In many rare disease Phase II clinical trials, two objectives are of interest to an investigator: maximising the statistical power and maximising the number of patients responding to the treatment. These two objectives are competing, therefore, clinical trial designs offering a balance between them are needed. Recently, it was argued that response-adaptive designs such as families of multi-arm bandit (MAB) methods could provide the means for achieving this balance. Furthermore, response-adaptive designs based on a concept of context-dependent (weighted) information criteria were recently proposed with a focus on Shannon’s differential entropy. The information-theoretic designs based on the weighted Renyi, Tsallis and Fisher informations are also proposed. Due to built-in parameters of these novel designs, the balance between the statistical power and the number of patients that respond to the treatment can be tuned explicitly. The asymptotic properties of these measures are studied in order to construct intuitive criteria for arm selection. A comprehensive simulation study shows that using the exact criteria over asymptotic ones or using information measures with more parameters, namely Renyi and Tsallis entropies, brings no sufficient gain in terms of the power or proportion of patients allocated to superior treatments. The proposed designs based on information-theoretical criteria are compared to several alternative approaches. For example, via tuning of the built-in parameter, one can find designs with power comparable to the fixed equal randomisation’s but a greater number of patients responded in the trials.
Large, open-source datasets, such as the Human Connectome Project and the Autism Brain Imaging Data Exchange, have spurred the development of new and increasingly powerful machine learning approaches for brain connectomics. However, one key question remains: are we capturing biologically relevant and generalizable information about the brain, or are we simply overfitting to the data? To answer this, we organized a scientific challenge, the Connectomics in NeuroImaging Transfer Learning Challenge (CNI-TLC), held in conjunction with MICCAI 2019. CNI-TLC included two classification tasks: (1) diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) within a pre-adolescent cohort; and (2) transference of the ADHD model to a related cohort of Autism Spectrum Disorder (ASD) patients with an ADHD comorbidity. In total, 240 resting-state fMRI (rsfMRI) time series averaged according to three standard parcellation atlases, along with clinical diagnosis, were released for training and validation (120 neurotypical controls and 120 ADHD). We also provided Challenge participants with demographic information of age, sex, IQ, and handedness. The second set of 100 subjects (50 neurotypical controls, 25 ADHD, and 25 ASD with ADHD comorbidity) was used for testing. Classification methodologies were submitted in a standardized format as containerized Docker images through ChRIS, an open-source image analysis platform. Utilizing an inclusive approach, we ranked the methods based on 16 metrics: accuracy, area under the curve, F1-score, false discovery rate, false negative rate, false omission rate, false positive rate, geometric mean, informedness, markedness, Matthew’s correlation coefficient, negative predictive value, optimized precision, precision, sensitivity, and specificity. The final rank was calculated using the rank product for each participant across all measures. Furthermore, we assessed the calibration curves of each methodology. Five participants submitted their method for evaluation, with one outperforming all other methods in both ADHD and ASD classification. However, further improvements are still needed to reach the clinical translation of functional connectomics. We have kept the CNI-TLC open as a publicly available resource for developing and validating new classification methodologies in the field of connectomics.
An important role in the specific protection of the body, as well as energy and metabolic supply belongs to blood and, above all, erythrocytes involved in maintaining the body's dynamic homeostasis. The blood antigen-antibody AB0 system belongs to the systems of structural and functional support of the body's vital activity and, like any body system, is subject to the influence of external and internal factors. Currently, new data is emerging on the functional specificity of the AB0 system antigens, which contributes to a better understanding of their role. Our data obtained in model experiments show that low molecular weight metabolites - pyruvate, lactate and ethanol, due to direct and indirect effects, change the antigen-antibody interaction of the AB0 system, which is proved by fluctuations in two agglutination reaction parameters: the degree and the onset time of erythrocyte agglutination. Individual differences in the parameters, the agglutination degree and agglutination onset time, are evidently due to the difference in the structure of AB0 antigens and monoclonal antibodies to them.
