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Consent for publication | Not applicable. | PMC10476380 | ||
Competing interests | FB reports consulting fees from Löwenstein Medical and Air Liquid Medical Systems and research support from Covidien and Getinge Group, outside this work, and research support from GE Healthcare related to this work. JCR reports part‐time salary for research activities from Air Liquide Medical Systems and grants from Creative Air Liquide, outside this work. PYO reports personal fees from Air Liquid Medical Systems, outside this work. AL is a PhD student in the Med | PMC10476380 | ||
References | PMC10476380 | |||
Key Points | PMC10346120 | |||
Question | viral suppression | Does the Friendship Bench intervention improve antiretroviral therapy (ART) adherence, viral suppression, and mental health symptoms in people living with HIV in rural Zimbabwe? | PMC10346120 | |
Findings | In this cluster randomized trial of 516 participants, the intervention showed no significant effect on adherence to ART. | PMC10346120 | ||
Meaning | The intervention did not affect adherence, possibly due to the absence of skill-based adherence training and the ceiling effect. | PMC10346120 | ||
Importance | CMD, depression, anxiety, Common mental disorders | Common mental disorders (CMD), which include depression and anxiety, are prevalent among people living with HIV and are associated with suboptimal antiretroviral therapy (ART) adherence. | PMC10346120 | |
Objective | virologic suppression | To assess the effect of a lay health worker–led psychological intervention on ART adherence, virologic suppression, and mental health symptoms. | PMC10346120 | |
Design, Setting, and Participants | CMD, psychosis | DISEASE, RECRUITMENT | Open-label pragmatic cluster trial with 1:1 block randomization of 16 health facilities in rural Bikita, Zimbabwe. Recruitment occurred from October 2018 to December 2019, and participants were followed up for 12 months, ending in December 2020. Participants were adults aged 18 years and older, who spoke English or Shona, screened positive for CMD (Shona Symptoms Questionnaire [SSQ]-14 score ≥9), received first-line ART for 6 or more months, had no World Health Organization stage 4 disease, no psychosis, were not pregnant, and provided informed consent. Data were analyzed from March 2021 to February 2022. | PMC10346120 |
Intervention | The Friendship Bench, consisting of 6 lay health worker–led weekly problem-solving therapy sessions and optional peer-led group support. | PMC10346120 | ||
Main Outcomes and Measures | SECONDARY | The primary outcome was mean adherence during 2 to 6 months of follow-up, and the secondary outcomes were mean adherence during 1 to 12 months of follow-up, change in SSQ-14 and Patient Health Questionnaire (PHQ-9) scores (3, 6, 9, and 12 months), and viral load suppression (6 and 12 months). | PMC10346120 | |
Results | A total of 516 participants were recruited (244 in Friendship Bench and 272 in enhanced standard care facilities); 438 (84.9%) were female and the mean (SD) age was 45.6 (10.9) years. Mean (SD) adherence between 2 to 6 months was 89.9% (18.4%) in the Friendship Bench group and 87.2% (20.1%) in the control group. The intervention had no statistically significant effect on adherence between 2 to 6 months (unadjusted mean difference, 1.93 percentage points; 95% CI, −1.20 to 5.06 percentage points; | PMC10346120 | ||
Conclusions and Relevance | CMD | In this randomized trial of HIV-positive participants with CMD, the Friendship Bench intervention had no effect on adherence and viral suppression, possibly due to the absence of skill-based adherence training and a ceiling effect. | PMC10346120 | |
Trial Registration | ClinicalTrials.gov Identifier: | PMC10346120 | ||
Introduction | HIV is vital for improving mental health, HIV in 2020.Treating mental disorders | Zimbabwe carries a high HIV burden, with an estimated 1.2 million people living with HIV in 2020.Treating mental disorders in people with HIV is vital for improving mental health | PMC10346120 | |
Methods | PMC10346120 | |||
Ethics Statement | Ethics committees of the Medical Research Council of Zimbabwe, the Research Council of Zimbabwe, and the Canton of Bern, Switzerland approved the study. Individuals provided written informed consent. This report follows the Consolidated Standards of Reporting Trials ( | PMC10346120 | ||
Study Design | The study was a pragmatic cluster randomized open-label superiority trial in 16 health facilities in rural Zimbabwe (see | PMC10346120 | ||
Setting | AIDS | AIDS | Bikita is a rural district about 300 km south of Harare. From 18 facilities participating in the International Epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA),ART followed national treatment guidelines, except for additional CD4 testing at baseline and additional viral load testing at baseline, 6, and 12 months. | PMC10346120 |
Randomization and Masking | RECRUITMENT | We randomized 16 health facilities in a 1:1 ratio to intervention or control group. Randomization was stratified by health facility size (3 strata). All facilities were randomized at the same time using block randomization with a block size of 2 within each stratum. Treatment assignment was known to participants, clinicians, evaluators, and data analysts. Participant recruitment occurred after randomization. See eMethods in | PMC10346120 | |
Participants | psychotic symptoms, CMD | DISEASE | We assessed study eligibility of individuals waiting for ART clinic appointment. Adults aged 18 years or older from Bikita who spoke English or Shona, screened positive for CMD (Shona Symptoms Questionnaire [SSQ]-14 score ≥9), had received first-line ART for at least 6 months, had no World Health Organization (WHO) stage 4 disease, no psychotic symptoms, were nonpregnant, and provided informed consent were eligible ( | PMC10346120 |
Trial Profile | ART indicates antiretroviral therapy; SSQ-14, Shona Symptoms Questionnaire-14; WHO, World Health Organization. | PMC10346120 | ||
