Spatial Decoding for Gaze Independent Brain-Computer Interface Based on Covert Visual Attention Shift Using Electroencephalography.

The gaze-independent brain-computer interface (BCI) device is used to re-establish interaction for individuals who have abnormal eye movement. It may be possible to control the BCI by shifting your attention spatially. However, spatial attention is rarely employed to increase the effectiveness of target detection and is typically used to provide a simple "yes" or "no" response to the target recognition inquiry. To improve the effectiveness of detecting target, it is crucial to take advantage of the possible advantages of spatial attention. N2-posterior-contralateral (N2pc) component reflects correlates of visual spatial attention and is used to determine target position. In this study, a long-short-term memory (LSTM) network is used to answer "yes/no" questions by decoding covert spatial attention based on N2pc characteristics using EEG signals. The proposed LSTM-based model's average decoding accuracy is 92.79%. The target detection efficiency was successfully increased by about 4% when compared to conventional machine learning algorithms. The proposed model is tested on the independent dataset to validate its performance. The results of this work show that N2pc characteristics can be employed in gaze-independent BCIs for tracking covert attention shifts, which may help persons with poor eye mobility to connect with their environment.

Human gut microbiota and Parkinson's disease.

The bidirectional communication between the gut and the brain has come up very fascinating in recent years. Many studies have reported that the onset of gastrointestinal issues appears long before the actual manifestation of Parkinson's disease (PD) symptoms. Disturbances in the gut-brain axis have been found to be linked with PD. PD-linked neuropathological changes in the enteric nervous system and significant alteration of gut microbiota suggest a vital role of gut microbiota in PD pathogenesis. Studies have also suggested that aggregation of α-synuclein, one of the major proteins associated with PD neuropathology, might start from the gut and move to the central nervous system (CNS) through the vagus nerve and olfactory bulb. Inflammation in the gut has been suggested to be associated with PD initiation and progression. The flushing out of healthy gut microbiota and replacing with pathogens induces gut inflammation and promotes neuroinflammation in the CNS. Therefore, it is intriguing to understand the mechanism of gut-brain communications associated with the development of PD. This review sheds light on the PD pathology, the gut dysbiosis that is associated with PD and its medications, altered gene expression, pathways and microbial metabolites during PD.

A protocol for production of perdeuterated OmpF porin for neutron crystallography.

Hydrogen atoms are at the limit of visibility in X-ray structures even at high resolution. Neutron macromolecular crystallography (NMX) is an unambiguous method to locate hydrogens and study the significance of hydrogen bonding interactions in biological systems. Since NMX requires very large crystals, very few neutron structures of proteins have been determined yet. In addition, the most common hydrogen isotope 1H gives rise to significant background due to its large incoherent scattering cross-section. Therefore, it is advantageous to substitute as many hydrogens as possible with the heavier isotope 2H (deuterium) to reduce the sample volume requirement. While the solvent exchangeable hydrogens can be substituted by dissolving the protein in heavy water, complete deuterium labelling - perdeuteration - requires the protein to be expressed in heavy water with a deuterated carbon source. In this work, we developed an optimized method for large scale production of deuterium-labelled bacterial outer membrane protein F (OmpF) for NMX. OmpF was produced using deuterated media with different carbon sources. Mass spectrometry verified the integrity and level of deuteration of purified OmpF. Perdeuterated OmpF crystals diffracted X-rays to a resolution of 1.9 Å. This work lays the foundation for structural studies of membrane protein by neutron diffraction in future.

Lanthanide (Ln3+) complexes of bifunctional chelate: Synthesis, physicochemical study and interaction with human serum albumin (HSA).

