Feasibility of group telerehabilitation for individuals with chronic acquired brain injury: integrating clinical care and research.

BACKGROUND: Acquired brain injury (ABI) is a leading cause of lifelong disability, but access to treatment in the chronic stages has significant barriers. Group-based, remotely delivered neurorehabilitation reduces costs, travel barriers, and infection risk; however, its feasibility for patients with ABI is not well-established. OBJECTIVES: To investigate the feasibility of remotely group-based cognitive and mood therapies for persons with chronic ABI. METHODS: Three hundred and eighty-eight adults with chronic ABI participated in group tele-neurorehabilitation modules comprising Cognitive Behavioral Therapy, Goal Management Training®, Relaxation and Mindfulness Skills Training, and/or a novel Concussion Education & Symptom Management program. Assessments comprised quantitative metrics, surveys, as well as qualitative semi-structured interviews in a subset of participants. RESULTS: High retention, adherence, and satisfaction were observed. Facilitators of treatment included accessibility, cost-effectiveness, and convenience. Adoption of technology was high, but other people's technological interruptions were a barrier. Self-reported benefits specific to group-based format included improved mood, stress management, coping, interpersonal relationships, cognitive functioning, and present-mindedness. CONCLUSIONS: The present study examined chronic ABI patients' perceptions of telerehabilitation. Patients found remotely delivered, group-based mood, and cognitive interventions feasible with easy technology adoption. Group format was considered a benefit. Recommendations are provided to inform design of remotely delivered ABI programs.

Group-based mood and cognitive telerehabilitation is feasible for persons with chronic acquired brain injury, with high reported satisfaction.Screening for technical proficiency and providing ongoing technical support improves therapy adherence and retention.Integration of clinical care and research is feasible for delivering remote therapies to persons with brain injury.

2D-QSAR, molecular docking and MD simulation based virtual screening of the herbal molecules against Alzheimer's disorder: an approach to predict CNS activity.

Acetylcholinesterase (AChE) is one of the key enzyme targets that have been used clinically for the management of Alzheimer's Disorder (AD). Numerous reports in the literature predict and demonstrate in-vitro, and in-silico anticholinergic activity of herbal molecules, however, majority of them failed to find clinical application. To address these issues, we developed a 2D-QSAR model that could efficiently predict the AChE inhibitory activity of herbal molecules along with predicting their potential to cross the blood-brain-barrier (BBB) to exert their beneficial effects during AD. Virtual screening of the herbal molecules was performed and amentoflavone, asiaticoside, astaxanthin, bahouside, biapigenin, glycyrrhizin, hyperforin, hypericin, and tocopherol were predicted as the most promising herbal molecules for inhibiting AChE. Results were validated through molecular docking, atomistic molecular dynamics simulations and Molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) studies against human AChE (PDB ID: 4EY7). To determine whether or not these molecules can cross BBB to inhibit AChE within the central nervous system (CNS) for being beneficial for the management of AD, we determined a CNS Multi-parameter Optimization (MPO) score, which was found in the range of 1 to 3.76. Overall, the best results were observed for amentoflavone and our results demonstrated a PIC50 value of 7.377 nM, molecular docking score of -11.5 kcal/mol, and CNS MPO score of 3.76. In conclusion, we successfully developed a reliable and efficient 2D-QSAR model and predicted amentoflavone to be the most promising molecule that could inhibit human AChE enzyme within the CNS and could prove beneficial for the management of AD.Communicated by Ramaswamy H. Sarma.

Computational investigation of the impact of potential AT2R polymorphism on small molecule binding.