Interventions | CMD, psychiatric | Participants in the intervention group were offered the FB intervention in addition to enhanced standard of care (SC). Participants in the control group received SC only.The FB intervention consisted of 6 weekly individual counseling sessions and an optional peer-led group support. Trained lay health workers facilitated these sessions, following a structured approach to identify problems, including adherence issues, and to foster a positive attitude toward resolving them. Lay health workers were selected from the existing pool of village health workers, regardless of sex or HIV status. Two FB trainers trained lay health workers in the FB program’s manualized protocol. Clinic nurses, trained in FB supervision, regularly supervised lay health workers. The intervention was delivered on a park bench at the health facilities or in clinic consultation rooms, making it easily accessible for individuals.After 4 sessions, participants were invited to join a peer-led group activity where they were trained in income-generating skills (eg, producing bags from recycled plastic). The support groups were initiated and facilitated by the lay health workers who provided the individual counseling sessions. These groups offered continuous support from lay health workers and peers. The FB intervention is described in detail elsewhere.SC consisted of nurse-led brief counseling, education regarding CMD, prescription of an antidepressant (fluoxetine), or referral to a psychiatric facility if indicated (see eMethods in | PMC10346120 | |
Measures | EVENT | We used the Medication Event Monitoring System (MEMS) electronic pill box (AARDEX) to measure adherence. We calculated monthly mean adherence as the percentage of days participants opened the box once or twice (depending on the regimen). We treated adherence of less than 10% as missing, assuming participants did not use their MEMS device. We assessed self-reported baseline adherence according to 30-day recall. eMethods in Research assistants administered the SSQ-14 | PMC10346120 | |
Outcomes | CMD, depression | The primary outcome was mean adherence between 2 to 6 months of follow-up. Secondary outcomes included mean adherence between 1 to 12 months; change from baseline SSQ-14 and PHQ-9 score at 3, 6, 9, and 12 months; and change in viral suppression (viral load <1000 copies per mL) at months 6 and 12; and positive screening for CMD (SSQ-14 score ≥9) and depression (PHQ-9 score ≥11) at 3, 6, 9, and 12 months. | PMC10346120 | |
Sample Size | The study was powered to detect an absolute 10% difference in mean adherence | PMC10346120 | ||
Statistical Analysis | viral suppression | SECONDARY | The primary analysis was per intention to treat. We first calculated participants’ monthly mean adherence scores and then analyzed these scores using linear mixed-effects models to assess the difference in mean adherence. Models included a random intercept and slope to account for the correlation within participants. A random intercept accounted for the clustering of individuals in health facilities, indicators defined treatment assignment, the month of analysis time (categorical), and interactions between the 2. Subsequently, we calculated the average difference in mean adherence between months 2 to 6 and 1 to 12 based on contrasts. We estimated odds ratios (ORs) for the difference in the proportion of participants with viral suppression at 6 and 12 months using logistic mixed-effect models. We conducted prespecified adjusted analyses of mean adherence and viral suppression, controlling for facility size, age, and sex. In post hoc sensitivity analyses, we adjusted for facility size, age, sex, self-reported baseline adherence, baseline SSQ-14 score, ART regimen, PHQ-9 score, WHO clinical stage, CD4 cell count, viral suppression, AUDIT-C score, MOS-SS score, and travel cost. We also assessed the difference in change from baseline in SSQ-14 and PHQ-9 scores using the same linear mixed-effects model as described previously but adjusted for the baseline score. We used the logistic mixed-effect models described previously to assess the difference in the proportion of participants with an SSQ-14 score of 9 or higher and a PHQ-9 score of 11 or higher at 3, 6, 9, and 12 months. We repeated analyses of primary and secondary outcomes using a per-protocol analysis, excluding participants who did not receive the allocated intervention and those with missing adherence data between months 2 to 6. Missing data were imputed using multiple imputation by chained equations. | PMC10346120 |
Results | PMC10346120 | |||
Participants and Baseline Characteristics | In this study, 516 individuals (mean [SD] age 45.6 [10.9] years; 438 [84.9%] female) were included, with 244 participants in 8 clusters in the FB group and 272 participants in 8 clusters in the control group ( | PMC10346120 | ||
Sociodemographic and Clinical Characteristics of Participants at Baseline | depressive | DISORDERS | Abbreviations: ART, antiretroviral therapy; AUDIT-C, Alcohol Use Disorders Identification Test-Concise Test; HFIS, Household Food Insecurity Access Scale; MOS-SS, Medical Outcomes Study Social Support; NNRTI, nonnucleoside reverse transcriptase inhibitors; PHQ, Patient Health Questionnaire; SSQ, Shona Symptoms Questionnaire; WHO, World Health Organization.The SSQ-14 score ranges from 0 (no symptom) to 14 (all symptoms present).The PHQ-9 score is ranging from 0 (no depressive symptoms) to 27 (severe depressive symptoms).To recruit this sample, we assessed the eligibility of 3706 individuals between October 5, 2018, and December 19, 2019, and excluded 3190 participants (86.1%) ( | PMC10346120 |
Outcomes | In unadjusted analyses, the primary outcome of mean (SD) ART adherence between months 2 and 6 was slightly higher in the FB group (89.9% [18.4]) than in the SC group (87.2% [20.1]) (mean difference, 1.93 percentage points; 95% CI, −1.20 to 5.06 percentage points; | PMC10346120 | ||