The evolution of virtual reality (VR) technologies requires setting boundaries of its use. In this study, 3 female participants were experiencing VR scenarios with stressful content and their activity of the autonomic nervous system and EEG were recorded. It has been discovered that virtual reality can evoke acute stress reactions accompanied by activation of the sympathetic nervous system and a decrease in the activity of the parasympathetic nervous system. The high-stress response is accompanied by a decrease in the power of the EEG, and, on the contrary, the activation of the avoidance reaction is accompanied by an increase in the power of the EEG alpha waves. Therefore, the use of stressful VR content can cause high emotional stress to a user and restrictions should be considered.
The left frontal aslant tract (FAT) has been proposed to be relevant for language, and specifically for spontaneous speech fluency. However, there is missing causal evidence that stimulation of the FAT affects spontaneous speech, and not language production in general. We present a series of 12 neurosurgical cases with awake language mapping of the cortex near the left FAT. Tasks for language mapping included the commonly used action picture naming, and sentence completion, tapping more specifically into spontaneous speech. A task dissociation was found in 10 participants: while being stimulated on specific sites, they were able to name a picture but could not complete a sentence. Overlaying of these sites on preoperative white-matter tract reconstructions revealed that in each individual case they were located on cortical terminations of the FAT. This corroborates the language functional specificity of the left FAT as a tract underlying fluent spontaneous speech.
Although CDK7 inhibitors are considered to be potential anticancer drugs, all inhibitors developed so far have significant disadvantages preventing their further use. We have developed a new CDK7 inhibitor scaffold lacking hepatotoxicity using molecular dynamics (MD) and free energy perturbation (FEP/MD) methods, and were able to double its binding affinity after additional research. The combination of MD and FEP/MD methods was shown to be a valuable instrument for the development of novel and potent CDK7 inhibitors for anticancer therapy.
Insomnia is one of the most widespread health problems in the general population . It has been estimated that one-third of the general population experience at least one of the insomnia symptoms . According to DSM-5, insomnia is defined as difficulty in initiating or maintaining sleep or early morning awakening accompanied by considerable distress or clinical disturbance . Insomnia is considered as a disorder characterized by nocturnal symptoms (difficulty falling or maintaining asleep) and daytime symptoms (i.e., deterioration in daytime functioning).
The review summarizes studies of chemical and biological processes occurring in human body upon exposure to coronaviruses, in particular SARS-CoV-2. The mechanisms of viral particles penetration into the cell and their replication, impact on the immune system and oxygen transport systems are considered. The mechanisms of complications occurring as a consequence of viral infection - vasculitis, thrombosis, cytokine storm and lung fibrosis are discussed. The review also includes data on the latest research in the field of small molecule medication to counteract the virus. Molecular targets and possible vectors of exploiting them are considered. The review is written primarily for specialists who want to understand the chains of activation, replication, actions and methods of protection/inhibition of SARS-CoV-2. Due to the short period of such studies, the data on complexes of small molecule compounds and possible protein targets are not numerous, but they will be useful in search and synthesis of new potentially effective drugs.
Prevalence of oral diseases among children is an urgent problem that poses a threat to the health of the growing population in Russia. Dental pathology among children with disabilities has specific characteristics regarding its development, prevalence and intensity of the lesion. Statistically, dental morbidity of children with disabilities is much higher than in somatically healthy. This is due to a number of factors: a slowdown in the perception rate, underdevelopment of the cognitive sphere, violation of behavioral reactions and, as a consequence, inadequate compliance with necessary hygienic procedures. The authors consider that the major etiological factor resulting in the development of diseases of oral mucosa and periodontal condition in patients with neuropsychiatric pathology is absence or poor hygienic care of the oral cavity. The aim of the study is to assess the dental status of children with disabilities and autism spectrum disorders aged 3 – 8 years old. To determine this status, the method of defining and calculating indices reflecting the state of oral tissues was employed. The following indexes were used in the study: Fedorov-Volodkina hygienic index; simplified index of oral hygiene (OHI-S/GAMES-Y),; papillary-marginal-alveolar index (PMA); Index of tooth decay kp, KPU+kp. Dental examination revealed a high prevalence of dental diseases in children with ASD and cerebral palsy; in particular, multiple lesions of hard tissues of the teeth, periodontal inflammation were identified. The findings of the study showed that caries in children with limited abilities is mainly due to their low motivation to develop a habit of individual manual teeth brushing ritual.