ASOptimizer: Optimizing antisense oligonucleotides through deep learning for IDO1 gene regulation.

Recent studies have highlighted the effectiveness of using antisense oligonucleotides (ASOs) for cellular RNA regulation, including targets that are considered undruggable; however, manually designing optimal ASO sequences can be labor intensive and time consuming, which potentially limits their broader application. To address this challenge, we introduce a platform, the ASOptimizer, a deep-learning-based framework that efficiently designs ASOs at a low cost. This platform not only selects the most efficient mRNA target sites but also optimizes the chemical modifications for enhanced performance. Indoleamine 2,3-dioxygenase 1 (IDO1) promotes cancer survival by depleting tryptophan and producing kynurenine, leading to immunosuppression through the aryl-hydrocarbon receptor (Ahr) pathway within the tumor microenvironment. We used ASOptimizer to identify ASOs that target IDO1 mRNA as potential cancer therapeutics. Our methodology consists of two stages: sequence engineering and chemical engineering. During the sequence-engineering stage, we optimized and predicted ASO sequences that could target IDO1 mRNA efficiently. In the chemical-engineering stage, we further refined these ASOs to enhance their inhibitory activity while reducing their potential cytotoxicity. In conclusion, our research demonstrates the potential of ASOptimizer for identifying ASOs with improved efficacy and safety.

Brief Report: Self-Reported HIV-Positive Status but Subsequent HIV-Negative Test Results in Population-Based HIV Impact Assessment Survey Participants-11 Sub-Saharan African Countries, 2015-2018.

BACKGROUND: HIV testing is a critical step to accessing antiretroviral therapy (ART) because early diagnosis can facilitate earlier initiation of ART. This study presents aggregated data of individuals who self-reported being HIV-positive but subsequently tested HIV-negative during nationally representative Population-Based HIV Impact Assessment surveys conducted in 11 countries from 2015 to 2018. METHOD: Survey participants aged 15 years or older were interviewed by trained personnel using a standard questionnaire to determine HIV testing history and self-reported HIV status. Home-based HIV testing and counseling using rapid diagnostic tests with return of results were performed by survey staff according to the respective national HIV testing services algorithms on venous blood samples. Laboratory-based confirmatory HIV testing for all participants identified as HIV-positives and self-reported positives, irrespective of HIV testing results, was conducted and included Geenius HIV-1/2 and DNA polymerase chain reaction if Geenius was negative or indeterminate. RESULTS: Of the 16,630 participants who self-reported as HIV-positive, 16,432 (98.6%) were confirmed as HIV-positive and 198 (1.4%) were HIV-negative by subsequent laboratory-based testing. Participants who self-reported as HIV-positive but tested HIV-negative were significantly younger than 30 years, less likely to have received ART, and less likely to have received a CD4 test compared with participants who self-reported as HIV-positive with laboratory-confirmed infection. CONCLUSIONS: A small proportion of self-reported HIV-positive individuals could not be confirmed as positive, which could be due to initial misdiagnosis, deliberate wrong self-report, or misunderstanding of the questionnaire. As universal ART access is expanding, it is increasingly important to ensure quality of HIV testing and confirmation of HIV diagnosis before ART initiation.

Altered platelet-megakaryocyte endocytosis and trafficking of albumin and fibrinogen in RUNX1 haplodeficiency.

ABSTRACT: Platelet α-granules have numerous proteins, some synthesized by megakaryocytes (MK) and others not synthesized but incorporated by endocytosis, an incompletely understood process in platelets/MK. Germ line RUNX1 haplodeficiency, referred to as familial platelet defect with predisposition to myeloid malignancies (FPDMMs), is associated with thrombocytopenia, platelet dysfunction, and granule deficiencies. In previous studies, we found that platelet albumin, fibrinogen, and immunoglobulin G (IgG) were decreased in a patient with FPDMM. We now show that platelet endocytosis of fluorescent-labeled albumin, fibrinogen, and IgG is decreased in the patient and his daughter with FPDMM. In megakaryocytic human erythroleukemia (HEL) cells, small interfering RNA RUNX1 knockdown (KD) increased uptake of these proteins over 24 hours compared with control cells, with increases in caveolin-1 and flotillin-1 (2 independent regulators of clathrin-independent endocytosis), LAMP2 (a lysosomal marker), RAB11 (a marker of recycling endosomes), and IFITM3. Caveolin-1 downregulation in RUNX1-deficient HEL cells abrogated the increased uptake of albumin, but not fibrinogen. Albumin, but not fibrinogen, partially colocalized with caveolin-1. RUNX1 KD resulted in increased colocalization of albumin with flotillin and fibrinogen with RAB11, suggesting altered trafficking of both proteins. The increased uptake of albumin and fibrinogen, as well as levels of caveolin-1, flotillin-1, LAMP2, and IFITM3, were recapitulated by short hairpin RNA RUNX1 KD in CD34+-derived MK. To our knowledge, these studies provide first evidence that platelet endocytosis of albumin and fibrinogen is impaired in some patients with RUNX1-haplodeficiency and suggest that megakaryocytes have enhanced endocytosis with defective trafficking, leading to loss of these proteins by distinct mechanisms. This study provides new insights into mechanisms governing endocytosis and α-granule deficiencies in RUNX1-haplodeficiency.