Bifunctional chelate EDTA-bis amide (N,N'-bis (tyramide)ethylenediamine-N,N'-diacetic acid) that has ability to mimic natural amino acids was synthesized and analyzed by various spectroscopic techniques. The physicochemical studies were performed to calculate the various thermodynamic and kinetic parameters for the synthesized poly-amino carboxylate ligand. The two protonation constant (pka's = 3.460 and 6.722) of the prepared ligand and stability constants (log KML's = 15.8, 18.1, 16.2, 18.4, 17.5, 18.9, 13.6 and 12.8) of the complexes formed with Ce3+, Sm3+, Eu3+, Gd3+, Tb3+, Lu3+, Zn2+ and Cu2+ were determined by potentiometric titration using 0.1 M Me4NOH as non-aqueous base. The formation kinetics of [EuEDTA-TA2]+ and [CeEDTA-TA2]+ was studied and the rate constants were found to be 2.95 × 10-5 s-1 and 4.414 × 10-5 s-1respectively including the exchange reaction of [EuEDTA-TA2]+ with Zn2+ and Cu2+ spectrophotometrically. The Eu(III) complex of EDTA(TA)2 gives three emission bands at 480 nm, 540 nm and 610 nm (λmax = 270 nm, excitation) which shows efficacy of the ligand as an optical imaging agent. Molecular docking studies with Human Serum Albumin (HSA: PDB 1E78) showed binding pattern with the residues Arg218, Arg222, Lys195 and Lys444 in sub domain II A of site I via hydrogen bond and identifies the ligand-HSA interaction and specific insight for transportation to the target sites. Subsequently, fluorescence spectroscopy was performed at λex = 350 nm binding constant for HSA was 5.847 × 104 M-1 which showed effective quenching effect.

Ultrasound-guided transversus abdominis plane block versus caudal block for postoperative analgesia in children undergoing inguinal hernia surgery: A comparative study.

BACKGROUND AND AIMS: Ultrasound-guided (USG) transversus abdominis plane (TAP) block has emerged as a safe and effective regional anesthesia technique as it provides adequate postoperative pain relief for lower abdominal surgeries. Caudal block is a gold standard technique in pediatric surgeries. Our aim was to compare the duration of postoperative analgesia between TAP block and caudal block in children undergoing inguinal hernia surgeries. MATERIAL AND METHODS: In a prospective, randomized, controlled study, 112 children of age 2-8 years and ASA grade I and II, undergoing elective inguinal hernia surgery were randomly allocated into two groups: Group T (n = 56) received USG-guided TAP block with 0.5mL/kg of 0.2% ropivacaine and Group C (n = 56) received caudal block with 1mL/kg of 0.2% ropivacaine. The primary outcome variable was the duration of postoperative analgesia and the secondary outcome variables included variation in hemodynamic parameters and adverse effects, if any. RESULTS: There was no significant difference in median of CHEOPS score till 5 postoperative hours, thereafter till 24 postoperative hours, significantly lower CHEOPS score were found in Group T. Mean duration of analgesia was 523.44 ± 61.30 min in Group T, whereas in Group C, it was 352.59 ± 32.54 min. No significant difference was observed in hemodynamic variations and adverse effects. CONCLUSION: TAP block and caudal block both are effective in providing postoperative analgesia in children undergoing inguinal herniotomy. USG-guided TAP block was found to be superior as it provided longer duration of analgesia and reduced rescue analgesic dose without any significant adverse effects as compared with caudal block after inguinal herniotomy.

Clinical characteristics, predisposing factors, and treatment outcome of Curvularia keratitis.

PURPOSE: To report clinical characteristics, predisposing factors, and treatment outcome of Curvularia keratitis. METHODS: Retrospective chart review of consecutive culture-proven Curvularia keratitis patients who presented to a tertiary eye care center in north India. Patients with mixed infections with Curvularia as one of the pathogens were also included. Standard case report form was developed to capture demographic information, clinical features, etiology, treatment, and outcome. Binary logistic regression was done to ascertain the effect of identified variables on final visual acuity. RESULTS: Medical records of 97 patients of Curvularia keratitis were reviewed. Median age of patients was 45.3 years. Seventy-nine (79.4%) patients presented during the months of September to November. History of corneal trauma was present in 69.1%. Trauma from sugarcane leaf was identified in 66.1% of cases with corneal trauma with vegetative matter. Presenting visual acuity was worse than 20/60 in 57.8% of patients. Hypopyon and pigmented plaque-like infiltrate was present in 16.5% and 28.8% of patients, respectively. Mixed infection was reported in 14.4% of cases. Median time of antifungal therapy was 24.5 days. Surgical intervention was required in 18.5% cases. Of all, 11.1% patients achieved final VA of more than 20/200 who were managed surgically as compared to 68 (86%) patients who were managed medically. Younger age, absence of comorbidities, and lesser infiltrate size were found associated with good final visual acuity. CONCLUSION: Working males were most affected by Curvularia keratitis. Corneal trauma with sugarcane leave was the most common predisposing factor in the study area. Most of the cases presented with worse visual acuity but could be managed medically.

Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis.

Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (-0.80 vs. -0.84 T40, -0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.

Predicting likelihood of psychological disorders in PlayerUnknown's Battlegrounds (PUBG) players from Asian countries using supervised machine learning.

Multiplayer Online Battle Arena (MOBA) has become one of the most popular genre of online video games played by gamers worldwide. Previous studies have exhibited that excessive engagement in games can lead to Internet Gaming Disorder (IGD). Internet Gaming Disorder has been associated with psychological disorders like impulsivity, anxiety and Attention Deficit Hyperactivity Disorder (ADHD). In this study, we propose an approach to use the game and player statistics along with self-esteem measure of a PlayerUnknown's Battlegrounds (PUBG, a MOBA game) player to predict whether he/she suffers from IGD and psychological disorders namely ADHD and Generalized Anxiety Disorder (GAD). We extract the game and player statistics of PUBG players from Asian countries and then run several state of the art supervised machine learning models to predict the occurrence of IGD, ADHD, and GAD. Initial experiments and results show that we are able to predict IGD, ADHD, and GAD with an accuracy of 93.18%, 81.81% and 84.9% respectively. Game statistics of PUBG players show strong positive correlation with IGD and ADHD indicating detrimental effects of MOBA games.

Thiophene Scaffold as Prospective Central Nervous System Agent: A Review.

BACKGROUND: Heterocyclic compounds are extensively dispersed in nature and are vital for life. Various investigational approaches towards Structural Activity Relationship that focus upon the exploration of optimized candidates have become vastly important. METHOD: Literature studies tell that for a series of compounds that are imperative in industrial and medicinal chemistry, thiophene acts as parent. Among various classes of heterocyclic compounds that have potential central nervous system activity, thiophene is the most important one. In the largely escalating chemical world of heterocyclic compounds showing potential pharmacological character, thiophene nucleus has been recognized as the budding entity. RESULT: Seventeen Papers were included in this review article to define the central nervous system potential of thiophene. This review article enlightens the rationalized use and scope of thiophene scaffold as novel central nervous system activity such as anticonvulsant, acetylcholinesterase inhibitor, cyclin-dependent kinase 5 (cdk5/p25) inhibitors, CNS depressant, capability to block norepinephrine, serotonin and dopamine reuptake by their respective transporters etc. CONCLUSION: The Finding of this review confirm the importance of thiophene scaffold as potential central nervous system agents. From this outcome, ideas for future molecular modifications leading to the novel derivatives with better constructive pharmacological potential may be derived.

Ventilating Patient with Refractory Hypercarbia: Use of APRV Mode.

A 70-year-old patient referred to our critical care unit with the diagnosis of type II respiratory failure with shock. Patient was a known case of COPD for last 20 years. His chest radiology revealed bilateral infiltrates. Patient was managed conservatively in the form of antibiotics, vasopressor and ventilatory support with SIMV/VC mode. After ventilation with SIMV/VC mode for half an hour his blood gases revealed increasing PaCO2 levels. The same result was obtained with PC mode and ASV and his PaCO2 level reached above 170 mmHg. Then APRV mode was tried with modified settings. The results obtained were satisfactory and in next 24 hours PaCO2 decreased to <66mmHg along with an increasing P/F ratio. APRV is the not recommended as primary mode of ventilation in COPD but in resistant cases it can be helpful as it improves alveolar recruitment and pressure support is added to reduce hypercapnia.

Studies for development of novel quinazolinones: new biomarker for EGFR.

