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Correlation analysis among metabolome, microbiome, and phenotypes | anxiety | Then, Spearman correlations were carried out to investigate association among the gut microbiota genera (top 6), 13 differential metabolites, and anxiety symptom (Spearman correlation analysis among anxiety-behavior, gut microbiota, and fecal metabolites. Spearman’s rank correlation coefficient among anxiety symptom scores, 13 metabolites in | PMC10077425 |
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Discussion | anxiety, insomnia, depression, anxiety-related mental disorders, cancers, gastrointestinal disorders | COMPLICATIONS | The academic examination is the primary source of brief naturalistic stress for college students, which has been used frequently as a stress model to investigate the psychological stress responses together with gut microbiota changes and to evaluate the influences of probiotics or prebiotics on stress-induced complications (The anxiety, depression, and insomnia levels were measured by the most commonly used mental health questionnaires, such as HAMA-14, HDRS-17, and AIS-8 (Considering evidence suggested that probiotic interventions could balance microbial populations thereby create healthy intestinal homeostasis to support the life system. There is an assumption that a higher gut microbiota diversity generally means a better gut environment, which has been proved by several conditions (e.g., cancers, gastrointestinal disorders, and stress-related conditions) accompanied by a reduced gut microbial diversity (Our results showed that the content of Furthermore, gut microbial metabolic actions or gut microorganism-originated metabolites are the major pathways promoting the communication between gut and brain Among them, 13 variables formed a subset related to probiotic JYLP-326 treatment (Although the potential role of JYLP-326 in remodeling the disturbed gut microbiota has been illustrated in this study, it’s still unclear whether this efficacy was caused by probiotic administration or individual differences among subjects. It would be better to take into account the impact of gut microbiome heterogeneity on the results of gut microbiota and its metabolism by collecting fecal samples before the treatments as additional control groups for further comparative analysis. Moreover, the underlying mechanisms of JYLP-326 in relieving the test anxiety-related mental disorders also should be explored deeply by using anxious/depression animal models and advanced molecular techniques, particularly in how to link the microbiota-gut-brain axis with the biological functions of probiotic JYLP-326 in the future, a critical issue on the applying of probiotics in the clinic. | PMC10077425 |
Conclusions | dysbiosis of the gut microbiota, insomnia, anxiety/depression, anxiety | DISORDERS | In Conclusion, the present study observed that the probiotic JYLP-326 administration could significantly alleviate the anxiety/depression and insomnia symptoms in test anxious college students. The structure and composition of the gut microbiota were altered by the pressure to pass a vital examination with fierce involution, as well as the same to the changes in fecal metabolites. Specifically, JYLP-326 treatment protected against this exam stress-induced dysbiosis of the gut microbiota and the disturbances of fecal metabolomic. Furthermore, the changed gut microbiota genera and fecal metabolites were closely associated with stress-related symptoms like anxiety/depression and insomnia, indicating they might be regarded as biomarkers for diagnosing and treating stress and anxiety disorders. | PMC10077425 |
Data availability statement | The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: PRJNA883039 (SRA) and ST002475 ( | PMC10077425 |
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Ethics statement | The study was approved by the Institutional Review Board (or Ethics Committee) on medical research of the Second Affiliated Hospital of Nanchang University (Examination and approval No. is Review [2020] No. (038)). The patients/participants provided their written informed consent to participate in this study. | PMC10077425 |
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Author contributions | HL | Conceptualization, TC. Methodology, RZ and SL. Software, RZ. Validation, TC and SL. Formal analysis, SL. Investigation, YF, HL, SZ, RF and YL. Resources, JW. Data curation, RZ. Writing—original draft preparation, SL and RZ. Writing—review and editing, SL, TC, SZ and LWW. Visualization, RZ and SL. Supervision, TC and JW. Project administration, TC. Funding acquisition, TC, SL and LFW. All authors contributed to the article and approved the submitted version. | PMC10077425 |
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Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10077425 |
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Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10077425 |
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Supplementary material | The Supplementary Material for this article can be found online at: Click here for additional data file.Click here for additional data file.Click here for additional data file. | PMC10077425 |
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References | PMC10077425 |
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Rationale | anxiety | DISORDERS | The administration of glucocorticoids (GC) as an adjunct to exposure represents a promising strategy to improve one-session exposure outcome in anxiety disorders. It remains to be determined whether similar effects can be induced with the use of acute stress. Furthermore, the possible modulation of exposure effects by hormonal factors (e.g., use of oral contraceptives (OCs)) was not explored so far. | PMC10102109 |
Objectives | We investigated whether acute stress prior to one-session exposure for spider fear affects its efficacy in women using oral contraceptives ( | PMC10102109 |
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Methods | Women with fears of spiders and cockroaches were randomly assigned to a | PMC10102109 |
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Results | Acute stress did not influence exposure-induced reduction in fear and avoidance of the treated stimuli (spiders). Similarly, stress had no effect on the generalization of exposure-therapy effects towards untreated stimuli (cockroaches). Exposure-induced reduction in subjective fear and self-report measures for treated stimuli was less evident in women using OC specifically after pre-exposure stress. Women using OC had higher levels of subjective fear and scored higher in self-report measures at post-treatment (24 h after exposure) and follow-up (4 weeks after exposure). | PMC10102109 |
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Conclusions | OC intake may represent an important confounding factor in augmentation studies using stress or GC.