Adherence, Viral Load Suppression, Shona Symptoms Questionnaire (SSQ)-14 Score, and Patient Health Questionnaire (PHQ)-9 Score by Group | Figure shows mean monthly adherence scores (A), proportions of participants with viral load of less than 1000 copies/mL (B), mean SSQ-14 scores, and mean PHQ-9 scores. Error bars represent 95% CIs for means and proportions. FB indicates Friendship Bench; SC, standard care. | PMC10346120 | ||
Effect of the Friendship Bench Intervention on Adherence, Viral Load, and Mental Health | Abbreviations: PHQ, Patient Health Questionnaire; SSQ, Shona Symptoms Questionnaire.All analyses were prespecified and accounted for clustering of individuals in health facilities.Adjusted for facility size, age, and sex. | PMC10346120 | ||
Retention | Retention in the FB and adherence interventions was high ( | PMC10346120 | ||
Retention in Mental Health and Adherence Interventions | Abbreviations: NA, not applicable; VL, viral load. | PMC10346120 | ||
Safety Outcomes | deaths, psychiatric, self-harm | EVENT | In total, 16 participants reported self-harm or attempted self-harm; 11 (4.5%) were in the FB group and 5 (1.8%) were in the SC group. In the FB group, 9 participants (3.7%) reported a history of self-harm before baseline, and 2 participants (0.8%) reported a new incident self-harm event after baseline. No new incident self-harm event after baseline was reported in the SC group. No psychiatric hospitalizations occurred. Five participants died in the FB group and 1 in the SC group. All deaths were unrelated to study procedures, and no deaths by suicide were recorded or suspected (eTable 3 in | PMC10346120 |
Discussion | depression, CMD, virologic suppression, viral suppression | In this cluster randomized trial, we examined the effect of the FB intervention on ART outcomes and mental health symptoms in adults with HIV in rural Zimbabwe. The intervention did not demonstrate a clear effect on ART adherence, viral suppression, and symptoms of depression (PHQ-9 scores) but had a beneficial effect on CMD symptoms (SSQ-14 scores). Characteristics of the study population at enrollment, including the high proportion of women, high baseline adherence, high baseline viral suppression rates, and relatively low mean PHQ-9 scores, may have contributed to the negative findings of this trial. The FB intervention was found to be a feasible and acceptable approach to address the mental health care needs of the rural study population. Implementing this psychological intervention led by lay health workers in rural health facilities was successful, with almost 90% of participants attending all 6 individual counseling sessions, reflecting their satisfaction and intervention appropriateness.With the present study, 3 trials show that the FB intervention can reduce CMD symptoms (eFigure in Two of the 3 trials examined virologic suppression (this study and the trial among adolescents | PMC10346120 | |
Strengths and Limitations | CMD | Our study’s strengths include a large sample size, long follow-up, and pragmatic study design resembling clinical practice conditions in rural Zimbabwe. Further strengths of our study include using electronic pill bottles for adherence monitoring and using a locally developed tool to measure CMD symptoms.Our study has several limitations. First, the mental health screening tools used in this study have been validated in Harare but not in the rural study setting, where our study took place. | PMC10346120 | |
Conclusions | nonadherence, CMD, virologic failure | The FB intervention had no effect on adherence and viral suppression, possibly due to the absence of skill-based adherence training and ceiling effect. The intervention improved CMD symptoms, but the effect was smaller than previously shown in an urban setting. More work is needed to evaluate the effect of the approach on HIV outcomes in different populations, including young adults, men, and populations with more severe symptoms at higher risk of nonadherence and virologic failure. The further development of the FB intervention to incorporate adherence training may be a promising approach to reach those at high risk of poor HIV outcomes. | PMC10346120 | |
Objective | METASTASIS | Lumbosacral vertebral osteoblastic metastasis is treated with percutaneous vertebroplasty (PVP) combined with | PMC10731753 | |
Methods | METASTASES | We retrospectively analyzed 62 patients with lumbosacral vertebral osseous metastases treated at our hospital between 2016 and 2019. All the patients met the inclusion criteria for | PMC10731753 | |
Results | pain | Compared to the PVP treatment group, the pain level in the combined treatment group was significantly reduced ( | PMC10731753 | |
Conclusions | PVP combined | PMC10731753 | ||
Keywords | PMC10731753 | |||
Material and Methods | PMC10731753 | |||
Clinical data collection | Low back pain, pain, organ failure, primary malignant tumor, Cancer | PRIMARY TUMOR, DISEASES OF THE HEART, SPINAL METASTASES, CANCER | The subjects of this study were inpatients in the Department of Orthopedics, Chengdu Seventh People’s Hospital (Affiliated Cancer Hospital of Chengdu Medical College), between February 2016 and June 2019.The inclusion criteria were (a) clinical diagnosis of spinal metastases with a pathological diagnosis of the primary tumor or diseased vertebral body, (b) osteogenetic destruction of the lumbosacral vertebrae, (c) Low back pain is the main clinical manifestation, (d) expected survival time > 3 months, (e) Frankel classification of spinal cord function evaluation grade D, Karnofsky Performance Status (KPS) score > 60 points, (f) systemic conditions permit the procedure; no serious diseases of the heart and brain and other important organs, and ability to lie in the prone position for 1–2 h (g) persistent pain, no significant improvement with drugs, physical therapy, among others. (h) All patients received conventional chemotherapy and other comprehensive treatments according to the primary tumor regimen after the operation.The exclusion criteria were as follows: (a) diagnosed as primary malignant tumor of the spine, (b) refused or unable to cooperate with the completion of clinical data collection or follow-up because of objective reasons, (c) patients or their family members refuse surgical treatment, (d) KPS score ≤ 40 or combined with heart, lung and other organ failure and unable to tolerate surgery. | PMC10731753 |