The binding capabilities of a series of novel quinazolinone molecules were established and stated in a comprehensive computational methodology as well as by in vitro analysis. The main focus of this work was to achieve more insight of the interactions with crystal structure of PDB ID: 1M17 and predict their binding mode to EGFR. Three molecules were screened for further examination, which were synthesized and characterized using spectroscopic techniques. The persuasive affinity of these molecules towards EGFR inhibition (IC50 for QT=45nM) was established and validated from specific kinase assay including the cell viability spectrophotometric assay (QT=12nM). Drug likeliness property were also considered by analysing, the ADME of these molecules by using scintigraphic techniques. The result showed antitumour activity of QT (4.17 tumour/muscle at 4h). Further photo physical properties were also analysed to see in vitro HSA binding to QT.

Discrepancy in optical & mechanical method in coagulation tests in a turbid sample.

Automated coagulation analyzers have replaced manual methods to meet the ever-increasing test load in many laboratories. Of the different methods, two distinct methods exist based on optical and mechanical clot detection (magnetic steel ball method). In optical method the detection of clot formation is measured by a change in optical density (OD) of a test sample. Mechanical clot detection technology, involves monitoring the movement of a steel ball within the test solution using a magnetic sensor. There are limited studies comparing both these methods and they have conflicting results regarding the effect of plasma turbidity on the final result. We report a case where a plasma factor (lipemia) caused prolongation of both PT and APTT, as measured by the photo optical method.

Bis(methylpyridine)-EDTA derivative as a potential ligand for PET imaging: synthesis, complexation, and biological evaluation.

A novel transitional metal ligand derivatized from EDTA-conjugated 2-amino-4-methyl pyridine, an acyclic vehicle (EDTA-Mepy2 ) was designed, synthesized, and characterized for PET imaging with 68Ga. The drug likeliness and appropriate lipophilicity were first analyzed by molecular docking studies which shows interactive property of ligand with serum albumin protein (HSA: PDB 1E78), at Lys199, Arg257, and His242 residues, which make it more appropriate in transportation as a specific ligand for PET imaging. As a confirmation, binding constant of the ligand with human serum albumin was calculated at λex = 350 nm which was found to be 4.9 × 10³ m⁻¹. The pharmacokinetics of (68) Ga-EDTA-Mepy2 was analyzed by blood kinetics (t(1/2) slow: 3 h 56 min and t(1/2) fast: 32 min) and biodistribution (maximum % ID/g was found in kidney at 1 h). Further the capability of this ligand was analyzed as optical marker also, by recording λex = 380 nm, RFU = 8000; 710 nm, RFU = 1000 units at fixed λem = 280 nm. Additionally, in physiological conditions where its stability was calculated, suggests 15-20 times selectivity over the endogenously present metal ions (KG aL /KZ nL = 14.3, KG aL /KC uL = 18.1).

Design, synthesis, and biological evaluation of catecholamine vehicle for studying dopaminergic system.

Catecholamine mimetic EDTA-bis(tyramide) was synthesized and characterized by various spectroscopic techniques (NMR, mass spectroscopy) and λem 310 nm for the excitation at 270 nm. Molecular docking studies were performed with human serum albumin (PDB 1E78), showing binding pattern with amino acid residues Arg218, Arg222, and Lys444, identifies the ligand-human serum albumin interaction for the transportation affinity of the ligand at the specific site of the target. Subsequently, binding study with human serum albumin at λex  = 350 nm found to be 5.847 × 10(4)  m(-1) shows effective quenching effect. Additionally, to go more insight, acetylcholinesterase binding affinity was investigated, which shows 90% binding affinity for the 10 mm concentration. IC50 value was found 18.60 µm for MAO-B inhibition. Finally, EDTA-bis(tyramide) labeled with (99m) Tc to investigate its in vivo radiopharmaceutical efficiency having 97% binding affinity with 98% radiochemical purity. In vivo studies were carried out for (99m) Tc-EDTA-bis(tyramide) included blood kinetics showed a quick wash out from the circulation via renal route, and biodistribution revealed that maximum %ID/g was found in kidney at 1 h, and its scintigraphy image shows 3.96% brain uptake with respect to whole body.

Investigation for the interaction of tyramine-based anthraquinone analogue with human serum albumin by optical spectroscopic technique.

