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Conflicts of Interest | The authors declare no conflicts of interest. | PMC10780457 | ||
References | BLOOD | Study design. S1, S2, S3, S4—study series; LH–TL—live high–train low protocol; DAA—D-aspartic acid.Blood serum testosterone (Training program during the experiment.Selected hematological variables and area under the curve for testosterone (AUC T), free testosterone (AUC fT), cortisol (AUC C), and luteinizing hormone (AUC LH) during the experiment in DAA and C groups.*** | PMC10780457 | |
1. Introduction | abortion, menstrual abnormalities, ±, uterine adenomyosis, reduced menorrhagia, infertility, dysmenorrhea, adenomyosis, muscular hypertrophic, menorrhagia, Adenomyosis | ENDOMETRIOSIS, OBSTETRICAL COMPLICATIONS, DYSMENORRHEA, ADENOMYOSIS, SECONDARY, MENORRHAGIA, ADENOMYOSIS | Beneficial and detrimental effect of surgical adenomyomectomy is still controversial in infertile women with severely diffuse adenomyosis. The primary objective of this study was to assess whether a novel method of fertility-preserving adenomyomectomy could improve pregnancy rates. The secondary objective was to evaluate whether it could improve dysmenorrhea and menorrhagia symptoms in infertile patients with severe adenomyosis. A prospective clinical trial was conducted between December 2007 and September 2016. Fifty women with infertility due to adenomyosis were enrolled in this study after clinical assessments by infertility experts. A novel method of fertility-preserving adenomyomectomy was performed on 45 of 50 patients. The procedure included T- or transverse H-incision of the uterine serosa followed by preparation of the serosal flap, excision of the adenomyotic tissue using argon laser under ultrasonographic monitoring, and a novel technique of suturing between the residual myometrium and serosal flap. After the adenomyomectomy, the changes in the amount of menstrual blood, relief of dysmenorrhea, pregnancy outcomes, clinical characteristics, and surgical features were recorded and analyzed. All patients obtained dysmenorrhea relief 6 months postoperatively (numeric rating scale [NRS]; 7.28 ± 2.30 vs 1.56 ± 1.30, Adenomyosis is a pathological finding characterized by heterotopic growth of endometrial glands and stroma into the myometrium and is accompanied by a varying degree of muscular hypertrophic changes. Adenomyosis has been suggested to be associated with menstrual abnormalities, and affected women have compromised fertility; they often need assisted reproductive technology (ART) for reproduction.Like endometriosis, adenomyosis can impair successful pregnancy during ART, although the relation between uterine adenomyosis and infertility is not clearly defined. Adenomyosis can affect uterine or endometrial receptivity, and it leads to increased abortion rates.Several studies reported that various surgical methods, including endometrial resection, open or laparoscopic myometrial reduction by electrocautery, and excision of adenomyosis, reduced menorrhagia and dysmenorrhea as well as the need for hysterectomy in patients with adenomyosis.We modified previously reported conservative methods to facilitate effective reduction of diffuse adenomyotic lesions by including T- or transverse H-incision, utilization of an argon laser, sonographic measurement of the pathological lesion during the operation, and a novel suture technique for uterine reconstruction. We intended to improve menstrual symptoms, increase pregnancy rates, and decrease obstetrical complications after maximal reduction of pathologic adenomyotic tissue while preserving the endometrium and normal myometrial tissues. Uterus-sparing surgery appears to be an attractive option for treating adenomyosis and preserving fertility, but there is a paucity of well-designed prospective studies evaluating fertility and pregnancy outcomes after surgery.The primary objective of this study was to assess whether this novel method of adenomyomectomy could improve pregnancy rates, and secondary goal was to evaluate whether it could improve dysmenorrhea and menorrhagia symptoms in infertile patients with severe adenomyosis via a well-designed prospective trial. | PMC10063302 |
2. Materials and methods | PMC10063302 | |||
2.1. Study participants | adenomyosis, ovulation disorder, infertility, dysmenorrhea | EXCESSIVE MENSTRUAL FLOW, SECONDARY INFERTILITY, ADENOMYOSIS, DYSMENORRHEA, BLOCKED FALLOPIAN TUBES, IRON DEFICIENCY ANEMIA | A prospective clinical trial was conducted between December 2007 and September 2016 at Dongguk University Ilsan Hospital, South Korea. Fifty study participants were selected based on the following criteria: patients diagnosed with diffuse adenomyosis via pelvic ultrasonography and magnetic resonance imaging (MRI); patients who had excessive menstrual flow (≥80 mL by pictogram) and severe dysmenorrhea (numeric rating scale [NRS] ≥ 6) that disrupted daily life; patients who had been diagnosed with primary or secondary infertility for more than a year, and their infertility was determined to be due to adenomyosis based on clinical assessment by an infertility expert; patients who did not have any other medical conditions, excluding iron deficiency anemia; patients who failed to conceive after treatment with drugs, such as gonadotropin-releasing hormone agonist (GnRHa); and infertile patients who had adenomyosis and other infertility factors, such as ovulation disorder and blocked fallopian tubes, yet their implantation failure was determined to be due to adenomyosis after more than 2 failed attempts to conceive through in vitro fertilization and embryo transfer (IVF-ET) and/or ovulation induction.All patients underwent gynecological examinations and workup, including pelvic ultrasonography and MRI (Fig. Representative images of MRI and trans-vaginal ultrasonography. (a) MRI scans of 4 different patients show adenomyosis. (b) Trans-vaginal ultrasonography was used to measure the adenomyotic lesion. (c) Trans-vaginal ultrasonography 3 to 6 mo follow-up after surgery. MRI = magnetic resonance imaging. | PMC10063302 |
2.2. Ethical approval | The Institutional Review Board of Dongguk University Ilsan Hospital approved this study (IRB No. 2007-24). Written informed consent was obtained from all participants. All study procedures were performed in accordance with the guideline of Act on Bioethics and Sefety of South Korea. This study has been registered in Clinical Research Information Service, Republic of Korea (KCT0004135, July 11, 2019). | PMC10063302 | ||
2.3. Adenomyomectomy procedure | bleeding, cancer, dysmenorrhea, adenomyosis, menorrhagia | BLEEDING, CANCER, DYSMENORRHEA, ADENOMYOSIS, REMISSION, MENORRHAGIA, COMPLICATIONS | We designed a novel operative procedure consisting of the following methods. First, an initial measurement of the adenomyotic lesion was made using ultrasonography and MRI (Fig. Schematic (a–e) and actual images (f–j) of the adenomyomectomy procedure. (a & f) A T-shaped incision is made on the uterine wall. (b & g) The serosal flap exposes adenomyotic tissue. (c & h) The adenomyotic tissue is shaved using the Argon laser. (d & i) The border between the serosal flap and residual myometrium is sutured. (e & j) The serosal flap is closed and fixed to the underlying myometrium via fixation suture.The adenomyotic region was wide and lacked clear boundaries; hence, an argon laser (ValleylabAs illustrated in Figure After adenomyomectomy, the weight of the resected adenomyotic tissue, time of operation, amount of bleeding, and complications were recorded. Before and after the reductive operation, all patients received 3 cycles of GnRHa therapy, and their serum cancer antigen 125 (CA125) levels were measured. Symptom relief of menorrhagia and dysmenorrhea were evaluated by pictogram and by NRS, respectively. MRI and ultrasonography were used to confirm the remission of adenomyosis. | PMC10063302 |
2.4. Antepartum management | PRETERM BIRTH | After 6 months of adenomyomectomy, participants could try to conceive and the method of pregnancy was left to the patients’ preference, including natural means or ART.In antepartum, to prevent preterm birth and uterine rupture during pregnancy, progestin treatment was provided to all patients for up to 34 weeks of gestation. They were administered vaginally once a day (Utrogestan, vaginal capsule 200 mg, Hanwha Pharma, Seoul, Korea) or injected intramuscularly every week (Progesterone Depot 250 mg, Jenapharm, Jena, Germany), depending on the patients’ preferences. A cesarean section was recommended as the delivery mode. Delivery timing was individualized, but we generally planned for birth at the early term in accordance with the recommendations set by the American College of Obstetricians and Gynecologists. | PMC10063302 | |
2.5. Statistical analysis | ±, SD | The data are presented as mean ± SD or median with ranges. Comparison of clinical outcomes before and after surgery was performed using the paired | PMC10063302 | |
3. Results | PMC10063302 | |||