Surgical materials and instruments |
Bone cement injection molding instruments and medicinesDOMEStic PVP instruments, including a puncture needle and screw-in syringe pressure device (Shandong Guanlong Company) (Fig. Percutaneous vertebroplasty devicesRadioactive sourceThe closed radioactive isotope Contrast agentWe used 76% compound meglumine injection, packaged in 20 mL/15.2 g, with an iodine content of 370 mg/mL as a contrast agent (Schering (Guangzhou) Pharmaceutical Co., Ltd., China). | PMC10731753 | ||
Research methods | tumor, isodose | TUMOR | The injection doses of bone cement and I ions, as well as the needle insertion coordinates and depth indications of the applicator, were calculated using the treatment planning system (TPS) software. Specifically, routine preoperative examinations included routine blood tests, blood type, coagulation, blood sugar, liver and kidney function, electrocardiogram, chest radiography, anterior and lateral radiographs of the diseased vertebra, computed tomography (CT), magnetic resonance imaging (MRI), and whole-body bone scans. If conditions permit, a positron emission tomography-computed tomography (PET-CT) examination was performed. Before surgery, CT/MRI images of each patient were scanned into the TPS software for three-dimensional digital image reconstruction. Three-dimensional icons, isodose curves, and absorbed dose indications were accurately formulated and drawn based on the size, location, and relationship with the surrounding normal tissues of the lesion. At the same time, the initial dose of the radiation source required for clinical use, needle insertion coordinates, and depth indications of the applicator are determined, and the treatment plan table is printed out.The treatment plan was determined based on the tumor source, lesion segment, spinal stability, and degree of intraspinal compression after discussion in the department, and an individualized comprehensive treatment plan was determined. The patients and their families were informed of the treatment plan, and informed consent was obtained from all patients. | PMC10731753 |
Patient grouping | The patients treated with PVP combined with | PMC10731753 | ||
Clinical data collection | pain | We explained the purpose and significance of the clinical investigation to the patient, solicited their cooperation and trust, determined the initial visual analog pain scale (VAS) and KPS scores, and recorded the results. | PMC10731753 | |
Postoperative treatment | dehydration, infection | DEHYDRATION, INFECTION, LEAKAGE | Postoperative CT scans were used to observe the distribution of bone cement and particles in the vertebral body, whether there was bone cement leakage, among others; observe the symptoms and signs of the patient, whether there was an infection, among others; and provide preventive anti-inflammatory, hemostasis, dehydration, etc., and nutritional nerve processing. | PMC10731753 |
Postoperative follow-up | The patients were instructed to retest the VAS before surgery and at 1 month, 3 months, 6 months, 1 year, and 3 years after surgery to evaluate recovery. The KPS was monitored before surgery and at 1 month after surgery. | PMC10731753 | ||
Statistical methods | PRIMARY TUMOR, REGRESSION, METASTASIS | All data were analyzed using SPSS version 20.0 software (IBM Corp., Armonk, N.Y., USA). A All patients in this group were scored using the KPS scoring system before and 1 month after the operation, and a Univariate analysis (Kaplan–Meier analysis) was conducted. Patients were divided into groups according to sex, age, location, KPS score, VAS score, primary tumor growth, organ metastasis, and surgical method. Univariate survival analysis was performed between the groups and the Kaplan–Meier method was used to analyze the survival time of patients and determine whether each factor affected survival time.For each prognostic factor (sex, age, location, KPS score, VAS score, primary tumor growth, organ metastasis, and surgical method), a multivariate Cox proportional hazards regression model was used. | PMC10731753 | |
Results | PMC10731753 | |||
Basic information on the selected patients | METASTASIS, BONE METASTASES | In total, 62 patients with lumbosacral bone metastases were randomly divided into a PVP combined with Preclinical data analysis of 62 cases of osteoblastic metastasis in patients with lumbosacral vertebral | PMC10731753 | |
Evaluation of clinical efficacy | All patients in the combined treatment group were followed up after surgery, and the patients and their families cooperated to complete the evaluation of various efficacy indicators. At the end of the study, 14 of the 31 patients survived. Similarly, all patients in the pure PVP group were followed up after surgery, and they were willing to cooperate in evaluating various efficacy indicators. At the end of the study, five of the 31 patients survived. | PMC10731753 | ||
Univariate analysis | PMC10731753 | |||