For more than a century, the renin-angiotensin system (RAS) has been acknowledged for playing a crucial part in the physiological control of arterial pressure, as well as sodium and fluid balance. It is now generally acknowledged that one of the receptor of RAS system i.e. angiotensin type 2 receptor (AT2R) functions as a repair system during pathophysiologic circumstances and performs a significant protective role. Efforts have been made previously to design suitable agonist and antagonist molecules to potentially modulate AT2R. One of the agonists and antagonists, named C21 and EMA401, has been studied in a number of pathological conditions. Additionally, a wide panel of single nucleotide polymorphisms (SNPs) has been reported for AT2R, which might potentially affect the efficacy of these molecules. Therefore, computational investigations have been carried out to analyze all the SNPs (1151) reported in NCBI to find potential SNPs affecting the active site of AT2R, as this domain is still unexplored. Structures of these polymorphic forms were modeled, and in silico drug interaction studies with C21 and EMA401 were carried out. The two mutants (rs868939201 and rs1042852794) that significantly affect the binding affinity as that of the wild type were subjected to molecular dynamics simulations. Our analysis of native and mutant AT2R and their complexes with C21 and EMA401 indicated that the occurrence of these mutations affects the conformation of the protein and has affected the binding of these ligand molecules. The study's findings will aid in the development of better, more versatile medications in the near future, and also in vitro and in vivo studies might be planned in accordance with recent findings.Communicated by Ramaswamy H. Sarma.

New Insights Into Accelerometer-Measured Habitual Physical Activity and Sedentary Time During Early Recovery in Pediatric Concussion.

PURPOSE: Concussion management is shifting away from a rest-is-best approach, as data now suggest that exercise-is-medicine for this mild brain injury. Despite this, we have limited data on habitual physical activity following concussion. Therefore, our objective was to quantify accelerometer-measured physical activity and sedentary time in children with concussion (within the first month of injury) and healthy controls. We hypothesized that children with concussion would be less active than their healthy peers. METHODS: We performed a secondary analysis of prospectively collected accelerometer data. Our sample included children with concussion (n = 60, 31 females) and historical controls (n = 60) matched for age, sex, and season of accelerometer wear. RESULTS: Children with concussion were significantly more sedentary than controls (mean difference [MD], 38.3 min/d, P = .006), and spent less time performing light physical activity (MD, -19.5 min/d, P = .008), moderate physical activity (MD, -9.8 min/d, P < .001), and vigorous physical activity (MD, -12.0 min/d, P < .001); these differences were observed from 8:00 AM to 9:00 PM. Sex-specific analyses identified that girls with concussion were less active and more sedentary than both boys with concussion (P = .010) and healthy girls (P < .010). CONCLUSION: There is an activity deficit observed within the first month of pediatric concussion. Physical activity guidelines should address this while considering sex effects.

Nitric oxide modulates NMDA receptor through a negative feedback mechanism and regulates the dynamical behavior of neuronal postsynaptic components.

Nitric oxide (NO) is known to be an important regulator of neurological processes in the central nervous system which acts directly on the presynaptic neuron and enhances the release of neurotransmitters like glutamate into the synaptic cleft. Calcium influx activates a cascade of biochemical reactions to influence the production of nitric oxide in the postsynaptic neuron. This has been modeled in the present work as a system of ordinary differential equations, to explore the dynamics of the interacting components and predict the dynamical behavior of the postsynaptic neuron. It has been hypothesized that nitric oxide modulates the NMDA receptor via a feedback mechanism and regulates the dynamic behavior of postsynaptic components. Results obtained by numerical analyses indicate that the biochemical system is stimulus-dependent and shows oscillations of calcium and other components within a limited range of concentration. Some of the parameters such as stimulus strength, extracellular calcium concentration, and rate of nitric oxide feedback are crucial for the dynamics of the components in the postsynaptic neuron.

Emergent dynamics in an astrocyte-neuronal network coupledvianitric oxide.