Association of plasma amyloid-ß oligomerization with theta/beta ratio in older adults.

Background: Oligomeric Aß (OAß) is a promising candidate marker for Alzheimer's disease (AD) diagnosis. Electroencephalography (EEG) is a potential tool for early detection of AD. Still, whether EEG power ratios, particularly the theta/alpha ratio (TAR) and theta/beta ratio (TBR), reflect Aß burden-a primary mechanism underlying cognitive impairment and AD. This study investigated the association of TAR and TBR with amyloid burden in older adults based on MDS-OAß levels. Methods: 529 individuals (aged ≥60 years) were recruited. All participants underwent EEG (MINDD SCAN, Ybrain Inc., South Korea) and AlzOn™ test (PeopleBio Inc., Gyeonggi-do, Republic of Korea) for quantifying MDS-OAß values in the plasma. EEG variables were log-transformed to normalize the data distribution. Using the MDS-OAß cutoff value (0.78 ng/mL), all participants were classified into two groups: high MDS-OAß and low MDS-OAß. Results: Participants with high MDS-OAß levels had significantly higher TARs and TBRs than those with low MDS-OAß levels. The log-transformed TBRs in the central lobe (ß = 0.161, p = 0.0026), frontal lobe (ß = 0.145, p = 0.0044), parietal lobe (ß = 0.166, p = 0.0028), occipital lobe (ß = 0.158, p = 0.0058), and temporal lobe (beta = 0.162, p = 0.0042) were significantly and positively associated with increases in MDS-OAß levels. After adjusting for the Bonferroni correction, the TBRs in all lobe regions, except the occipital lobe, were significantly associated with increased MDS-OAß levels. Conclusion: We found a significant association of MDS-OAß with TBR in older adults. This finding indicates that an increase in amyloid burden may be associated with an increase in the low-frequency band and a decrease in the relatively high-frequency band.

Altered Platelet-Megakaryocyte Endocytosis and Trafficking of Albumin and Fibrinogen in RUNX1 Haplodeficiency.

Platelet α-granules have numerous proteins, some synthesized by megakaryocytes (MK) and others not synthesized but incorporated by endocytosis, an incompletely understood process in platelets/MK. Germline RUNX1 haplodeficiency, referred to as familial platelet defect with predisposition to myeloid malignancies (FPDMM), is associated with thrombocytopenia, platelet dysfunction and granule deficiencies. In previous studies, we found that platelet albumin, fibrinogen and IgG levels were decreased in a FPDMM patient. We now show that platelet endocytosis of fluorescent-labeled albumin, fibrinogen and IgG is decreased in the patient and his daughter with FPDMM. In megakaryocytic human erythroleukemia (HEL) cells, siRNA RUNX1 knockdown (KD) increased uptake of these proteins over 24 hours compared to control cells, with increases in caveolin-1 and flotillin-1 (two independent regulators of clathrin-independent endocytosis), LAMP2 (a lysosomal marker), RAB11 (a marker of recycling endosomes) and IFITM3. Caveolin-1 downregulation in RUNX1-deficient HEL cells abrogated the increased uptake of albumin, but not fibrinogen. Albumin, but not fibrinogen, partially colocalized with caveolin-1. RUNX1 knockdown increased colocalization of albumin with flotillin and of fibrinogen with RAB11 suggesting altered trafficking of both. The increased albumin and fibrinogen uptake and levels of caveolin-1, flotillin-1, LAMP2 and IFITM3 were recapitulated by shRNA RUNX1 knockdown in CD34 + -derived MK. These studies provide the first evidence that in RUNX1- haplodeficiency platelet endocytosis of albumin and fibrinogen is impaired and that megakaryocytes have enhanced endocytosis with defective trafficking leading to loss of these proteins by distinct mechanisms. They provide new insights into mechanisms governing endocytosis and α-granule deficiencies in RUNX1- haplodeficiency. Key points: Platelet content and endocytosis of α-granule proteins, albumin, fibrinogen and IgG, are decreased in germline RUNX1 haplodeficiency. In RUNX1 -deficient HEL cells and primary MK endocytosis is enhanced with defective trafficking leading to decreased protein levels.