Kaplan–Meier analysis | tumor | PRIMARY TUMOR, TUMOR, METASTASIS, METASTASES | The log-rank method was used to compare the effects of sex, age, location, KPS score, spinal segment, primary tumor growth, organ metastasis, and surgical method on the survival rate of patients. Survival curves of the survival rates are shown in Table Survival time for 62 cases of lumbosacral vertebral osteoblastic metastasisKaplan–Meier analysis and the log-rank test comparing the influence of factors, such as sex, age, tumor metastases, viscera metastasis, KPS score, spine transfer section, and primary tumor growth, surgical approach on patients’ survivalThe results showed that there was no significant difference in the survival rate between male and female patients with lumbosacral osteoblastic metastases (The survival rate of patients with a preoperative KPS score of 60–70 was significantly lower than that of patients with a score of 80–100 (To determine the effects of different surgical methods on the progression-free survival rate of patients with lumbosacral osteoblastic metastases, we used the Kaplan–Meier log-rank method for comparison. The survival curves comparing the different surgical modalities are shown in Fig. | PMC10731753 |
Cox regression multivariate analysis | REGRESSION, METASTASIS, METASTASES, PRIMARY TUMOR | As a multivariate survival analysis model, the Cox regression model can effectively process the final examination data, control various confounding factors, quantitatively analyze the effect strength and direction of the observation indicators, and comprehensively analyze the effect of prognostic factors. To further determine the factors affecting the survival rate of patients with lumbosacral osteoblastic metastases, we analyzed all covariates using the Cox regression equation.The patient’s sex, age, location, preoperative KPS score, spinal segment, primary tumor growth, organ metastasis, and surgical method were included in the multivariate Cox proportional hazards regression model. The variables and their respective values that finally contributed to the effect equation are presented in Table Sixty-two cases of lumbosacral vertebral osteoblastic metastasis multivariate Cox regression analysisCox regression analysis showed that age, primary tumor, and metastatic spinal segment were independent predictors of long-term survival in patients with lumbosacral osteoblastic metastases. | PMC10731753 | |
Relative risk (RR value) | death, prostate cancer, pain | PRIMARY TUMOR, REGRESSION, PROSTATE CANCER | For each level of age, the risk of death increased by 3.170 times. Similarly, for each level of the spinal segment, the risk of death increased by 1.909 times, and for each level of primary tumor nature, the risk of death increased by 2.298 times.The prognostic index (PI) can be calculated according to the prognostic factors determined using the Cox regression model and has important clinical significance. The larger the PI, the worse the prognosis; the smaller the PI, the better the prognosis (PI = 1.154 × age + 0.832 × primary tumor + 0.647 × spinal segment). Typical cases are shown in Figs. Male patient, 64 years old, with well-differentiated prostate cancer in February after combined treatment, Back pain 2 weeks preoperative VAS score of 8.7. Male patient, 59 years old, well-differentiated prostate cancer after combined therapy for 1 year, back pain 8 months, preoperative VAS score of 8.5. Female patients, 4 years after radical resection of the right lung, L5PVP combined with | PMC10731753 |
Acknowledgements | Not applicable. | PMC10731753 | ||
Authors’ contributions | Zuozhang | Lei Xu and Xin Huang performed the surgical operation. Yan Lou and Wei Xie performed the postoperative follow-up. Jun He and Zuozhang Yang performed statistical analysis. Yihao Yang and Ya Zhang collected the clinical data and performed the preoperative preparation. | PMC10731753 | |
Funding | This work was supported by the Chengdu Medical Research Project (2022220). | PMC10731753 | ||
Availability of data and materials | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10731753 | ||
Declarations | PMC10731753 | |||
Ethics approval and consent to participate | Cancer | CANCER | This study was approved by the Department of Orthopedics, Chengdu Seventh People’s Hospital (Affiliated Cancer Hospital of Chengdu Medical College). All the patients were consented to participate. | PMC10731753 |
Consent for publication | All the patients gave consent for publication. | PMC10731753 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10731753 | ||
References | PMC10731753 | |||
Background | peripheral facial paresis | One year after persistent peripheral facial paresis (PFP), prescriptions of conventional rehabilitation are often downgraded into maintenance rehabilitation or discontinued, the patient entering what is seen as a chronic stage. This therapeutic choice is not consistent with current knowledge about behavior-induced plasticity, which is available all life long and may allow intense sensorimotor rehabilitation to remain effective. This prospective, randomized, multicenter single-blind study in subjects with chronic unilateral PFP evaluates changes in facial motor function with a Guided Self-rehabilitation Contract (GSC) | PMC10084642 | |
Methods | nerve injury | Eighty-two adult subjects with chronic unilateral PFP (> 1 year since facial nerve injury) will be included in four tertiary, maxillofacial surgery (2), otolaryngology (1) and rehabilitation (1) centers to be randomized into two rehabilitation groups. In the experimental group, the PM&R specialist will implement the GSC method, which for PFP involves intensive series of motor strengthening performed daily on three facial key muscle groups, | PMC10084642 | |
Discussion | peripheral facial paresis | This study will increase the level of knowledge on the effects of intense facial motor streng-
Facial paralysisthening prescribed through a GSC in patients with chronic peripheral facial paresis. | PMC10084642 | |
Trial registration | ClinicalTrials.gov, | PMC10084642 | ||
Protocol version | Version N°4.0—04/02/2021. | PMC10084642 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12883-023-03096-8. | PMC10084642 | ||
Keywords | PMC10084642 | |||
