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Background and ObjectivesBrain-computer interfaces (BCIs) are being developed to restore mobility, communication, and functional independence to people with paralysis. Though supported by decades of preclinical data, the safety of chronically implanted microelectrode array BCIs in humans is unknown. We report safety results from the prospective, open-label, nonrandomized BrainGate feasibility study (NCT00912041), the largest and longest-running clinical trial of an implanted BCI.MethodsAdults aged 18–75 years with quadriparesis from spinal cord injury, brainstem stroke, or motor neuron disease were enrolled through 7 clinical sites in the United States. Participants underwent surgical implantation of 1 or 2 microelectrode arrays in the motor cortex of the dominant cerebral hemisphere. The primary safety outcome was device-related serious adverse events (SAEs) requiring device explantation or resulting in death or permanently increased disability during the 1-year postimplant evaluation period. The secondary outcomes included the type and frequency of other adverse events and the feasibility of the BrainGate system for controlling a computer or other assistive technologies.ResultsFrom 2004 to 2021, 14 adults enrolled in the BrainGate trial had devices surgically implanted. The average duration of device implantation was 872 days, yielding 12,203 days of safety experience. There were 68 device-related adverse events, including 6 device-related SAEs. The most common device-related adverse event was skin irritation around the percutaneous pedestal. There were no safety events that required device explantation, no unanticipated adverse device events, no intracranial infections, and no participant deaths or adverse events resulting in permanently increased disability related to the investigational device.DiscussionThe BrainGate Neural Interface system has a safety record comparable with other chronically implanted medical devices. Given rapid recent advances in this technology and continued performance gains, these data suggest a favorable risk/benefit ratio in appropriately selected individuals to support ongoing research and development.Trial Registration InformationClinicalTrials.gov Identifier:NCT00912041.Classification of EvidenceThis study provides Class IV evidence that the neurosurgically placed BrainGate Neural Interface system is associated with a low rate of SAEs defined as those requiring device explantation, resulting in death, or resulting in permanently increased disability during the 1-year postimplant period.

Summarized results of investigation of regulation of electron transport and associated processes in the photosynthetic membrane using methods of mathematical and computer modeling carried out at the Department of Biophysics, Faculty of Biology, Lomonosov Moscow State University, are presented in this review. Detailed kinetic models of processes in the thylakoid membrane were developed using the apparatus of differential equations. Fitting of the model curves to the data of spectral measurements allowed us to estimate the values of parameters that were not determined directly in experiments. The probabilistic method of agent-based Monte Carlo modeling provides ample opportunities for studying dynamics of heterogeneous systems based on the rules for the behavior of individual elements of the system. Algorithms for simplified representation of Big Data make it possible to monitor changes in the photosynthetic apparatus in the course of culture growth in a photobioreactor and for the purpose of environmental monitoring. Brownian and molecular models describe movement and interaction of individual electron carrier proteins and make it possible to study electrostatic, hydrophobic, and other interactions leading to regulation of conformational changes in the reaction complexes. Direct multiparticle models explicitly simulate Brownian diffusion of the mobile protein carriers and their electrostatic interactions with multienzyme complexes both in solution and in heterogeneous interior of a biomembrane. The combined use of methods of kinetic and Brownian multiparticle and molecular modeling makes it possible to study the mechanisms of regulation of an integral system of electron transport processes in plants and algae at molecular and subcellular levels.

A common complication that can arise with analyses of high-dimensional data is the repeated use of hypothesis tests. A second complication, especially with small samples, is the reliance on asymptotic p-values. Our proposed approach for addressing both complications uses a scientifically motivated scalar summary statistic, and although not entirely novel, seems rarely used. The method is illustrated using a crossover study of seventeen participants examining the effect of exposure to ozone versus clean air on the DNA methylome, where the multivariate outcome involved 484,531 genomic locations. Our proposed test yields a single null randomization distribution, and thus a single Fisher-exact p-value that is statistically valid whatever the structure of the data. However, the relevance and power of the resultant test requires the careful a priori selection of a single test statistic. The common practice using asymptotic p-values or meaningless thresholds for “significance” is inapposite in general.

