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Diagnosis of AMD | mydriasis | Fundus photography was performed on all study participants without previous pharmacological mydriasis by using a 35° color digital fundus camera (Canon CR-2 PLUS AF; Canon U.S.A., Inc., New York, USA). Fundus images were graded according to the Wisconsin AMD grading system [ | PMC10586687 | |
Other characteristics and methods | Anthropometric measurements were performed in a standard manner using certified equipment. Body weight and height were measured with the participants barefoot and wearing lightweight indoor clothing. Body mass index was calculated as weight (kg)/(height [m]) | PMC10586687 | ||
Statistical analysis | REGRESSION | Statistical analyses were performed using the R statistical package (version 4.1.3), with the α-value set to 0.05. Quantitative variables were compared between groups using the Mann–Whitney U-test or Student t-test for independent samples, as applicable. The normal distribution of the study variables was verified using the Shapiro–Wilk test, and the homogeneity of their variances was verified using Levene’s test. Mean differences (MDs) and odds ratios (ORs) were calculated, along with their 95% confidence intervals (CIs). The relationships between categorical variables were analyzed using the chi-square test. Univariate and multivariable logistic regression models were created using AMD as the outcome variable. The results were presented as ORs with 95% CIs. To verify the significance and goodness of fit of the models, the chi-square statistic and Nagelkerke pseudo-RThe study was conducted in accordance with the provisions of the Declaration of Helsinki, and all participants provided written informed consent prior to enrollment. The Bioethics Committee of the Medical University of Białystok approved the study protocol (approval number R-I-002/108/2016 of 31 March 2016). | PMC10586687 | |
Results | The study sample consisted of 436 patients aged 50–80 years (252 women). Detailed characteristics of the study participants are listed in | PMC10586687 | ||
Demographic, clinical, and densitometric characteristics of study participants. | AMD-1, AMD | AGE-RELATED MACULAR DEGENERATION | * Variables with normal distributions were compared using the Student t-test, and those with non-normal distributions were compared using Wilcoxon’s test for independent samples.AMD-0: group without AMD; AMD-1: group with AMD.AMD, age-related macular degeneration; BMD, bone mineral density.Women in the AMD-0 group were younger than those in the AMD-1 group, and the two groups did not differ in terms of body mass index, height, body weight, or serum 25(OH)D concentration. Men were homogenous in terms of age and biometric parameters.Significant differences in femoral BMD and femur T-scores between the AMD-0 and AMD-1 groups were observed only in men (MD = 0.11 [0.02; 0.13]; p = 0.012 for femoral BMD and MD = 0.73 [0.015; 0.94]; p = 0.011 for femur T-score). The parameters of femoral neck BMD were worse in the AMD-1 group than in the AMD-0 group, with the between-group difference nearing the statistical significance. No association was observed between BMD and AMD in women. 25(OH)D status was not associated with the prevalence of AMD or the risk of a low femoral BMD in men or women.The proportions of men in the AMD-0 and AMD-1 groups who had decreased T-scores for femoral BMD were 15% and 46%, respectively, demonstrating a statistically significant difference (OR = 4.65 (1.81; 11.97); p = 0.001) The presence of AMD did not exert a significant effect on the occurrence of decreased T-score values among women (p = 0.633), ( | PMC10586687 |
The relationship between T-Score (Cutoff, −1.0) for femoral BMD and the occurrence of age-related macular degeneration in women and men. | AMD | REGRESSION, AGE-RELATED MACULAR DEGENERATION | AMD-0: group without AMD; AMD-1: group with AMD.AMD, age-related macular degeneration; CI, confidence interval.Femoral BMD was a significant predictor of AMD in men based on univariate logistic regression models. A one-unit increase in femoral BMD was associated with a 98% decrease in the risk of being in the AMD-1 group (95% CI = <0.01; 0,80; p = 0.043), whereas a one-unit increase in the femur T-score was associated with a 42% risk reduction (95% CI = 0.34; 0.96; p = 0.041)). For women only age was a significant predictor of AMD, the odds for AMD were growing with age, one-year growth was increasing odds for AMD by 8% (95% CI = 1.02; 1.15; p = 0.012). Femoral BMD as well as femur T-score were not significantly associated with occurrence of AMD in women (p = 0.352 in both cases), ( | PMC10586687 |
Univariate logistic regression models with age-related macular degeneration as an outcome variable in women and men. | AMD | REGRESSION | BMD, bone mineral density.Two multivariable logistic regression models were created for women and men, both with AMD as the outcome variable: the predictors were age and crude femoral BMD in one ( | PMC10586687 |
Multivariable logistic regression model with age-related macular degeneration as an outcome variable and age and femoral BMD as independent variables in women and men. | BMD, bone mineral density. | PMC10586687 | ||
Multivariable logistic regression model with age-related macular degeneration as an outcome variable and age and femur T-score as independent variables in women and men. | PMC10586687 | |||
Discussion | AMD, bone loss, osteopenia, senile osteoporosis, osteoporosis | FRAGILITY FRACTURE, BONE LOSS, OSTEOPENIA, BONE DISEASES, SENILE OSTEOPOROSIS, PATHOGENESIS, OSTEOPOROSIS | Our study revealed an association between a decrease in femoral BMD and the occurrence of AMD in men older than 50 years. In contrast, we did not observe any differences in the densitometric parameters of women in relation to AMD prevalence. The results of our study provide grounds for actively screening for AMD among patients with osteopenia. Routine screening diagnostics in the form of the Amsler grid eye test should be considered in patients with low bone density.Published data on the coincidence of osteoporosis and AMD are scarce. The first such study included only Caucasian women aged >75 years from the USA [The pathogenesis of AMD is multifactorial, and the molecular mechanisms underlying its development are still not understood. Its pathogenesis involves environmental and genetic factors, disorders of the complement system, lipid abnormalities, angiogenic and inflammatory pathways, and the extracellular matrix [One possible reason for the coexistence of AMD with bone loss or decreased BMD is the impairment of autophagy observed in both conditions. Both AMD and senile osteoporosis are associated with decreased autophagic activity. Impaired autophagy plays a pivotal role in the onset and progression of osteoporosis [P62/SQSTM1 may also be involved in bone diseases, as a high frequency of The prevalence of AMD in our study was 10.8%. Although the global prevalence of AMD is estimated at 8.7%, a meta-analysis has suggested that its prevalence is higher in European countries (12.3%–18.3%) [Our study is not without limitations. First, it was limited by its observational