In the brain, both neurons and glial cells work in conjunction with each other during information processing. Stimulation of neurons can induce calcium oscillations in astrocytes which in turn can affect neuronal calcium dynamics. The 'glissandi' effect is one such phenomenon, associated with a decrease in infraslow fluctuations, in which synchronized calcium oscillations propagate as a wave in hundreds of astrocytes. Nitric oxide molecules released from the astrocytes contribute to synaptic functions based on the underlying astrocyte-neuron interaction network. In this study, by defining an astrocyte-neuronal (A-N) calcium unit as an integrated circuit of one neuron and one astrocyte, we developed a minimal model of neuronal stimulus-dependent and NO-mediated emergence of calcium waves in astrocytes. Incorporating inter-unit communicationviaNO molecules, a coupled network of 1000 such A-N calcium units is developed in which multiple stable regimes were found to emerge in astrocytes. We examined the ranges of neuronal stimulus strength and the coupling strength between A-N calcium units that give rise to such dynamical behaviors. We also report that there exists a range of coupling strength, wherein units not receiving stimulus also start showing oscillations and become synchronized. Our results support the hypothesis that glissandi-like phenomena exhibiting synchronized calcium oscillations in astrocytes help in efficient synaptic transmission by reducing the energy demand of the process.

Effect of co-pigments on anthocyanins of Rhododendron arboreum and insights into interaction mechanism.

The impact of intermolecular copigmentation between five phenolic acids, two flavonoid and three amino acids with R. arboreum anthocyanins (ANS) and its isolated cyanidin-3-O-monoglycosides were investigated through experimental and theoretical approach. On addition of different copigments, phenolic acid induced strong hyperchromic (0.26-0.55 nm) and bathochromic shift (6.6-14.2 nm). The color intensity and stability of ANS with, storage at 4 °C & 25 °C, sunlight, oxidation and heat were evaluated by chromaticity, anthocyanin content, kinetic and structural simulation analysis. The strongest copigmentation reaction was observed with narningin (NA) and also showed high thermostability and highest half-life i.e. 3.39 h-1.24 h at 90-160 °C. The cyanidin-3-O-monoglycosides were analysed for their copigmentation effect and observations revealed that NA displayed best copigmentation effect to cyanidin-3-O-arabinoside (B) followed by cyanidin-3-O-galactoside (A), and cyanidin-3-O-rhamnoside (C). Additionally, structural simulation and steered molecular dynamics insights NA is the most favourable co-pigment involving π-π stacking and H-bonding.

Genetic analysis of polymorphism rs10937405 of TP63 gene in breast and ovarian cancer patients of North Indian Cohort.

Introduction: Ovarian and breast cancers are highly prevalent in the population of Jammu and Kashmir (J&K). However, case-control association studies on breast and ovarian cancers are lacking in this population. Moreover, no case-control study is available on variant rs10937405 of TP63 in breast and ovarian cancers. Thus, we designed to replicate the cancer susceptible variant rs10937405 of TP63 in ovarian and breast cancers in the population of J&K because the TP63 gene act as a tumor suppressor gene and was previously associated with various cancers. Materials and Methods: This case-control association study conducted at the Shri Mata Vaishno Devi University, includes 150 breast, 150 ovarian cancer cases, and 210 healthy controls (age and sex-matched). Variant rs10937405 of the TP63 gene was determined by the TaqMan assay. Hardy-Weinberg equilibrium for the variant was assessed using the Chi-square test. The allele and genotype-specific risks were estimated by odds ratios (ORs) with 95% confidence intervals (CI). Results: In this study, variant rs10937405 of TP63 gene did not show any risk with ovarian and breast cancer with (P-value = 0.70) having OR 0.94, (0.69-1.28 at 95% CI) and (P-value = 0.16) having OR 0.80, (0.59-1.10). Discussion: Our results indicate that the variant rs10937405 of the TP63 gene did not impart any risk of breast and ovarian cancer in the population of J&K. Our results indicate that a larger sample size is needed for further statistical validation. As the study was for a particular variant, it warrants the analysis of other variants of this gene.

Effects of High-Intensity Interval Training Protocols on Blood Lactate Levels and Cognition in Healthy Adults: Systematic Review and Meta-Regression.

