to elucidate potential barriers and facilitators of the implementation process across five major domains: Reach, Efficacy, Adoption, Implementation, and Maintenance. The analysis of 23 clinician interviews demonstrated a limited reach and adoption of the new tool and identified areas for improvement in implementation and maintenance. Future implementation efforts of machine learning tools should support the proactive engagement of a wide range of clinical users since the very initiation of the predictive analytics project, provide higher transparency of the underlying algorithms, employ broader onboarding of all potential users on a periodic basis, and collect feedback from clinicians on an ongoing basis.
A longitudinal study of childhood maltreatment, subcortical development, and subcortico-cortical structural maturational coupling from early to late adolescence

Abstract Background Examining neurobiological mechanisms that may transmit the effects of childhood maltreatment on mental health in youth is crucial for understanding vulnerability to psychopathology. This study investigated associations between childhood maltreatment, adolescent structural brain development, and mental health trajectories into young-adulthood. Methods Structural magnetic resonance imaging data was acquired from 144 youth at three time points (age 12, 16, and 18 years). Childhood maltreatment was reported to occur prior to the first scan. Linear mixed models were utilized to examine the association between total childhood maltreatment, neglect, abuse and (i) amygdala and hippocampal volume development, and (ii) maturational coupling between amygdala/hippocampus volume and the thickness of prefrontal regions. We also examined whether brain development mediated the association between maltreatment and depressive and anxiety symptoms trajectories from age 12 to 28. Results Total maltreatment, and neglect, were associated with positive maturational coupling between the amygdala and caudal anterior cingulate cortex (cACC), whereby at higher and lower levels of amygdala growth, maltreatment was associated with lower and higher PFC thinning, respectively. Neglect was also associated with maturational coupling of the hippocampus with prefrontal regions. While positive amygdala-cACC maturational coupling was associated with greater increases in anxiety symptoms, it did not significantly mediate the association between maltreatment and anxiety symptom trajectories. Conclusion We found maltreatment to be associated with altered patterns of coupling between subcortical and prefrontal regions during adolescence, suggesting that maltreatment is associated with the development of socio-emotional neural circuitry. The implications of these findings for mental health require further investigation.
Host genetic background is a barrier to broadly effective vaccine–mediated protection against tuberculosis

Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin–induced (BCG-induced) immunity against Mycobacterium tuberculosis, we studied 24 unique collaborative cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG and challenged with aerosolized M. tuberculosis. Since BCG protects only half of the CC strains tested, we concluded that host genetics has a major influence on BCG-induced immunity against M. tuberculosis infection, making it an important barrier to vaccine-mediated protection. Importantly, BCG efficacy is dissociable from inherent susceptibility to tuberculosis (TB). T cell immunity was extensively characterized to identify components associated with protection that were stimulated by BCG and recalled after M. tuberculosis infection. Although considerable diversity is observed, BCG has little impact on the composition of T cells in the lung after infection. Instead, variability is largely shaped by host genetics. BCG-elicited protection against TB correlated with changes in immune function. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.
The Importance of Being FAIR and FAST - The Clinical Epidemiology and Study Platform of the German Network University Medicine (NUKLEUS)

The COVID-19 pandemic has urged the need to set up, conduct and analyze high-quality epidemiological studies within a very short time-scale to provide timely evidence on influential factors on the pandemic, e.g. COVID-19 severity and disease course. The comprehensive research infrastructure developed to run the German National Pandemic Cohort Network within the Network University Medicine is now maintained within a generic clinical epidemiology and study platform NUKLEUS. It is operated and subsequently extended to allow efficient joint planning, execution and evaluation of clinical and clinical-epidemiological studies. We aim to provide high-quality biomedical data and biospecimens and make its results widely available to the scientific community by implementing findability, accessibility, interoperability and reusability - i.e. following the FAIR guiding principles. Thus, NUKLEUS might serve as role model for FAIR and fast implementation of clinical epidemiological studies within the setting of University Medical Centers and beyond.
State Medicaid and private telemedicine coverage requirements and telemedicine use, 2013–2019