nature, relatively small number of patients, and lack of detailed data on AMD status. Second, we did not analyze the effects of other factors involved in the coincident development of AMD and osteoporosis, e.g., smoking, alcohol consumption, and dietary calcium intake. We did not have access to fragility fracture data or a fall registry for the study population. Furthermore, the health data of the study participants were obtained at a single timepoint. As certain parameters, such as BMD, body mass index, calcium intake, and serum vitamin D level, change over time, this factor should be considered a potential confounder. Third, the group of women with AMD was older than that without AMD. As the risks of AMD and osteoporosis both increase with age, this factor may explain the lack of a significant relationship between AMD and low BMD in women in this study. Differences in BMD between men with and those without AMD were detected only in the femoral region and not in the lumbar spine. We could not further explore this association, as dual-energy X-ray absorptiometry does not provide insights into bone quality and structure. Despite these limitations, this is the first study in which the link between a low hip BMD and AMD was demonstrated in a Polish population.In conclusion, further longitudinal research with a larger group of participants is required to confirm the link and potential pathogenic association between AMD and a low BMD in the Polish population. | PMC10586687 |
Keywords | Communicated by Michael I Lindinger.The use of sodium bicarbonate (NaHCO | PMC10363041 | ||
Introduction | Sodium bicarbonate (NaHCOErgogenic benefits of NaHCOOne limitation of the work to date is passive rest periods between intervals have been employed. It is intuitive to suggest that active recovery periods could lead to greater acid base balance recovery, and clearance of HIf NaHCOIt is unknown, however, if improvements can be seen during interval swimming in a highly trained cohort or if long-term supplementation can improve training adaptation. Evidence from studies using NaHCO | PMC10363041 | ||
Methods | PMC10363041 | |||
Participants | Fourteen trained male competitive swimmers (BM: 73 ± 8 kg) participated in this double-blind, randomised, crossover study. Randomisation was completed using a 4 × 4 block design (NaHCO | PMC10363041 | ||
Exercise protocol | All participants completed the exercise protocol during their normal training time and at the same time of day (± 1 h) (range: 5–8 pm). Following a familiarisation trial that entailed completing the interval sets, the experimental protocol was repeated on two occasions 1 week apart. Each participant was asked to swim 50 m (front crawl), from a competitive diving block, at their maximum effort and repeat this 8 times. After each 50 m sprint, participants undertook a 50 m active recovery swim requiring them to swim at their normal warm–up pace. Each exercise bout was run off a 5 min base, which left the participants with approximately 3 min passive recovery. Although similar exercise protocols have utilised passive recovery (Gao et al. On both testing sessions participants ingested either a solution of NaHCOFingertip capillary blood samples were taken at three time points; baseline (pre-ingestion), 60 min post-NaHCO | PMC10363041 | ||
Statistical analysis | Data were initially checked for normality using Shapiro–Wilk and standard geographical methods (e.g. Q–Q plots and Histograms). For time to complete each 50 m set, a two-way (treatment: NaHCO | PMC10363041 | ||
Results | PMC10363041 | |||
Heart rate, GI and RPE | There were no differences in HR at any time point between NaHCO | PMC10363041 | ||
Discussion | This study aimed to investigate the effects of NaHCOThe current study corroborates with previous research reporting improvements in interval swimming performance following NaHCOAs a group, there was an improvement in swim performance during the latter half of the repeated sprints (sprints 5–8). However, the ergogenic effects of NaHCOThe group mean increase in HCOWhilst the current study was more applied in nature, it does offer insight into the mechanism of action for NaHCOApplied studies are always open to limitations, and this study presents limitations in the ingestion strategy adopted and the lack of mechanistic insight. Recently, a string of studies (Gough et al. | PMC10363041 | ||
Conclusion | To conclude, this study reports that the ingestion of NaHCO | PMC10363041 | ||
Acknowledgements | We would like to thank the participants for taking part in the research. | PMC10363041 | ||
Author contributions | MP | LAG and MP designed this work. LAG, MP, and JWN collected data. LAG drafted the work with contributions from MP and JWN. MP and JWN reviewed and approved the manuscript. All the authors are accountable for the accuracy and integrity of the work. | PMC10363041 | |
Funding | The study received no funding. | PMC10363041 | ||
Data availability | Data is available upon request to the corresponding author. | PMC10363041 | ||
Declarations | PMC10363041 | |||
Conflict of interest | All the authors have no competing interests to declare. | PMC10363041 | ||
References | PMC10363041 | |||
Background | anxiety disorder, SAD | SECONDARY | There is growing evidence that Internet-based cognitive behavioral therapy (ICBT) is as effective as a stand-alone treatment and helps facilitating access to treatment. Given the complexity of the treatment, we argue that the effect of ICBT could be even greater if guided by a therapist, as this could increase treatment adherence. We modified an established and well-evaluated treatment approach and developed a mobile application for treating social anxiety disorder (SAD). In the present study, we compare the efficacy of app use alone (APP) with video-based, therapist-guided app use (TG-APP) and with a wait-list control group (WLC) in terms of symptom reduction, and various secondary outcomes such as increase in quality of life or decrease of general psychological distress. | PMC9974392 |
Methods/design | depression, Anxiety, SAD | A within-between interaction design with randomization to one of three conditions will be used. In the APP condition, patients receive only the app without any additional contact with therapists, while in the TG-APP condition, therapists provide 8 sessions of video-based treatment in addition to using the app. The study will be conducted in two university outpatient treatment centers with reliably diagnosed SAD patients. The primary outcome will be defined as change in SAD symptoms, as measured by the Liebowitz Social Anxiety Scale (expert rating). Furthermore, a wide range of self-reports and clinician ratings for other symptoms (depression, general psychopathology) or quality of life will be used. A simulation-based power analysis for a 3 × 2 interaction effect (group × time) on the primary outcome in a linear mixed model resulted in a total sample size of | PMC9974392 | |
Discussion | SAD | The present study will be one of the first to examine the additional benefit of therapist-guided video sessions regarding the use of an app treating SAD. Study results are pivotal to future treatment application in SAD. | PMC9974392 | |