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Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10102109 |
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Introduction | Specific fears are highly prevalent in the general population (cf. Wardenaar et al. Exposure therapy is an effective therapeutic intervention to reduce fear and avoidance in patients with specific fears (Hoffman and Smits Behavioral interventions and pharmacological manipulations have been proposed to promote extinction learning and exposure therapy outcome (Craske et al. Stress might equally promote exposure therapy outcome (Meir Drexler et al. Pre-extinction stress can promote subsequent fear extinction learning and extinction retrieval (Meir Drexler et al. In the present study, we recruited women with multiple fears (spiders and cockroaches) and asked whether pre-exposure stress induction via socially evaluated cold-pressor test (SECPT; Schwabe et al. | PMC10102109 |
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Methods | PMC10102109 |
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Participants | DISORDER, ENDOCRINE DISORDERS | The study was preregistered on ClinicalTrials.gov (Identifier: NCT03505437). Female participants with a fear of spiders and cockroaches were recruited via various advertisements (e.g., social media groups and online bulletin boards). Participants with a history of a mental disorder, other than a specific fear for spiders and cockroaches, were not invited to the study. Other exclusion criteria involved the presence of neurological and/or endocrine disorders, pregnancy, current pharmacological treatment, and current smoking (> than five cigarettes per month). Finally, participants with a body mass index (BMI) greater than 27 or smaller than 19 kg/mA total of 104 individuals took part in a pre-experimental telephone screening to check for inclusion/exclusion criteria. Participants were not required to fulfill the diagnosis of a specific phobia although they had to present a substantial degree of fear towards spiders and/or cockroaches. The latter was ascertained on the basis of specific self-report measures, i.e. the Fear of spiders questionnaire (FSQ; Rinck et al. The final sample, therefore, included 48 women who were assigned to either the stress or the No-Stress group. In particular, 15 All experimental procedures were approved by the ethics committee of the Faculty of Psychology of the Ruhr University Bochum and carried out in accordance with the Declaration of Helsinki. All participants provided written informed consent and received a compensation of 60€ for the completion of the study. | PMC10102109 |
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Measures | PMC10102109 |
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Anxiety and depression questionnaires | depression, anxiety | Possible differences in anxiety and depression levels between the stress and No-Stress group were assessed with the Beck depression inventory-II (BDI-II; Hautzinger et al. | PMC10102109 |
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Spider and cockroach fear-related questionnaires | Different aspects related to the fear of spiders and cockroaches were assessed by using a battery of questionnaires. We used (1) the German version of the FSQ (Rinck et al. | PMC10102109 |
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Behavioral approach test (BAT) | COLD | Both fear and avoidance of spiders and cockroaches were assessed with separate and independent BATs at the beginning of the first experimental session (“Pre”), at the post-stress-treatment and guided spider exposure efficacy evaluation stage (“Post”), as well as during the long term fear reduction stability assessment and generalization stage (“Follow-up”; Fig. Outline of the experimental design and main outcome measures. At the beginning of the experiment the participants underwent two BATs (spider and cockroach), and thereafter, presented with spider and cockroach-related questionnaires (Pre-SECPT treatment stage). Thereafter, the participants underwent the SECPT either under the stress condition with hands submerged in cold water or under the no-stress condition with hands submerged in warm water. Twenty-five minutes after the SECPT, all participants received a short psychoeducation and in-vivo guided spider exposure. After a delay of 24 h, the spider BAT was repeated and both the spider and the cockroach fear-related questionnaires were presented (Post-treatment phase). Long-term effects of exposure were evaluated four weeks later (Follow-up phase). At follow-up, both spider and cockroach BATs were repeated and spider and the cockroach fear-related questionnaires were presented. Abbreviations: BAT: Behavioral avoidance test, SECPT: Socially evaluated cold-pressor testBoth the spider and cockroach BATs were scaled in approach distance which comprised fifteen different steps according to a modified and expanded version of the BAT introduced by Lass-Hennemann and Michael ( | PMC10102109 |
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Subjective units of distress scale (SUDS) | Raeder | The participant’s subjective fear at the initial and final approach distance during the BAT was recorded (Raeder et al. | PMC10102109 |
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Socially evaluated cold-pressor test (SECPT) | Participants were exposed to either the stress or the control condition of the SECPT (adapted from Schwabe et al. | PMC10102109 |
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One-session exposure treatment | fourteen-step | The exposure session consisted of the first eight steps of a standardized fourteen-step fear hierarchy progression procedure (steps increased in difficulty; see Mystkowski et al. | PMC10102109 |
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Experimental design and procedure | The study comprised three experimental phases which were conducted on three separate days (see Fig. | PMC10102109 |
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Statistical analyses | Statistical analyses were performed with SPSS Statistics for Macintosh, Version 27.0 (Armonk, NY: IBM Corp.). Pre-exposure participant characteristics and stress ratings were compared using a series of two-way ANOVAs with the between-subjects factors “ | PMC10102109 |
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Results | PMC10102109 |
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Stress-response manipulation check | PMC10102109 |
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Stress-effects on salivary cortisol concentrations | Two participants were excluded from data analysis, because of undetectable cortisol concentrations, resulting in a sample size of 23 participants in both the Stress and No-Stress groups. The trajectory of salivary cortisol concentrations across the measures 1–7 on experimental Day 1, measures 8–9 on experimental Day 2, and measures 10–11 on Day 3 is illustrated in Fig. Monitoring of salivary cortisol concentrations of the Stress and No-Stress groups. Each data point represents mean and SEM salivary cortisol concentrations that have been measured during 7 sampling points on experimental day 1, two sampling points on day 2 and another two sampling points on experimental day 3 (see Table | PMC10102109 |