Abstract Objective To examine the association between state Medicaid and private telemedicine coverage requirements and telemedicine use. A secondary objective was to examine whether these policies were associated with health care access. Data Sources and Study Setting We used nationally representative survey data from the 2013–2019 Association of American Medical Colleges Consumer Survey of Health Care Access. The sample included Medicaid‐enrolled (4492) and privately insured (15,581) adults under age 65. Study Design The study design was a quasi‐experimental two‐way‐fixed‐effects difference‐in‐differences analysis that took advantage of state‐level changes in telemedicine coverage requirements during the study period. Separate analyses were conducted for the Medicaid and private requirements. The primary outcome was the past‐year use of live video communication. Secondary outcomes included same‐day appointment, always able to get needed care, and having enough options for where to go to receive care. Data Collection/Extraction Methods N/A. Principal Findings Medicaid telemedicine coverage requirements were associated with a 6.01 percentage‐point increase in the use of live video communication (95% CI, 1.62 to 10.41) and an 11.12 percentage‐point increase in always being able to access needed care (95% CI, 3.34 to 18.90). While generally robust to various sensitivity analyses, these findings were somewhat sensitive to included study years. Private coverage requirements were not significantly associated with any of the outcomes considered. Conclusions Medicaid telemedicine coverage during 2013–2019 was associated with significant and meaningful increases in telemedicine use and health care access. We did not detect any significant associations for private telemedicine coverage policies. Many states added or expanded telemedicine coverage policies during the COVID‐19 pandemic, but states will face decisions about whether to maintain these enhanced policies now that the public health emergency is ending. Understanding the role of state policies in promoting telemedicine use may help inform policymaking efforts going forward.
Naringenin ameliorates aluminum toxicity-induced testicular dysfunctions in mice by suppressing oxidative stress and histopathological alterations

Abstract Environmental aluminum intoxication has shown increasingly alarming negative consequences on reproductive health. This needs mechanistic exploration and preventive management using medicines like herbal supplementation. The ameliorative effects of naringenin (NAR) against AlCl3-induced reproductive toxicity were thus evaluated in this study by assessing testicular dysfunction in albino male mice. A group of mice was treated with AlCl3 (10 mg/kg b.w./day) and then with NAR (10 mg/kg b.w./day) for a total of sixty-two days. Results show that treatment of AlCl3 significantly reduced the body weight and testis weight of mice. AlCl3 caused oxidative damage in mice as evidenced by an increase in the concentration of nitric oxide, advanced oxidation of protein product, protein carbonylation, and lipid peroxidation. Furthermore, diminished activity of antioxidant moieties included superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, reduced glutathione, and oxidized glutathione. Several histological changes, such as spermatogenic cell degeneration, germinal epithelium detachment, and structural abnormalities in seminiferous tubules, were observed in AlCl3-treated mice. Oral administration of NAR was found to restore body weight and testes weight and ameliorated reproductive dysfunctions. NAR decreased oxidative stress, replenished the antioxidant defense system, and improved histopathological alterations in the AlCl3-treated testes. Therefore, the present study suggests that the supplementation of NAR may be a beneficial strategy to mitigate AlCl3-induced reproductive toxicity and testicular dysfunction.
Energetic parameters in approximation of discrete systems: a MIMO extension problem

An extension of the use of three model reduction techniques to the MIMO linear discrete time systems is presented, in this paper. The main idea is the use of some intrinsic ingredient of the complete order original system namely the impulse response gramian of the complete order system and the Hankel singular values in the construction of various approximants. These models have been compared to the same order reduced model given by the internal projections method. To see the efficiency of each algorithm, these methods are implemented and several simulations are done. From an illustrative example and by means of two important norms, we can better appreciate the most efficient one.
Paediatric obesity and metabolic syndrome associations with cognition and the brain in youth: Current evidence and future directions