Supplementary Information | The online version contains supplementary material available at 10.1186/s13063-023-07168-5. | PMC9974392 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC9974392 | ||
Administrative information |
Trial registration: ClinicalTrials.gov, NCT05554718. Registered 16 September 2022, The pilot study was registered in the German Clinical Trials Register (DRKS), DRKS00029701. Registered 01 August 2022. J. M. Schittenhelm: Goethe Universitaet Frankfurt, GermanyC. von Borell: Technische Universitaet Dresden, GermanyC. Clément: Goethe Universitaet Frankfurt, GermanyJ. Schüller: Goethe Universitaet Frankfurt, GermanyU. Stangier: Goethe Universitaet Frankfurt, GermanyJ. Hoyer: Technische Universitaet Dresden, Germany | PMC9974392 | ||
Introduction | mental disorders, SAD | DISORDER, WELLS | Social anxiety disorder (SAD) is characterized by the fear of behaving in a way that is negatively perceived by others [On the one hand, there are ways to treat SAD. For example, a recent meta-analysis demonstrated that individualized cognitive therapy (CT) based on the model of Clark and Wells [Addressing these treatment barriers, Lee and Stapinski [Previous studies that have examined the effectiveness of ICBTs have largely used treatment programs delivered via a computer. Today, however, the use of a smartphone including its apps is even more widespread, rendering mobiles a promising option for the treatment of mental disorders. It might even have more advantages than ICBTs delivered via a computer, as apps seem to be easily integrated into daily routines [This raises the important research question of whether the effectiveness of apps can be enhanced by accompanying face-to-face sessions with a therapist. To date, few studies have addressed this question. The authors assume that therapist guidance could additionally increase compliance with ICBT treatment as well as the motivation to complete it. Another advantage of therapist-guided ICBT over nonguided ICBT could be higher patient safety, as the therapist can assist when questions or ambiguities arise, or when adverse side effects of ICBT occur, such as worsening of symptoms, negative well-being, or noncompliance [Particularly as a result of the COVID-19 pandemic, new ways of providing therapeutic support have been developed: Due to the limitations of physical contact, the use of videoconferencing has increased dramatically. A meta-analysis has shown that video-based psychotherapy typically has large effect sizes and that the difference to in-person therapy is negligible [In summary, the use of ICBT delivered via a smartphone application could improve the accessibility of psychotherapy and integrate interventions into everyday life, making it a promising approach for the future treatment of SAD. However, few studies have attempted to implement Clark and Wells’ [ | PMC9974392 |
Objectives | anxiety disorder, psychological impairment, phobic, psychological distress, deterioration of SAD-related symptoms, depression | SECONDARY, WELLS | The main goal of the present study is to evaluate whether the use of the app-based intervention helps to decrease symptoms of social anxiety disorder and has positive effects on mental health. There will be two experimental treatment conditions: App-based CT (APP) and app-based CT plus 8 therapist-guided video-delivered therapy sessions (TG-APP). Both will be compared to a wait-list control group (WLC). The therapists will be trained in Cognitive Therapy based on the model of Clark and Wells [Hypothesis 1a: In the APP and TG-APP condition, SAD-related symptoms, as measured by the LSAS, will decrease significantly more from baseline to post-treatment than in the WLC condition.Hypothesis 1b: The TG-APP condition results in a significantly greater reduction in SAD-related symptoms, as measured by the LSAS, than the APP and the WLC conditions, from baseline to post-treatment.Hypothesis 1c: In the APP and the TG-APP condition, there will be no significant deterioration of SAD-related symptoms, as measured by the LSAS, from post-treatment to follow-up.Hypothesis 2a: In the APP and TG-APP conditions, significant improvements in secondary outcome variables, including social phobic cognitions, depression symptoms, general psychological distress, psychological impairment, quality of life, and interpersonal pleasure, are achieved from baseline to post-treatment compared to the WLC condition.Hypothesis 2b: In the TG-APP condition, improvements in secondary outcome variables from baseline to post-treatment will be significantly larger than in the APP condition.Hypothesis 2c: In the APP and TG-APP condition, there will be no significant deterioration in secondary outcome variables from post-treatment to follow-up.Hypothesis 3: Individual learning styles contribute significantly to predicting success in both treatment conditions.Hypothesis 4: The increase in social approach behavior will mediate the effect of the TG-APP versus APP condition. | PMC9974392 |
Trial design | Anxiety | The design of the planned bi-centric randomized controlled superiority trial will be based on a within-between interaction group design with three groups (WLC, APP, TG-APP) and parallel group assignment. The primary outcome criterion is the change in symptom severity of SAD, as measured by the Liebowitz Social Anxiety Scale (LSAS) [ | PMC9974392 | |
Methods | PMC9974392 | |||
Design and sample size | SAD | We conducted a simulation-based a priori power analysis for a 3 × 2 interaction (group ( time) in a linear mixed model for the primary outcome of SAD symptom severity (according to the LSAS), using the R package “simr” [We chose these effect sizes as conservative estimates based on the results of a recent meta-analysis reporting moderate effect sizes in ICBTs for SAD [We based our power analysis on an iterative simulation of increasing sample sizes with starting values of Study flowchartAs a robustness check, we additionally conducted a power analysis based on the simulation of a 3 × 3 interaction (group × time) that included the estimated effect sizes at | PMC9974392 | |
Procedure | anxiety disorder | The study will be conducted in Germany at the outpatient psychotherapy unit of the Clinical Psychology department of the Goethe University of Frankfurt as well as the outpatient psychotherapy unit of the Clinical Psychology department of the Technische Universitaet Dresden and two further CBT training centers in Dresden. For reporting purposes, we followed the SPIRIT reporting guidelines [In the first step, all persons that register for participating in the study will be screened using an online self-report assessment. If participants exceed the cut-off of 25-points or find themselves within the criteria for social anxiety disorder, they are referred to another online self-assessment and then invited for an interview with a clinical rater. Beforehand, they will be informed about the study and provided with written informed consent (either personally or via email if necessary). Interviews to determine the patient's formal diagnosis are conducted by blinded and independent psychologists (with at least a master’s degree) who have been trained in the appropriate interviews. Eligible patients are then randomly assigned to one of three groups (WLC, APP, TG-APP). Participation in each of the groups lasts 3 months. Participants in the WLC group then have the option of using the app if they wish. The outcome measures will be assessed by blinded and independent raters at baseline, post-treatment (3 months after start), as well as 6 months after the post-treatment interview (follow-up). Furthermore, participants will complete self-report questionnaires online at baseline, at mid-treatment (at 6 weeks), post-treatment (at 12 weeks), and follow-up (at 36 weeks; see Fig. Prior to the start of the study, we will conduct a pilot study to improve usability and evaluate the mobile application and the applicability of therapist-guided video therapy and the videoconferencing tool. | PMC9974392 | |