Correlation between electrodiagnostic severity and Boston carpal tunnel questionnaire in surgically treated carpal tunnel syndrome patients.

OBJECTIVE: The objectives of this study were to (1) investigate whether electrodiagnostic (EDX) findings reflect the preoperative symptom severity and functional impairment in patients with carpal tunnel syndrome (CTS) and (2) evaluate the relationship between EDX findings and the clinical outcomes reported according to the self-administered patient questionnaires. METHODS: Patients diagnosed with idiopathic CTS who underwent carpal tunnel release between May 2016 and July 2018 were included. Carpal tunnel syndrome was clinically diagnosed and confirmed based on the EDX findings. The association between EDX findings, such as motor latency, motor amplitude, sensory latency, sensory amplitude, and severity (mild, moderate, and severe), and the Boston symptom and function scores were analyzed. The change in the Boston symptom and function scores from the preoperative baseline values (visit 1) to those recorded 1 year postoperatively (visit 5) was assessed. The effect of disease severity based on the EDX findings on the change in Boston symptom and function scores by visit was also investigated. RESULTS: The EDX severity, motor latency, motor amplitude, sensory latency, and sensory amplitude were not correlated with the Boston symptom and function scores preoperatively and postoperatively. Electrodiagnostic severity did not affect the improvement in the Boston symptom and function scores recorded at each visit. CONCLUSION: We found no association between the EDX severity and perioperative Boston questionnaire scores, and the degree of improvement in patient symptoms and function did not differ according to the CTS severity based on the EDX findings. LEVEL OF EVIDENCE: Level IV, Prognostic study.

Limited output transcranial electrical stimulation 2023 (LOTES-2023): Updates on engineering principles, regulatory statutes, and industry standards for wellness, over-the-counter, or prescription devices with low risk.

The objective and scope of this Limited Output Transcranial Electrical Stimulation 2023 (LOTES-2023) guidance is to update the previous LOTES-2017 guidance. These documents should therefore be considered together. The LOTES provides a clearly articulated and transparent framework for the design of devices providing limited output (specified low-intensity range) transcranial electrical stimulation for a variety of intended uses. These guidelines can inform trial design and regulatory decisions, but most directly inform manufacturer activities - and hence were presented in LOTES-2017 as "Voluntary industry standard for compliance controlled limited output tES devices". In LOTES-2023 we emphasize that these standards are largely aligned across international standards and national regulations (including those in USA, EU, and South Korea), and so might be better understood as "Industry standards for compliance controlled limited output tES devices". LOTES-2023 is therefore updated to reflect a consensus among emerging international standards, as well as best available scientific evidence. "Warnings" and "Precautions" are updated to align with current biomedical evidence and applications. LOTES standards applied to a constrained device dose range, but within this dose range and for different use-cases, manufacturers are responsible to conduct device-specific risk management.

Gene silencing dynamics are modulated by transiently active regulatory elements.

Transcriptional enhancers have been extensively characterized, but cis-regulatory elements involved in acute gene repression have received less attention. Transcription factor GATA1 promotes erythroid differentiation by activating and repressing distinct gene sets. Here, we study the mechanism by which GATA1 silences the proliferative gene Kit during murine erythroid cell maturation and define stages from initial loss of activation to heterochromatinization. We find that GATA1 inactivates a potent upstream enhancer but concomitantly creates a discrete intronic regulatory region marked by H3K27ac, short noncoding RNAs, and de novo chromatin looping. This enhancer-like element forms transiently and serves to delay Kit silencing. The element is ultimately erased via the FOG1/NuRD deacetylase complex, as revealed by the study of a disease-associated GATA1 variant. Hence, regulatory sites can be self-limiting by dynamic co-factor usage. Genome-wide analyses across cell types and species uncover transiently active elements at numerous genes during repression, suggesting that modulation of silencing kinetics is widespread.

Nitric oxide acts as an inducer of Strategy-I responses to increase Fe availability and mobilization in Fe-starved broccoli (Brassica oleracea var. oleracea).

