Can a pathological model improve the abilities of the paretic hand in hemiplegic children? The PAM-AOT study protocol of a randomised controlled trial

IntroductionAction Observation Treatment (AOT) is an innovative therapeutic approach consisting in the observation of actions followed by subsequent repetition. In children with unilateral cerebral palsy (UCP), it improves upper limb function in daily activities. The standard paradigm of AOT requires the observation of healthy models; however, it has been demonstrated that the mirror neuron system of children with UCP is more activated by observation of pathological models, showing a similar motor repertoire, than by the healthy model, suggesting that AOT based on pathological models is superior to the standard paradigm of AOT in the functional rehabilitation of the affected upper limb of children with UCP.Methods and analysisThis protocol describes an active two-arm randomised controlled evaluator-blinded trial. Twenty-six children with UCP will participate in 3 weeks of intensive AOT: the experimental group will observe a pathological model, while the control group will observe a typically developed model. The primary outcome is the spontaneous use of the paretic hand, measured with the Assisting Hand Assessment. Secondary outcome measures are the Melbourne Assessment of Unilateral Upper Limb Function, the ABILHAND-Kids and the Activities Scale for Kids-performance. Assessments will be performed at baseline (T0), at the end of intensive AOT (T1), at 8–12 weeks (T2) and at 24–28 weeks (T3) after the end of intensive AOT.Ethics and disseminationThe trial was approved by the Area Vasta Emilia Nord Ethics Committee (AVEN prot. n. 133117, 29 November 2018), and it was prospectively registered on ClinicalTrials.gov. The results will be submitted for publication to a peer-reviewed journal, discussed with parents of children participating in the trial and disseminated at suitable conferences.Trial registration numberNCT04088994; Pre-results.

Transcriptomic Studies Suggest a Coincident Role for Apoptosis and Pyroptosis but Not for Autophagic Neuronal Death in TBEV-Infected Human Neuronal/Glial Cells

Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, Flavivirus genus, is responsible for neurological symptoms that may cause permanent disability or death. With an incidence on the rise, it is the major arbovirus affecting humans in Central/Northern Europe and North-Eastern Asia. Neuronal death is a critical feature of TBEV infection, yet little is known about the type of death and the molecular mechanisms involved. In this study, we used a recently established pathological model of TBEV infection based on human neuronal/glial cells differentiated from fetal neural progenitors and transcriptomic approaches to tackle this question. We confirmed the occurrence of apoptotic death in these cultures and further showed that genes involved in pyroptotic death were up-regulated, suggesting that this type of death also occurs in TBEV-infected human brain cells. On the contrary, no up-regulation of major autophagic genes was found. Furthermore, we demonstrated an up-regulation of a cluster of genes belonging to the extrinsic apoptotic pathway and revealed the cellular types expressing them. Our results suggest that neuronal death occurs by multiple mechanisms in TBEV-infected human neuronal/glial cells, thus providing a first insight into the molecular pathways that may be involved in neuronal death when the human brain is infected by TBEV.

How to model DNA replication in stochastic models of synthetic genetic circuits (and why)

Biocircuit modeling sometimes requires explicit tracking of a self-replicating DNA species. The most obvious, straightforward way to model a replicating DNA is structurally unstable and leads to pathological model behavior. We describe a simple, stable replication mechanism with good model behavior and show how to derive it from a mechanistic model of ColE1 replication.

Optimizing Antiviral Therapy for COVID-19 With Learned Pathogenic Model

COVID-19 together with variants have caused an unprecedented amount of mental and economic turmoil with ever increasing fatality and no proven therapies in sight. The healthcare industry is racing to find a cure with multitude of clinical trials underway to access the efficacy of repurposed antivirals, however the much needed insights into the dynamics of pathogenesis of SARS-CoV-2 and corresponding pharmacology of antivirals are lacking. This paper introduces systematic pathological model learning of COVID-19 dynamics followed by derivative free optimization based multi objective drug rescheduling. The pathological model learnt from clinical data of severe COVID-19 patients treated with Remdesivir could additionally predict immune T cells response and resulted in a dramatic reduction in Remdesivir dose and schedule leading to lower toxicities, however maintaining a high virological efficacy.