Background | PFP, Peripheral facial paresis, motor impairments, Bell’s palsy | DISORDER | Peripheral facial paresis (PFP) is a common disorder, which often affects adults between 40 and 50, with no gender predominance. PFP results from an injury to the facial nerve, from its pontine nucleus to its neuromuscular junctions; its severity depends on lesion location, cause and degree of injury. Seventy percent of cases are idiopathic, called Bell’s palsy, with a lifetime incidence of 1 in 60 people [Regarding clinical evaluation of PFP, heterogeneity in assessments makes comparisons between various interventions difficult [In terms of rehabilitation, evidence from randomized controlled trials (RCT) is still insufficient, partly because of this lack of precise and objective quantification tools for facial motor function. Most publications on facial rehabilitation pertain to acute and subacute stages of PFP and involve prescriptions for physical therapy and/or speech therapy [To our knowledge, there is no RCT analyzing motor strengthening in chronic stages (> 1 year since injury), when motor impairments are often considered permanent [The government-funded VISAGE project is a French multicentric RCT in which 82 patients with chronic stable unilateral PFP of any cause will be randomized into two six-month rehabilitation programs – motor strengthening through Guided Self-rehabilitation Contract | PMC10084642 |
Objectives | nerve injury | The primary objective of this study is to evaluate changes in subjective facial motor function after six months of Guided Self-rehabilitation Contract compared to conventional therapy alone, in chronic stages following facial nerve injury. Secondary objectives include the evaluation of differences in changes between the two treatment groups in: i) specific PFP-related quality of life; ii) overall quality of life; iii) aesthetic considerations; iv) mood; v) objective 3D facial motor function. | PMC10084642 | |
Methods/design | PMC10084642 | |||
Ethical approval and trial registration | The VISAGE study has been designed in accordance with the Helsinki Declaration. The study protocol, patient information letter, and informed consent form have been approved by the Institutional Review Board ‘Est-III’ (Nancy, France) on October 3 | PMC10084642 | ||
Research design | peripheral facial paresis, nerve injury | VISAGE is a single-blind, prospective, controlled, randomized multicenter study in 82 participants with chronic unilateral peripheral facial paresis (> 1 year since facial nerve injury). The trial will be run in four tertiary centers, including maxillofacial surgery (2), otolaryngology (1) and neurorehabilitation (1) units. For all participants, the study will begin at inclusion (Day-30). At that time point, the investigator will implement computerized randomization to assign a group treatment to the patient, between Guided Self-rehabilitation Contract (GSC) and conventional therapy (CONV) alone, for six months. A delay of one month between inclusion (D-30) and the first assessment (D1) is anticipated to account for the time to find a therapist and to ensure timely rehabilitation onset (D1) for the participants in the CONV group. In the GSC group, the participants will be free to continue potential preexistent conventional therapy if there was any. The total duration of subject participation in the study is seven months. Study data will be analyzed through intention-to-treat and per-protocol analyses. | PMC10084642 | |
Interventions | PMC10084642 | |||
Conventional therapy | In the Conventional Physical Therapy group (CONV), the study PM&R specialist prescribes physiotherapy and/or speech therapy sessions at inclusion (D-30), for a six-month period starting at D1. For this purpose, a list of physical and speech therapists specialized in PFP rehabilitation and working in the Greater Paris area is provided to each subject. Each therapist of that list has personally agreed to potentially take care of patients of the VISAGE study in due course. Such community-based therapy sessions are universally and indefinitely covered by public health insurance in France. Whichever the study group, subjects already undergoing community-based rehabilitation are free to pursue that rehabilitation during the six months of the study. Indeed, the discontinuation of previous rehabilitation might lead to nocebo effects, which is well known in rehabilitation RCT studies [ | PMC10084642 | ||
Outcome measures | Anxiety, nerve injury, paralysis, synkinesis, Depression, depressive disorders | To evaluate motor function beyond one year after facial nerve injury, the primary outcome measure will be the composite score of the Sunnybrook Facial Grading System. This scale, created by Ross et al. in 1996, assesses resting symmetry compared to the normal side for each third of the face through rating of resting symmetry, of symmetry of voluntary movements on a five-grade scale during five facial movements, and associated synkinesis. A composite score is then calculated, ranging from 0 (total paralysis) to 100 (normal) [Secondary outcome measures will include:Specific PFP-related quality of life evaluated through the Facial Clinimetric Evaluation (FaCE), a self-questionnaire validated in French [Overall perceived quality of life evaluated through the Short Form version 12 (SF 12): this is a self-questionnaire comprising 12 items evaluating quality of life. The scoring system is ordinal. Two scores are calculated, a Physical Composite Score (PCS on 26) and a Mental Composite Score (MCS on 30) [Aesthetic self-assessment collected using the FACE-Q scale; this is a ten-item self-questionnaire questioning the patient on facial aesthetics [Anxiety and depressive disorders using the Hospital Anxiety and Depression Scale (HADS): [Evaluation of compliance to and amount of self-rehabilitation in the GSC group, through the filling ratio of the diary over six months.Evaluation of the amount and type of conventional therapy in both groups, through collected data on the mean frequency and techniques used over six months.Subjective facial motor function quantification during the Créteil Scale. The Créteil Scale (CS) has been developed by Gracies and Baude in 2012 [Objective 3D facial motor function quantification through 3D wearable (helmet) facial motion analysis through the Cara™ system. Asymmetry ratios and Procuste analysis will be performed at rest (during a 30-s period), during twelve maximal movement efforts and during spontaneous smile [ | PMC10084642 | |