BACKGROUND: Some health benefits from high-intensity interval training (HIIT) are facilitated by peripheral blood lactate levels. However, the lactate response from HIIT is variable and dependent on protocol parameters. OBJECTIVES: We aimed to determine the HIIT protocol parameters that elicited peak lactate levels, and how these levels are associated with post-HIIT cognitive performance. STUDY DESIGN: We conducted a systematic review with meta-regression. METHODS: MEDLINE, Embase, CENTRAL, SPORTDiscus, and CINAHL + were searched from database inception to 8 April, 2022. Peer-reviewed primary research in healthy adults that determined lactate (mmol/L) and cognitive performance after one HIIT session was included. Mixed-effects meta-regressions determined the protocol parameters that elicited peak lactate levels, and linear regressions modelled the relationship between lactate levels and cognitive performance. RESULTS: Study entries (n = 226) involving 2560 participants (mean age 24.1 ± 4.7 years) were included in the meta-regression. A low total work-interval volume (~ 5 min), recovery intervals that are about five times longer than work intervals, and a medium session volume (~ 15 min), elicited peak lactate levels, even when controlling for intensity, fitness (peak oxygen consumption) and blood measurement methods. Lactate levels immediately post-HIIT explained 14-17% of variance in Stroop interference condition at 30 min post-HIIT. CONCLUSIONS: A HIIT protocol that uses the above parameters (e.g., 8 × 30-s maximal intensity with 90-s recovery) can elicit peak lactate, a molecule that is known to benefit the central nervous system and be involved in exercise training adaptations. This review reports the state of the science in regard to the lactate response following HIIT, which is relevant to those in the sports medicine field designing HIIT training programs. TRIAL REGISTRY: Clinical Trial Registration: PROSPERO (CRD42020204400).

Sex-specific differences in resting-state functional brain activity in pediatric concussion.

Pediatric concussion has a rising incidence and can lead to long-term symptoms in nearly 30% of children. Resting state functional magnetic resonance imaging (rs-fMRI) disturbances are a common pathological feature of pediatric concussion, though no studies have explicitly examined sex-differences with respect to this outcome, precluding a sex-specific understanding of the functional neuropathology of pediatric concussion. Therefore, we performed a secondary data analysis of rs-fMRI data collected on children with concussion (n = 29) recruited from in a pediatric hospital setting, with greater than 12:1 matched control data accessed from the open-source ABIDE-II database. Seed-based and region of interest (ROI) analyses were used to examine sex-based rs-fMRI differences; threshold-free cluster enhancement (TFCE) and a family-wise error (FWE) corrected p-values were used to identify significantly different clusters. In comparing females with concussion to healthy females, groupwise differences were observed irrespective of seed selected. Notably, we observed (in order of largest effect) hypo-connectivity between the anterior cingulate cortex of the salience network and the thalamus and precuneus (TFCE = 1473.5, p-FWE < 0.001) and the cingulate gyrus (TFCE = 769.3, p-FWE = 0.009), and the seed (posterior cingulate cortex (PCC)) of the default mode network and the paracingulate gyrus (TFCE = 1275.7, p-FWE < 0.001), occipital pole right (TFCE = 1045.0, p-FWE = 0.001), and sub-callosal cortex (TFCE = 844.9, p-FWE = 0.005). Hyper-connectivity was observed between the salience network seed and the cerebellum (TFCE = 1719.3, p-FWE < 0.001) and the PCC and the thalamus (TFCE = 1198.3, p-FWE < 0.001), cuneal cortex (1070.9, p-FWE = 0.001), and lateral occipital cortex left (TFCE = 832.8, p-FWE = 0.006). ROI analyses showed 10 and 5 significant clusters of hypo- and hyper-connectivity in females, respectively. Only one cluster of difference was found between males with concussion and healthy males on seed-based analyses, and 3 clusters on ROI analyses. There are alterations in rs-fMRI in females with concussion at one-month post-injury that are minimally present in males, which provides further evidence that recovery timelines in pediatric concussion may differ by sex.

A multiscale modeling framework to study the interdependence of brain, behavior, and pandemic.