3.1. Clinical and surgical outcomes | ±, cancer, SD, dysmenorrhea, premature ovarian insufficiency, NRS | PREMATURE OVARIAN INSUFFICIENCY, CANCER, DYSMENORRHEA | The clinical characteristics and surgical features of the patients are summarized in Table Clinical and surgical features of enrolled patients.Values are presented as mean ± SD, n (%) and median (range).POI = premature ovarian insufficiency.Six months postoperatively, all patients obtained symptom relief of dysmenorrhea (NRS; 7.28 ± 2.30 vs 1.56 ± 1.30, Clinical outcomes of adenomyomectomy in infertile patients.Values are presented as median (range) and mean ± SD.CA125 = cancer antigen 125.Evaluated by the Wilcoxon signed rank test.Evaluated by the paired Evaluated by Numeric Rating Score (NRS) score.Evaluated by pictogram. | PMC10063302 |
3.2. Pregnancy outcomes | Pregnancy outcomes are shown in Table Pregnancy outcomes in infertile patients following adenomyomectomy.Data are n (%).Two cases of twin pregnancies and 1 patient who successfully gave birth twice.Flowchart reporting the pregnancy outcome of study subjects after adenomyomectomy. | PMC10063302 | ||
4. Discussion | ovarian insufficiency, ureter fistula, postoperative ovarian insufficiency, infertility, dysmenorrhea, adenomyosis, Pelvic pain, premature ovarian insufficiency, menorrhagia, hematoma, adenomyotic lesion, comorbid diseases | ENDOMETRIOSIS, PREMATURE OVARIAN INSUFFICIENCY, RECURRENCE, ABNORMAL UTERINE BLEEDING, POSTOPERATIVE COMPLICATIONS, PATHOLOGICAL PROCESS, UTERUS, COMPLICATIONS, DYSMENORRHEA, ADENOMYOSIS, MENORRHAGIA, HEMATOMA, DISEASES, UTERUS | The present study evaluated the clinical efficacy of conservative debulking surgery in infertile patients with severely diffuse adenomyosis. Our novel method of fertility-preserving adenomyomectomy resulted in increased pregnancy rates with successful outcomes, as well as symptom relief of dysmenorrhea and menorrhagia. These results suggested that this method of reductive operation could be effective in preserving fertility in infertile women with adenomyosis. To the best of our knowledge, this is one of the few reports on the clinical pregnancy outcomes of uterus-sparing surgery in diffuse adenomyosis through a prospective clinical trial.Although several studies have been conducted to determine the efficacy of adenomyosis reductive operation, many outcomes have been limited to the relief of menstrual symptoms. The relationship between adenomyosis reductive operation and fertility and pregnancy outcomes in diffuse adenomyosis remains poorly understood.In our cohort, 54.5% (18/33) of patients conceived postoperatively either by natural means, IVF-ET, or thawing ET. After reduction surgery, all patients were recommended to try to conceive through ART. However, some patients refused ART procedures or became pregnant naturally. Our result, which was relatively higher than those of previous studies, is remarkable considering the strict criteria used to select patients with severe adenomyosis. All participants enrolled in this study consisted of infertile patients who failed to conceive via IVF-ET. Although it is difficult to compare the results directly, in a retrospective study included 241 IVF cycles of women with adenomyosis, the pregnancy rate was low at 25.2% to 39.5% without surgery.The proportion of patients who attempted pregnancy was different among studies, accounting for the widely variable pregnancy rates.Although adenomyomectomy primarily aims to increase pregnancy success rates, relieving dysmenorrhea and menorrhagia is also crucial because if symptoms persist, many patients are forced to abandon their active pursuit of pregnancy. Pelvic pain, especially dysmenorrhea, can also be caused by other diseases accompanying adenomyosis, especially endometriosis, which are described as different expressions of the same pathological process.There were 4 cases of postoperative complications in the beginning of the study: subfascial hematoma, ureter fistula, shrinkage of the uterus, and premature ovarian insufficiency (Table To minimize these complications, meticulous and careful procedures are essential. In addition, pre- and postoperative GnRHa treatments may be helpful in improving surgical outcomes by minimizing the endometriosis-induced inflammatory reaction and reversible adenomyotic lesion prior to the operation. These treatment methods also aid in uterine muscular healing postoperatively by blocking menstrual blood from integrating into the intramuscular collection. To avoid postoperative ovarian insufficiency, preoperative cryopreservation of the embryo can be considered in high-risk patients with ovarian insufficiency.Although this study was conducted before the Morphological Uterus Sonographic Assessment consensus was published, the adenomyosis diagnostic criteria used in this were not significantly different from those of Morphological Uterus Sonographic Assessment consensus.CA125 screening, though currently not typically recommended for routine follow-up, is instrumental in fully assessing the efficacy of adenomyosis treatment and evaluating the recurrence of adenomyosis. High CA125 levels commonly present in individuals with adenomyosis, and numerous studies show that CA125 levels positively correlate with development and severity of adenomyosis. Recent research has also established a positive correlation between CA125 levels and the amount of adenomyosis remaining postadenomyomectomy and demonstrated that a reduction in CA125 levels were evident in successful treatments of adenomyosis.The association between adenomyosis and other diseases still requires extensive clinical and molecular investigation. However, in any situation, the presence of adenomyosis does not exclude the possibility of comorbid diseases, so if there are symptoms such as abnormal uterine bleeding, efforts should be made to initially exclude adenomyosis as the primary cause.We found it most difficult to select patients who fit this study criteria due to the controversial nature of conducting clinical research. Finding the right timing for surgery will be an essential research task in the future in order to prevent delayed surgeries that result in infertility and premature surgeries, resulting from hasty decision making, that are ultimately harmful and/or unnecessary.The limitation of this study was the relatively small sample size and not the comparative study without surgery; hence, future studies with more patients will be helpful in evaluating the efficacy of this surgical method. Therefore, we are planning a randomized controlled trial comparing the reproductive and pregnancy outcomes between women who have conducted this novel adenomyomectomy and those who have not in infertile women with diffuse adenomyosis.In conclusion, this study reports successful pregnancy rates and outcomes after reduction surgery. These findings imply that the novel method of adenomyomectomy as a uterus-sparing surgery can alleviate the symptoms of dysmenorrhea and menorrhagia, improve pregnancy rates, and conserve fertility potential in infertile women with severely diffuse adenomyosis. | PMC10063302 |
Acknowledgments | Jimin J. are greatly acknowledged for helping the preparation of the manuscript. | PMC10063302 | ||
Abbreviations: | adenomyosis | ADENOMYOSIS | assisted reproductive technologycancer antigen 125gonadotropin-releasing hormone agonistin vitro fertilization and embryo transfermagnetic resonance imagingnumeric rating scaleTrial registration: This study has been registered in Clinical Research Information Service, Republic of Korea (KCT0004135).The authors have no funding and conflicts of interest to disclose.The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.How to cite this article: Yoon SH, Lee GJ, Cho HJ, Kwon H, Yun BS, Lee CH, Park HS, Roh J-W. Clinical efficacy of a novel method of fertility-preserving adenomyomectomy in infertile women with diffuse adenomyosis. Medicine 2023;102:13(e33266). | PMC10063302 |
References | PMC10063302 | |||
Abstract | Shared last authorship. | PMC10441870 | ||
Background | PD, cancer | CANCER | Psychological distress (PD) and fear of cancer recurrence (FCR) are common consequences of surviving cancer. Online self-help training could help many cancer survivors deal with PD and FCR at low costs. | PMC10441870 |
Purpose | PD, CAncer, CAREST | To evaluate the long-term effectiveness of the CAncer REcurrence Self-help Training (CAREST trial) to reduce PD and FCR. Moreover, to evaluate the relation between FCR and PD across time and identify subgroups representing different change trajectories in FCR over time and their predictors. | PMC10441870 | |
Methods | PD, Cancer | FEMALE BREAST CANCER, RECURRENCE, CANCER | This multicenter randomized controlled trial included 262 female breast cancer survivors, assigned to online self-help training or care as usual. Participants completed questionnaires at baseline and four times during the 24-month follow-up. The primary outcomes were PD and FCR (Fear of Cancer Recurrence Inventory). Latent growth curve modeling (LGCM) and repeated measures latent class analysis (RMLCA) were performed, both according to the intention‐to‐treat principle. | PMC10441870 |
