A Novel Combinatorial Regimen Using Sorafenib and Uttroside B, A US FDA-designated 'Orphan Drug', for the Treatment of Hepatocellular Carcinoma.

INTRODUCTION: Sorafenib (Sor) is the first-line treatment option in clinics for treating advanced unresectable hepatocellular carcinoma (HCC). However, acquired chemoresistance and adverse side effects associated with Sor monotherapy limit its clinical benefits. We have previously reported the exceptional anti-HCC potential of uttroside B (Utt-B), a furostanol saponin isolated in our lab from Solanum nigrum Linn. leaves. The current study has evaluated the supremacy of a combinatorial regimen of Sor and Utt-B over Sor monotherapy. METHODS: MTT assay was used for In vitro cytotoxicity studies. A clonogenic assay was conducted to assess the anti-proliferative effect of the combination. Annexin V/PI staining, confocal microscopy, FACS cell cycle analysis, and Western blotting experiments were performed to validate the pro-apoptotic potential of the combination in HepG2 and Huh7 cell lines. Pharmacological safety evaluation was performed in Swiss albino mice. RESULTS: Our results indicate that Utt-B augments Sor-induced cytotoxicity in HepG2 and Huh7 cells. The combination inhibits the proliferation of liver cancer cells by inducing apoptosis through activation of the caspases 7 and 3, leading to PARP cleavage. Furthermore, the combination does not induce any acute toxicity in vivo, even at a dose five times that of the effective therapeutic dose. CONCLUSION: Our results highlight the potential of Utt-B as an effective chemosensitizer, which can augment the efficacy of Sor against HCC and circumvent Sor-induced toxic side effects. Moreover, this is the first and only report to date on the chemosensitizing potential of Utt-B and the only report that demonstrates the therapeutic efficacy and pharmacological safety of a novel combinatorial regimen involving Utt-B and Sor for combating HCC.

Corrigendum: High-definition transcranial direct current stimulation for upper extremity rehabilitation in moderate-to-severe ischemic stroke: a pilot study.

[This corrects the article DOI: 10.3389/fnhum.2023.1286238.].

Changes in alcohol consumption and binge drinking during the COVID-19 pandemic among American Indians residing in California and Oklahoma.

Background: This study explored the increased quantity and frequency of alcohol use in the American Indian (AI) population during the COVID-19 pandemic.Objectives: The aims of this study were to explore possible associations between covariables and both binge drinking and alcohol consumption during COVID-19.Methods: This cross-sectional survey study analyzed data from a sample of AI individuals (63% female) residing in California (n = 411) and Oklahoma (n = 657) between October 2020-January 2021. Analysis included summary statistics and multivariable logistic regression, including a variety of socio-economic, COVID-19 concern, and tobacco and marijuana use variables.Results: One or more alcohol binge episodes were reported between October 2020-January 2021 in 19.3% of participants and elevated overall alcohol consumption was reported by 21.6% of participants. Higher odds of elevated alcohol consumption occurred in women and those following more social distancing measures. The odds of binge drinking or elevated alcohol consumption in those using both marijuana and tobacco (aOR/ adjusted odds ratio:18.9, 95% CI = 8.5, 42.2, and aOR:3.9, 95% CI = 1.7, 8.6, respectively) were higher compared to those using neither. Similarly, the odds of binge drinking or elevated alcohol consumption in those using tobacco only (aOR:4.7, 95% CI = 2.9, 7.7 and aOR: 2.0, 95% CI = 1.1, 3.5, respectively) were higher compared to those using neither.Conclusions: This study found high rates of alcohol use and bingeing during the COVID-19 pandemic. Offering collaborative, culturally sensitive, and affordable support services are important components of intervention and preparation for future stressful events on local, as well as global levels.

Sex differences in interacting genetic and functional connectivity biomarkers in Alzheimer's disease.

As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer's disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer's disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer's participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment.

Susceptibility to e-cigarette use and associated factors in high school youth, Oklahoma Youth Tobacco Survey, 2021-2022.