A newly synthesized anthraquinone derivative 'N-(2-methylanthraquinone)-4-(2-aminoethyl) phenol' (Tyan) were characterized as a fluorophore from photophysical analysis by measuring the UV-Vis absorptive (λ(ex) = 325 nm) and fluorescence emitive (λ(em) = 660 nm) values. Density functional theory additionally supported the spectroscopic data by modulation of highest occupied molecular orbital rather than lowest unoccupied molecular orbital due to the affect of tyramine moiety present in Tyan. The pharmacological importance of Tyan was evaluated by molecular docking with human serum albumin. The molecular docking of the Tyan was performed with the crystal structure of human serum albumin (PDB entry 1E78), which shows binding in all the three domains of human serum albumin corresponding to -7.74 as the GScore. Moreover, the interactions of human serum albumin with Tyan were assessed employing fluorescence spectroscopy under simulative physiological conditions, and the binding constant for the interaction at 25 °C was found to be 0.6 × 10(3)/M.

Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: In a pilot study, lithium treatment slowed progression of amyotrophic lateral sclerosis (ALS). We aimed to confirm or disprove these findings by assessing the safety and efficacy of lithium in combination with riluzole in patients with ALS. METHODS: We did a double-blind, placebo-controlled trial with a time-to-event design. Between January and June, 2009, patients with ALS who were taking a stable dose of riluzole for at least 30 days were randomly assigned (1:1) by a centralised computer to receive either lithium or placebo. Patients, caregivers, investigators, and all site study staff with the exception of site pharmacists were masked to treatment assignment. The primary endpoint was the time to an event, defined as a decrease of at least six points on the revised ALS functional rating scale score or death. Interim analyses were planned for when 84 patients had been allocated treatment, 6 months later or after 55 events, and after 100 events. Analysis was by intention to treat. The stopping boundary for futility at the first interim analysis was a p value of at least 0.68. We used a log-rank test to compare the distributions of the time to an event between the lithium and placebo groups. This trial is registered with ClinicalTrials.gov, NCT00818389. FINDINGS: At the first interim analysis, 22 of 40 patients in the lithium group had an event compared with 20 of 44 patients in the placebo group (log rank p=0.51). The hazard ratio of reaching the primary endpoint was 1.13 (95% CI 0.61-2.07). The study was stopped at the first interim analysis because criterion for futility was met (p=0.78). The difference in mean decline in the ALS functional rating scale score between the lithium group and the placebo group was 0.15 (95% CI -0.43 to 0.73, p=0.61). There were no major safety concerns. Falls (p=0.04) and back pain (p=0.05) were more common in the lithium group than in the placebo group. INTERPRETATION: We found no evidence that lithium in combination with riluzole slows progression of ALS more than riluzole alone. The time-to-event endpoint and use of prespecified interim analyses enabled a clear result to be obtained rapidly. This design should be considered for future trials testing the therapeutic efficacy of drugs that are easily accessible to people with ALS. FUNDING: National Institute of Neurological Disorders and Stroke, ALS Association, and ALS Society of Canada.

Toward more efficient clinical trials for amyotrophic lateral sclerosis.

More than 30 phase II or III clinical trials have been carried out in amyotrophic lateral sclerosis (ALS). Only riluzole, however, has been shown to extend survival and/or time to tracheostomy. Many early ALS trials lacked solid pharmacodynamic and pharmacokinetic data for the treatment being tested, challenging the interpretation of the efficacy and pathway relevance. Understanding of the genetics and pathophysiology of ALS has improved considerably in the past decade, but biomarkers of disease activity remain lacking. A more efficient approach to early phase clinical trials is needed to accelerate the identification of useful agents for ALS. Here we summarize our current thinking about phase II design options and the potential benefits of a clinical trial network for phase II trials in ALS.

ALS drug development: reflections from the past and a way forward.

Tremendous advances in our understanding of pathogenesis of amyotrophic lateral sclerosis (ALS) have provided a rich pipeline of drugs for clinical trialists. At least 32 unique compounds have been tested. Nevertheless, riluzole is currently the only treatment that prolongs survival. We present a critical overview of past clinical trials, how therapies are selected for testing in people, challenges with ALS clinical trial design and conduct, and ways to best move forward.