Obesity and components of the metabolic syndrome (MetS) are associated with differences in brain structure and function and in general and food‐related cognition in adults. Here, we review evidence for similar phenomena in children and adolescents, with a focus on the implications of extant research for possible underlying mechanisms and potential interventions for obesity and MetS in youth. Current evidence is limited by a relative reliance on small cross‐sectional studies. However, we find that youth with obesity and MetS or MetS components show differences in brain structure, including alterations in grey matter volume and cortical thickness across brain regions subserving reward, cognitive control and other functions, as well as in white matter integrity and volume. Children with obesity and MetS components also show some evidence for hyperresponsivity of food reward regions and hyporesponsivity of cognitive control circuits during food‐related tasks, altered brain responses to food tastes, and altered resting‐state connectivity including between cognitive control and reward processing networks. Potential mechanisms for these findings include neuroinflammation, impaired vascular reactivity, and effects of diet and obesity on myelination and dopamine function. Future observational research using longitudinal measures, improved sampling strategies and study designs, and rigorous statistical methods, promises to further illuminate dynamic relationships and causal mechanisms. Intervention studies targeted at modifiable biological and behavioural factors associated with paediatric obesity and MetS can further inform mechanisms, as well as test whether brain and behaviour can be altered for beneficial outcomes.
Post Hoc Sample Size Estimation for Deep Learning Architectures for ECG-Classification

Deep Learning architectures for time series require a large number of training samples, however traditional sample size estimation for sufficient model performance is not applicable for machine learning, especially in the field of electrocardiograms (ECGs). This paper outlines a sample size estimation strategy for binary classification problems on ECGs using different deep learning architectures and the large publicly available PTB-XL dataset, which includes 21801 ECG samples. This work evaluates binary classification tasks for Myocardial Infarction (MI), Conduction Disturbance (CD), ST/T Change (STTC), and Sex. All estimations are benchmarked across different architectures, including XResNet, Inception-, XceptionTime and a fully convolutional network (FCN). The results indicate trends for required sample sizes for given tasks and architectures, which can be used as orientation for future ECG studies or feasibility aspects.
Predictive value of fetal growth trajectory from 20 weeks of gestation onwards for severe adverse perinatal outcome in low‐risk population: secondary analysis of IRIS study

The placental dysfunction underlying fetal growth restriction (FGR) may result in severe adverse perinatal outcome (SAPO) related to fetal hypoxia. Traditionally, the diagnostic criteria for FGR have been based on fetal size, an approach that is inherently flawed because it often results in either over‐ or underdiagnosis. The anomaly ultrasound scan at 20 weeks' gestation may be an appropriate time at which to set a benchmark for growth potential of the individual fetus. We hypothesized that the fetal growth trajectory from that point onwards may be informative regarding third‐trimester placental dysfunction. The aim of this study was to investigate the predictive value for SAPO of a slow fetal growth trajectory between 18 + 0 to 23 + 6 weeks and 32 + 0 to 36 + 6 weeks' gestation in a large, low‐risk population.
Association of Procedure Time With Clinical and Procedural Outcome in Patients With Basilar Occlusion Undergoing Embolectomy

Background and Objectives Previous studies have demonstrated the association between the procedure time (PT) and outcomes for patients with proximal large vessel occlusion; however, whether the relationship remains for patients with acute basilar artery occlusion (ABAO) was not clear. We aimed to characterize the association between PT and other procedure-related variables on clinical outcomes among patients with ABAO who underwent endovascular treatment (EVT). Methods Patients with ABAO who underwent EVT with a documented PT in the EVT for Acute Basilar Artery Occlusion (BASILAR) study from January 2014 to May 2019 among 47 comprehensive centers in China were included. Multivariable analysis was performed to reveal the association between PT and 90-day modified Rankin Scale score, mortality, complications, and all-cause death at 1 year. Results Of the 829 patients from the BASILAR registry, 633 eligible patients were included. Longer PT were associated with a lower rate of favorable outcome (by 30 minutes, adjusted OR 0.82 [95% CI 0.72–0.93], p = 0.01). In addition, a PT ≤ 75 minutes was associated with a favorable outcome (adjusted OR 2.03 [95% CI 1.26–3.28]). The risk of complications and mortality increased by 0.5% and 1.5% with every 10 minutes increase in PT, respectively (R2 = 0.64 and R2 = 0.68, p < 0.01). The cumulative rates of favorable outcomes and successful recanalization plateaued after 120 minutes (2 attempts). Restricted cubic spline regression analysis for the probability of favorable outcomes had an L-shape association (p nonlinearity = 0.01) with PT with significant benefit loss before 120 minutes and then appeared relatively flat. Discussion For patients with ABAO, procedures that exceeded 75 minutes were associated with an increased risk of mortality and lower odds of a favorable outcome. A careful assessment of futility and the risks of continuing the procedure should be made after 120 minutes.
User Satisfaction with Recently Deployed Electronic Health Records