Introduction: Susceptibility predicts subsequent uptake of e-cigarettes (EC) by youth. This study identified factors associated with EC susceptibility among high school students who have never used a tobacco/nicotine product. Methods: The Oklahoma Youth Tobacco Survey was administered to a random sample of 36 Oklahoma High Schools during the 2021-2022 school year (n = 1,220 participating students). Associations between EC susceptibility and covariates were identified using stepwise logistic regression for weighted survey data. Results: More than one third of Oklahoma high school students who had never used tobacco or nicotine products (36.4%) were susceptible, and males had higher susceptibility than females (38.8 and 33.9%, respectively). In males, EC susceptibility was associated with race (Black, American Indian, and other were less susceptible), psychological distress (aOR = 2.4, 95% CI = 1.1, 4.8), disagreement that all tobacco products are dangerous (aOR = 3.1, 95% CI = 1.2, 7.9), and perception of little/no harm from secondhand vapor (aOR = 3.4, 95% CI = 2.1, 5.3). In females, identifying as gay, lesbian, or bisexual (aOR = 2.1, 95% CI = 1.1, 3.9), poor academic performance (aOR = 4.5, 95% CI = 1.6, 12.6), psychological distress (aOR = 2.6, 95% CI = 1.2, 5.5) and interacting with EC content on social media (aOR = 5.9, 95% CI = 1.9, 18.1) were associated with EC susceptibility. Conclusion: Males and females had different patterns of susceptibility to EC use. Understanding groups of adolescents most susceptible to using nicotine products can help target prevention efforts at home, in schools, and within communities.

Alteration in Resting-State Brain Activity in Stroke Survivors After Repetitive Finger Stimulation.

OBJECTIVE: This quasi-experimental study examined the effect of repetitive finger stimulation on brain activation in eight stroke and seven control subjects, measured by quantitative electroencephalogram. METHODS: We applied 5 mins of 2-Hz repetitive bilateral index finger transcutaneous electrical nerve stimulation and compared differences pre- and post-transcutaneous electrical nerve stimulation using quantitative electroencephalogram metrics delta/alpha ratio and delta-theta/alpha-beta ratio. RESULTS: Between-group differences before and after stimulation were significantly different in the delta/alpha ratio ( z = -2.88, P = 0.0040) and the delta-theta/alpha-beta ratio variables ( z = -3.90 with P < 0.0001). Significant decrease in the delta/alpha ratio and delta-theta/alpha-beta ratio variables after the transcutaneous electrical nerve stimulation was detected only in the stroke group (delta/alpha ratio diff = 3.87, P = 0.0211) (delta-theta/alpha-beta ratio diff = 1.19, P = 0.0074). CONCLUSIONS: The decrease in quantitative electroencephalogram metrics in the stroke group may indicate improved brain activity after transcutaneous electrical nerve stimulation. This finding may pave the way for a future novel therapy based on transcutaneous electrical nerve stimulation and quantitative electroencephalogram measures to improve brain recovery after stroke.

Determining the effects of targeted high-definition transcranial direct current stimulation on reducing post-stroke upper limb motor impairments-a randomized cross-over study.

BACKGROUND: Stroke is one of the leading causes of death in the USA and is a major cause of serious disability for adults. This randomized crossover study examines the effect of targeted high-definition transcranial direct current transcranial brain stimulation (tDCS) on upper extremity motor recovery in patients in the post-acute phase of stroke recovery. METHODS: This randomized double-blinded cross-over study includes four intervention arms: anodal, cathodal, and bilateral brain stimulation, as well as a placebo stimulation. Participants receive each intervention in a randomized order, with a 2-week washout period between each intervention. The primary outcome measure is change in Motor Evoked Potential. Secondary outcome measures include the Fugl-Meyer Upper Extremity (FM-UE) score, a subset of FM-UE (A), related to the muscle synergies, and the Modified Ashworth Scale. DISCUSSION: We hypothesize that anodal stimulation to the ipsilesional primary motor cortex will increase the excitability of the damaged cortico-spinal tract, reducing the UE flexion synergy and enhancing UE motor function. We further hypothesize that targeted cathodal stimulation to the contralesional premotor cortex will decrease activation of the cortico-reticulospinal tract (CRST) and the expression of the upper extremity (UE) flexion synergy and spasticity. Finally, we hypothesize bilateral stimulation will achieve both results simultaneously. Results from this study could improve understanding of the mechanism behind motor impairment and recovery in stroke and perfect the targeting of tDCS as a potential stroke intervention. With the use of appropriate screening, we anticipate no ethical or safety concerns. We plan to disseminate these research results to journals related to stroke recovery, engineering, and medicine. TRIAL REGISTRATION: ClinicalTrials.gov NCT05479006 . Registered on 26 July 2022.