Results | PD | LGCM showed no differences between the average latent slope in both groups for both PD and FCR. The correlation between FCR and PD at baseline was moderate for the intervention group and strong for the CAU group and did not significantly decrease over time in both groups. RMLCA revealed five latent classes and several predictors of class membership. | PMC10441870 | |
Conclusions | PD, cancer recurrence and psychological distress, breast cancer | BREAST CANCER | We did not find a long-term effect of the CBT‐based online self-help training in reducing PD or FCR, nor in their relation. Therefore, we recommend adding professional support to online interventions for FCR. Information about FCR classes and predictors may contribute to improvement of FCR interventions.This study shows that women who survived breast cancer stay distressed and fearful for a long time, and that online self-help training alone is not effective in reducing their fear of cancer recurrence and psychological distress. This study underlines the importance of developing further effective psychological interventions, for example with professional support | PMC10441870 |
Introduction | breast) cancer, cancer, PD, breast cancer | CANCER, BREAST CANCER | Advances in the diagnosis and treatment of (breast) cancer have resulted in increased survival rates. As a result, there is an increasing group of breast cancer survivors that have to cope with the long-term consequences of cancer. Fear of cancer recurrence (FCR) is one of the most common long-term psychological consequences of surviving breast cancer [Given the burden of FCR and PD for cancer survivors, there is a need to develop (tailored) interventions to efficiently address FCR and also to reduce PD [In the current paper, we will evaluate the long-term effectiveness (>15 months) of this online self-help training in reducing both FCR and PD and identify subgroups representing different change trajectories in FCR over time and their predictors. To meet this aim, we use three longitudinal latent variable models, each focusing on a different research question. First, in a multi-group latent growth model, we will evaluate change in FCR and PD (research question 1; RQ1). We hypothesize greater FCR and PD reduction in the intervention group compared to CAU at 15 and 24 months. Second, in a multivariate multi-group latent growth model, we will evaluate the relation between FCR and PD at baseline and across time (research question 2; RQ2). We hypothesized a strong relation ( | PMC10441870 |
Materials and Methods | CAREST | The CAREST trial was registered in the Dutch Trial Register (NTR4119). The Medical Ethical Committee of the Maasstad hospital (TWOR) in Rotterdam approved this trial (reference number 2013/41) and all participating hospitals provided local ethics approval. The study protocol of this trial has been published [ | PMC10441870 | |
Design | We conducted a multicenter randomized controlled trial (RCT) with two conditions. The intervention group received a CBT-based online self-help training to reduce FCR. Both the intervention group and the control group received care as usual (CAU), standard care in their own hospital.The original sample size calculation mentioned in the study protocol does not apply for the statistical analyses in the current study [Participants were assessed through online self-report questionnaires at baseline (T0), three months (T1; after intervention), nine months (T2), 15 months (T3), and 24 months (T4). More details on the study design are described in the study protocol [ | PMC10441870 | ||
Participants | breast cancer | DISEASE, RECURRENCE, METASTATIC DISEASE, BREAST CANCER | Women were eligible to participate when they had a diagnosis of breast cancer 1–5 years ago, had no signs of local or regional recurrence or metastatic disease (according to their oncologist or oncology nurse), were capable of completing questionnaires in Dutch, were 18 years or older at disease onset, and had access to a computer with an internet connection [ | PMC10441870 |
Recruitment | Cancer | MAY, RECURRENCE, CANCER | Eligible patients were recruited consecutively during their regular checkup at the outpatient clinic of a hospital or by sending them a comprehensive information letter by mail (differed because of pragmatic reasons) between April 2014 and May 2016. Participating hospitals (all situated in the Netherlands) were the Maasstad hospital in Rotterdam, St Antonius hospital in Utrecht, Admiraal de Ruyter hospital in Vlissingen, Reinier de Graaf hospital in Delft, Antonius hospital in Sneek, ETZ in Tilburg, Catharina hospital in Eindhoven, and UMCG in Groningen. After 2 weeks, patients were reminded of the study by the researcher. Patients who decided to participate, returned a signed informed consent form. On this form, they indicated whether they agreed to participate in the RCT or only to complete the Dutch version of the Fear of Cancer Recurrence Inventory (FCRI-NL) once [ | PMC10441870 |
Randomization | Participants were randomly allocated to either the online self-help training (intervention) or CAU with an allocation ratio of 1:1, stratified by hospital. Block randomization (block size 10) was carried out through the sealed envelope system. Randomization was conducted by a researcher who was not otherwise involved in the study. The researchers had no influence on (and were blinded for) the randomization process. We used coding and separating personal data from the research data to anonymize the data [ | PMC10441870 | ||
Intervention | POSITIVE | In short, the intervention is a CBT-based online self-help to reduce FCR. The program included two generic modules containing psycho-education about FCR and the basic principles of CBT, and four optional modules: (a) Stop worrying; (b) Positive actions; (c) Relax; and (d) Reassurance [ | PMC10441870 | |
Measures | breast cancer, PD, Cancer | BREAST CANCER, RECURRENCE, CANCER | Socio-demographic and medical variables were self-reported and assessed at baseline and at all time points, respectively. The self-report questionnaires were assessed at all time points.The primary outcomes FCR and PD were both assessed with the Dutch translation of the Fear of Cancer Recurrence Inventory (FCRI-NL) [Since there was no measure for self-efficacy for online self-help available, self-efficacy was assessed with a 15-item questionnaire developed for this RCT and described in the study protocol, which measured: (1) general internet use (3 items); (2) health-related behavior (7 items); and (3) patients’ expectations of online self-help training for FCR (5 items) [Psychosocial problems and risk factors were assessed with the Psychosocial Distress Questionnaire-Breast Cancer (PDQ-BC), a 35-item multidimensional screening instrument specific for breast cancer patients [ | PMC10441870 |
Statistical Analyses | Prior to data analysis, we checked the normality assumptions. When the assumption of multivariate normality was not met, we executed transformations of the dependent variable. When transformation did not lead to multivariate normality, we used robust maximum likelihood estimation (MLR) to fit the model. | PMC10441870 | ||
RQ1: Long-Term Effectiveness of Online Self-Help Training in Reducing FCR and PD | PD | To answer the first research question (i.e., do the intervention and CAU group differ in the change in FCR/PD over time), a multi-group second-order latent growth model was estimated. A second-order growth model estimates individual growth curves for each participant based on the individual FCR or PD item scores. A multi-group extension allows testing differences between interventions in the growth model parameters. The parameter of main interest was the average latent slope estimate in both the intervention and CAU groups and whether these differed between the groups. We estimated the model separately for FCR and PD, because the multivariate model for both FCR and PD did not converge (most likely, the model was too large for the data). Each of the FCR/PD models was built in five steps, first testing the assumption of longitudinal measurement invariance, followed by two models to test the null hypothesis that the difference between the groups in the latent slope is equal to zero. Growth model analyses were estimated with maximum likelihood estimation, using R statistical software (version 3.5.3), with software packages Lavaan (R package for Structural Equation Modeling, version 0.6-9) and BaylorEdPsych (R-package used for checking missing data for random occurrences, version 0.5) [ | PMC10441870 | |
RQ2: Relation Between FCR and PD Over Time | PD | Answering the second research question (i.e., does the association between FCR and PD decrease over time), we started with a multivariate multi-group growth model including both FCR and PD scores over time. However, as this multivariate second order growth model did not converge, we used a first order growth model that models the growth parameters based on FCR and PD factor scores at each time point instead of on the questionnaire item scores. We first estimated the factor scores of the FCR and PD measurement models at each of the five time points, and subsequently used these factor scores in a multivariate multi-group first order growth model (Model 5) to investigate how change in FCR scores over time was related to change in PD scores over time and how these relations differed between the CAU and intervention group. To test whether the correlations between FCR and PD were equal over time, we added restrictions in Models 6 and 7, respectively, to the intervention and CAU group. We assessed and interpreted the goodness-of-fit of the latent growth models as described above. | PMC10441870 | |