Radiomics-based model for predicting early recurrence of intrahepatic mass-forming cholangiocarcinoma after curative tumor resection

To investigate the ability of CT-based radiomics signature for pre-and postoperatively predicting the early recurrence of intrahepatic mass-forming cholangiocarcinoma (IMCC) and develop radiomics-based prediction models. Institutional review board approved this study. Clinicopathological characteristics, contrast-enhanced CT images, and radiomics features of 125 IMCC patients (35 with early recurrence and 90 with non-early recurrence) were retrospectively reviewed. In the training set of 92 patients, preoperative model, pathological model, and combined model were developed by multivariate logistic regression analysis to predict the early recurrence (≤ 6 months) of IMCC, and the prediction performance of different models were compared using the Delong test. The developed models were validated by assessing their prediction performance in test set of 33 patients. Multivariate logistic regression analysis identified solitary, differentiation, energy- arterial phase (AP), inertia-AP, and percentile50th-portal venous phase (PV) to construct combined model for predicting early recurrence of IMCC [the area under the curve (AUC) = 0.917; 95% CI 0.840–0.965]. While the AUC of pathological model and preoperative model were 0.741 (95% CI 0.637–0.828) and 0.844 (95% CI 0.751–0.912), respectively. The AUC of the combined model was significantly higher than that of the preoperative model (p = 0.049) or pathological model (p = 0.002) in training set. In test set, the combined model also showed higher prediction performance. CT-based radiomics signature is a powerful predictor for early recurrence of IMCC. Preoperative model (constructed with homogeneity-AP and standard deviation-AP) and combined model (constructed with solitary, differentiation, energy-AP, inertia-AP, and percentile50th-PV) can improve the accuracy for pre-and postoperatively predicting the early recurrence of IMCC.

Derivation and Validation of a Prognostic Scoring Model Based on Clinical and Pathological Features for Risk Stratification in Oral Squamous Cell Carcinoma Patients: A Retrospective Multicenter Study

ObjectiveTo develop and validate a simple-to-use prognostic scoring model based on clinical and pathological features which can predict overall survival (OS) of patients with oral squamous cell carcinoma (OSCC) and facilitate personalized treatment planning.Materials and MethodsOSCC patients (n = 404) from a public hospital were divided into a training cohort (n = 282) and an internal validation cohort (n = 122). A total of 12 clinical and pathological features were included in Kaplan–Meier analysis to identify the factors associated with OS. Multivariable Cox proportional hazards regression analysis was performed to further identify important variables and establish prognostic models. Nomogram was generated to predict the individual’s 1-, 3- and 5-year OS rates. The performance of the prognostic scoring model was compared with that of the pathological one and the AJCC TNM staging system by the receiver operating characteristic curve (ROC), concordance index (C-index), calibration curve, and decision curve analysis (DCA). Patients were classified into high- and low-risk groups according to the risk scores of the nomogram. The nomogram-illustrated model was independently tested in an external validation cohort of 95 patients.ResultsFour significant variables (physical examination-tumor size, imaging examination-tumor size, pathological nodal involvement stage, and histologic grade) were included into the nomogram-illustrated model (clinical–pathological model). The area under the ROC curve (AUC) of the clinical–pathological model was 0.687, 0.719, and 0.722 for 1-, 3- and 5-year survival, respectively, which was superior to that of the pathological model (AUC = 0.649, 0.707, 0.717, respectively) and AJCC TNM staging system (AUC = 0.628, 0.668, 0.677, respectively). The clinical–pathological model exhibited improved discriminative power compared with pathological model and AJCC TNM staging system (C-index = 0.755, 0.702, 0.642, respectively) in the external validation cohort. The calibration curves and DCA also displayed excellent predictive performances.ConclusionThis clinical and pathological feature based prognostic scoring model showed better predictive ability compared with the pathological one, which would be a useful tool of personalized accurate risk stratification and precision therapy planning for OSCC patients.