Sex difference in brain functional connectivity of hippocampus in Alzheimer's disease.

Alzheimer's disease (AD), affecting nearly 6.5 million people, is the fifth leading cause of death in individuals 65 years or older in the USA. Prior research has shown that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research has linked these sex differences to neuroimaging markers of brain pathology, such as hippocampal volumes. Specifically, research from our lab found that functional connectivity from the hippocampus to the precuneus cortex and brain stem was significantly stronger in males than in females with mild cognitive impairment. The aim of this study was to extend our understanding to individuals with AD and to determine if these potential sex-specific functional connectivity biomarkers extend through different disease stages. The resting state fMRI and T2 MRI of cognitively normal individuals (n = 32, female = 16) and individuals with AD (n = 32, female = 16) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the Functional Connectivity Toolbox (CONN). Our results demonstrate that males had a significantly stronger interhemispheric functional connectivity between the left and right hippocampus compared to females. These results improve our current understanding of the role of the hippocampus in sex differences in AD. Understanding the contribution of impaired functional connectivity sex differences may aid in the development of sex-specific precision medicine for improved AD treatment.

Targeting acid ceramidase enhances antitumor immune response in colorectal cancer.

INTRODUCTION: Acid ceramidase (hereafter referred as ASAH1) is an enzyme in sphingolipid metabolism that converts pro-survival ceramide into sphingosine. ASAH1 has been shown to be overexpressed in certain cancers. However, the role of ASAH1 in colorectal cancer still remain elusive. OBJECTIVE: The present study is aimed to understand how ASAH1 regulates colorectal cancer (CRC) progression and resistance to checkpoint inhibitor therapy. METHODS: Both pharmacological and genetic silencing of ASAH1 was used in the study. In vitro experiments were done on human and mouse CRC cell lines. The in vivo studies were conducted in NOD-SCID and BALB/c mice models. The combination of ASAH1 inhibitor and checkpoint inhibitor was tested using a syngeneic tumor model of CRC. Transcriptomic and metabolomic analyses were done to understand the effect of ASAH1 silencing. RESULTS: ASAH1 is overexpressed in human CRC cases, and silencing the expression resulted in the induction of immunological cell death (ICD) and mitochondrial stress. The ASAH1 inhibitor (LCL-521), either as monotherapy or in combination with an anti-PD-1 antibody, resulted in reduction of tumors and, through induction of type I and II interferon response, activation of M1 macrophages and T cells, leading to enhanced infiltration of cytotoxic T cells. Our findings supported that the combination of LCL-521 and ICIs, which enhances the antitumor responses, and ASAH1 can be a druggable target in CRC.

Avoidance of medical care among American Indians with a history of cancer during the coronavirus pandemic.

Objectives: Assess the percentage of cancer-related appointment delays, cancelations, and the unavailability of medications experienced by American Indian participants during the COVID-19 pandemic. Methods: This cross-sectional survey study was completed between October 2020 and July 2021 by 360 individuals with cancer who lived in California and Oklahoma. Binary and multivariate logistic regression analysis was completed in SAS 9.4. Results: During the initial Covid-19 pandemic, almost one-third (30%) of respondents delayed cancer-related appointments, 42% canceled cancer-related appointments, and one-quarter (24%) were unable to access prescription medications or over-the-counter medications (27%) due to COVID-19. People who underwent testing for COVID-19 were five times more likely to delay a medical appointment [adjusted odds ratio (aOR) = 5.3, 95% CI:2.4, 11.7] and people who followed three or more social distancing measures were more than six times more likely to cancel medical appointments (aOR:6.3, 95% CI:2.9, 13.9). Conclusion: This study identifies delays, cancelations, and medication inaccessibility people identifying as American Indian faced during the coronavirus pandemic. Disparities in healthcare delivery could contribute to increased morbidity and mortality rates of cancer.