Ethical issues | psychiatric | ADVERSE EFFECTS | The study was approved by the Ethics Committee of the Department of Psychology at Goethe University Frankfurt. If post-trial care is required (e.g., in case of serious adverse effects), this will be provided by the outpatient clinics in Frankfurt and Dresden, and participants will be referred to a hospital or psychiatric clinic if necessary. | PMC9974392 |
Recruitment | Advertisements for participation include print media (e.g., brochures or text in print media), posts on social media, and outreach to mental health professionals, inpatient and outpatient facilities, and general practitioners to identify appropriate participants. | PMC9974392 | ||
Eligibility criteria | Anxiety, Acute suicidalityActive substance abuse | Inclusion criteria:Current diagnosis of Social Anxiety DisorderWritten informed consent before the start of the studyAge: 18 to 65 yearsPossession of smartphoneFamiliarity with using appsExclusion criteria:Acute suicidalityActive substance abuse or dependenceSevere medical conditions (e.g., chronic cardiovascular disease)Severe depressionPsychotic disorderBipolar disorderBorderline personality disorderCurrent psychotherapeutic treatmentCurrent psychopharmacological treatmentNo proficient skills in the German languageFurthermore, patients may be withdrawn from the study for the following reasons:Request of patientPost-hoc observation of criteria for exclusionThreat to patient’s mental or physical health due to participating in the study | PMC9974392 | |
Allocation and randomization | Randomization is performed using a randomization list in which, based on 165 randomly generated numbers sorted by size, each of the available options is assigned according to the planned sample size (WLC = 43, APP = 61, TG-APP = 61). The list is then sorted by sequential number. A study coordinator who is not involved in the diagnosis or treatment process will enter the subjects into the randomization list according to the order of inclusion. The result is communicated to the patients via email and remains hidden from the clinical evaluators. The email to the participant contains the result and, if the person belongs to one of the two intervention groups, all the necessary information to use the app. | PMC9974392 | ||
Treatment | attention on external stimuli., anxiety, SAD | WELLS | The app offers an adaptation of scientifically proven techniques in the treatment of SAD based on Clark and Wells [Clark and Wells’ model [Module 1—Learning and Understanding: The goal of this module of the app is to provide the user with key information about SAD and to create an individualized model based on Clark and Wells’ approach. The information used to derive the model is based on patients’ self-reports of anxiety-provoking situations. The model is developed in a stepwise manner, prompted by feedback from the app.Module 2—Attention Training: The goal of the second module is to change self-focused attention. The training uses recorded audio exercises that train the ability to focus attention on external stimuli.Module 3—Behavioral experiments: This key module of the app consists of four phases. Each phase includes specific types of behavioral experiments, as well as various forms and questions for planning the experiments and recording the results and key findings.The first phase provides an experiment on how increasing or decreasing safety behaviors and self-focused attention affects anxiety. The experiment is supplemented by video feedback, in which patients are asked to record themselves in a simulated social situation (e.g., a presentation) and subsequently correct dysfunctional beliefs about their appearance or behavior.The second phase involves testing the dysfunctional beliefs that emerge in real social situations while simultaneously reducing safety behaviors and directing their attention outward.The third phase focuses on testing beliefs about the assumed negative impact of supposedly embarrassing behaviors on how they are evaluated by others (e.g., “If I pause during a presentation, I will appear awkward, and others will think I am an idiot”). Patients are instructed to explicitly demonstrate certain critical behaviors (e.g., pausing during a presentation) and to question the validity of their (possibly erroneous) beliefs.The fourth phase involves integrating behavioral experiments into daily life by continually testing SAD-related beliefs that interfere with personal goals.In the therapist-guided app condition (TG-APP), use of the app is accompanied by eight therapist-guided video sessions. Based on the manual by Stangier et al. [First session: establishing a therapeutic alliance, exploring the symptoms and giving an introduction to the appSecond session: answering questions based on the individualized model of the app, deriving a second cognitive model by exploring safety behaviors and establishing motivation for changeThird session: performing a video recorded behavioral experiment to modify safety behaviors and self-focused attentionFourth session: analyzing the recorded video to test dysfunctional self-evaluation (video feedback)Fifth session: conducting a therapist-guided behavioral experiment testing a dysfunctional beliefSixth session: conducting a therapist-guided behavioral experiment deliberately showing critical behavior and testing the evaluation by othersSeventh session: motivating the patient to implement behavioral experiments into the everyday life and debriefing of previous behavioral experimentsEighth session: relapse prevention (summary of helpful techniques, pursuing personal goals, cognitive interventions for strengthening the self-esteem) | PMC9974392 |
Therapists | Therapists will be recruited mainly from the outpatient units of the Universities of Dresden and Frankfurt. All therapists must be either licensed psychotherapists or in advanced post-graduate CBT training (at least 1.5 years of training). Study-specific training will focus on how to use the app, how to conduct and analyze behavioral experiments, and how to use techniques of cognitive restructuring. Therapists are required to apply the TG-APP procedures with a pilot patient to gain experience and expertise in this particular form of blended therapy. All treatments will be supervised by psychotherapists with at least five years of clinical experience under their state licensure to ensure adherence to intervention protocols. | PMC9974392 | ||