A major constraint of the behavioral epidemiological models is the assumption that human behavior is static; however, it is highly dynamic, especially in uncertain circumstances during a pandemic. To incorporate the dynamicity of human nature in the existing epidemiological models, we propose a population-wide multi-time-scale theoretical framework that assimilates neuronal plasticity as the basis of altering human emotions and behavior. For that, variable connection weights between different brain regions and their firing frequencies are coupled with a compartmental susceptible-infected-recovered model to incorporate the intrinsic dynamicity in the contact transmission rate ( ß ). As an illustration, a model of fear conditioning in conjunction with awareness campaigns is developed and simulated. Results indicate that in the presence of fear conditioning, there exists an optimum duration of daily broadcast time during which awareness campaigns are most effective in mitigating the pandemic. Further, global sensitivity analysis using the Morris method highlighted that the learning rate and firing frequency of the unconditioned circuit are crucial regulators in modulating the emergent pandemic waves. The present study makes a case for incorporating neuronal dynamics as a basis of behavioral immune response and has further implications in designing awareness campaigns.

Longitudinal Patterns of Functional Connectivity in Moderate-to-Severe Traumatic Brain Injury.

Longitudinal neuroimaging studies aid our understanding of recovery mechanisms in moderate-to-severe traumatic brain injury (TBI); however, there is a dearth of longitudinal functional connectivity research. Our aim was to characterize longitudinal functional connectivity patterns in two clinically important brain networks, the frontoparietal network (FPN) and the default mode network (DMN), in moderate-to-severe TBI. This inception cohort study of prospectively collected longitudinal data used resting-state functional magnetic resonance imaging (fMRI) to characterize functional connectivity patterns in the FPN and DMN. Forty adults with moderate-to-severe TBI (mean ± standard deviation [SD]; age = 39.53 ± 16.49 years, education = 13.92 ± 3.20 years, lowest Glasgow Coma Scale score = 6.63 ± 3.24, sex = 70% male) were scanned at approximately 0.5, 1-1.5, and 3+ years post-injury. Seventeen healthy, uninjured participants (mean ± SD; age = 38.91 ± 15.57 years, education = 15.11 ± 2.71 years, sex = 29% male) were scanned at baseline and approximately 11 months afterwards. Group independent component analyses and linear mixed-effects modeling with linear splines that contained a knot at 1.5 years post-injury were employed to investigate longitudinal network changes, and associations with covariates, including age, sex, and injury severity. In patients with TBI, functional connectivity in the right FPN increased from approximately 0.5 to 1.5 years post-injury (unstandardized estimate = 0.19, standard error [SE] = 0.07, p = 0.009), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.21, SE = 0.11, p = 0.009), and marginally declined afterwards (estimate = -0.10, SE = 0.06, p = 0.079). Functional connectivity in the DMN increased from approximately 0.5 to 1.5 years (estimate = 0.15, SE = 0.05, p = 0.006), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.19, SE = 0.08, p = 0.021), and was estimated to decline from 1.5 to 3+ years (estimate = -0.04, SE = 0.04, p = 0.303). Similarly, the left FPN increased in functional connectivity from approximately 0.5 to 1.5 years post-injury (estimate = 0.15, SE = 0.05, p = 0.002), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.18, SE = 0.07, p = 0.008), and was estimated to decline thereafter (estimate = -0.04, SE = 0.03, p = 0.254). At approximately 0.5 years post-injury, patients showed hypoconnectivity compared with healthy, uninjured participants at baseline. Covariates were not significantly associated in any of the models. Findings of early improvement but a tapering and possible decline in connectivity thereafter suggest that compensatory effects are time-limited. These later reductions in connectivity mirror growing evidence of behavioral and structural decline in chronic moderate-to-severe TBI. Targeting such declines represents a novel avenue of research and offers potential for improving clinical outcomes.

An insight from computational approach to explore novel, high-affinity phosphodiesterase 10A inhibitors for neurological disorders.