Summary The design of any study, whether experimental or observational, that is intended to estimate the causal effects of a treatment condition relative to a control condition refers to those activities that precede any examination of outcome variables. As defined in our 1983 article (Rosenbaum & Rubin, 1983), the propensity score is the unit-level conditional probability of assignment to treatment versus control given the observed covariates; so the propensity score explicitly does not involve any outcome variables, in contrast to other summaries of variables sometimes used in observational studies. Balancing the distributions of covariates in the treatment and control groups by matching or balancing on the propensity score is therefore an aspect of the design of the observational study. In this invited comment on our 1983 article, we review the situation in the early 1980s and recall some apparent paradoxes that propensity scores helped to resolve. We demonstrate that it is possible to balance an enormous number of low-dimensional summaries of a high-dimensional covariate, even though it is generally impossible to match individuals closely for all the components of a high-dimensional covariate. In a sense, there is only one crucial observed covariate, the propensity score, and there is one crucial unobserved covariate, the principal unobserved covariate. The propensity score and the principal unobserved covariate are equal when treatment assignment is strongly ignorable, that is, unconfounded. Controlling for observed covariates is a prelude to the crucial step from association to causation, the step that addresses potential biases from unmeasured covariates. The design of an observational study also prepares for the step to causation: by selecting comparisons to increase the design sensitivity, by seeking opportunities to detect bias, by seeking mutually supportive evidence affected by different biases, by incorporating quasi-experimental devices such as multiple control groups, and by including the economist’s instruments. All of these considerations reflect the formal development of sensitivity analyses that were largely informal prior to the 1980s.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Monitoring of the photosynthetic activity of natural and artificial biocenoses is of crucial importance. Photosynthesis is the basis for the existence of life on Earth, and a decrease in primary photosynthetic production due to anthropogenic influences can have catastrophic consequences. Currently, great efforts are being made to create technologies that allow continuous monitoring of the state of the photosynthetic apparatus of terrestrial plants and microalgae. There are several sources of information suitable for assessing photosynthetic activity, including gas exchange and optical (reflectance and fluorescence) measurements. The advent of inexpensive optical sensors makes it possible to collect data locally (manually or using autonomous sea and land stations) and globally (using aircraft and satellite imaging). In this review, we consider machine learning methods proposed for determining the functional parameters of photosynthesis based on local and remote optical measurements (hyperspectral imaging, solar-induced chlorophyll fluorescence, local chlorophyll fluorescence imaging, and various techniques of fast and delayed chlorophyll fluorescence induction). These include classical and novel (such as Partial Least Squares) regression methods, unsupervised cluster analysis techniques, various classification methods (support vector machine, random forest, etc.) and artificial neural networks (multilayer perceptron, long short-term memory, etc.). Special aspects of time-series analysis are considered. Applicability of particular information sources and mathematical methods for assessment of water quality and prediction of algal blooms, for estimation of primary productivity of biocenoses, stress tolerance of agricultural plants, etc. is discussed.

The paper presents the results of recent work at the Department of Biophysics of the Biological Faculty, Lomonosov Moscow State University on the kinetic and multiparticle modeling of processes in the photosynthetic membrane. The detailed kinetic models and the rule-based kinetic Monte Carlo models allow to reproduce the fluorescence induction curves and redox transformations of the photoactive pigment P700 in the time range from 100 ns to dozens of seconds and make it possible to reveal the role of individual carriers in their formation for different types of photosynthetic organisms under different illumination regimes, in the presence of inhibitors, under stress conditions. The fitting of the model curves to the experimental data quantifies the reaction rate constants that cannot be directly measured experimentally, including the non-radiative thermal relaxation reactions. We use the direct multiparticle models to explicitly describe the interactions of mobile photosynthetic carrier proteins with multienzyme complexes both in solution and in the biomembrane interior. An analysis of these models reveals the role of diffusion and electrostatic factors in the regulation of electron transport, the influence of ionic strength and pH of the cellular environment on the rate of electron transport reactions between carrier proteins. To describe the conformational intramolecular processes of formation of the final complex, in which the actual electron transfer occurs, we use the methods of molecular dynamics. The results obtained using kinetic and molecular models supplement our knowledge of the mechanisms of organization of the photosynthetic electron transport processes at the cellular and molecular levels.