Outcomes | PMC9974392 | |||
Primary outcome measure | Anxiety | We defined the clinician-rated Liebowitz Social Anxiety Scale (LSAS) [ | PMC9974392 | |
Self-rating scales | Pain, depression, Depression, Disability, SAD | SECONDARY | As the secondary outcome measure for SAD, we use the Social Phobia Inventory (SPIN) [We also use the German version of the Social Cognitions Questionnaire (SCQ, German version: SPK) [Symptoms of depression and general psychological distress will be assessed using the Beck Depression Inventory Fast Screen (BDI-FS) [To assess the quality of life, we will use specific domains of the WHO-QOL-BREF [To measure the amount of distress caused by the mental illness, we used the Pain and Disability Index (PDI) [To assess if individual learning styles influence treatment effects, we included Kolb’s Learning Style Inventory (LSI) [Treatment satisfaction will be measured by using the Client Satisfaction Questionnaire (CSQ) [Finally, we will also assess negative side effects which are specific to patients with SAD. Drawing on the results of Boettcher et al. [ | PMC9974392 |
Clinician-rated measures | borderline personality disorder, Depressive, BPD | The interview will include the Structured Clinical Interview for DSM 5 (SCID-5) [To screen for borderline personality disorder (BPD), we use a set of 5 questions suggested by Wongpakaran et al. [We further use the Clinical Global Impression (CGI) [Finally, the Quick Inventory of Depressive Symptomatology (QIDS-C) [Schedule of enrolment, allocation, interventions, and assessments | PMC9974392 | |
Statistical methods | PMC9974392 | |||
Sample | All analyses will be conducted in the intent-to-treat (ITT) sample, including all participants that were randomized into one of the three groups. | PMC9974392 | ||
Primary analysis | For our primary analysis, we plan to fit a linear mixed model with random intercepts for participants in the R package lme4 [ | PMC9974392 | ||
Secondary analyses | phobic, depression, anxiety, pain | ADVERSE EFFECTS, SECONDARY, ADVERSE EFFECT | As secondary analyses, we will evaluate treatment effects (from baseline to post-treatment, as described in hypothesis 2a and from post-treatment to follow-up, as described in hypothesis 2c) on quality of life, as measured by the WHO-QOL-BREF, interpersonal pleasure, as measured by the ACIPS, further SAD-related symptoms, as measured by the SPIN and the CGI, social phobic cognitions, as measured by the SPK, symptoms of depression, as measured by the BDI-FS and the QIDS-C, general psychological distress, as measured by the BSI, and limitations in everyday life, as measured by the PDI. We will also assess adverse effects measured by the self-developed adverse effect scale. Moreover, we will compare posttreatment LSAS scores with scores at follow-up, as stated in hypothesis 1c, using the linear mixed model described earlier.To control for moderating effects on decreases in social anxiety symptoms, as indicated in hypothesis 3, we include the scores of the individual learning style, as measured by Kolb’s LSI and experienced pain in social situations, as measured by the SPQ-5, as predictors in the model and specify three-way interactions with treatment conditions and time for all these factors. We will conduct a similar analysis to test whether social approach behavior measured by the SPWSS has a mediating effect on social anxiety symptoms, as we hypothesized in hypothesis 4. We will test all interactions by comparing the full to a reduced model without the respective interaction term via likelihood ratio tests (LRTs) [To evaluate effects between two conditions at a given time, e.g., between the APP and TG-APP conditions at post-treatment, as indicated in hypothesis 1b and 2b, we will calculate the statistical significance of pairwise differences in LSAS based on the linear mixed model using the R package “emmeans” [We will fit all measures as outcome variables in linear mixed models including the same predictors as in the primary analysis and add the average weekly time participants spent using the app and the number of behavioral experiments conducted as additional explanatory predictors.Besides that, we will analyze and compare responder rates between the different treatment conditions at post-treatment using a chi-squared test. Response to treatment will be defined as a 29% score decrease of the clinician-rated LSAS from baseline to post-treatment according to Glischinski et al. [ | PMC9974392 |
Drop-out analyses | We define as “drop-out” any participant who did not complete the post-treatment measurement. Systematic differences in dropout rates between the three groups will be analyzed by a Fisher exact test. In addition, differences between participants and drop-outs in terms of sociodemographic and clinical variables will be considered. | PMC9974392 | ||
Interim analysis | In case of a rejection of the licensing process by the inspecting federal institute for drugs and medical devices, an interim analysis of the treatment effect of the APP condition on outcomes of the main study (LSAS, WHO-QOL-BREF, PDI) could turn out to be necessary. Such interim analysis will be blinded, that is, performed by different researchers than the respective research teams of the study and after reaching a sample size of | PMC9974392 | ||
Discussion | anxiety disorder, SAD | WELLS | Based on a recent meta-analysis, there is evidence that internet- or app-based interventions have moderate effect sizes in the treatment of SAD [We hypothesize that the addition of therapist-guided sessions will result in larger effect sizes than using the app alone. In agreement with Stott et al. [To summarize, our results will demonstrate (a) the efficacy of a new app-based intervention using the Clark and Wells approach in another well-designed and preregistered independent trial and (b) whether additional face-to-face therapy is beneficial to patients in terms of increased symptom reduction of SAD compared to app use alone. The results will be critical for service delivery and treatment planning for social anxiety disorder. | PMC9974392 |
Organizational structure | PMC9974392 | |||
Coordinating center and trial steering committee | The present study is a bicentric study which is designed and coordinated in a cooperation between the Goethe University Frankfurt and the Technische Universitaet Dresden. The study team has weekly meetings. There is no additional steering committee.Support for the trial is provided by:Principal investigator: provides supervision for the treatment, has medical responsibility of the patients, designs and plans the studyStudy coordinator: coordinates study procedures, responsible for administrative tasks, reviews study progressStudy therapists: responsible for the implementation of the therapiesClinical raters: responsible for conducting independent clinical evaluations with respect to outcome criteria and inclusion and exclusion criteria | PMC9974392 | ||