The enzyme Phosphodiesterase 10A (PDE10A) plays a regulatory role in the cAMP/protein kinase A (PKA) signaling pathway by means of hydrolyzing cAMP and cGMP. PDE10A emerges as a relevant pharmacological drug target for neurological conditions such as psychosis, schizophrenia, Parkinson's, Huntington's disease, and other memory-related disorders. In the current study, we subjected a set of 1,2,3-triazoles to be explored as PDE10A inhibitors using diverse computational approaches, including molecular docking, classical molecular dynamics (MD) simulations, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations, steered MD, and umbrella sampling simulations. Molecular docking of cocrystallized ligands papaverine and PFJ, along with a set of in-house synthesized molecules, suggested that molecule 3i haded the highest binding affinity, followed by 3h and 3j. Furthermore, the structural stability studies using MD and MM-PBSA indicated that the 3h and 3j formed stable complexes with PDE10A. The binding free energy of -240.642 kJ/mol and -201.406 kJ/mol was observed for 3h and 3j, respectively. However, the cocrystallized ligands papaverine and PFJ exhibited comparitively higher binding free energy values of -202.030 kJ/mol and -138.764 kJ/mol, respectively. Additionally, steered MD and umbrella sampling simulations provided conclusive evidence that the molecules 3h and 3j could be exploited as promising candidates to target PDE10A.Communicated by Ramaswamy H. Sarma.

Exploring the relationship between resting-state intra-network connectivity and accelerometer-measured physical activity in pediatric concussion: a cohort study.

Our objective was to explore the association between resting-state functional connectivity and accelerometer-measured physical activity in pediatric concussion. Fourteen children with concussion (aged 14.54 ± 2.39 years, 8 female) were included in this secondary data analysis of a larger study. Participants had neuroimaging at 15.3 ± 6.7 days postinjury and subsequently a mean of 11.1 ± 5.0 days of accelerometer data. Intra-network connectivity of the default mode network (DMN), sensorimotor network (SMN), salience network (SN), and frontoparietal network (FPN) was computed using resting-state MRI. We found that, per general linear models (GLMs), only intra-network connectivity of the DMN was associated with physical activity levels. More specifically, increased intra-network connectivity of the DMN was significantly associated with higher levels of subsequent accelerometer-measured light physical activity (LPA; F(2, 11) = 7.053, p = 0.011, Ra2 = 0.562; ß = 0.469), moderate physical activity (MPA; F(2, 11) = 6.159, p = 0.016, Ra2 = 0.528; ß = 0.725), and vigorous physical activity (VPA; F(2, 11) = 10.855, p = 0.002, Ra2 = 0.664; ß = 0.792). Intra-network connectivity of the DMN did not significantly predict sedentary time. Therefore, these preliminary findings suggest that there is a positive association between the intra-network connectivity of the DMN and device-measured physical activity in children with concussion.

Methylxanthines as Potential Inhibitor of SARS-CoV-2: an In Silico Approach.

The aim of the present study was to test the binding affinity of methylxanthines (caffeine/theine, methylxanthine, theobromine, theophylline and xanthine) to three potential target proteins namely Spike protein (6LZG), main protease (6LU7) and nucleocapsid protein N-terminal RNA binding domain (6M3M) of SARS-CoV-2. Proteins and ligand were generated using AutoDock 1.5.6 software. Binding affinity of methylxanthines with SARS-CoV-2 target proteins was determined using Autodock Vina. MD simulation of the best interacting complexes was performed using GROMACS 2018.3 (in duplicate) and Desmond program version 2.0 (academic version) (in triplicate) to study the stabile interaction of protein-ligand complexes. Among the selected methylxanthines, theophylline showed the best binding affinity with all the three targets of SARS-CoV-2 (6LZG - 5.7 kcal mol-1, 6LU7 - 6.5 kcal mol-1, 6M3M - 5.8 kcal mol-1). MD simulation results of 100 ns (in triplicate) showed that theophylline is stable in the binding pockets of all the selected SARS-CoV-2 proteins. Moreover, methylxanthines are safer and less toxic as shown by high LD50 value with Protox II software as compared to drug chloroquine. This research supports the use of methylxanthines as a SARS-CoV-2 inhibitor. It also lays the groundwork for future studies and could aid in the development of a treatment for SARS-CoV-2 and related viral infections. Supplementary Information: The online version contains supplementary material available at 10.1007/s40495-021-00276-3.

Effects of high-intensity interval training on blood lactate levels and cognition in healthy adults: protocol for systematic review and network meta-analyses.