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Stress effects on systolic and diastolic blood pressure | Assessments of systolic and diastolic blood pressure (cf. Table Post-hoc analyses indicated that Stress and No-Stress groups showed similar systolic and diastolic blood pressure during the baseline measurement prior to stress induction (Systolic blood pressure: T[46] = -0.547; P = 0.587, Diastolic blood pressure: T[45] = -0.941; P = 0.352). As expected the Stress group had significantly higher systolic and diastolic blood pressure during the stress induction as compared to the No-Stress group (Systolic blood pressure: T[46] = -5.124; P < 0.001, Diastolic blood pressure: T[45] = -4.802; P < 0.001). The Stress group showed a significantly higher systolic, but not diastolic, blood pressure after the SECPT as compared to the No-Stress group (Systolic blood pressure: T[46] = -2.077; P = 0.043, Diastolic blood pressure: T[45] = -1.308; P = 0.197), suggesting that there was a small after-effect of stress induction, that, however, as indicated by the diastolic blood pressure measure, was likely in a process of rapid decline. In line with the significant effects of the stress-treatment on physiological parameters, the Stress group also experienced the SECPT as being more difficult (Main effect of | PMC10102109 |
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Effects of stress and OC on spider exposure efficacy: Spider BAT Behavioral approach/avoidance | The participants’ approach behavior towards spiders increased across the 3 BAT trials (Main effect of | PMC10102109 |
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Subjective fear ratings (SUDS) | The analysis of the initial approach distance measure of the BAT suggested that the participants experienced a reduction in their subjective fear levels across the 3 trials (Main effect of Post-hoc analyses of the Stress group indicated that Subjective fear at the initial approach distance. A-B. Subjective fear ratings (SUDS) during the spider-BAT during pre-exposure, post-exposure, and follow-up measurements of the Stress and No-Stress groups. The subjective fear levels at the final approach distance during the pre- and follow-up BATs suggested that the participants showed a significant reduction of their subjective fear assessments (Main effect of | PMC10102109 |
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Spider fear-related questionnaires | PMC10102109 |
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Fear of spider questionnaire (FSQ) | Spider phobia | ORAL CONTRACEPTIVES | Across the 3 measurements (Spider and cockroach-related questionnaires. Pre-, post-exposure and follow-up assessment of spider- and cockroach-related questionnaires of the Stress and No-Stress groups. A.-F. Bars represent mean and SEM of the fear of spiders, spider beliefs and spider phobia scores, respectively. G.-J. Bars represent mean and SEM of the fear of cockroach, and cockroach beliefs scores, respectively. Abbreviations: FC: Free-cycling, OC: Oral contraceptive, FSQ: Fear of spiders questionnaire, SBQ: Spider beliefs questionnaire, SPQ: Spider phobia questionnaire, FCQ: Fear of cockroaches questionnaire, CBQ: Cockroach beliefs questionnaire. *: p < 0.05; T-test for independent samples | PMC10102109 |
Spider beliefs questionnaire (SBQ) | Participants showed a significant decrease in their spider belief scores across the Pre, Post and Follow-up measurements (Main effect of | PMC10102109 |
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Spider phobia questionnaire (SPQ) | Similar to the fear of spider and spider beliefs results presented above, participants showed a significant decrease in their spider phobia scores across the In sum, these results suggest | PMC10102109 |
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Effects of OC and Stress on the generalization of guided spider exposure effects to other fear stimuli: Cockroach BAT | PMC10102109 |
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Behavioral approach/avoidance | The participants’ approach behavior towards cockroaches increased from the pre-exposure measurement to the follow-up BAT measurement (Main effect of Approach behavior towards cockroaches was not affected by the factor | PMC10102109 |
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Subjective fear ratings (SUDS) | The subjective fear levels at the initial approach distance during the pre- and follow-up BATs suggested that participants experienced a significant reduction in their subjective fear levels (Main effect of The subjective fear levels at the final approach distance measured during the | PMC10102109 |
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Cockroach fear-related Questionnaires | PMC10102109 |
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Fear of cockroach questionnaire (FCQ) | Participants showed a significant decrease in their fear of cockroach scores across the 3 assessments ( | PMC10102109 |
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Cockroach beliefs questionnaire (CBQ) | Similar to the fear of cockroach scores, participants showed a significant decrease in their cockroach belief scores across the | PMC10102109 |
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Discussion | Raeder, reduction of fear and avoidance, De Quervain | We have investigated the effects of acute stress on one-session exposure outcome and generalization in women with fear of spiders and cockroaches. Acute stress, administered prior to exposure, had no overall effect on exposure-induced reduction in fear and avoidance for the treated stimuli (spiders). Likewise, participants’ approach behavior towards untreated stimuli (cockroaches) increased from the pre-stress and pre-exposure measurement to the follow-up measurement, but no effect of stress induction was found. Similar findings have been obtained for subjective and self-report measures. This pattern of results suggests no effect of stress on exposure efficacy and generalization in women. However, the exposure-induced reduction in subjective fear and self-report measures for treated stimuli was reduced in women using OC specifically after pre-exposure stress induction. These results underline the importance of sex hormones as potential modulators of the efficacy and outcome of an one-session exposure treatment.Our finding differs from previous exposure therapy augmentation studies showing that GC administration (that is associated with high cortisol levels) prior to exposure therapy leads to stronger symptom reduction as compared to a placebo condition (De Quervain et al. In contrast to these studies, the present results suggest that acute stress (and the accompanying physiological cortisol increase) does not promote exposure-induced reduction of fear and avoidance towards treated stimuli in women. More specifically, in The absence of beneficial effects of pre-exposure stress on exposure efficacy and generalization was not due to a failure to induce stress. A multi-factorial manipulation check demonstrated that the Stress groups showed increased blood pressure, salivary cortisol concentrations and stress ratings after stress induction as compared to a baseline measurement immediately before stress induction. More specifically, Another aim of this study was to investigate possible effects of stress on generalization of exposure therapy effects towards untreated stimuli (Preusser et al. Therapy generalization effects might be related to a generalized mastery experience or an increase in self-efficacy beliefs after exposure to the treated stimuli (Raeder et al. Nevertheless, stress did not influence the generalization of exposure-induced benefit across different fear stimuli. Basic research on the effects of stress on stimulus-based fear extinction is very limited (but see Hagedorn et al. Potential limitations of our study might be related to the relatively small sample size or individual differences in the amount of cortisol released following a lab stressor (van Eck et al. | PMC10102109 |