Data monitoring committee | ADVERSE EFFECTS | There is no data monitoring committee and no independent auditing process. The quality of the data is assured by the blinded clinical raters and there are no known serious adverse effects. If serious adverse effects occur, they will be reported to the principal investigator, who will then interview the patient in question and refer them to a psychiatry if needed. Adherence to therapeutic measures is ensured by regular supervision by the principal investigators. Completeness of data will be regularly verified by the study coordinators. | PMC9974392 | |
Data management and confidentiality | Questionnaires will be answered online. The screening is the only time participants enter personal contact information. In the subsequent assessments and questionnaires, participants are identified by a random computer-generated code. Other than the study coordinators, only therapists and clinical raters know the participant’s name. The anonymized data is stored in an encrypted folder on a protected research server at Goethe University Frankfurt. There is also a separate encrypted list that contains only contact information and the code so that participants can be contacted if needed. This list is deleted after the study, so that only the codes with the assigned data remain. The program R is used to analyze the data. The results of the study will be published only in peer-reviewed journals. The informed consent form will be kept in a locker at the outpatient clinics of the universities of Frankfurt and Dresden. | PMC9974392 | ||
Relevant concomitant care and interventions that are permitted or prohibited during the trial | There is no concomitant care additional to the intervention groups that we already described. If there are medical conditions of the patients, that need to be treated right away, patients will be send to a physician. If patients start a different psychotherapy while being part of the study, they will drop out. | PMC9974392 | ||
Trial status | RECRUITMENT, RECRUITMENT | Recruitment began in July 2022. The current protocol is version 2 of 16 December 2022. There have been no patients enrolled into the trial so far (16 September 2022). Approximate date of completed recruitment: 31 December 2023. | PMC9974392 | |
Authors’ contributions | US and JH: principal investigators. JMS: protocol development, trial coordination. JS: trial coordination, administrative tasks. CB: design of statistical analysis, trial coordination. CC: optimizing the protocols. All authors participated in the development of the app, contributed to the manuscript, and approved the final version. | PMC9974392 | ||
Funding | Open Access funding enabled and organized by Projekt DEAL. This study is funded by Mindable Health GmbH, Berlin, Germany. The funders do not have a role in collection, analysis, and interpretation of data. | PMC9974392 | ||
Availability of data and materials | The data used in this study, including for example, the R code for randomization, are available from the corresponding authors upon reasonable request. | PMC9974392 | ||
Declarations | PMC9974392 | |||
Ethics approval and consent to participate | The study has been approved by the ethics committee of the psychology department of the Goethe University Frankfurt. All participants provide written informed consent. All substantial amendments will be reported to the responsible ethics committee, e.g., if there are changes that need to be made because it might affect the mental or physical health of participants. | PMC9974392 | ||
Consent for publication | Not applicable—no identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. Informed consent materials are available from the corresponding author on request. | PMC9974392 | ||
Competing interests | The authors declare that they have no competing interests. | PMC9974392 | ||
References | PMC9974392 | |||
Objective | knee arthroplasty, VTE, venous thromboembolism | To investigate the optimal duration of applying a venous foot pump (VFP) in the prevention of venous thromboembolism (VTE) following hip and knee arthroplasty. | PMC10691185 | |
Methods | intermuscular DVT, pain, Postoperative blood coagulation, DVT | DEEP VEIN THROMBOSES, DVT | A total of 230 patients undergoing hip and knee arthroplasty between March 2021 and March 2022 in orthopaedic departments of four major teaching hospitals were prospectively enrolled. Patients were randomly divided into five groups based on the duration of the VFP application. Postoperative deep vein thromboses (DVT), including proximal, distal, and intermuscular DVT, were recorded for analysis. Postoperative blood coagulation examinations, such as D-dimer and active partial thromboplastin time (APTT), pain outcome, and degree of comfort were also collected. | PMC10691185 |
Results | DVT | DVT | Two of the 230 patients withdrew due to early discharge from the hospital, and 228 patients were included in the final analysis. The mean age was 60.38 ± 13.33 years. The baseline characteristics were comparable among the five groups. Compared with the other groups, patients treated with 6-hour VFP had the lowest incidence of DVT (8.7%, 4/46), followed by those treated with 1-hour VFP (15.2%, 7/46), 12-hour VFP (15.6%, 7/45), 18-hour VFP(17.8%, 8/45) and 20-hour VFP(21.7%, 10/46), but with no significant difference ( | PMC10691185 |
Conclusions | knee arthroplasty, VTE, postoperative blood coagulation, pain | Six hours may be the optimal duration of applying VFP for the prevention of VTE in patients undergoing hip and knee arthroplasty in terms of VTE incidence, postoperative blood coagulation examinations, pain outcomes, and comfort scores. | PMC10691185 | |
Supplementary Information | The online version contains supplementary material available at 10.1186/s12891-023-06921-w. | PMC10691185 | ||
Keywords | PMC10691185 | |||
Background | knee arthroplasty, abnormal coagulation of blood in the vein, VTE | COMPLICATIONS, VENOUS THROMBOEMBOLISM | Venous thromboembolism (VTE) is a serious health issue worldwide. It refers to the abnormal coagulation of blood in the vein. VTE is one of the most important complications after orthopaedic surgery [Currently, the preventive strategies for VTE mainly include pharmacologic and mechanical thromboprophylaxis among patients treated with knee and/or hip replacement. Pharmacologic thromboprophylaxis included direct or indirect thrombin inhibitors, vitamin K antagonists, and factor Xa inhibitors. Mechanical thromboprophylaxis includes graduated compression stockings, intermittent pneumatic compression, venous foot pumps (VFPs), and transcutaneous electrical nerve stimulation [Therefore, the present study aimed to investigate the optimal duration of applying VFP for the prevention of VTE in patients receiving hip and knee arthroplasty. A multicenter prospective clinical trial was conducted to generate high-quality evidence. | PMC10691185 |
Patients and methods | PMC10691185 | |||
Patients and study design | knee arthroplasty, VTE | A total of 230 patients undergoing hip and knee arthroplasty between March 2021 and March 2022 in orthopaedic departments of four major teaching hospitals, including the First Medical Center of Chinese PLA General Hospital, the Fourth Medical Center of Chinese PLA General Hospital, Hainan Hospital of Chinese PLA General Hospital, and the First Affiliated Hospital of Suzhou University, were prospectively enrolled. The inclusion criteria were as follows: (1) patients receiving hip and/or knee arthroplasty, (2) aged ≥ 18 years, (3) had a Caprini score of ≥ 3 points [