Setting and recruitment | This multicenter trial involves four French centers: the Neurorehabilitation and the Maxillo-facial & Plastic Surgery departments at | PMC10084642 | ||
Procedures | MONDOR | This is a single-blind controlled trial, with randomization into two parallel groups, inclusion and randomization being computerized online (Cleanweb Telemedecine Technologies, France) in each investigator center. Clinical assessments, video recordings and 3D analyses of included subjects will be performed in a single investigating center: the Neurorehabilitation department at Henri Mondor University Hospitals, Créteil, France (evaluation center).Screening visits will take place during regular clinic visits in each center. Participants meeting the selection criteria (see Table Inclusion and exclusion criteriaRandomization will be performed on inclusion day (D-30) by the chief investigator of each center, between the Conventional therapy group (CONV) and the Guided Self-rehabilitation Contract (GSC) group (see Randomization procedure below). Each participant will thus be randomly assigned to one of the two arms and will receive a rehabilitation program depending on the randomized arm, to be carried out over six months. In order to minimize any nocebo effect for the conventional treatment group, the study coordinator will not disclose details of the Guided Self-rehabilitation Contract to the physicians and physiotherapists who treat participants in the CONV group, nor to the CONV participants themselves.Facial rehabilitation will begin the day after the first evaluation (D1).In practice, two PM&R neurorehabilitation study physicians, a blinded assessor and an unblinded rehabilitation prescriber and coach, will separately meet each participant at D1, D90 and D180, for an assessment visit and a rehabilitation visit: 1) during the assessment visit, the blinded evaluator will run the clinical scales, self-questionnaires, and the 3D facial analysis (except for D90); 2) during the rehabilitation clinic visit, the unblinded PM&R physician will organize the rehabilitation. After receiving the result of the randomization at D-30, he/she will: 1) inform the participant on the arm that has been randomized; 2) teach the GSC, for those participants randomized in the GSC group; 3) find a community-based therapist through a dedicated listing, for those participants randomized in the CONV group; 4) give a rehabilitation booklet to the participant, according to the arm being randomized; 5) schedule the first visit (D1). Table Study schedule: enrolment, interventions and assessments | PMC10084642 | |
Randomization procedure | The randomization list will be computer-generated by a statistician from the Clinical Research Unit of | PMC10084642 | ||
Study population | Eligible patients must be diagnosed with stable, chronic,— | PMC10084642 | ||
Data management | All information required by the protocol will be entered in the eCRF. Data will be collected as they are obtained. Any missing data will be coded. Every site will have access to the eCRF via a web-based data collection system. Investigators will be given a document offering guidance on using this tool. Each investigator will be responsible for the accuracy, quality and relevance of all the data entered. An audit trail of all changes will be saved. The computer file used for this research is implemented in accordance with French (amended “Informatique et Libertés” law governing data protection) and European (General Data Protection Regulation – GDPR) regulations. The sponsor has obtained the authorization of the CNIL (“ | PMC10084642 | ||
Data monitoring | A Clinical Research Associate (CRA) appointed by the sponsor will be responsible for the proper processing of the study, for collecting, documenting, recording and reporting all handwritten data, in accordance with the Standard Operating Procedures applied within the ‘DRCI’ (Clinical Research and Innovation Department at | PMC10084642 | ||
Harms | ADVERSE EVENTS | In this study involving human participants (as defined in category 2 of art. L1121-1 of the French Public Health Code), adverse events (serious or not) will not be notified to the sponsor. Notification will be implemented within the framework of the vigilance set up in usual care procedures. No data monitoring committee is needed. | PMC10084642 | |
Audit | EVENT | In accordance with Good Clinical Practice, the sponsor is responsible for obtaining the agreement of all parties involved in the research to ensure direct access to all research sites, source data, source documents and reports for quality control and audit purposes by the sponsor. Investigators will make the documents and individual data available to persons in charge of monitoring and quality control, in the event of an audit, in accordance with the legislative and regulatory provisions in force. | PMC10084642 | |
Statistical methods | PMC10084642 | |||
Sample size | paresis | MINOR, PARESIS, SECONDARY | The required number of subjects has been determined to be 82, from preliminary data in literature: to our knowledge the sole RCT about rehabilitation in subacute/chronic stages of PFP (participants enrolled from 9 months into the onset of paresis) using SFGS included 50 participants, among whom only 24 benefited from rehabilitation (waiting list without any rehabilitation in the other group) [In contrast with that trial, participants of the control group of the present study will benefit from an intervention (physiotherapy and/or speech therapy), which will be associated with the potential to improve clinical status. We thus hypothesize that there will be a minor improvement of + 10 points in the Sunnybrook composite score in that group. Based on that hypothesis and to demonstrate an improvement of + 20 points (with a standard deviation up to 13) for the experimental group, considering a 5% alpha risk (bilateral test) and a statistical power of 90%, we will include 41 patients per group for 36 analyzed (assuming a 10% loss of follow-up).Regarding the secondary objectives, it should be noted that this sample size will be comparable to other reliability and validity studies for the FaCE scale ( | PMC10084642 |