High-definition transcranial direct current stimulation for upper extremity rehabilitation in moderate-to-severe ischemic stroke: a pilot study.

Introduction: Previous studies found that post-stroke motor impairments are associated with damage to the lesioned corticospinal tract (CST) and hyperexcitability of the contralesional cortico-reticulospinal tract (CRST). This proof-of-concept study aims to develop a non-invasive brain stimulation protocol that facilitates the lesioned CST and inhibits the contralesional CRST to improve upper extremity rehabilitation in individuals with moderate-to-severe motor impairments post-stroke. Methods: Fourteen individuals (minimum 3 months post ischemic stroke) consented. Physician decision of the participants baseline assessment qualified eight to continue in a randomized, double-blind cross-over pilot trial (ClinicalTrials.gov Identifier: NCT05174949) with: (1) anodal high-definition transcranial direct stimulation (HD-tDCS) over the ipsilesional primary motor cortex (M1), (2) cathodal HD-tDCS over contralesional dorsal premotor cortex (PMd), (3) sham stimulation, with a two-week washout period in-between. Subject-specific MR images and computer simulation were used to guide HD-tDCS and verified by Transcranial Magnetic Stimulation (TMS) induced Motor Evoked Potential (MEP). The motor behavior outcome was evaluated by an Fugl-Meyer Upper Extremity score (primary outcome measure) and the excitability of the ipslesoinal CST and contralesional CRST was determined by the change of MEP latencies and amplitude (secondary outcome measures). Results: The baseline ipsilesional M1 MEP latency and amplitude were correlated with FM-UE. FM-UE scores were improved post HD-tDCS, in comparison to sham stimulation. Both anodal and cathodal HD-tDCS reduced the latency of the ipsilesional M1 MEP. The contralesional PMd MEP disappeared/delayed after HD-tDCS. Discussion: These results suggest that HD-tDCS could improve the function of the lesioned corticospinal tract and reduce the excitability of the contralesional cortico-reticulospinal tract, thus, improving motor function of the upper extremity in more severely impaired individuals.

Predictors of Cessation in Men Using a Tobacco Quitline: A Follow-Up Study.

INTRODUCTION: Although the effectiveness of tobacco quitline services for people who smoke cigarettes is well established, less is known about other forms of tobacco. This study aimed to compare quit rates and factors contributing to tobacco abstinence in men reporting dual use (smokeless tobacco and one additional combustible tobacco product), smokeless tobacco use only, and cigarette use only. METHODS: Self-reported 30-day point-prevalence tobacco abstinence at the 7-month follow-up was calculated in males who registered with the Oklahoma Tobacco Helpline and completed a 7-month follow-up survey (N=3,721) (July 2015-November 2021). Logistic regression analysis completed in March 2023 identified variables associated with abstinence in each group. RESULTS: Abstinence was reported by 33% in the dual-use group, 46% in the smokeless-tobacco-use-only group, and 32% in the cigarette-use-only group. Eight or more weeks of nicotine replacement therapy provided by the Oklahoma Tobacco Helpline was associated with tobacco abstinence in men who reported dual use (AOR=2.7, 95% CI=1.2, 6.3) and exclusive smoking (AOR=1.6, 95% CI=1.1, 2.3). The use of all nicotine replacement therapy was associated with abstinence in men who used smokeless tobacco (AOR=2.1, 95% CI=1.4, 3.1) and who smoked (AOR=1.9, 95% CI=1.6, 2.3). The number of helpline calls was associated with abstinence in men who used smokeless tobacco (AOR=4.3, 95% CI=2.5, 7.3). CONCLUSIONS: Men in all three tobacco-use groups who fully utilized quitline services showed a greater likelihood of tobacco abstinence. These findings underscore the importance of quitline intervention as an evidence-based strategy for people who use multiple forms of tobacco.

Determinants of healing and readiness for prosthetic fitting after transtibial amputation: Integrative literature review.