A flowchart of patient enrolment processAll patients voluntarily participated in the study and written informed consent was obtained from each patient. This study was approved by the Medical Ethics Committee of Chinese PLA General Hospital (No. 2021-002-01) and the First Affiliated Hospital of Suzhou University (No. 2,021,053). We registered our study in the Chinese Clinical Trial Registry (02/01/2022) (ChiCTR2200055166). Data and materials are available upon reasonable request with the permission of the corresponding authors.According to the expert consensus on mechanical prevention of VTE in China, the longest recommended time was ≥ 18 h per day. A previous study pointed out that 6–9 h per day could also be effective in the prevention of VTE [ | PMC10691185 | |
Sample calculation | The study referred to the formula of multiple independent sample rates: n = | PMC10691185 | ||
Randomization and blinding | Patients were randomly divided into five groups by computer random method based on the duration of the VFP application. SPSS26.0 software was used to generate a random sequence, and the random assignment scheme was saved in light-tight envelopes. Envelopes were opened sequentially in the order of enrollment, and patients were assigned to the assigned group according to the assignment scheme in the envelope. Four centers enrolled participants at the same time. Enrollment was terminated when the total number of participants reached the final required sample size. Because patients and study operators were aware of device use, the study was blinded only to study personnel who performed the ultrasonography. | PMC10691185 | ||
Interventions | All patients received pharmacologic and mechanical thromboprophylaxis [
The foot venous pump worn by the patient | PMC10691185 | ||
Primary outcome | DVTs, DVT, intermuscular DVT, thromboses, postoperative DVT, dilated vena cava | DVT | The primary outcome was postoperative DVT, including proximal DVTs such as thromboses in the popliteal vein, femoral vein, or iliac vein, distal DVTs such as thromboses in the anterior tibial vein, posterior tibial vein, or peroneal vein, and intermuscular DVT. DVT was examined using colour Doppler flow imaging at postoperative day 3. The diagnostic criteria of DVT were: (1) dilated vena cava, (2) substantial echo, and (3) intraluminal filling defect. If the symptoms of PE were observed in patients, pulmonary arteriography was applied. | PMC10691185 |
Secondary outcome | postoperative blood coagulation, pain | SECONDARY | The secondary outcome included postoperative blood coagulation examinations, such as D-dimer and active partial thromboplastin time (APTT), pain outcome, and the degree of comfort. D-dimer and APTT were recorded on postoperative days 1 and 3. The visual analog scale (VAS) [ | PMC10691185 |
Variables and definitions | blood loss, diabetes | BLOOD LOSS, HYPERTENSION, DIABETES | Patient’s baseline characteristics included (1) demographics such as age, sex, nationality, body mass index (BMI), temperature, heart rate, respiration rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), blood type, hypertension, and diabetes, (2) surgery-related information such as the type of surgery, type of anesthesia, blood loss, operation time, catheterization, blood transfusion, perioperative use of hemostatics, drainage, and perioperative use of the hormone, and (3) preoperative laboratory examinations such as thrombin time (TT), APTT, prothrombin time (PT), D-dimer, fibrin, hemoglobin, platelet count, and erythrocyte sedimentation rate (ESR). The patient’s temperature, heart rate, respiration rate, SBP, and DBP were collected on the first day after hospitalization. Operation time was defined as the time from skin incision to skin closure. | PMC10691185 |
Quality control | dehydration, bleeding, thrombus, VTE | DEHYDRATION, BLEEDING, THROMBUS | A series of measures were considered to guarantee the quality of the study. Firstly, all investigators were trained on how to evaluate patients using the Caprini thrombus risk assessment scale, and all patients received the same education on thrombus prevention, including signs and symptoms of VTE and bleeding, the importance of seeking help if symptoms develop, and conservative measures to prevent VTE such as ambulation and avoiding dehydration. Secondly, an ultrasound physician with the same qualification was designated to complete the ultrasound examination and diagnosis of VTE for enrolled patients in each center. In addition, ultrasound physicians were blinded to the patient’s categories. Thirdly, Each center designated a responsible nurse as a researcher in the center to collect the data. The unified data collection form and the same type of measuring instrument were used to ensure the compliance of data collection and reduce measurement bias. The data were regularly recorded and summarized, and quality control was monitored and audited at any time to ensure the integrity and accuracy of all data. | PMC10691185 |
Statistical analysis | DVT | DVT | Categorical variables were expressed as proportion and continuous variables as the mean ± standard deviation. The chi-square test was utilized to evaluate differences between categorical variables and analysis of variance (ANOVA) was used to compare the means between three or more groups for continuous variables. Repeated measures ANOVA was used to analyze D-dimer and APTT. If sphericity was violated (Mauchly’s Test of Sphericity), Greenhouse-Geisser correction was applied. Multivariate analysis was used to screen potential risk factors for predicting DVT, and the area under the receiver operating characteristic (AUROC) curve was used to evaluate the predictive performance of each significant variable. All data were analyzed using SPSS (Version 26.0) or R programing language (Version 4.1.2). A P-value of less than 0.05 (two-sided) was considered statistically significant. | PMC10691185 |
Results | PMC10691185 | |||
Baseline characteristics | Two of the 230 patients withdrew due to early discharge from the hospital. Thus, 228 patients were included in the final analysis. The mean age was 60.38 ± 13.33 years. The majority of patients were females, accounting for 63.2% of all patients. Regarding the surgical site, the right knee accounted for 31.6%, followed by the left hip (21.1%) and right hip (20.2%). The mean BMI was 25.70 ± 4.23 kg/m
Baseline characteristicsBMI: body mass index; TT: thrombin time; APTT: active partial thromboplastin time; PT: prothrombin time; ESR: erythrocyte sedimentation rate | PMC10691185 | ||
Comparison of the incidence of DVT among the five groups | VTE, venous thromboembolism, DVT | DEEP VEIN THROMBOSES, DVT | Compared with the other groups, patients treated with 6-hour VFP had the lowest incidence of DVT (8.7%, 4/46), followed by 1-hour VFP (15.2%, 7/46) and 12-hour VFP (15.6%, 7/45) (
Histogram of patient groups with venous thromboembolism.