RQ3: Change Trajectories in FCR Over Time and Their Predictors | For the last research question (i.e., can we distinguish characteristics of patients for whom the intervention worked), we modeled a repeated measures latent class analysis (RMLCA) within the intervention group. RMLCA analyses were performed with Latent Gold (version 5.0.0) [
| PMC10441870 | ||
Results | PMC10441870 | |||
Response Rate and Sample Characteristics | CAREST | Details about enrollment, intervention allocation, follow-up, and drop-out can be found in the flowchart (CONSORT diagram for participant inclusion and retention up to 24 months in the CAREST randomized controlled trial. Women in the RCT had a mean age of 55.8 years ( | PMC10441870 | |
RQ1: Long-Term Effectiveness of Online Self-help Training in Reducing FCR and PD | PD | When testing the assumption of longitudinal measurement invariance for FCR, the multi-group univariate second order latent growth model indicated no differences between the loadings of the five longitudinal factors across time, based on the chi-square difference test comparing sub-models 0a and 1a (Latent Growth Models Supporting Research Questions 1 and 2, Increasing in Complexity
For PD, the results were similar (For FCR, the RMSEA fit index was slightly higher than the recommended criterion of .06, and for PD the RMSEA fit index was around .06, suggesting an almost adequate fit of these models to the data. The CFI and TLI suggested a somewhat poor fit of the FCR models to the data. The TLI suggested an almost adequate fit and the CFI indicated a good fit for the PD models. Both AIC and BIC suggest a better fit for the models including equal intercepts of individual items across time (2a and 2b) and for the models including equal latent slopes in the intervention and CAU group (4a and 4b). Answering the first research question (difference between the groups in effect of FCR and PD over time), this corroborates the findings mentioned above that long-term effects did not differ between the intervention group and the CAU group over time, for both FCR and PD models. In other words: the self-help was not effective in reducing FCR and PD in the intervention group long-term. | PMC10441870 | |
RQ2: Relation Between FCR and PD Over Time | PD, cancer recurrence and psychological distress | In line with the findings of the second order growth model, the results of the first order growth model indicate no significant change in FCR across time, for both the intervention (The results of these chi-square difference tests were confirmed by the model fit indices. Both AIC and BIC suggest a slightly better fit to the data for models 6 and 7 that constrained the correlations between FCR and PD to be equal at each time point. The CFI, TLI and RMSEA similarly indicated good fit for both models 6 and 7 to the data. In short, the model fit indices indicate that the relation between FCR and PD remains equal in both groups over time. The correlation between fear of cancer recurrence and psychological distress (a), the mean change in fear of cancer recurrence (b) and psychological distress (c) across time for both the intervention and the care as usual (CAU) group. | PMC10441870 | |
RQ3: Change Trajectories in FCR Over Time and Their Predictors | Cancer | RECURRENCE, POSITIVE, CANCER | First, we identified the optimal number of latent classes, where each class represents a distinct change pattern of FCRI for participants in the intervention group. BIC showed that a model with three different classes fitted the data best, while AIC and AIC3 suggested a model with five different classes. Because of the consensus between AIC and AIC3, we chose the model with five different classes. For each of those five classes, Fear of cancer recurrence (measured with the Fear of Cancer Recurrence Inventory-severity subscale; FCRI-S) across time for five latent classes.Second, we determined predictors of class membership. Clinical and Socio-demographic Predictors of Fear of Cancer Recurrence Latent Class Membership (Research Question 3)Bold values: values of >2 or <−2 are used to determine which class(es) significantly contribute to the effect of the predictor. Positive values show that participants in that class show higher than average scores on that predictor; negative values show that participants in that class show lower than average scores on that predictor.
Significant predictors for the latent classes. − Significantly less; + significantly more. Our results show quite stable FCR trajectories for four (out of five) latent classes over time (indicating stable severe, moderate, mild, and low FCR over time). At first view, one of the classes shows a decrease of five points on the severity subscale of the FCRI over 24 months. Looking closer, we see the decrease occurs after 9 months (6 months after the intervention); hence we do not expect this to be a treatment effect of our online self-help. In conclusion, RMLCA did not reveal classes who benefit from the intervention. | PMC10441870 |
Sensitivity Analyses | More than one-third (37%) of the intervention group reported they did not actually follow the online self-help training, although they had access to the intervention. However, participants who followed the online self-help intervention and participants who did not follow the intervention did not differ from one another in class membership ( | PMC10441870 | ||
Discussion | PD, cancer, anxiety | CANCER | The current study is one of the few studies that investigate the effect of an online self-help training for FCR with a follow-up of 24 months. Results indicate no change of both FCR and PD across time, for both the intervention and CAU group, nor any effect of the intervention on the relation between FCR and PD, nor did we find a class of participants that benefitted from our online self-help training. Although some This result is largely in line with a recent literature review about online interventions aimed at reducing FCR and PD in cancer patients. They found partial support for reduction in PD, and limited evidence for reducing anxiety after online interventions [The baseline correlations between FCR and PD that we found in this study, were in line with previous research [Moreover, we identified five latent classes that capture different patterns in FCR across time. Our results showed quite stable FCR trajectories for four of the latent classes over time (stable severe, moderate, mild, and low FCR). One of the classes has moderate baseline FCR and starts to decrease 6 months after the intervention, but we do not expect this to be an effect of our online self-help training. Recently, some studies have been published about FCR classes and trajectories [ | PMC10441870 |
Limitations and Strengths | PD, Depression, Anxiety | SENSITIVITY | This study had several limitations. First, since R package Lavaan gave a warning for all growth models using both MLR estimation and other robust estimators, ML estimation was used to fit the model. Presumably, the model with several hundred parameters was too large for our data. The ML estimator is not robust against deviations from normally distributed data, which can lead to biased model parameters. This should be considered when interpreting significant results. However, (full information) ML is a good estimator to handle missing data and to use as much data as possible in longitudinal analyses. Second, the high percentage of nonusers may have distorted the results, although this shows probably a realistic picture of usage of online self-help interventions. Sensitivity analyses showed that the nonusers did probably not influence the treatment effect of the intervention: when leaving the participants who did not actually follow the online self-help training out of the analyses, also no significant treatment effect was found for the intervention group compared to CAU. Third, we used a subscale of the FCRI to measure PD, while most other studies used different questionnaires for PD, such as the Hospital Anxiety and Depression Scale (HADS) [An important strength of our study design is the long follow-up period of 24 months. The effect studies mentioned above, reported follow-up periods ranging from immediately after intervention to 12 months after baseline [ | PMC10441870 |
Clinical Implications | PD, breast cancer | BREAST CANCER | Levels of FCR and PD seem to be stable over time (showed no significant natural decrease), which underlines the importance to develop interventions for both FCR and PD in breast cancer survivors. In the current study, we found no (long-term) effect of our online self-help training. To retain the benefits of online interventions, such as easy accessibility, low costs, and work at their own pace, we suggest to study whether online interventions with professional support, for example, from general practice mental health professionals (GP-MHPs) might be effective (as also suggested in our earlier publication) [ | PMC10441870 |