BACKGROUND: High-intensity interval training (HIIT) has shown to confer cognitive benefits in healthy adults, via a mechanism purportedly driven by the exercise metabolite lactate. However, our understanding of the exercise parameters (e.g., work interval duration, session volume, work-to-rest ratio) that evoke a peak blood lactate response in healthy adults is limited. Moreover, evidence relating HIIT-induced blood lactate and cognitive performance has yet to be reviewed and analyzed. The primary objective of this systematic review is to use network meta-analyses to compare the relative impact of different HIIT work-interval durations, session volumes, and work-to-rest ratios on post-exercise blood lactate response in healthy adults. The secondary objective is to determine the relationship between HIIT-induced blood lactate and acute post-HIIT cognitive performance. METHODS: A systematic review is being conducted to identify studies measuring blood lactate response following one session of HIIT in healthy adults. The search was carried out in (1) MEDLINE, (2) EMBASE, (3) Cochrane Central Register of Controlled Trials, (4) Sport Discus, and (5) Cumulative Index to Nursing and Allied Health Literature Plus with Full Text (CINAHL+). After abstract and full-text screening, two reviewers will independently extract data on key outcomes variables and complete risk of bias assessment using the Cochrane Risk of Bias Tool and the Risk of Bias in Non-Randomized Studies of Interventions tool. Network meta-analyses will be used to generate estimates of the comparative effectiveness of blood lactate on cognitive outcomes using corresponding rankings for each work-interval duration, session volume, and work-to-rest ratio category. Where applicable, meta-regressions analyses will be performed to test the relationship between changes in the blood lactate and changes in cognitive performance. Analyses will be conducted using MetaInsight Software. DISCUSSION: This study will provide evidence on how to structure a HIIT protocol to elicit peak blood lactate response in healthy adults and will increase our understanding of the relationship between HIIT-induced blood lactate response and associated cognitive benefits. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020204400.

Exploring AT2R and its Polymorphism in Different Diseases: An Approach to Develop AT2R as a Drug Target beyond Hypertension.

The Angiotensin II type 2 Receptor (AT2R) is one of the critical components of the renin- angiotensin system (RAS), which performs diverse functions like inhibiting cell differentiation, cell proliferation, vasodilatation, reduces oxidative stress and inflammation. AT2R is relatively less studied in comparison to other components of RAS despite its uniqueness (sex-linked) and diverse functions. The AT2R is differentially expressed in different tissues, and its gene polymorphisms are associated with several diseases. The molecular mechanism behind the association of AT2R and its gene polymorphisms with the diseases remains to be fully understood, which hinders the development of AT2R as a drug target. Single nucleotide polymorphisms (SNPs) in AT2R are found at different locations (exons, introns, promoter, and UTR regions) and were studied for association with different diseases. There may be different mechanisms behind these associations as some AT2R SNP variants were associated with differential expression, the SNPs (A1675G/ A1332G) affect the alternate splicing of AT2R mRNA, A1332G genotype results in shortening of the AT2R mRNA and subsequently defective protein. Few SNPs were found to be associated with the diseases in either females (C4599A) or males (T1334C). Several other SNPs were expected to be associated with other similar/related diseases, but studies have not been done yet. The present review emphasizes on the significance of AT2R and its polymorphisms associated with the diseases to explore the precise role of AT2R in different diseases and the possibility to develop AT2R as a potential drug target.

Pharmacokinetic and molecular docking studies to design antimalarial compounds targeting Actin I.

OBJECTIVE: Malaria is an ancient disease that still causes more than 200 million of cases 7 with high mortality globally. Identification of new drug targets and development of novel antimalarial drugs with unique mode of action encounter the drug resistance and reduce the mortality by Plasmodium parasites. Actin protein is one of the key proteins in Plasmodium falciparum playing multifarious important roles including transport, cell motility, cell division, and shape determination. This study investigated Actin I as a drug target, in silico screening of diverse molecules through molecular docking was considered. Further, pharmacokinetic parameters of the selected molecules from the docking and interaction studies were planned to propose the lead molecules.b. METHODS: Molecules were selected according to score and protein ligand interaction and selected molecules were subjected for pharmacokinetic studies to investigate important drug parameters. RESULTS: The docked molecules were ranked according to the binding score and good interaction pattern was observed with Actin I within top 20 scoring molecules. The selected molecules also had optimum pharmacokinetic parameters. CONCLUSION: The current study provides a set of hit molecules which can be further explored through in vitro and in vivo experiments for the development of potential drugs against malaria, there by encountering drug resistance and establishing Actin I as an important drug target.