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Acknowledgements | The study was supported by grants from the Deutsche Forschungsgemeinschaft (German Research Foundation; SFB 874, project A1 to M.T.; SFB 1280 Extinction Learning project SFB1280 – project number 316803389, Project A13 awarded to A.Z. and J.M., project A09 to C.J.M. and O.T.W.; Heisenberg Grant ZL 59 4–1 and ZL 59 5–1 awarded to A.Z.). The funders had no role in study design, data collection and analysis, preparation of the manuscript and decision to publish. | PMC10102109 |
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Funding | Open Access funding enabled and organized by Projekt DEAL. | PMC10102109 |
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Data Availability | All data obtained during the current study are available from the corresponding author on reasonable request. | PMC10102109 |
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Declarations | PMC10102109 |
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Competing interest | None. | PMC10102109 |
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References | PMC10102109 |
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Aims | stroke | STROKE | To explore associations between visuospatial and executive function and 1) activity performance (mobility, self-care and domestic life) and 2) outcome after 6 weeks of conventional gait training and/or robotic gait training, long term (1–10 years) after stroke. | PMC9997896 |
Methods | stroke, Stroke | STROKE, STROKE | Participants (n = 45), living with stroke affecting walking ability and who could perform the items assessing visuospatial/executive function included in the Montreal Cognitive Assessment (MoCA Vis/Ex) were included as part of a randomized controlled trial. Executive function was evaluated using ratings by significant others according to the Dysexecutive Questionnaire (DEX); activity performance using 6-minute walk test (6MWT), 10-meter walk test (10MWT), Berg balance scale, Functional Ambulation Categories, Barthel Index and Stroke Impact Scale. | PMC9997896 |
Results | stroke | STROKE | MoCA Vis/Ex was significantly associated with baseline activity performance, long-term after stroke ( | PMC9997896 |
Conclusion | impaired mobility long-term after stroke | Visuospatial/executive function may significantly affect activity performance and the outcome of rehabilitation interventions for impaired mobility long-term after stroke and should be considered in the planning of such interventions. Patients with severely impaired visuospatial/executive function may benefit from robotic gait training since improvement was seen irrespective of visuospatial/executive function. These results may guide future larger studies on interventions targeting long-term walking ability and activity performance. | PMC9997896 |
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Trial registration | clinicaltrials.gov ( | PMC9997896 |
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Data Availability | All relevant data are within the paper and its | PMC9997896 |
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Introduction | death, Stroke, stroke, cognitive impairments, Cognitive impairments, hemiplegia | STROKE, STROKE | Stroke is one of the five most common causes of death and functional impairment in the world [Cognitive impairments are commonly reported after stroke [A number of studies have reported associations between cognition and activity performance after stroke, as well as cognition in the acute stage being an important predictor of both cognitive impairments and activity performance long term [To significantly improve gait function, short- and long-term after stroke, evidence indicate that effective gait training should be task-oriented and intensive [Moreover, to our knowledge, no studies have evaluated the impact of visuospatial and executive function on the effect of specific gait interventions. Thus, the aims of this study were achieved by exploring the potential associations between visuospatial and executive function, and 1) aspects of activity performance (mobility, self-care and domestic life), as well as 2) effects on mobility outcome after robotic and/or conventional gait training, in persons living with hemiplegia affecting walking ability long-term after stroke, followed up after the intervention (6 weeks) and at 6 months. | PMC9997896 |
Method | PMC9997896 |
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Design and implementation | knee joints | CONTRACTIONS | This study is based on analyses as part of a randomized controlled trial (RCT) [The RCT was single blinded, with an assessor blinded to group allocation. Randomization was performed according to block randomization (prepared by a statistician not otherwise involved in the study, using the SAS system, including the variables: blocks of three, treatment and patient). A nurse not otherwise involved in the study randomized the participants after the baseline testing, by pulling the participant’s ID-number one by one from a prepared envelope and placing them in the order of the block starting at the top of each block. The result of the randomization was photographed and saved in the study file. Participants were randomized into three groups 1) One intervention group received gait training with the exoskeleton Hybrid Assistive Limb (HAL) as well as conventional gait and mobility training (HAL-group), 2) A second intervention group received conventional gait and mobility training (Conventional group), and 3) a control group, continued with their usual activities (Control group). The two intervention groups were dose-matched to out rule any variations in intensity and scheduled three times a week for six weeks, (18 sessions). In the HAL-group each session was scheduled for a maximum of 60 minutes of gait training with HAL, plus a maximum of 30 minutes of conventional gait and mobility training to enhance generalizability of the acquired skills to everyday life activities. The HAL was used on a treadmill with a safety harness including body weight support (pre-set to 9 kg) to unburden the weight of the HAL-suit. HAL can be individually set to support movements of the hip and knee joints and includes a hybrid system with a voluntary mode where the level of assistance is individually adjusted and triggered by muscle contractions detected by surface- electromyography (EMG) [ | PMC9997896 |
Participants | stroke, hemorrhagic stroke, hemiparesis | STROKE, HEMORRHAGIC STROKE | Eligible participants for the RCT were aged 18–70 years, had suffered a first ever ischemic or hemorrhagic stroke 1–10 years earlier and were living with stroke related hemiparesis in the lower extremity, affecting walking ability. Participants were recruited from rehabilitation units, in collaboration with physiotherapists in outpatient care in the Stockholm region. Written and oral information was provided to the eligible participants before a written consent was given. Inclusion and exclusion criteria are further described in the published RCT [ | PMC9997896 |
Data collection | Data for the RCT was collected between October 2015 and March 2020 [ | PMC9997896 |
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Assessment methods | PMC9997896 |