Iron (Fe) deficiency causes reduced growth and yield in broccoli. This study elucidates how sodium nitroprusside (SNP), known as nitric oxide (NO) donor, mitigates the retardation caused by Fe deficiency in broccoli. The SNP caused substantial nitric oxide accumulation in the roots of Fe-deficient plants, which resulted in a significant improvement in chlorophyll levels, photosynthetic efficiency, and morphological growth parameters, showing that it has a favorable influence on recovering broccoli health. Ferric reductase activity and the expression of BoFRO1 (ferric chelate reductase) gene in roots were consistently increased by SNP under Fe deficiency, which likely resulted in increased Fe mobilization. Furthermore, proton (H+) extrusion and BoHA2 (H+-ATPase 2) expression were significantly increased, suggesting that they may be involved in lowering rhizospheric pH to restore Fe mobilization in roots of bicarbonate-treated broccoli plants. The levels of Fe in root and shoot tissues and the expression of BoIRT1 (Fe-regulated transporter) both increased dramatically after SNP supplementation under Fe deprivation. Furthermore, SNP-induced increase in citrate and malate concentrations suggested a role of NO in improved Fe chelation in Fe-deficient broccoli. A NO scavenger (cPTIO) ceased the elevated FCR activity and IAA (indole-3-acetic acid) concentration in Fe-starved plants treated with SNP. These findings suggest that SNP may play a role in initiating Fe availability by elevated IAA concentration and BoEIR1 (auxin efflux carrier) expression in the roots of broccoli during Fe shortage. Therefore, SNP may improve Fe availability and mobilization by increasing Strategy-I Fe uptake pathways, which may help broccoli tolerate Fe deficiency.

RUNX1-deficient human megakaryocytes demonstrate thrombopoietic and platelet half-life and functional defects.

Heterozygous defects in runt-related transcription factor 1 (RUNX1) are causative of a familial platelet disorder with associated myeloid malignancy (FPDMM). Because RUNX1-deficient animal models do not mimic bleeding disorder or leukemic risk associated with FPDMM, development of a proper model system is critical to understanding the underlying mechanisms of the observed phenotype and to identifying therapeutic interventions. We previously reported an in vitro megakaryopoiesis system comprising human CD34+ hematopoietic stem and progenitor cells that recapitulated the FPDMM quantitative megakaryocyte defect through a decrease in RUNX1 expression via a lentiviral short hairpin RNA strategy. We now show that shRX-megakaryocytes have a marked reduction in agonist responsiveness. We then infused shRX-megakaryocytes into immunocompromised NOD scid gamma (NSG) mice and demonstrated that these megakaryocytes released fewer platelets than megakaryocytes transfected with a nontargeting shRNA, and these platelets had a diminished half-life. The platelets were also poorly responsive to agonists, unable to correct thrombus formation in NSG mice homozygous for a R1326H mutation in von Willebrand Factor (VWFR1326H), which switches the species-binding specificity of the VWF from mouse to human glycoprotein Ibα. A small-molecule inhibitor RepSox, which blocks the transforming growth factor ß1 (TGFß1) pathway and rescued defective megakaryopoiesis in vitro, corrected the thrombopoietic defect, defects in thrombus formation and platelet half-life, and agonist response in NSG/VWFR1326H mice. Thus, this model recapitulates the defects in FPDMM megakaryocytes and platelets, identifies previously unrecognized defects in thrombopoiesis and platelet half-life, and demonstrates for the first time, reversal of RUNX1 deficiency-induced hemostatic defects by a drug.

Corrigendum: Use of electroencephalogram, gait, and their combined signals for classifying cognitive impairment and normal cognition.

[This corrects the article DOI: 10.3389/fnagi.2022.927295.].

Regulation of Na+/H+ exchangers, Na+/K+ transporters, and lignin biosynthesis genes, along with lignin accumulation, sodium extrusion, and antioxidant defense, confers salt tolerance in alfalfa.