Statistical analysis | paresis | REGRESSION, PARESIS, SECONDARY | Descriptive statistical analysis will be carried out to evaluate randomization groups in terms of demographic, and initial clinical and kinematic characteristics, including PFP cause, delay since injury, side of paresis, previous drug treatments, and comorbidities. Quantitative data will be described using means (± SD) or medians (with IQR), depending on the normality of distributions, and qualitative data will be reported as numbers or percentages.Changes in the Sunnybrook Composite score between D1 and D180 will be evaluated by Student’s Comparative analysis of binary parameters will be run through Chi-square or Fisher’s exact tests, depending on conditions. Multivariable analysis will be generated through logistic regression models. Intra- and inter-rater reliability studies will use frequencies of agreement, intraclass correlation coefficients, Cohen and Fleiss kappa coefficients and coefficients of variation. Spearman or Pearson coefficients will be calculated between scores on the various scales, depending on conditions. Complementary analyses on the primary outcome and all analyses regarding secondary outcomes will be performed in both ITT and per protocol (PP) populations to describe the excluded patients of the PP population and to evaluate the robustness of the results.All missing or invalid data will be systematically sought for verification in patient charts. In addition to the analysis performed on complete cases without missing data for the primary outcome, sensitivity analysis will be performed using various methods of replacement of missing data, including the LOCF method (Last Observation Carry Forward), the worst-case assumption, and multiple account assignment by chained equations (MICE). Participants who terminate the study prematurely will not be replaced. All analyzes will be performed with Stata software v14.1 (StataCorp, College Station, TX, USA). | PMC10084642 |
Safety | Assistance Publique—Hôpitaux de Paris (APHP), sponsor of this research, has contracted an insurance for the duration of the study, in compliance with the law on biomedical research, guaranteeing its own civil liability, as well as that of any investigator or staff involved in conducting the research. | PMC10084642 | ||
Discussion | muscle overactivity, central motor disorders, chronic facial paresis, peripheral facial paresis | To our knowledge, this study will be the first controlled study evaluating a facial motor strengthening program, through the strategy of Guided Self-rehabilitation Contracts, in the challenging treatment of chronic facial paresis. The study also represents uncommon involvement of a neurorehabilitation team, classically involved with central motor disorders, into the field of peripheral facial paresis. There are a number of arguments that support the plausibility that motor strengthening might help patients: (i) recover better emotional facial animation and (ii) reduce facial muscle overactivity. | PMC10084642 | |
Why facial motor strengthening in chronic facial paresis? | muscle overactivity | FACIAL PARESIS | The goal of a motor strengthening program for facial paresis is to provide for a fitter In terms of peripheral transmission of the emotional motor command, the phenomenon of activity-dependent plasticity of peripheral In terms of muscle overactivity and excitability of the peripheral motoneurone, a number of studies show that increased descending muscle activation through strength training actually | PMC10084642 |
Characteristics of the two rehabilitation groups | muscle overactivity | CONTRACTIONS | Several differences may be anticipated between the two rehabilitation treatments. Neither quality not quantity of rehabilitation have been imposed on the therapists involved in the control group, in order to best reflect real life. It is thus likely that frequency, techniques, duration of rehabilitation sessions will be highly heterogeneous in the control group. We have planned to collect these rehabilitation parameters (D90 and D180) in order to estimate the work carried out in that control group. Technically, in the rehabilitation techniques used in current practice, motor strengthening efforts are rarely recommended and used, particularly at maximal intensity as mentioned above, because of the concern or belief that this might trigger muscle overactivity. As a consequence, the amount of rehabilitative work classically performed typically avoids intensity and may thus be insufficient to exploit behavior-induced nervous system plasticity. From a psychological point of view, patient responsibilization and implication in the rehabilitation program to achieve higher work intensity levels constitute the essence of the Guided Self-rehabilitation Contract strategy. The patient has an active responsibility to accomplish the prescribed daily work and to notify it in the quantitative diary, in stark contrast with the common passive expectation of community therapy sessions in current practice.Overall, this study should increase the level of knowledge on the effects of facial motor strengthening through Guided Self-rehabilitation Contracts in chronic stages. It will also improve the level of knowledge on facial motion quantification at rest and during voluntary and emotional facial contractions. The validation of a new clinical scale (the Créteil Scale) and of a wearable 3D motion analysis system of facial movements will help to better quantify PFP. | PMC10084642 |
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