Conclusions | cancer, PD | CANCER | In conclusion, five latent classes and several predictors of class membership were found. Knowing more about the specific needs of FCR groups, may contribute to the improvement of interventions for FCR.Furthermore, there was no (long-term) effect of the CBT‐based online self-help training “Less fear after cancer” in reducing both FCR and PD. Therefore, we recommend adding professional support, like email contact or face‐to‐face assistance, to future online interventions for FCR and PD. | PMC10441870 |
Supplementary Material | Click here for additional data file. | PMC10441870 | ||
Acknowledgements | der | DER | This research is funded by a grant from Pink Ribbon, the Netherlands (2012.WO43.C158), awarded to Dr. M.L. van der Lee. We are grateful to the patients for their participation in this trial and to oncology nurses, nurse practitioners, and oncologists from the Maasstad hospital in Rotterdam, St. Antonius hospital in Utrecht, Admiraal de Ruyter hospital in Vlissingen, Reinier de Graaf hospital in Delft, Antonius hospital in Sneek, Elisabeth TweeSteden Ziekenhuis in Tilburg, Catharina hospital in Eindhoven, and University Medical Center Groningen (all situated in the Netherlands) for informing patients about the trial. We would like to thank Eltica de Jager Meezenbroek, Irma Manuputy, Mirjam Koppenol, and Iris Verschoor for their administrative support. | PMC10441870 |
Funding | DER | This study was funded by Pink Ribbon (2012.WO43.C158) awarded to Dr Marije L. van der Lee. Pink Ribbon was not involved in the collection, analysis, and interpretation of data, in writing manuscripts or deciding to submit manuscripts for publication. | PMC10441870 | |
Compliance with Ethical Standards | PMC10441870 | |||
References | PMC10441870 | |||
Methods | malaria, malaria infection | MALARIA, REGRESSION, SECONDARY | The trial was a community randomized control in which there were two malaria prevalence cross-sectional household surveys each year (June and December) from 2015 to 2017 in Muleba. In this study we conducted a secondary data analysis of the December surveys only. Multilevel Poisson regression analysis was used to assess factors associated with malaria infection. | PMC10734997 |
Results | malaria, malaria infection | MALARIA | A total of 10,941 children and 4,611 households were included in this study. Overall malaria prevalence was 35.8%, 53.3% and 54.4% in the year 2015, 2016 and 2017 respectively. Living in an area with standard LLIN as opposed to the novel PBO synergist LLIN, being a male child, above 5 years of age, living in a house with open eaves, living in house without IRS, having head of household with no formal education, lower socioeconomic status and survey year were associated with increased risk of malaria infection. | PMC10734997 |
Conclusions | malaria infection | Using PBO LLIN reduced the risk of malaria infection. However, additional measures could further reduce malaria infection in areas of insecticide resistance such as housing improvement. | PMC10734997 | |
Data Availability | Data in Tanzania are governed by strict law and cannot be shared outside the country without a Data Transfer agreement (DTA.pdf (nimr.or.tz)) and appropriate ethical approval. There was no provision under this study to share the data widely outside and was not mentioned in the consent form. A DTA process will need to be completed by interested researchers. | PMC10734997 | ||
Background | malaria | MALARIA, WEST, DISEASE | After a decade of successful control, malaria is on the rise again in Sub- Saharan Africa [In Tanzania, malaria accounts for 30% to 40% of all disease burden and 7% of all mortality [LLIN has been a core component of the Tanzanian malaria control strategy since 2009 [In 2008, Kagera region in North West Tanzania had the highest reported malaria prevalence (41%) across the country [ | PMC10734997 |
Materials and methods | PMC10734997 | |||
Data source | malaria, malaria infection | MALARIA, MALARIA | The trial was a four arms, single-blinded, cluster randomized factorial design conducted in Muleba district in the northwestern part of Tanzania from 2015 to 2017. This trial is registered with ClinicalTrials.gov, number NCT02288637. The detail of the parent study procedures have been described elsewhere [Standard LLNs (Olyset ® Net, Sumitomo Chemicals, Japan)PBO LLIN (Olyset ® Plus, Sumitomo Chemicals, Japan)Standard LLIN with IRS (Actellic® 300CS, Syngenta, Switzerland)PBO LLIN with IRS (Actellic® 300CS, Syngenta, Switzerland)To assess the effectiveness of each intervention, household cross-sectional surveys were conducted in June and December of each year. A questionnaire was administered to obtain information on household and individual social demographic and economic factors including the availability and use of malaria prevention measures. Children aged 6 months to 14 years were tested for malaria infection using a rapid diagnostic test (CareStart Malaria HRP2/pLDH (pf/PAN) Combo, DiaSys, UK). | PMC10734997 |
Description of the sub- study | The cross-sectional data from December surveys was used for risks factors analysis over the three year’ life span of the LLINs. The type of LLIN was considered as the primary exposure therefore the arms receiving the same type of LLIN (Standard LLIN or PBO LLIN) were combined to form two arms regardless of IRS. Sample size was calculated for the first analysis of the RCT and is presented elsewhere [ | PMC10734997 | ||
Data management and statistical analysis | Data were extracted from the parent study database which was in Microsoft Access (Microsoft Corporation, Redmond, USA) format and transferred into STATA version13 (Stata-Corp, College Station, TX, USA) for further cleaning and statistical analysis. A description of all the independent variables included in the study is indicated in | PMC10734997 | ||
Description of the study variables. | malaria, malaria infection | MALARIA, REGRESSION, INTERACTIONS, INTERACTION | For categorical variables, numbers and proportions (percentages) in each level were calculated. For continuous variable median and inter-quartile range (IQR) were calculated.Given that malaria prevalence was more than 40% in the study area; Poisson regression was used as an alternative to logistic regression to determine factors associated with malaria infection. Poisson regression estimates risk ratio (prevalence ratio) instead of odd ratio. For rare outcome (less than 10%) odds ratio approximates prevalence ratio or risks ratio, that’s why odds are used to present the risk. However when the outcome is very common odds tend to overestimate the risk [A Multilevel modelling technique was used to estimate the risk ratio, given the hierarchical nature of the data (as the children are nested within a household and households are nested within clusters/villages). Household and village level variation in malaria prevalence was assessed from a null multilevel model that included only a random intercept term. The likelihood showed no variability at the household level; hence only village/cluster level was considered as random effect during this analysis. Multilevel mixed-effect generalized liner mixed model (meglm) with a Poisson distribution (family) and log link function was used in Stata.A step-wise by backward elimination method was used for all factors associated with malaria infection with a p-value of 0.2 in the univariate model into a multivariable multilevel Poisson regression model. Interactions between study arm with LLIN usage and survey rounds were investigated. Interaction between household IRS status and survey round was also included. Akaike Information Criteria (AIC) was used to assess the model with and without interaction. The between cluster variability and Intracluster correlation coefficient (ICC) were also calculated and presented. Complete case analysis was considered. | PMC10734997 |
Ethics statement | SECONDARY | The main trial was approved by the ethics review committees of the Kilimanjaro Christian Medical University College, the London School of Hygiene & Tropical Medicine, and the Tanzanian Medical Research Coordinating Committee (NIMR/HQ/R.8a/VolIX/1803). Written informed consent from parents or guardians was obtained for each survey. Ethical clearance to perform secondary analysis was obtained from the Kilimanjaro Christian Medical University College Research and Ethics Committee, Tanzanian (No.2119). Participant’s confidentiality was maintained by ensuring the use of participant identification number during data extraction and analysis. | PMC10734997 | |
Results | PMC10734997 | |||
Participants and household characteristics | malaria, malaria infection | MALARIA | A total of 48 clusters were surveyed at each time point. For the three surveys, data were available for 5,221 households with children aged 6 months to 14 years and 11,275 children were tested for malaria. About 11% of selected children in each survey year were not tested for malaria infection. After data cleaning and merging, 88% of all eligible households and 97% of selected children in each survey were analysed ( | PMC10734997 |