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Measures of visuospatial and executive function | Dysexecutive Syndrome | For clinical assessment of visuospatial and executive function, the MoCA Vis/Ex was used [To assess rated executive function, the Dysexecutive Questionnaire (DEX), included in the Behavioral Assessment of Dysexecutive Syndrome (BADS) test battery, was used [ | PMC9997896 |
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Measures of mobility | stroke | STROKE | To assess mobility, the following clinical tests were used: 6MWT, the primary outcome, to evaluate walking distance during a 6 minute walk [Minimally Clinical Important Difference (MCID) in a stroke population: 34.4 meters] [ | PMC9997896 |
Measures of self-care and domestic life | Self-perceived performance of activities in daily life was evaluated using subscale 5, included in the SIS, hereby called SIS-ADL [total score ranging from 0 (maximal limitation)– 100 (no limitation)] [ | PMC9997896 |
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Statistics | stroke | REGRESSION, STROKE | The power of the RCT was calculated using F-test for One-Way ANOVA, with the 6MWT as a primary outcome, based on results from a previous study on perceived and measured change in walking distance in the long-term phase after stroke [Analyses of the collected data were carried out using the SPSS Analytics version 22 [To further interpret the statistically significant associations, linear regression analyses were carried out to calculate the coefficient of determination ( | PMC9997896 |
Results | PMC9997896 |
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Participants | A total of 45 participants were included in this study and a flow chart of the inclusion is presented in | PMC9997896 |
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Flow chart of included participants. | M1 = Baseline assessment, M2 = 6-week assessment, M3 = 6-month assessment.Descriptive data of the participants are presented in | PMC9997896 |
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Baseline characteristics. | aphasia, Stroke | STROKE | Values shown in median (m) and Interquartile range (IQR), or frequency (n) and percent (%). NIHSS = National Institute of Health Stroke Scale, MoCA = Montreal Cognitive Assessment, Fugl-Meyer LE = Fugl-Meyer Lower Extremity. FAC = Functional Ambulation Classification, SIS-Mob = Stroke Impairment Scale domain 6 mobility, SIS-ADL = Stroke Impairment Scale domain 5 activities of daily living. Data missing due to aphasia (≥1 item missing):* n = 38,^ n = 13,¨ n = 14, ¤ n = 11. | PMC9997896 |
Associations between baseline visuospatial and executive function and activity performance | In the analysis of the assessed baseline variables, as presented in | PMC9997896 |
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Correlation matrix including baseline visuospatial and executive function and baseline measures of assessed and self-perceived activity performance. | Stroke | REGRESSION, STROKE | MoCA Vis/Ex = Montreal Cognitive Assessment Visuospatial/Executive domain, DEX-SO = Dysexecutive Questionnaire rated by significant other, FAC = Functional Ambulation Classification, SIS-Mob = Stroke Impairment Scale domain 6 mobility, SIS-ADL = Stroke Impairment Scale domain 5 activities of daily living.* = Significance at adjusted alpha-level Results from the multivariable linear regression analyses are presented in | PMC9997896 |
Results of the multivariable linear regression analyses, presented as coefficient of determination ( | Stroke | REGRESSION, STROKE | Note: Presented are values for MoCA Vis/Ex, when adjusted for significant covariates, along with significant models.SIS-Mob = Stroke Impairment Scale domain 6 mobility, SIS-ADL = Stroke Impairment Scale domain 5 activities of daily living. MoCA Vis/Ex = MoCA Visuospatial/executive domain, NIHSS = National Institute of Health Stroke Scale. N/A: Nonsignificant in the multivariable linear regression analysis. | PMC9997896 |
Association between visuospatial and executive function and mobility outcome after intervention | Descriptive data on mobility outcome at 6 weeks and 6 months, can be seen in | PMC9997896 |
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Scatterplots of the association between MoCA Vis/Ex and the effect on mobility outcome at 6 weeks (ΔM2-M1) and 6 months (ΔM3-M1), for the intervention groups together. | Red line = 0. Green line = Minimally Clinical Important Difference (MCID). 6MWT = 6-minute walk test, 10MWT = 10-meter walk test, BBS = Berg Balance Scale. Adjusted alpha-level = | PMC9997896 |
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The effect on mobility outcome at 6 weeks (ΔM2-M1) and 6 months (ΔM3-M1). | Note: Values are displayed as median and interquartile range (IQR).M1 = Baseline assessment, M2 = 6-week assessment, M3 = 6 months assessment, 6MWT = 6-minute walk test, 10MWT = 10-meter walk test, FAC = Functional Ambulation Classification, BBS = Berg balance scale.Number due to dropout:* n = 14,^ n = 15,¨n = 12As illustrated in the scatterplots in Further, when observing the association between the DEX-SO and effects on mobility outcome at 6 weeks and 6 months, only the 10MWT at 6 weeks presented a significant correlation ( | PMC9997896 |
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Associations ( | M1 = Baseline assessment, M2 = 6-week assessment, M3 = 6 months assessment, 6MWT = 6-minute walk test, 10MWT = 10-meter walk test, FAC = Functional Ambulation Classification, BBS = Berg balance scale.* = Significance at adjusted alpha-level N/A = Outcome measures not included in the groupwise analysis. | PMC9997896 |
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Associations between visuospatial and executive functions and achieved walking distance after robotic or conventional gait training | The association between MoCA Vis/Ex and the effect on 6MWT at 6 weeks and 6 months according to group allocation, are presented in | PMC9997896 |
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Scatterplots of the association between Montreal Cognitive Assessment visuospatial/executive domain (MoCA Vis/Ex) and effect on 6-minute walk test (6MWT) at 6 weeks and 6 months, for all groups separately. | REGRESSION | Correlations by Spearman’s rho = In the linear regression analyses exploring the association between the MoCA Vis/Ex score when dichotomized (1-2/3-5 points) and the effect on 6MWT at 6 weeks and 6 months, no significant associations were found in the HAL group at 6 weeks ( | PMC9997896 |