BACKGROUND: Healing after an amputation is a critical step in the recovery process. Delayed wound healing can lead to deconditioning and flexion contractures which reduce a patient's ability to use a prosthesis, ambulate independently, and return to community participation. The purpose of this integrative literature review was to determine the evidence-based physiological factors, comorbidities, postoperative management, and outcome measures associated with healing after transtibial amputation and address how these factors clinically guide readiness for prosthetic intervention. METHODS: Authors completed Google Scholar searches to identify the most effective search terms to locate salient publications. Authors also completed literature searches of Ovid MEDLINE and Epub Ahead of Print, In-Process, and Other Nonindexed Citations and Daily <1946 to August 6, 2020>; Embase Classic + Embase <1947 to August 6, 2020>; and CINAHL Complete <1946 to August 6, 2020> databases using the following search terms: "transtibial," "trans-tibial," "below knee," "BKA," "amputation," amputation stump," "amputee," "wound healing," and "heal/s/ed/ing." The authors decided to include all levels of evidence to capture the maximum number of articles related to the determinants of healing and readiness for prosthetic fitting after transtibial amputation. RESULTS: The searches identified 2067 potential articles for review, and after removing articles not relevant to the topic, authors completed full-text assessment on 20 articles. These included review and synthesis on three randomized controlled trials and 12 cohort studies. CONCLUSION: Preamputation assessment is most critical in patients who present with a longer list of comorbidities and suboptimal physiologic factors known to predict wound complications. Clinical judgment is most subjective when determining the degree of healing over time. Readiness for prosthetic treatment need not wait for complete healing of the residuum. Future research is needed to assess transcutaneous oxygen profusion along with other noninvasive measures of blood flow and perfusion as a more objective way to track progression of healing over time. This objective methodology would quantify healing, reduce subjectivity, and promote research to compare different enhanced recovery after surgery protocols for their impact on healing after amputation.

Cortical Reorganization of Early Somatosensory Processing in Hemiparetic Stroke.

The cortical motor system can be reorganized following a stroke, with increased recruitment of the contralesional hemisphere. However, it is unknown whether a similar hemispheric shift occurs in the somatosensory system to adapt to this motor change, and whether this is related to movement impairments. This proof-of-concept study assessed somatosensory evoked potentials (SEPs), P50 and N100, in hemiparetic stroke participants and age-matched controls using high-density electroencephalograph (EEG) recordings during tactile finger stimulation. The laterality index was calculated to determine the hemispheric dominance of the SEP and re-confirmed with source localization. The study found that latencies of P50 and N100 were significantly delayed in stroke brains when stimulating the paretic hand. The amplitude of P50 in the contralateral (to stimulated hand) hemisphere was negatively correlated with the Fügl-Meyer upper extremity motor score in stroke. Bilateral cortical responses were detected in stroke, while only contralateral cortical responses were shown in controls, resulting in a significant difference in the laterality index. These results suggested that somatosensory reorganization after stroke involves increased recruitment of ipsilateral cortical regions, especially for the N100 SEP component. This reorganization delays the latency of somatosensory processing after a stroke. This research provided new insights related to the somatosensory reorganization after stroke, which could enrich future hypothesis-driven therapeutic rehabilitation strategies from a sensory or sensory-motor perspective.

Natural, longitudinal recovery of adults with COVID-19 using standardized rehabilitation measures.

Background: While studies recommend rehabilitation following post-hospitalization recovery from COVID-19, few implement standardized tools to assess continued needs. The aim of this study was to identify post-hospitalization recommendations using an interdisciplinary needs assessment with standardized rehabilitation measures. A secondary aim was to use these tools to measure recovery over a 30-day period. Materials and methods: Using a 30-day longitudinal design, we completed weekly rapid needs assessments in this convenience sample of 20 people diagnosed with COVID-19 discharged from the hospital to home. We computed summary statistics and used the Wilcoxon Signed Rank Test to assess change over the 4-week course of the study with alpha level = 0.05. Results: Our sample (65% male, 47% over 50 years of age, 35% White, 37% with a confirmed diagnosis of diabetes, and 47% obese) included no patients who had required mechanical ventilation. Initial assessments demonstrated the majority of our participants were at an increased risk of falls, had disability in activities of daily living (ADL) and instrumental activities of daily living (IADL), mild cognitive impairment, and dyspnea. At the 30-day follow-up, most were independent in mobility and basic ADLs, with continued disability in IADLs and cognitive function. Discussion: In this sample of patients who were not mechanically-ventilated, early and individualized rehabilitation was necessary. The results of this study suggest patients would benefit from a multi-disciplinary team needs assessment after medical stabilization to minimize fall risk and disability, and to prevent secondary complications resulting from post-hospital deconditioning due to COVID-19.