Dynamics of Cyclooxygenase-1 Positive Microglia/Macrophage in the Retina of Pathological Model Mice as a Biomarker of the Retinal Inflammatory Diseases

In an intraocular inflammatory state, microglia residing in the retina become active and migrate inside the retina. In this study, we investigated whether cyclooxygenase-1 (COX-1) expressed by retinal microglia/macrophage can be a biomarker for the diagnosis of retinal diseases. COX-1 was immunopositive in microglia/macrophage and neutrophils, while COX-2 was immunopositive in astrocytes and neurons in the inner layer of normal retina. The number of COX-1 positive cells per section of the retinal tissue was 14 ± 2.8 (mean ± standard deviation) in normal mice, which showed significant increase in the lipopolysaccharide (LPS)-administrated model (62 ± 5.0, p = 8.7 × 10−9). In addition to microglia, we found neutrophils that were positive for COX-1. In the early stage of inflammation in the experimental autoimmune uveoretinitis (EAU), COX-1 positive cells, infiltrating from the ciliary body into the retinal outer nuclear layer, were observed. The number of infiltrating COX-1 positive cells correlated with the severity of EAU. Taken together, the increased number of COX-1 positive microglia/macrophage with morphological changes were observed in the retinas of retinal inflammatory disease models. This suggests that COX-1 can be a marker of disease-related activities of microglia/macrophage, which should be useful for the diagnosis of retinal diseases.

Brain Iron Imaging Markers in the Presence of White Matter Hyperintensities

PurposeTo investigate the relationship between pathological brain iron deposition and white matter hyperintensities (WMHs) in cerebral small vessel disease (CSVD), via Monte Carlo simulations of magnetic susceptibility imaging and a novel imaging marker called the Expected Iron Coefficient (EIC).MethodsA synthetic pathological model of a different number of impenetrable spheres at random locations was employed to represent pathological iron deposition. The diffusion process was simulated with a Monte Carlo method with adjustable parameters to manipulate sphere size, distribution, and extracellular properties. Quantitative susceptibility mapping (QSM) was performed in a clinical dataset to study CSVD to derive and evaluate QSM, R2*, the iron microenvironment coefficient (IMC), and EIC in the presence of WMHs.ResultsThe simulations show that QSM signals increase in the presence of increased tissue iron, confirming that the EIC increases with pathology. Clinical results demonstrate that while QSM, R2*, and the IMC do not show differences in brain iron, the EIC does in the context of CSVD.ConclusionThe EIC is more sensitive to subtle changes in brain iron deposition caused by pathology, even when QSM, R2*, and the IMC do not.

Urine metabolomics of rats with chronic atrophic gastritis

Background/aim To use liquid chromatography-mass spectrometry (LC-MS) to identify endogenous differential metabolites in the urine of rats with chronic atrophic gastritis (CAG). Materials and methods Methylnitronitrosoguanidine (MNNG) was used to produce a CAG model in Wistar rats, and HE staining was used to determine the pathological model. LC-MS was used to detect the differential metabolic profiles in rat urine. Diversified analysis was performed by the statistical method. Results Compared with the control group, the model group had 68 differential metabolites, 25 that were upregulated and 43 that were downregulated. The main metabolic pathways were D-glutamine and D-glutamic acid metabolism, histidine metabolism and purine metabolism. Conclusion By searching for differential metabolites and metabolic pathways in the urine of CAG rats, this study provides effective experimental data for the pathogenesis and clinical diagnosis of CAG.

The Crisis of Humanities in Contemporary Society: Causes and Effects

This article analyses the impact of information revolutions on culture, society, and education, as well as the individual. Contemporary technological consumer society presents a pathological model of relations between human beings and being – a situation that results in many social and cultural problematic features. This article explores these features of modern civilization from a philosophical (ontological) viewpoint, demonstrating that the current crises of humanities is rooted in this deeper ontological situation. The described features of modern information and cognitive metabolism in culture and education show the situation of the “ontological impasse”. In the current sociocultural situation, individuals have lost themselves as thinking entities and education has lost itself both as an institution and as a means of realizing the potential of a person’s spiritual and cognitive transformation. Knowledge has lost its value and sacredness, becoming based on pragmatism, usefulness and comfort. To overcome this situation, deep existential and ontological shifts are required. Keywords: person, culture, education, information and cognitive metabolism, writing, orality, knowledge, understanding, awareness.