Flow chart of selected households and children included in the study, Muleba Tanzania. | A total of 10,941 children with a median age of 7 (IQR: 4, 10) years were analysed. There were an almost equal number of children between study arms across all surveys. LLIN usage dropped over survey time. However, the proportion was almost balanced between arms, except during the second year of the trial in 2016, 1221 (62.3%) of children in standard LLIN arm use LLIN and 1086 (57.2%) in PBO LLIN arm. A total of 4,611 households were analysed and were equally distributed between arms and almost half of the households in each arm were sprayed in 2015. Overall, within each survey year, LLIN ownership and access were almost similar between the two arms, but there was a drop over time ( | PMC10734997 | ||
Household and individual characteristics of study participants by study arm for 2015–2017 surveys, Muleba Tanzania. | *Two households (0.3%) missing. | PMC10734997 | ||
Malaria prevalence and factors associated with malaria infection | malaria | MALARIA | The malaria prevalence increased over the years from 35.8% in 2015 to 54.4% in 2017. Overall malaria prevalence was 41.6% in the PBO LLIN arm and 51.6% among children living in the standard LLIN arm ( | PMC10734997 |
Univariate multilevel Poisson regression of factors associated with malaria infection among children in Muleba, Tanzania. | malaria, malaria infection | REGRESSION, MALARIA | In the univariate multilevel Poisson regression analysis, all factors except for the household IRS status had a statistically significant association with malaria infection among the selected children (In the multivariable multilevel analysis, about 5% (ICC = 0.05) of the total variability in the risk of malaria infection was attributed to the cluster/village. Based on the empty model (A model with outcome and cluster effect, before adding other variables) 6% of the variability in risk of malaria was due to clustering.Findings from the multivariable multilevel Poisson analysis suggest age of the child, sex, household IRS status in year 1, household SES, head of house education, study arm and survey year remain significantly associated with risk of malaria infection after adjusting for other factors ( | PMC10734997 |
Multivariable multilevel Poisson regression analysis of factors associated with malaria infection among children in Muleba, Tanzania(N = 10,880). | infection, malaria infection | MALARIA, INFECTION, SECONDARY | *Risk ratio adjusted for all variables in the table.The age of the child was highly associated with malaria infection, children aged 5 to 10 years and above 10 years had 27% and 26% higher risk respectively compared to those less than 5 years of age with (aRR = 1.27; 95%CI: 1.18, 1.36) and (aRR = 1.26; 95%CI: 1.18, 1.36). Girls had a 9% lower risk of having malaria infection than boys (Children in the least poor household SES had a 15% lower risk compared to those in the poorest SES. On the other hand, households whose head had secondary or higher education level, children were less likely to have malaria infection as compared to those with no education. Living in the house with open eaves was associated with a 12% increased risk of infection compared to those in the house with closed eaves (Children in the PBO LLIN arm had 32% lower risk of malaria infection compared to those living in the standard LLIN arm in the year 2015, 30% lower risk in 2016 and 20% lower risk of having malaria infection in 2017. However, the difference was not statistically significant (aRR = 0.80; 95%CI: 0.62, 1.03). In 2015 survey, children in a household without IRS had a 47% higher risk of malaria infection ( | PMC10734997 |
Discussion | malaria, infection, malaria infection | MALARIA, INFECTION | The results show an overall increase in malaria prevalence in the study area over the years. Prevalence was higher amongst children living in areas with standard LLINs as opposed to those living in villages with PBO LLINs. Other factors associated with malaria infection were being a male and greater than 5 years old. Children living in households of lower socio-economic status, those with open eaves, house without IRS and whose head of household had no formal education had increased risk of malaria infection.The observed increase in malaria prevalence over the years could be explained by a decrease in mosquito net usage and in PBO concentration in the PBO LLIN. LLINs usage dropped from 80% to 50%. Findings from the same randomized control trial by Protopopoff et al. [Throughout the study period, children living in the area with standard LLINs as opposed to those living in villages with PBO LLINs were more likely to have malaria infection regardless of LLIN usage. Data from the same trial demonstrated that after 20 months of use, there were less mosquitoes blood fed inside PBO nets compared to the standard LLINs. Suggesting that despite development of holes PBO LLINs provided better personal protection than standard LLINs arm [Inconsistent with other reports [Similar to other studies [In line with other studies, this study also found that lower household SES [Other studies have reported important environmental factors which contribute to malaria infection such as land cover, land surface temperature and precipitation [ | PMC10734997 |
Conclusions | malaria infection | The present analysis suggests that using of PBO LLINs reduced the risk of malaria infection in this area of high pyrethroid resistance compared to Standard LLIN. However, the overall prevalence still remains high and increased during the 3 years of the trial. This suggest increasing coverage of the PBO LLINs as well as educational and communication campaigns to promote appropriate and consistent use of LLINs.Furthermore, to lower prevalence and meet the national target, additional measures such as house improvements (closing eaves, screening doors and windows) and programs are needed to protect children in the household with poor SES, house with open eaves, low head education level and older children. | PMC10734997 | |
Supporting information | PMC10734997 | |||
STROBE statement—checklist of items that should be included in reports of observational studies. | MALARIA | (DOC)Click here for additional data file.Would like to convey our gratitude to Ifakara Health Institute-IHI, Tanzania under clinical trial unit and DELTAS Sub-Saharan Africa Consortium for Advanced Biostatistics (SSACAB) Training Programme for financial support during the MSc. Training. Authors would like to acknowledge staffs at Department of Epidemiology and Biostatistics, Kilimanjaro Christian Medical University College for their valuable inputs and support. Also, would like to acknowledge the guidance of Mr. Jim Todd on data analysis. Lastly, we would like to thanks staffs of Pan-African Malaria Vector Research Consortium, Kilimanjaro Christian Medical University College, Moshi, Tanzania (PAMVERC), particularly Muleba office for making the study possible. | PMC10734997 | |
References | PMC10734997 | |||
Background | postoperative pain, musculoskeletal injuries | Postoperative intravenous diclofenac reduces patient opioid demand and is commonly used in surgical units. Orphenadrine is mainly used in combination with diclofenac for musculoskeletal injuries and postoperative pain control. The objective of this study was to compare the analgesic efficacy of diclofenac-orphenadrine, diclofenac alone and saline. | PMC9938044 | |
Methods | delirium | We performed a double-blind, randomized, placebo-controlled, parallel-group, single-center clinical study investigating the opioid-sparing effect of a combination of diclofenac and orphenadrine versus diclofenac alone versus isotonic saline solution. Initially 72 patients were included and received total intravenous anesthesia during cruciate ligament surgery. All patients were postoperatively treated with a patient-controlled analgesia (PCA) device containing hydromorphone. Pharmacological safety was assessed by laboratory parameters, vital signs, and delirium detection scores. | PMC9938044 | |
Results | ± | There was no significant difference between the groups in cumulative dose of PCA analgesics required after 24 h postsurgery, with 5.90 mg (SD ± 2.90 mg) in the placebo group, 5.73 mg (SD ± 4.75 mg) in the diclofenac group, and 4.13 mg (SD ± 2.57 mg) in the diclofenac-orphenadrine group. Furthermore, there was no significant difference between the groups in cumulative dose of PCA analgesics required 2 h postsurgery ( | PMC9938044 | |
Conclusion | postoperative pain | Orphenadrine-diclofenac failed to significantly reduce postoperative opioid requirements. However, in an exploratory post hoc analysis the diclofenac-orphenadrine and the diclofenac group combined versus placebo showed a tendency to reduce opioid demand in postoperative pain control. Further research is required to determine the value of orphenadrine as an adjuvant in a multimodal approach for postoperative pain management. | PMC9938044 | |
Keywords | Open access funding provided by Medical University of Vienna. | PMC9938044 | ||