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Discussion | stroke, cognitive impairments, visuospatial/executive impairments, visuospatial and executive impairments, Cognitive impairments | STROKE, RECRUITMENT | The current study indicates that associations between visuospatial and executive function and activity performance, previously demonstrated in the early stage after stroke, remain long-term. Notably, visuospatial/executive function was associated with the effect of conventional gait training both at 6 weeks and 6 months, where a higher level of visuospatial/executive function indicated a larger improvement. In the HAL-group no such association was found, indicating improvements all over the spectrum of assessed visuospatial/executive function. Executive function rated by significant others did not present any notable associations.Cognitive impairments in general have been associated with activity performance in several studies in the acute and subacute stages [Visuospatial and executive function have been positively associated with long-term improvement in balance, up to one year after stroke [In the analysis of the association between visuospatial/executive function and the effect of the gait interventions, a larger impact on walking distance and -speed was seen at 6 months, compared to 6 weeks. These results indicate that generalization of training results to everyday activities can be negatively affected by visuospatial and executive impairments impacting on problem-solving, interpretation of the body and environment, processing of feedback, self-regulation and initiative [When comparing the groups separately, the HAL-group gained improvements in walking distance at 6 months all over the spectrum of assessed visuospatial/executive function. In contrast, the conventional group showed that visuospatial/executive function was associated with the outcome of the gait intervention, where those with a lower score generally acquired small or no improvements at 6 weeks and 6 months. Based on these results, it is plausible that HAL-training may be more suitable than conventional gait training for participants with more severe visuospatial/executive impairments. On the other hand, for those with more preserved visuospatial/executive function, conventional gait training seems to have more beneficial effects in terms of MCID, indicating cognitive capacity enabling engagement in rehabilitation interventions and generalization to everyday activities, promoting long-term sustainability of achieved improvements.Considering the association between level of visuospatial/executive impairments and limitations in walking, as shown in the baseline analysis, finding effective gait training interventions for people with visuospatial and executive impairments is crucial. Since the HAL-training is both task-specific and repetitive, HAL-training may have the potential to improve walking ability among patients with more severe visuospatial/executive impairments. Theories of neuroplasticity in the central nervous system support this hypothesis, where a reorganization of recruitment patterns and -areas in the brain can be seen as a response to altered input and demands, both in healthy subjects and in a stroke population [Although participants with visuospatial/executive impairments gained improvement at 6 months in the HAL-group, only a few acquired effects exceeding the MCID. These results can though be set in comparison to the control group, where a decline in walking distance at 6 months was seen. The results further imply that even with a well preserved visuospatial/executive function, a decline in activity performance may be seen long-term. This highlights the need of individualized interventions to preserve activity performance over time, even long-term after stroke when rehabilitation interventions usually are sparse [Results from this study may not be generalized to the whole stroke population but targets a younger subgroup living with moderately severe impairments and limitations in walking long-term after stroke.The measures used for evaluating the visuospatial and executive function were MoCA Vis/Ex as a clinical assessment of visuospatial and executive function, as well as the DEX-SO for the perceived everyday impairments related to executive function. The MoCA is commonly used in clinical contexts and assesses multiple domains of cognition, enabling the use of sub scores for specific domains [In the data analysis, action was taken to prevent errors due to multiple comparisons (Type-1 error) by applying the adjusted alpha level. On the other hand, the relatively small number of participants in the analysis of the association between visuospatial/executive function and the effect of gait training, can limit the ability of reaching statistical significance, as a Type-2 error. Altogether, the few significant associations presented can be assumed robust, results not reaching statistical significance can still be discussed as they might show tendencies of interest for future research. In the analysis of the groups separately, the results must be considered preliminary, due to the low number of participants, where changes or drop-outs of a few participants may have affected the results.As described earlier, it is of great importance to investigate the effect of cognitive impairments on rehabilitation outcome, since it has been associated with poorer activity performance, both short- and long term after stroke [ | PMC9997896 |
Conclusion | stroke, cognitive impairments, visuospatial/executive impairments | STROKE | The results of the current study indicate that the previously shown associations between visuospatial and executive function, and activity performance, in the early stage after stroke, remain long-term. Additionally, visuospatial/executive function was associated with the effect of conventional gait training both at 6 weeks and 6 months, where a higher level of visuospatial/executive function indicated a larger improvement. In the HAL-group no such association was found, indicating improvements all over the spectrum of assessed visuospatial/executive function. These results imply that HAL-training may be suitable for persons with more severe visuospatial/executive impairments who may not benefit from conventional gait and mobility training. However, additional studies are needed to explore this association further. Also, future research is suggested to evaluate specific aspects of visuospatial and executive functions, measured by a larger battery of cognitive assessment tools, to identify aspects especially important in predicting mobility outcome after an intervention. This can improve the accuracy in individualizing gait interventions to achieve the largest improvements also among persons with more severe cognitive impairments. | PMC9997896 |
Supporting information | PMC9997896 |
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HAL-project plan for ethical approval. | (DOCX)Click here for additional data file. | PMC9997896 |
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CONSORT checklist. | (PDF)Click here for additional data file.(XLS)Click here for additional data file. | PMC9997896 |
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References | PMC9997896 |
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Subject terms | coronavirus disease 2019 | CORONAVIRUS, CORONAVIRUS DISEASE 2019, SEVERE ACUTE RESPIRATORY SYNDROME | This study aimed to evaluate the efficacy of 3 mouthwashes in reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in the saliva of coronavirus disease 2019 (COVID-19) patients at 30 min, 1, 2 and 3 h after rinsing. This pilot study included 40 admitted COVID-19 positive patients (10 in each group). Saliva samples were collected before rinsing and at 30 min, 1, 2 and 3 h after rinsing with: | PMC10403620 |
Introduction | carious lesions, deaths | CORONAVIRUS, VIRUS, CORONAVIRUS DISEASE 2019, SEVERE ACUTE RESPIRATORY SYNDROME | Coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also commonly known as coronavirus, was declared a pandemic in 2020 by the World Health Organization (WHO) presenting with more than 500 million confirmed cases and 6 million deaths worldwideMost measures initially adopted on preventing and limiting transmission of the virus focused on performing good respiratory and hand hygiene, maintaining physical distance, wearing facial masks, and self-isolating. Despite that, different approaches have been proposed as viricidal strategies to target coronaviruses and to interfere with the viral lipid envelopeMouthwashes have been widely advocated as an adjunctive treatment to mechanical oral hygiene to reduce carious lesions, formation of dental biofilm and gingivitisDespite the current findings and promising results of early trials, clinical information regarding efficacy of mouthwashes containing substances such as CHX, H | PMC10403620 |