Comparison of the incidence of VTE between groupsVTE: venous thromboembolism; DVT: deep vein thromboses | PMC10691185 |
Comparison of D-dimer and APTT AMONG the five groups | timeP | SECONDARY | D-dimer significantly increased on a postoperative day 1 compared with that on preoperative 1 day, and it significantly decreased on postoperative day 3 among all five groups (
Radar chart of secondary outcomes in the five groups.
Comparison of D-dimer levels and APTT between the five groups before and after surgeryAPTT: active partial thromboplastin timeP | PMC10691185 |
Comparison of pain and comfort outcomes among the five groups | pain | The 6-hour VFP group had the lowest pain score (
Comparison of pain and comfort scores between five groups before and after surgeryVAS: visual analogue scaleP | PMC10691185 | |
Analysis of risk factors for predicting DVT | DEEP VEIN THROMBOSIS | Multivariate analysis revealed that older age (
The area under the receiver operating characteristic curves for variables used to predict deep vein thrombosis.
Multivariate analysis of risk factors for predicting deep vein thrombosesOR: odds ratio; CI: confident interval; LL: lower limit; UP: upper limit; BMI: body mass index; TT: thrombin time; APTT: active partial thromboplastin time; PT: prothrombin time; ESR: erythrocyte sedimentation rate | PMC10691185 | |
Discussion | PMC10691185 | |||
Main findings | postoperative blood coagulation, DVT, knee arthroplasty, pain, VTE | DVT | The present study investigated the duration of applying VFP for the prevention of VTE in patients receiving hip and knee arthroplasty and found that six hours a day might be the optimal duration of using VFP in terms of VTE incidence, postoperative blood coagulation examinations, pain outcomes, and comfort scores. Patients treated with 6-hour VFP had the lowest incidence of DVT, lowest D-dimer, highest APTT, lowest pain score, and highest comfort score, compared with the other four groups, suggesting that 6-hour VFP was the most favorable duration of VFP application. Additionally, a series of risk factors for predicting DVT was identified in the study. To the best of our knowledge, this is the first study to explore the optimal duration of VFP application in patients undergoing hip and knee arthroplasty in a multicenter prospective clinical trial. | PMC10691185 |
Incidence of VTE in arthroplasty | knee arthroplasty, VTE | Previous studies showed that the incidence of VTE after hip and knee arthroplasty was 20.6–58.2% [In addition, our study showed that the D-dimer was decreased and APTT was increased after using VFP, and the difference was statistically significant ( | PMC10691185 | |
Duration of VFP application for prevention of VTE | VTE, pain | EVENTS | At present, there is no consensus on the duration of VFP application to prevent VTE events in patients undergoing knee and hip orthopaedic surgery. Some studies have proposed the continuous application of 20-hour VFP, while others have recommended a 30-minute to 1-hour VFP application. Charalambous et al. [Comfort scores improved in all groups after VFP application, and pain scores gradually decreased, all with statistically significant differences ( | PMC10691185 |
Mechanism of using VFP for prevention of VTE | intermuscular DVT, VTE, DVT | STASIS, CONTRACTION, DVT | The mechanism of using VFP for the prevention of VTE involves venous hemodynamics of the lower extremity, which is mainly relevant to the physiology of the human plantar venous pump. Through pulsatile pressure release, VFP promotes venous blood return by rapidly squeezing blood from the plantar venous plexus back into the lower limbs [However, VFP has a minimal impact on the venous blood flow between the calf muscles, which might explain why the incidence of intermuscular DVT was 12.7% and the distal DVT was only 3.1% in the present study. Hence, additional interventions are recommended to promote blood return to intermuscular veins of the lower leg when using VFP. Ankle pump exercises as one of the commonly used basic prophylactic measures can activate the calf muscle pump, which accelerates venous blood flow in the lower limbs and alleviates blood stasis through regular contraction and relaxation occurring in the calf flounder and tibialis anterior muscles [ | PMC10691185 |
Risk factors for predicting DVT | VTEs, DVT | DVT | Multivariate analysis demonstrated that older age, higher temperature, lower SBP, AB or B blood type, drainage, and lower platelet count were significantly positively associated with DVT. Previous studies found that older age [We also found that patients with non-O blood types—especially type B or AB—were at a significantly higher risk for DVT. Several previous studies reported that individuals with non-O blood types (A, B, and AB) had an increased risk of VTEs [ | PMC10691185 |
Limitations | VTE | COMPLICATIONS | This study has study several drawbacks. First, this study only investigated the early prognosis of applying VFP to prevent VTE; the follow-up was only three days after surgery, while relative long-term outcomes were not evaluated in the study. Second, this study did not assess the occurrence of complications such as skin pressure injuries, which is crucial to ensure the safety of VFP for the duration of application. Thus, validation studies are still warranted in the future. Finally, due to the small sample size of this study, no definite conclusion can be drawn. In the future, multi-center studies with large samples are needed to provide more robust evidence for the standardized application of plantar venous pumps in clinical practice. | PMC10691185 |
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