Introduction | Parkinson’s disease, hyperalgesia, pain | SECONDARY | The benefits of effective pain management after surgery and the favorable effect on fast recovery and outcome are well documented [Orphenadrine is a centrally acting muscle relaxant initially used for the treatment of Parkinson’s disease. In addition, it has anticholinergic and antihistaminic properties and a potential analgesic efficacy via an antagonistic effect on N‑methyl-D-aspartate (NMDA) receptors, as well as inhibiting effects on the norepinephrine re-uptake system. The exact mechanisms of its analgesic effects are unclear but a block of sodium channels could be a possible mechanism in its analgesic efficacy [The objective of this study was to investigate the potential opioid-sparing effect of a combination of diclofenac and orphenadrine versus diclofenac alone. We hypothesized that the addition of orphenadrine might also prevent opioid-induced secondary hyperalgesia after intraoperative use of potent opioids such as remifentanil. | PMC9938044 |
Methods | PMC9938044 | |||
Study design | The study was performed at the Vienna General Hospital, which is also the site of the Medical University of Vienna and provides more than 50,000 surgeries per year. The study was conducted as a double-blind, randomized, placebo-controlled, parallel-grouped, single-center clinical study. | PMC9938044 | ||
Ethics | This study was conducted in accordance with the declaration of Helsinki and the good clinical practice guidelines. The study protocol as well as the written consent form were approved (EK 1494/2016) by the Ethics Committee of the Medical University of Vienna (Chairperson: Univ.-Doz. Dr. Martin Brunner; Borschkegasse 8b/E06, 1090 Vienna, Austria) on 24 August 2016. Written informed consent was obtained from all study participants. | PMC9938044 | ||
Study population | Included were patients undergoing elective cruciate ligament surgery. Every patient received a standard of care total intravenous anesthesia consisting of an induction with propofol, remifentanil and, if relaxation required, rocuronium followed by a maintenance with remifentanil (0.15–0.25 μg⋅kgSample size calculations: from chart reviews, we derived a range of 4–6 mg hydromorphone usage within 24 h for patients with no prophylactic diclofenac intraoperatively, diclofenac, and diclofenac plus orphenadrine administration intraoperatively with a standard deviation of 2 mg. With an a‑error of 0.05 and a power (1-b) of 0.85, and a 1:1:1 allocation ratio 66 patients overall were calculated and 10% were added to compensate for study dropouts for ANOVA analysis, leading to 72 patients. | PMC9938044 | ||
Study intervention | Patients were randomly allocated in a 1:1:1 ratio to 1 of 3 study arms and received either 2×250 ml solutions of 75 mg diclofenac combined with 30 mg of orphenadrine, 2×250 ml solutions of 75 mg diclofenac or 2×250 ml solutions of isotonic saline in a double-blind setting. Randomization of the study patients in a 1:1:1 randomization ratio took place presurgery, using the web-based randomizer provided by the Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz (Graz, Austria, Flowchart of the study protocol. | PMC9938044 | ||
Statistics | delirium, pain | SECONDARY | The primary outcome of the study was the total dose of PCA analgesics required 24 h after surgery. The secondary outcomes were PCA analgesics required 2 h after surgery, pain intensity measured by visual analogue scales (VAS) 2 h and 24 h after surgery.Exploratory outcomes: furthermore, the local and systemic tolerability and safety of the clinical study medications were assessed, as were possible neurological side effects using the delirium detection score 2 h and 24 h after the first infusion [Results are reported as means with standard deviation (SD). Dichotomous outcomes are reported as absolute ( | PMC9938044 |
Discussion | postoperative pain, bleeding, hyperalgesia, low pain, allodynia, pain, renal dysfunction | THROMBOPHLEBITIS, EVENTS, BLEEDING, PCP | In the present study, there was no significant difference for the postoperative opioid PCA requirements between the diclofenac-orphenadrin, the diclofenac and the placebo group for the treatment of postoperative pain in patients receiving cruciate ligament surgery. However, a distinct trend towards a reduction of hydromorphone requirement in the first 24 h postsurgery was found when administering diclofenac-orphenadrine, albeit being non-significant. Furthermore, our findings are in line with existing literature regarding high interindividual differences of opioid effectiveness as well as responsiveness to pain and a wide variety in postoperative opioid demand after arthroscopic cruciate ligament surgery [Overall, subjective pain intensity was similar in all groups. Due to adequate dosing of rescue medication a difference in pain intensity between the groups was not to be expected. Following the development of PCA systems with the ability to record delivered dose in the early 1970s reduction of opioid consumption became a cornerstone for the assessment of pain medication [To the best of our knowledge there previously were three studies examining the intravenous use of a diclofenac-orphenadrine combination in a postoperative setting. However, two of these studies were published in Hungarian and in Czech, respectively [Orphenadrine binds to the phencyclidine (PCP) binding site of the NMDA receptor which has been shown to delay the emergence and maintenance of mechanical and thermal hyperalgesia and allodynia [The most extensively discussed AEs in the literature on diclofenac are renal dysfunction, cardiovascular events, bleeding and thrombophlebitis, all of which occur infrequently and at similar rates as in other NSAIDs [An additional limitation of this study is the lack of pain assessment during joint movement. A study by Cho et al. on perioperative use of pregabalin failed to detect a reduction in postoperative opioid demand in patients undergoing cruciate ligament surgery but resulted in a reduction in pain during joint movement [It seems possible that there is an opioid-sparing effect of orphenadrine-diclofenac which we failed to detect because of insufficient power. The effect size for the sample size analysis may have been overestimated, and more patients per group likely might have been needed. Finally, a significant difference for PCA analgesic consumption between placebo and diclofenac/orphenadrine-diclofenac was detected after removal of two datapoint outliers resulting from two patients excessively pressing their respective PCA pumps, while both reporting low pain levels post hoc. However, as we cannot exclude that this particular PCA activation was due to pain and not “PCA misuse” this result needs to be interpreted with caution and is exploratory.An additional limitation of our study is the lack of evaluation of further variables that might influence pain perception such as social and cultural background as well as ethnicity [ | PMC9938044 |
Acknowledgements | We want to thank Dr. Martina Hermann, Dr. Stefan Koch and Dr. Udo Eggenreich for their help with carrying out the study. | PMC9938044 | ||
Funding | This study was partially funded by Fresenius Kabi Austria GmbH (Graz, Austria). | PMC9938044 | ||
Author Contribution | S. Zeiner: conceptualization, formal analysis, methodology, project administration, validation, writing—original draft, visualization, data curation; T. Haider, O. Zotti, P. Höbart, E. Knolle: conceptualization, data curation, resources, writing—review & editing; O. Kimberger.: conceptualization, formal analysis, methodology, funding acquisition, validation, writing—review & editing, project administration | PMC9938044 | ||
Funding | Open access funding provided by Medical University of Vienna. | PMC9938044 | ||
Conflict of interest | Thomas | Professor Kimberger was a member of the advisory board of ZOLL Medical Österreich GmbH (Vienna, Austria) until 2019. Thomas Haider, Petra Höbart, Oliver Zotti, Katrin Thüringer, Erich Knolle and Sebastian Zeiner declare that they have no conflicts of interest. | PMC9938044 | |
References | PMC9938044 | |||