Accumulation of high sodium (Na+) leads to disruption of metabolic processes and decline in plant growth and productivity. Therefore, this study was undertaken to clarify how Na+/H+ exchangers and Na+/K+ transporter genes contribute to Na+ homeostasis and the substantial involvement of lignin biosynthesis genes in salt tolerance in alfalfa (Medicago sativa L.), which is poorly understood. In this study, high Na+ exhibited a substantial reduction of morphophysiological indices and induced oxidative stress indicators in Xingjiang Daye (XJD; sensitive genotype), while Zhongmu (ZM; tolerant genotype) remained unaffected. The higher accumulation of Na+ and the lower accumulation of K+ and K+/(Na+ + K+) ratio were found in roots and shoots of XJD compared with ZM under salt stress. The ZM genotype showed a high expression of SOS1 (salt overly sensitive 1), NHX1 (sodium/hydrogen exchanger 1), and HKT1 (high-affinity potassium transporter 1), which were involved in K+ accumulation and excess Na+ extrusion from the cells compared with XJD. The lignin accumulation was higher in the salt-adapted ZM genotype than the sensitive XJD genotype. Consequently, several lignin biosynthesis-related genes including 4CL2, CCoAOMT, COMT, CCR, C4H, PAL1, and PRX1 exhibited higher mRNA expression in salt-tolerant ZM compared with XJD. Moreover, antioxidant enzyme (catalase, superoxide dismutase, ascorbate peroxidase, and glutathione reductase) activity was higher in ZM relative to XJD. This result suggests that high antioxidant provided the defense against oxidative damages in ZM, whereas low enzyme activity with high Na+ triggered the oxidative damage in XJD. These findings together illustrate the ion exchanger, antiporter, and lignin biosysthetic genes involving mechanistic insights into differential salt tolerance in alfalfa.

Computational modeling of posteroanterior lumbar traction by an automated massage bed: predicting intervertebral disc stresses and deformation.

Spinal traction is a physical intervention that provides constant or intermittent stretching axial force to the lumbar vertebrae to gradually distract spinal tissues into better alignment, reduce intervertebral disc (IVD) pressure, and manage lower back pain (LBP). However, such axial traction may change the normal lordotic curvature, and result in unwanted side effects and/or inefficient reduction of the IVD pressure. An alternative to axial traction has been recently tested, consisting of posteroanterior (PA) traction in supine posture, which was recently shown effective to increase the intervertebral space and lordotic angle using MRI. PA traction aims to maintain the lumbar lordosis curvature throughout the spinal traction therapy while reducing the intradiscal pressure. In this study, we developed finite element simulations of mechanical therapy produced by a commercial thermo-mechanical massage bed capable of spinal PA traction. The stress relief produced on the lumbar discs by the posteroanterior traction system was investigated on human subject models with different BMI (normal, overweight, moderate obese and extreme obese BMI cases). We predict typical traction levels lead to significant distraction stresses in the lumbar discs, thus producing a stress relief by reducing the compression stresses normally experienced by these tissues. Also, the stress relief experienced by the lumbar discs was effective in all BMI models, and it was found maximal in the normal BMI model. These results are consistent with prior observations of therapeutic benefits derived from spinal AP traction.

The weekend effect on mechanical thrombectomy: A nationwide analysis before and after the pivotal 2015 trials.

OBJECTIVES: As hospitals rapidly implement mechanical thrombectomy (MT) into stroke protocols following the pivotal trials in 2015, access to and outcomes from MT may be poorer for weekend-admitted patients. We sought to investigate whether a "weekend effect" influences MT outcomes nationally. MATERIALS AND METHODS: We identified stroke patients from 2010-2014 (pre-trials) to 2015-2017 (posttrials) using the Nationwide Readmissions Database. On multivariate analyses, we determined factors independently associated with receiving MT. Among MT patients, we then determined whether weekend admission was independently associated with inpatient mortality and unfavorable discharge. RESULTS: We identified 2,121,462 patients from 2010 to 2014, of whom 1.11% of weekday-admitted and 1.08% of weekend-admitted patients underwent MT. Of the 1,286,501 patients identified from 2015 to 2017, MT was performed in 2.82% and 2.91%, respectively. In the earlier cohort, weekend admission was independently associated with reduced odds of MT (odds ratio [OR] = 0.92, 95% confidence interval [CI]: 0.89-0.95, P < 0.0001), although this was not statistically significant in the later cohort. During both periods, age >80 years was independently associated with a reduced likelihood of receiving MT, and status as a teaching or large bed-size hospital was associated with a greater likelihood. Weekend admission was independently associated with unfavorable discharge only in the 2015-2017 cohort (OR = 1.11, 95% CI: 1.02-1.22, P = 0.02). CONCLUSIONS: While nationwide access to MT has improved for weekend-admitted patients, the elderly and those at smaller, nonteaching hospitals remain underserved. Although we found no effect of weekend admission on inpatient mortality, since the major shift in practice, an emerging "weekend effect" may influence discharge outcomes. Data suggest that some hospitals are being challenged to provide this new standard of care efficiently and equitably.