Synchronous bursts of high frequency oscillations (‘ripples’) are hypothesized to contribute to binding by facilitating integration of neuronal firing across cortical locations. We tested this hypothesis using local field-potentials and single-unit firing from four 96-channel microelectrode arrays in supragranular cortex of 3 patients. Neurons in co-rippling locations showed increased short-latency co-firing, prediction of each-other’s firing, and co-participation in neural assemblies. Effects were similar for putative pyramidal and interneurons, during NREM sleep and waking, in temporal and Rolandic cortices, and at distances up to 16mm. Increased co-prediction during co-ripples was maintained when firing-rate changes were equated, and were strongly modulated by ripple phase. Co-ripple enhanced prediction is reciprocal, synergistic with local upstates, and enhanced when multiple sites co-ripple. Together, these results support the hypothesis that transcortical co-ripples increase the integration of neuronal firing of neurons in different cortical locations, and do so in part through phase-modulation.

Deep learning (DL)-based automatic segmentation models can expedite manual segmentation yet require resource-intensive fine-tuning before deployment on new datasets. The generalizability of DL methods to new datasets without fine-tuning is not well characterized.Evaluate the generalizability of DL-based models by deploying pretrained models on independent datasets varying by MR scanner, acquisition parameters, and subject population.Retrospective based on prospectively acquired data.Overall test dataset: 59 subjects (26 females); Study 1: 5 healthy subjects (zero females), Study 2: 8 healthy subjects (eight females), Study 3: 10 subjects with osteoarthritis (eight females), Study 4: 36 subjects with various knee pathology (10 females).A 3-T, quantitative double-echo steady state (qDESS).Four annotators manually segmented knee cartilage. Each reader segmented one of four qDESS datasets in the test dataset. Two DL models, one trained on qDESS data and another on Osteoarthritis Initiative (OAI)-DESS data, were assessed. Manual and automatic segmentations were compared by quantifying variations in segmentation accuracy, volume, and T2 relaxation times for superficial and deep cartilage.Dice similarity coefficient (DSC) for segmentation accuracy. Lin's concordance correlation coefficient (CCC), Wilcoxon rank-sum tests, root-mean-squared error-coefficient-of-variation to quantify manual vs. automatic T2 and volume variations. Bland-Altman plots for manual vs. automatic T2 agreement. A P value 0.05 was considered statistically significant.DSCs for the qDESS-trained model, 0.79-0.93, were higher than those for the OAI-DESS-trained model, 0.59-0.79. T2 and volume CCCs for the qDESS-trained model, 0.75-0.98 and 0.47-0.95, were higher than respective CCCs for the OAI-DESS-trained model, 0.35-0.90 and 0.13-0.84. Bland-Altman 95% limits of agreement for superficial and deep cartilage T2 were lower for the qDESS-trained model, ±2.4 msec and ±4.0 msec, than the OAI-DESS-trained model, ±4.4 msec and ±5.2 msec.The qDESS-trained model may generalize well to independent qDESS datasets regardless of MR scanner, acquisition parameters, and subject population.1 TECHNICAL EFFICACY: Stage 1.