Material and methods | This was a pilot study conducted in full accordance with the ethical principles of Declaration of Helsinki, revised in 2013 and Good Clinical Practice (GCP) Guidelines. The study protocol was independently reviewed and approved by the National Health Service (NHS) Solihull Research Ethics Committee (Reference number 21/WM/0068; IRAS Number 289334; initial approval 20/04/2021) and registered in a clinical trial registry (ClinicalTrial.gov NCT04723446; 25/01/2021). The study followed the CONSORT checklist for reporting a pilot study (S1 Table). | PMC10403620 |
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Participants and eligibility | head and neck radiotherapy, allergy, psychiatric, oropharyngeal lesions, hypersensitivity, lichen planus, chronic mucosal lesions | ALLERGY, HYPERSENSITIVITY, LICHEN PLANUS | Patients were identified in the inpatient wards of Newham University and The Royal London Hospitals (Barts Health NHS Trust, United Kingdom) between April and October 2021, during two peaks of the pandemic and when delta was the prevalent COVID-19 strainMales and females, ≥ 18 years old.COVID-19 positive confirmed via any diagnostic test and/or presented with COVID-19 clinical symptoms at time of consent.The exclusion criteria were:known pre-existing chronic mucosal lesions e.g., lichen planus or other oropharyngeal lesions, reported by patient or recorded in the existing patient’ medical notes;patients intubated or not capable of mouth rinsing or spitting;history of head and neck radiotherapy or chemotherapy;self-reported xerostomia;known allergy or hypersensitivity to chlorhexidine digluconate or any of the mouthwashes constituents;other severe acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with trial participation or could interfere with the interpretation of trial results and, in the judgement of the investigator, would make the subject inappropriate for entry into the trial.inability to comply with study protocol.The judgment of the investigator was based on the patients’ direct care medical team opinion/recommendation. Before approaching potential participants investigators communicated with patients’ direct care medical team to understand if patient was medically stable and if their participation in the study would not worsen their condition, as well as if they were mentally and physically able to consent and comply with the study protocol.Potential participants were then approached and provided with the study Patient Information Sheet (PIS) and received explanation about the study. The eligible patients interested in taking part in the study were then invited to sign an informed consent form. Whenever available, COVID-19 test results were confirmed before the patient entered the study. For those patients presenting COVID-19 clinical symptoms at time of consent, positive test status was confirmed within 2 weeks from the date the patient has been consented into the study.Out of 177 inpatients initially screened, 54 fulfilled the eligibility criteria and were consented for the study. Beyond the initial sample size (n = 40) more participants were recruited into the study, as some of the patients presenting with clinical symptoms at point of consent tested negative for COVID-19 (n = 4) and some of participants initially confirmed as COVID-19 positive by diagnostic test had undetectable SARS-CoV-2 viral RNA in the baseline saliva samples (7; 14.9%). Additionally, after enrolment, 1 participant withdrew consent and 2 were withdrawn from the study by the researcher due to deteriorating medical condition. Characteristics of patients consented but not included (n = 14) in the analysis are presented in the Table In addition, up to 5 COVID-19 negative participants were recruited and provided signed informed consent as volunteers from, Barts and The London School of Medicine and Dentistry, Institute of Dentistry, Queen Mary University of London to set up the saliva profile of COVID-19 negative patients for analysis. | PMC10403620 |
Medical history, oral hygiene habits and demographics | Medical history was obtained as part of the visit, including demographics, oral hygiene habits (e.g., use of mouthwashes and time of last oral hygiene procedure) and concomitant drug use information. Medical history also included relevant results of physical exam, biochemical analysis, diagnostic imaging, COVID-19 test and strain of SARS-CoV-2 variant.Source documents consisted of patient hospital records (paper or electronic notes) as well as COVID-19 test results/certificates. | PMC10403620 |
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Saliva sample collection | STERILE, VIRUS | All participants received a sealed self-test kit containing 5 self-collection saliva vials (OMNIgene Oral – OME-505, DNAgenotek, Ottawa, Canada), one for each different time point, and were given instruction to refrain from eating, drinking, chewing gum or performing oral hygiene for at least 30 minutes prior saliva collection (as per manufacturer’s instructions). Participants were then asked to collect a baseline sample of non-stimulated saliva by pooling saliva in the floor of their mouth without swallowing, and then to spit into the sterile vial until the amount of liquid saliva reached the 1 ml indication. At 30 minutes, 1, 2 and 3 hours after rinsing (test groups) or no rinsing (control group) participants were requested to collect saliva following the same recommendations than at baseline. After collecting saliva, patients were instructed to place the vials inside a sealed bag containing absorbent paper in case of opening or breaking of saliva tube. Samples collection was supervised by investigator conducting the study visit.The self-collection saliva vials contained solution used to inactivate the SARS-CoV-2 virus and stabilise viral nucleic acids at room temperature. After deactivation the saliva samples were stored at room temperature and then transferred to the Blizard Institute, Queen Mary University of London within 3 weeks for viral load analysis. Subsequently, samples were stored in a − 80 °C freezer until destruction in accordance with local guidelines and following the Human Tissue Authority (HTA) Code of Practice. | PMC10403620 |
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Mouthwash use | In the test groups (Group 1–3) patients also received as part of the self-test kit, mouthwash bottles. Immediately after baseline saliva collection, participants were instructed to vigorously rinse their mouth with 10 ml of Corsodyl Alcohol free (Group 1; 0.2% CHX), Colgate Peroxyl (Group 2; 1.5% HMeanwhile, participants in the Group 4 (non-rinsing) were instructed to not rinse their mouth with any solution, not even water. All patients were allowed to drink water as needed during the study period up to 30 min prior each saliva collection. | PMC10403620 |