Heat Shock Proteins and Antioxidant Genes Involved in Heat Combined with Drought Stress Responses in Perennial Rye Grass.

The frequent occurrence of heat and drought stress can severely reduce agricultural production of field crops. In comparison to a single stress, the combination of both heat (H) and drought (D) further reduce plant growth, survival and yield. This study aimed to explore the transcriptional responses of heat shock protein (HSP) and antioxidant genes under H combined D stress in perennial rye grass (PRG). The results demonstrated that oxidative stress indicators (hydrogen peroxide, lipid peroxidation) significantly increased, particularly in the case of combined H and D treatment, suggesting that oxidative stress-induced damage occurred in plants under the combined stresses. Transcriptional responses of heat shock protein 70 (HSP70), heat shock protein 90-6 (HSP90-6), and the mitochondrial small heat shock protein HSP26.2 (HSP26.2) occurred rapidly, and showed high level of expression particularly under H and D stress. Antioxidant genes including ascorbate peroxidase (APX), glutathione reductase (GR), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), catalase (CAT), copper-zinc superoxide dismutase (Cu/ZnSOD), peroxidase (POD), ferredoxin-thioredoxin (FTR), thioredoxin (Trx), 2-cysteine peroxiredoxin (2-Cys Prx) showed response to combined H and D, followed by either D or H stress alone in rye grass. An interactome map revealed the close partnership of these heat shock protein genes and antioxidant genes, respectively. These candidate genes were predominantly linked to stress responses and antioxidant defense in plants. These findings may advance our understanding about the HSP and the antioxidant genes underlying combined abiotic stress response and tolerance in perennial rye grass.

Digitalized transcranial electrical stimulation: A consensus statement.

OBJECTIVE: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES. METHODS: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided. RESULTS: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity. CONCLUSIONS: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases. SIGNIFICANCE: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials.

Use of electroencephalogram, gait, and their combined signals for classifying cognitive impairment and normal cognition.

Background: Early identification of people at risk for cognitive decline is an important step in delaying the occurrence of cognitive impairment. This study investigated whether multimodal signals assessed using electroencephalogram (EEG) and gait kinematic parameters could be used to identify individuals at risk of cognitive impairment. Methods: The survey was conducted at the Veterans Medical Research Institute in the Veterans Health Service Medical Center. A total of 220 individuals volunteered for this study and provided informed consent at enrollment. A cap-type wireless EEG device was used for EEG recording, with a linked-ear references based on a standard international 10/20 system. Three-dimensional motion capture equipment was used to collect kinematic gait parameters. Mild cognitive impairment (MCI) was evaluated by Seoul Neuropsychological Screening Battery-Core (SNSB-C). Results: The mean age of the study participants was 73.5 years, and 54.7% were male. We found that specific EEG and gait parameters were significantly associated with cognitive status. Individuals with decreases in high-frequency EEG activity in high beta (25-30 Hz) and gamma (30-40 Hz) bands increased the odds ratio of MCI. There was an association between the pelvic obliquity angle and cognitive status, assessed by MCI or SNSB-C scores. Results from the ROC analysis revealed that multimodal signals combining high beta or gamma and pelvic obliquity improved the ability to discriminate MCI individuals from normal controls. Conclusion: These findings support prior work on the association between cognitive status and EEG or gait, and offer new insights into the applicability of multimodal signals to distinguish cognitive impairment.

Computational Modeling of Deep Tissue Heating by an Automatic Thermal Massage Bed: Predicting the Effects on Circulation.

Automatic thermal and mechanical massage beds support self-managed treatment, including reduction of pain and stress, enhanced circulation, and improved mobility. As the devices become more sophisticated (increasing the degrees of freedom), it is essential to identify the settings that best target the desired tissue. To that end, we developed an MRI-derived model of the lower back and simulated the physiological effects of a commercial thermal-mechanical massage bed. Here we specifically estimated the tissue temperature and increased circulation under steady-state conditions for typical thermal actuator settings (i.e., 45-65°C). Energy transfer across nine tissues was simulated with finite element modeling (FEM) and the resulting heating was coupled to blood flow with an empirically-guided model of temperature-dependent circulation. Our findings indicate that thermal massage increases tissue temperature by 3-8°C and 1-3°C at depths of 2 and 3 cm, respectively. Importantly, due to the rapid (non-linear) increase of circulation with local temperature, this is expected to increase blood flow four-fold (4x) at depths occupied by deep tissue and muscle. These predictions are consistent with prior clinical observations of therapeutic benefits derived from spinal thermal massage.