User Participatory Design of a Wearable Focal Vibration Device for Home-Based Stroke Rehabilitation.

Stroke often leads to the significant impairment of upper limb function and is associated with a decreased quality of life. Despite study results from several interventions for muscle activation and motor coordination, wide-scale adoption remains largely elusive due to under-doses and low user compliance and participation. Recent studies have shown that focal vibration has a greater potential to increase and coordinate muscle recruitment and build muscle strength and endurance. This form of treatment could widely benefit stroke survivors and therapists. Thus, this study aimed to design and develop a novel wearable focal vibration device for upper limb rehabilitation in stroke survivors. A user participatory design approach was used for the design and development. Five stroke survivors, three physical therapists, and two occupational therapists were recruited and participated. This pilot study may help to develop a novel sustainable wearable system providing vibration-based muscle activation for upper limb function rehabilitation. It may allow users to apply the prescribed vibratory stimuli in-home and/or in community settings. It may also allow therapists to monitor treatment usage and user performance and adjust the treatment doses based on progression.

The Impact of Cognition on Motor Learning and Skill Acquisition Using a Robot Intervention in Infants With Cerebral Palsy.

Background: Cerebral Palsy (CP) is a neurodevelopmental disorder that encompasses multiple neurological disorders that appear in infancy or early childhood and persist through the lifespan of the individual. Early interventions for infants with CP utilizing assisted-motion robotic devices have shown promising effects in rehabilitation of the motor function skills. The impact of cognitive function during motor learning and skill acquisition in infants using robotic technologies is unclear. Purpose: To assess the impact of cognitive function of infants with and without CP on their motor learning using the Self-Initiated Prone Progression Crawler (SIPPC) robot. Methods: Statistical analysis was conducted on the data obtained from a randomized control trial in which the movement learning strategies in infants with or at risk for CP was assessed during a 16-week SIPPC robot intervention. Cognitive function was measured by the Bayley scales of Infant and Toddler Development-Third edition (Bayley-III) and motor function was measured by the Movement Observation Coding Scheme (MOCS). The infants were categorized into three distinct groups based on their cognitive scores at baseline: "above average" (n1 = 11), "below average" (n2 = 10), and "average" (n3 = 26). Tri-weekly averages of the MOCS scores (observations at five time points) were used for the analyses. This study involved computing descriptive statistics, data visualization, repeated measures analysis of variances (rmANOVA), and survival analyses. Results: The descriptive statistics were calculated for the MOCS and Bayley III scores. The repeated measures ANOVAs revealed that there was a statistically significant effect of time (p < 0.0001) on scores of all subscales of the MOCS. A statistically significant effect of interaction between group and time (p < 0.05) was found in MOCS scores of subscales 1 and 2. The survival analyses indicated that infants in different cognition groups significantly differed (p < 0.0001) in their ability to achieve the crawling milestone within the 16-week intervention period. Conclusion: The findings in this study reveal the key movement strategies required to move the SIPPC robot, assessed by the MOCS, vary depending on the infants' cognition. The SIPPC robot is well-matched to cognitive ability of infants with CP. However, lower cognitive ability was related to delayed improvement in their motor skills.

Multi-Phase Locking Value: A Generalized Method for Determining Instantaneous Multi-Frequency Phase Coupling.