Consolidation of memory is believed to involve offline replay of neural activity. While amply demonstrated in rodents, evidence for replay in humans, particularly regarding motor memory, is less compelling. To determine whether replay occurs after motor learning, we sought to record from motor cortex during a novel motor task and subsequent overnight sleep. A 36-year-old man with tetraplegia secondary to cervical spinal cord injury enrolled in the ongoing BrainGate brain-computer interface pilot clinical trial had two 96-channel intracortical microelectrode arrays placed chronically into left precentral gyrus. Single- and multi-unit activity was recorded while he played a color/sound sequence matching memory game. Intended movements were decoded from motor cortical neuronal activity by a real-time steady-state Kalman filter that allowed the participant to control a neurally driven cursor on the screen. Intracortical neural activity from precentral gyrus and 2-lead scalp EEG were recorded overnight as he slept. When decoded using the same steady-state Kalman filter parameters, intracortical neural signals recorded overnight replayed the target sequence from the memory game at intervals throughout at a frequency significantly greater than expected by chance. Replay events occurred at speeds ranging from 1 to 4 times as fast as initial task execution and were most frequently observed during slow-wave sleep. These results demonstrate that recent visuomotor skill acquisition in humans may be accompanied by replay of the corresponding motor cortex neural activity during sleep.

OBJECTIVE Pilocytic astrocytomas (PAs) have a generally favorable prognosis; however, progression or recurrence after resection is possible. The prognostic value of histopathological qualifiers (defined below) or BRAF alterations is not well understood. The aim of this study was to identify the prognostic value of genetic and histopathological features of pediatric PAs. METHODS Patients treated for a WHO grade I PA at a single institution were analyzed for histopathological and genetic features and outcomes. “Histopathological qualifier” refers to designations such as "WHO grade I PA with increased proliferative index." BRAF alterations include gene fusions and point mutations. Patients with neurofibromatosis type 1 were excluded. RESULTS A total of 222 patients were analyzed (51% female, mean age 9.6 years). Tumors were located in the cerebellum/fourth ventricle (51%), optic pathway/hypothalamus (15%), brainstem (12%), and cerebral cortex (11%). BRAF alterations were screened for in 77 patients and identified in 56 (73%). Histopathological qualifiers were present in 27 patients (14%). Resection was performed in 197 patients (89%), 41 (21%) of whom displayed tumor progression or recurrence after resection. Tumor progression or recurrence was not associated with histopathologic qualifiers (p = 0.36) or BRAF alterations (p = 0.77). Ki-67 proliferative indices were not predictive of progression or recurrence (p = 0.94). BRAF alterations, specifically KIAA1549 fusions, were associated with cerebellar/fourth ventricular tumor location (p < 0.0001) and younger patient age (p = 0.03). Patients in whom gross-total resection was achieved had lower rates of progression and recurrence (p < 0.0001). CONCLUSIONS Histopathological features/qualifiers and BRAF alterations were not associated with tumor recurrence/progression in pediatric PAs. The extent of resection was the only factor analyzed that predicted outcome.

The significant sex differences that exist in cancer mechanisms, incidence, and survival, have yet to impact clinical practice. We hypothesized that one barrier to translation is that sex differences in cancer phenotypes resemble sex differences in height: highly overlapping, but distinct, male and female population distributions that vary continuously between female- and male-biased extremes. A consequence of this variance is that sex-specific treatments are rendered unrealistic, and our translational goal should be adaptation of treatment to the unique mix of sex-biased mechanisms that are present in each patient. To develop a tool that could advance this goal, we applied a Bayesian Nearest Neighbor (BNN) analysis to 8370 cancer transcriptomes from 26 different adult and 4 different pediatric cancer types to establish patient-specific Transcriptomic Sex Indices (TSI). TSI precisely partitions an individual patient’s whole transcriptome into female- and male-biased components such that cancer type, patient sex, and transcriptomics, provide a novel and patient-specific mechanistic identifier that can be used for sex-adapted, precision cancer treatment planning.