1. Introduction | sore throat, nausea, myalgia, fatigue, fever, pain, cough, dizziness, skin rash, sleep problems, depressive, loss of taste and smell, headache, coronavirus disease 2019, Fatigue | SORE THROAT, VIRUS, CORONAVIRUS DISEASE 2019, VIRAL DISEASES, RESPIRATORY TRACT INFECTIONS, SYNDROME, CORONAVIRUS | The aim of this study was to compare the effectiveness of traditional neurological rehabilitation and neurological rehabilitation combined with a rehabilitation robot for patients with post-COVID-19 fatigue syndrome. Eighty-six participants transferred from intensive care units due to post-viral fatigue after COVID-19 were randomly divided into two groups: the intervention group and the control group. The control group received standard neurological rehabilitation for 120 min a day, while the intervention group received the same neurological rehabilitation for 75 min a day, complemented by 45 min of exercises on the rehabilitation robot. The Berg scale, Tinetti scale, six-minute walking test, isokinetic muscle force test, hand grip strength, Barthel Index, and Functional Independence Measure were used to measure the outcomes. Both groups improved similarly during the rehabilitation. Between groups, a comparison of before/after changes revealed that the intervention group improved better in terms of Functional Independence Measure (In recent years, a new global health problem emerged due to the novel coronavirus—SARS-CoV-2—causing coronavirus disease 2019 (COVID-19). This virus, which first appeared in China, has quickly spread worldwide, causing a global pandemic. In addition to the characteristic symptoms of respiratory tract infections, such as fever, cough, or fatigue, in the course of COVID-19, many other symptoms are likely to appear, including loss of taste and smell, sore throat, headache, muscle or joint pain, skin rash, nausea and vomiting, and dizziness [A similar phenomenon has also been reported for other viral diseases. Tansey et al. [Fatigue syndrome observed after COVID-19 is characterized by chronic fatigue, sleep problems, depressive symptoms, and myalgia [Various rehabilitation approaches are used to manage post-COVID symptoms [Due to the growing workload of medical staff as well as the ever-increasing costs of rehabilitation, new methods of patient therapy are also sought, involving advanced medical devices that have the potential to reduce the burden on multidisciplinary rehabilitation teams. In light of the abovementioned problems, robotic devices could greatly improve the ability of healthcare to manage post-COVID patients and their symptoms [ | PMC10575211 |
2. Materials and Methods | muscle contraction, fatigue | MUSCLE WEAKNESS, CONTRACTION, POLAND | A prospective randomized clinical trial was conducted in the Neuro-rehabilitation Ward of the Provincial Hospital in Poznan, Poland, between January and August 2022. The study has been registered with ClinicalTrials.gov, ID: NCT05130736.Participants who were transferred directly from Intensive Care Units (ICUs) due to post-viral fatigue after experiencing a severe course of COVID-19 according to the criteria presented by Carod-Artal [The CG received standard neurological rehabilitation for 120 min a day, while the IG received the same neurological rehabilitation for 75 min a day, complemented by 45 min of exercises on the rehabilitation robot (Egzotech sp. z o.o., Gliwice, Poland). The rehabilitation robot was a device constructed to support physiotherapists and patients during the rehabilitation process. Due to the fact that the robot is EMG-driven, the device is able to help patients with relatively low muscle strength perform active exercises. Even if muscle contraction, due to its weakness, is not visible, electrodes applied above the muscles record changes in their activity during the contraction. Those signals trigger the actuator, which moves the movable parts (extensions) of the device. A limb of the patient is attached to those extensions by straps, which allows them to perform a movement (such as flexion and extension of the elbow) and control the movement even in a situation when normal movement will not be possible due to muscle weakness. The intervention was described in detail in a previous feasibility study [ | PMC10575211 |
2.1. Measurement | hand dynamometer | Several measurement tools were used to assess functional physical ability (Berg scale, Tinetti scale, six-minute walking test (6MWT)), muscle strength (isokinetic muscle force of elbow flexors and extensors, hand grip strength (GS)), and independence in activities of daily living (Barthel Index, Functional Independence Measure).The Berg scale is used to assess balance and measures the static and dynamic balance using 14 motor tasks. Each task is scored from 0 to 4, where 0 means that the subject is not able to perform the task, and 4 is scored when the subject performed the task in the best way assigned to the task. The maximum total score is 56 points, and it indicates that the patient is fully independent in ambulation [The isokinetic muscle force test of elbow flexors and extensors in the dominant hand was performed on the rehabilitation robot. Patients were seated in a chair (dominant side toward the robot) with a straight back, hips and knees in 90 degrees of flexion, and feet on the floor. The dominant forearm was fixed by two straps and with the hand gripping a handle. The axis of the elbow was aligned with the axis of the dynamometer (The HGS test was performed for the dominant hand using the JAMAR hydraulic hand dynamometer (Sammons Preston Rolyan, Bolingbrook, IL, USA). The test was performed in accordance with the gold standard of the American Society of Hand Therapists [The Barthel Index is a scale used to assess independence and the need for assistance in performing activities related to toileting, sphincter control, transferring to and from a wheelchair, and ambulation [ | PMC10575211 | |
2.2. Statistical Analysis | POLAND | Statistical analysis was performed with Statistica 13.3 software (TIBCO Software/StatSoft Polska Sp. z o.o., Krakow, Poland). The threshold for statistical significance was set at | PMC10575211 | |
3. Results | A total of 86 participants were included in the study. However, due to various causes, five participants did not complete the study. Therefore, data from 81 participants (42 in IG and 39 in CG) were analyzed. There were significant differences between groups in terms of weight and BMI, yet groups did not differ in age, height, or any of the measured parameters at the baseline. Group characteristics comparison at the baseline is presented in A comparison of the results before and after rehabilitation in both groups is presented in In the analysis of the results of repeated measures ANOVA, taking into account the division into groups, no intra-group interactions were found in any parameter except the FIM motor subscale ( | PMC10575211 | ||
4. Discussion | stroke, fatigue, Kawasaki | STROKE, SYNDROME, KAWASAKI | The use of robots in rehabilitation gained significant traction in 1990 [Villafañe et al. [Some other authors found that robot-assisted rehabilitation can be more efficient than traditional rehabilitation. Dehem et al. [As stated previously, the majority of available studies using robots in rehabilitation were conducted on stroke patients; however, a few authors compared using rehabilitation robots with conventional rehabilitation on patients with different conditions. Kawasaki et al. [According to the available literature, rehabilitation using robots shows either similar effectiveness to classic rehabilitation, which is consistent with our results, or higher effectiveness than classic rehabilitation. The cost-effectiveness of this type of intervention remains an open issue that requires further research.To our knowledge, the current study is the first clinical trial to compare the effectiveness of traditional neurological rehabilitation and neurological rehabilitation combined with a rehabilitation robot for patients with post-COVID-19 fatigue syndrome. We consider this as a strength of this study. However, the study has some limitations. Due to the setting, we are not able to calculate the realistic cost-effectiveness of the intervention because participants had to undergo the whole rehabilitation process, and rather than achieving the predetermined goal, their improvement was measured. A further limitation results from organizational and financial reasons, due to which only exercises of the upper limb were performed using the EMG-driven robotic device.Human–robot interaction (HRI) is studied mainly in the area of social robotics. HRI may be different when a non-humanoid rehabilitation robot is used, like the one in the current study. Hertz and Wieze [ | PMC10575211 |
5. Conclusions | fatigue | SYNDROME | In light of the results of the present study, implementing EMG-driven robots in the rehabilitation of post-COVID-19 fatigue syndrome patients is effective. Substituting a part of traditional rehabilitation with robotic rehabilitation did not negatively alter rehabilitation outcomes. Our results indicate that the implementation of robotic rehabilitation for patients with post-coronavirus fatigue syndrome in rehabilitation programs can be supported. Further investigations aiming at achieving rehabilitation goals rather than completing a rehabilitation period should be conducted in the future to establish the realistic cost-effectiveness of such procedures. | PMC10575211 |
Author Contributions | Conceptualization, E.Z., D.K., S.T. and K.H.; formal analysis, T.T. and A.P. (Anna Pieczyńska); investigation, R.M.; methodology, T.T., D.K. and I.Z.; project administration, R.M. and E.Z.; resources, K.H., M.M. and A.P. (Anna Poświata); supervision, K.H.; writing—original draft, T.T.; writing—review and editing, T.T., S.T., A.P. (Anna Pieczyńska), E.Z., K.H., M.M., A.P. (Anna Poświata) and I.Z. All authors have read and agreed to the published version of the manuscript. | PMC10575211 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Bioethics Committee of Poznan University of Medical Sciences (Protocol No. 514/21). | PMC10575211 |
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