BACKGROUND: Many physical, biological and neural systems behave as coupled oscillators, with characteristic phase coupling across different frequencies. Methods such as n : m phase locking value (where two coupling frequencies are linked as: mf 1 = nf 2) and bi-phase locking value have previously been proposed to quantify phase coupling between two resonant frequencies (e.g. f, 2f/3) and across three frequencies (e.g. f 1, f 2, f 1 + f 2), respectively. However, the existing phase coupling metrics have their limitations and limited applications. They cannot be used to detect or quantify phase coupling across multiple frequencies (e.g. f 1, f 2, f 3, f 4, f 1 + f 2 + f 3 - f 4), or coupling that involves non-integer multiples of the frequencies (e.g. f 1, f 2, 2f 1/3 + f 2/3). NEW METHODS: To address the gap, this paper proposes a generalized approach, named multi-phase locking value (M-PLV), for the quantification of various types of instantaneous multi-frequency phase coupling. Different from most instantaneous phase coupling metrics that measure the simultaneous phase coupling, the proposed M-PLV method also allows the detection of delayed phase coupling and the associated time lag between coupled oscillators. RESULTS: The M-PLV has been tested on cases where synthetic coupled signals are generated using white Gaussian signals, and a system comprised of multiple coupled Rössler oscillators, as well as a human subject dataset. Results indicate that the M-PLV can provide a reliable estimation of the time window and frequency combination where the phase coupling is significant, as well as a precise determination of time lag in the case of delayed coupling. This method has the potential to become a powerful new tool for exploring phase coupling in complex nonlinear dynamic systems.

Functional intermuscular reduction in spasticity for people with multiple sclerosis.

BACKGROUND: Eighty-five percent of people with multiple sclerosis (MS) incur gait impairments debilitating enough to significantly impact their function. OBJECTIVES: The aim of this study was to determine if a novel combination of intermuscular electrical stimulation, followed by functional electrical stimulation combined with supported bodyweight treadmill training, would improve gait, decrease spasticity and fatigue, and improve muscle strength. METHODS: Using a pre-post experimental design, we implemented this combination six-week protocol in 16 individuals with MS. We completed summary statistics and longitudinal pre-post results using Wilcoxon sign rank tests with Bonferroni adjustment. RESULTS: Participants responded with median increases of 29.4 feet (p < 0.0001) during the Six Minute Walk Test, median decreases of 0.7 s (p = 0.0011) in the 25-Foot Walk Test, median increases of 3.8 toe taps to fatigue (p = 0.0306) and median increases of 5.0 heel raises (p = 0.0093). Significant changes were noted in the Modified Ashworth Scale, both after intermuscular electrical stimulation (median change = -0.5 p = 0.0039) and after treadmill walking (median change = -0.5, p < 0.0005). CONCLUSIONS: Results of this novel protocol suggest this intervention combination has the potential to decrease spasticity, and improve gait speed and endurance in individuals with MS. Observed changes in mobility occurred without accompanying increases in fatigue.

Smokeless Tobacco Point of Sale Advertising, Placement and Promotion: Associations With Store and Neighborhood Characteristics.

Introduction: Objectives of this study were to determine retail and neighborhood characteristics associated with smokeless tobacco (ST) product promotion, price promotion, and storefront advertising among retailers in Oklahoma. Methods: In this statewide point-of-sale study, we collected data from 1,354 ST retailers. Using store characteristics and census tract information, we estimated summary statistics and adjusted prevalence ratios during 2019-2020. Results: Of ST retailers audited, 11.0% demonstrated ST youth promotion, 43.0% ST price promotions, and 19.6% ST storefront advertising. The adjusted prevalence ratio (aPR) for convenience stores was higher for all three ST strategies: youth promotion (aPR = 3.4, 95% CI 1.9, 6.2), price promotion (aPR = 3.8, 95% CI 2.9, 5.0), and storefront advertising (aPR=16.4, 95% CI 6.7, 40.3) compared to other store types. Metropolitan tobacco retailers had higher aPRs for youth promotion (aPR = 1.7, 95% CI 1.12 2.6) and storefront advertising (aPR = 1.5, 95% CI 1.2, 1.9). Conclusions: Findings of this study suggest there are currently ample opportunities for youth and adults at risk for tobacco initiation to be exposed to ST products in the retail environment. Convenience stores, more likely to be found and utilized in rural areas compared to metropolitan areas, are disproportionately more likely to engage in marketing strategies that could lure youth into trying smokeless tobacco.