Genetic association of ARID5B with the risk of colorectal cancer within Jammu and Kashmir, India.

Colorectal cancer (CRC), which includes the development of cancer from the colon or rectum, is one of the highly prevalent cancers in the populations of Jammu and Kashmir (J&K) in India. However, case-control genetic association studies on CRC are lacking in this population. Various genome-wide association studies have previously shown that single-nucleotide polymorphisms (SNPs) of the AT-rich interaction domain 5B (ARID5B) gene located on chromosome 10q21.2 contribute substantially to the development of colorectal cancer. The association between ARID5B and CRC risk in north Indian population groups is still unknown. To understand the role of ARID5B SNPs in CRC in the population of J&K, we designed a case-control study to investigate the association of the cancer susceptibility variant rs10740055 of ARID5B with CRC in the population of J&K. The study included 180 cases and 390 healthy controls. Genotyping of the rs10740055 variant was performed by RT-PCR using the TaqMan assay technique. Hardy-Weinberg equilibrium of the variant was assessed using the chi-squared test. The allele- and genotype-specific risks were estimated by odds ratios (ORs) with 95% confidence intervals (CIs). The rs10740055 variant showed a higher risk for colorectal cancer with an OR of 3.35 (1.99-5.65 at 95% CI) and P = 0.000005 corrected for age, gender, ethnicity, BMI, alcohol intake and smoking. Our results indicate that the A allele of rs10740055 imparts risk to the population and also that a larger sample size is needed for further statistical validation. The association of other variants in other ARID family genes should also be tested as their role cannot be ruled out.

Comparison Between Inflammatory Biomarkers (High-Sensitivity C-Reactive Protein and Neutrophil-Lymphocyte Ratio) and Psychological Morbidity in Suicide Attempt Survivors Brought to Medicine Emergency.

OBJECTIVES: This study aimed to compare inflammatory biomarkers (high-sensitivity {hs} C-reactive protein, neutrophil-lymphocyte ratio) and psychological morbidity in suicide attempt survivors. METHODS: One hundred ninety-eight poisoning cases screened, 40 age-matched suicide attempt survivors (SAS), 40 healthy controls (HC) between the age of 18 years and 60 years were included. Complete hemogram, neutrophil-lymphocyte ratio (NLR), hsCRP values obtained, compared with Hospital Anxiety and Depression Scale (HADS), suicide intent scale, presumptive stressful life events scale (PSLES), general health questionnaire 12-item (GHQ-12) (Hindi version), and Hindi Mental State Examination (HMSE). RESULTS: A statistically significant difference was observed in hsCRP (p=0.016) and NLR (p=0.029) of depressed-suicidal participants vs healthy controls. hsCRP values of anxious-suicidal subjects vs healthy controls showed a statistically significant difference (p=0.001). There was a statistically significant difference between patients, healthy controls in HADS anxiety and HADS depression mean scores (p<0.001). The PSLES items were ranked according to the mean stress scores of all the items (mean±SD), highest four were excessive alcohol use by the family member 47.50 (±27.03), conflicts with in-laws 50 (±27.73), family conflict 50 (±29.42), marital conflict 50.63 (±32.76). There was a statistically significant difference in hemoglobin (p<0.001), red blood cells count (p<0.001), hematocrit (p<0.001) between suicide attempt survivors and healthy controls. CONCLUSION: Both hsCRP and NLR have emerged as potential inflammatory biomarkers for depressive patients with suicidal attempts. Additionally, there may be a link between anemia and suicide risk in patients with depression.