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Relative quantification of SARS-CoV-2 viral load using RT-qPCR | Saliva samples were thawed at room temperature and prior to nucleic acid extraction, saliva samples were spiked with Internal Extraction Control RNA (IEC; an exogenous RNA of rat Phogrin gene, NM_031600, amplicon 98 bp) from the genesig COVID-19 qPCR Assay kit (PrimerDesign Ltd., UK) to verify the successful extraction in case of a negative SARS-CoV-2 result (Fig. One-step RT-qPCR workflow for quantification of salivary SARS-CoV-2 viral load using MagMAX Viral/Pathogen Nucleic Acid Isolation Kit, genesig COVID-19 qPCR Assay. Figure created using CorelDRAW Graphics Suite 2017 (version 19.1.0.419) SARS-CoV-2 viral RNA were purified from saliva samples (100–200 µL) using MagMAX Viral/Pathogen Nucleic Acid Isolation Kit (Thermo Fisher Scientific Inc; Cat. A42352) according to manufacturer’s protocol. SARS-CoV-2 viral load were measured using a one-step RT-qPCR kit (genesig COVID-19 qPCR Assay, PrimerDesign, Cat. Z-Path-2019-nCov). As per genesig COVID-19 qPCR assay protocol, SARS-CoV-2 RdRp gene (C19, with FAM 465-510 probe), rat Phogrin gene (IEC, with VIC/HEX 533-580 probe) and a human endogenous control (HEC, with FAM 465-510 probe; ATCB gene, NM_001101, amplicon 92 bp) were measured from each eluted saliva RNA sample in quadruplicate RT-qPCR reactions using a LightCycler LC480 Instrument (Roche Diagnostics, UK). RT-qPCR amplification began with reverse transcription at 55 °C (10 min) followed by Hot-start activation at 95 °C (2 min) prior to 45 cycles of 95 °C (10 s) denaturation, 60 °C (60 s) annealing/extension/acquisition. Every qPCR assay plate included quadruplicate wells of no saliva extraction control, no template control and positive template control for assay quality assurance. The IEC exogenous RNA was used as a positive control for the nucleic acid extraction process. Successful IEC co-detection with SARS-CoV-2 would indicate that PCR inhibitors were not present at a high concentration. Samples with poor IEC amplification (crossing point; Cp > 45) were disqualified as these represented poor RNA extraction (containing inhibitors that interfered with qPCR). HEC gene was measured to confirm successful extraction of a valid biological sample of human origin. Samples with poor HEC amplification (Cp > 45) were disqualified as these indicated samples of insufficient human biological RNA yield. Viral load was calculated from sample Cp/Cq ratio values against a standard curve of Log viral load vs crossing point (Fig. SARS-CoV-2 viral load were normalised against both IEC and HEC to control for RNA quality and human RNA loading, respectively, in each sample. Samples with undetectable viral levels were assigned a Cp value of 45 for calculation. | PMC10403620 |
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Blinding | The investigator responsible for the SARS-CoV-2 viral load analysis was blinded to the study groups/arms. | PMC10403620 |
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Sample size | This pilot study included a convenience sample of up to 40 COVID-19 positive patients, as confirmed by their saliva samples, identified in the wards at the Newham University Hospital and at The Royal London Hospital, both Barts Health NHS Trust sites. The trial was designed considering the number of COVID-19 patients admitted at Barts NHS trust and predictions at time of project development. | PMC10403620 |
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Statistical analysis | REGRESSION | Interim analysis of saliva samples collected at baseline, 30 min, 1, 2 and 3 h after mouth rinsing, for the first 2 patients from each study group was performed to identify if a specific mouthwash was not effective in reducing SARS-CoV-2 viral load in the first 1 h and should be excluded from the study. As per interim analysis all mouthwashes were able to reduce viral load, none of them were excluded from the study.The four measurements for viral load (VL) for each patient at each time point were averaged by taking the mean value which was considered as the unit of measurement. Summary statistics (mean with standard deviation (SD), confidence interval (CI) and median with range) of the viral load at baseline, 30 min, 1, 2 and 3 h after rinsing (test groups) or after no rinsing (control) were determined. LogRandom effects linear regression analysis, incorporating all time points and an interaction term for times and groups, on the logA linear regression analysis, with the dependent variable being the logAssumptions of all regression analyses were checked and verified by a study of the residuals. Outliers with a clinical plausibility for exclusion were removed from the analysis (e.g., saliva sample contaminated with food debris, delayed sample collection).The data was analysed by SPSS (IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY: IBM Corp) and Stata (StataCorp. 2021. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC.) | PMC10403620 |
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Ethical approval | This study was conducted in full accordance with the ethical principles of Declaration of Helsinki, revised in 2013 and Good Clinical Practice (GCP) Guidelines. The study protocol was independently reviewed and approved by the National Health Service (NHS) Solihull Research Ethics Committee (Reference number 21/WM/0068; IRAS Number 289334; initial approval 20/04/2021). Written informed consent was obtained from all individual participants included in the study. | PMC10403620 |
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Results | PMC10403620 |
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Study participants | comorbidity, throat, COPD | ADVERSE EVENTS, COPD, CHRONIC OBSTRUCTIVE PULMONARY DISEASE | Forty patients (17 males and 23 females; mean age of 42.6 ± 14.2 years; range 18 – 74 years old), 10 in each group, with detectable SARS-CoV-2 viral RNA in the baseline saliva samples were included in the analysis. Participants characteristics was similar among study groups (Table Characteristics of study participants (n = 40) according to intervention group.Seventeen (42.5%) participants were White British or any other White background; 9 (22.5%) were Black, Black British, Caribbean, African or any other Black background; 8 (20%) were Asian, Asian British, Indian, or any other Asian background; and 4 were considered mixed or from another (10%) ethnic group (Table Type of comorbidities among the study participants (n = 40), in the study groups. Participants could have more than one comorbidity.Entries are frequency (percentage). COPD—Chronic obstructive pulmonary disease.All patients had their diagnosis confirmed, as standard of care at the respective hospitals, by reverse transcriptase-polymerase chain reaction (RT- PCR) assays on material collected by combined nasal and throat swab. On average, the time from last COVID-19 positive test result to sample collection was 2 days (ranging from − 5 to 10 days). Meanwhile, the mean time from the onset of symptoms to the study visit and saliva sample collection was around 8 days (ranging from 3–18 days). Most patients included in this study were diagnosed with SARS-CoV-2 variant Delta (lineage B.1.617.2). Among patients included in this study, only 17.5% were fully vaccinated (two doses) while 12.5% had the first dose of COVID-19 vaccine. The remaining patients were unvaccinated (37.5%) or did not have data available on vaccination status (32.5%).In terms of oral hygiene habits, 57.5% reported using mouthwash as part of their oral hygiene routine at home. The time reported by patient from last oral hygiene (OH) before sample collection ranged from 30 min to 10 days. None of the patients reported any adverse events related to the use of investigated mouthwashes or any of study procedures. | PMC10403620 |
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