The high investments in deploying a new Electronic Health Record (EHR) make it necessary to understand its effect on usability (effectiveness, efficiency, and user satisfaction). This paper describes the evaluation process related to user satisfaction over data gathered from three Northern Norway Health Trust hospitals. A questionnaire gathered responses about user satisfaction regarding the newly adopted EHR. A regression model reduces the number of satisfaction items from 15 to nine, where the result represents user EHR Features Satisfaction. The results show positive satisfaction with the newly introduced EHR, a result of proper EHR transition planning and the previous experience of the vendor with the hospitals involved.
Classification of Parkinson's Disease from Voice - Analysis of Data Selection Bias

A growing number of studies have been researching biomarkers of Parkinson's disease (PD) using mobile technology. Many have shown high accuracy in PD classification using machine learning (ML) and voice records from the mPower study, a large database of PD patients and healthy controls. Since the dataset has unbalanced class, gender and age distribution, it is important to consider appropriate sampling when assessing classification scores. We analyse biases, such as identity confounding and implicit learning of non-disease-specific characteristics and present a sampling strategy to highlight and prevent these problems.
Towards a free energy-based elastic network model and its application to the SARS-COV2 binding to ACE2

Classical normal mode analysis (cNMA) is a standard method for studying the equilibrium vibrations of macromolecules. A major limitation of cNMA is that it requires a cumbersome step of energy minimization that also alters the input structure significantly. Variants of normal mode analysis (NMA) exist that perform NMA directly on PDB structures without energy minimization, while maintaining most of the accuracy of cNMA. Spring-based NMA (sbNMA) is such a model. sbNMA uses an all-atom force field as cNMA does, which includes bonded terms such as bond stretching, bond angle bending, torsional, improper, and non-bonded terms such as van der Waals interactions. Electrostatics was not included in sbNMA because it introduced negative spring constants. In this work, we present a way to incorporate most of the electrostatic contributions in normal mode computations, which marks another significant step toward a free-energy-based elastic network model (ENM) for NMA. The vast majority of ENMs are entropy models. One significance of having a free energy-based model for NMA is that it allows one to study the contributions of both entropy and enthalpy. As an application, we apply this model to study the binding stability between SARS-COV2 and angiotensin converting enzyme 2 (or ACE2). Our results show that the stability at the binding interface is contributed nearly equally by hydrophobic interactions and hydrogen bonds.
Association between serum iron markers, iron supplementation and cardiovascular morbidity in pre-dialysis chronic kidney disease

ABSTRACT Background The optimal range of serum iron markers and usefulness of iron supplementation are uncertain in patients with pre-dialysis chronic kidney disease (CKD). We investigated the association between serum iron indices and risk of cardiovascular disease (CVD) events and the effectiveness of iron supplementation using Chronic Kidney Disease Japan Cohort data. Methods We included 1416 patients ages 20–75 years with pre-dialysis CKD. The tested exposures were serum transferrin saturation and serum ferritin levels and the outcome measures were any cardiovascular event. Fine–Gray subdistribution hazard models were used to examine the association between serum iron indices and time to events. The multivariable fractional polynomial interaction approach was used to evaluate whether serum iron indices were effect modifiers of the association between iron supplementation and cardiovascular events. Results The overall incidence rate of CVD events for a median of 4.12 years was 26.7 events/1000 person-years. Patients with serum transferrin saturation <20% demonstrated an increased risk of CVD [subdistribution hazard ratio (HR) 2.13] and congestive heart failure (subdistribution HR 2.42). The magnitude of reduction in CVD risk with iron supplementation was greater in patients with lower transferrin saturations (P = .042). Conclusions Maintaining transferrin saturation >20% and adequate iron supplementation may effectively reduce the risk of CVD events in patients with pre-dialysis CKD.