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Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC9965201 | ||
Author Contributions | Conceptualization, L.J.R., V.M. and M.B.; methodology, L.J.R., D.M.Z., V.M., A.M.R. and M.B.; formal analysis, L.J.R., V.M., M.B. and D.M.Z.; writing—original draft preparation, L.J.R., V.M. and S.G.; writing—review and editing, S.G., V.M., D.M.Z., A.M.R., M.B. and L.J.R.; visualization, S.G. and V.M.; supervision, V.M.; project administration, L.J.R. and V.M.; funding acquisition, L.J.R. and D.M.Z. All authors have read and agreed to the published version of the manuscript. | PMC9965201 | ||
Institutional Review Board Statement | Ethical approval was obtained from the Helsinki Committee of Asaf Harofe Hospital (0143-16 ASF), the Israel Ministry of Health (920090057), and the Tel Aviv University Ethics Committee. | PMC9965201 | ||
Informed Consent Statement | Written informed consent was obtained from all subjects involved in the study. | PMC9965201 | ||
Data Availability Statement | The data are available from the authors upon reasonable request. | PMC9965201 | ||
Conflicts of Interest | LJR has submitted expert opinions to the Israel Supreme Court on an administrative case about smoking by neighbors and is co-PI on a grant funded by the Justice Ministry on reducing child exposure to tobacco smoke by providing parents with biomarker information. D.Z. has no conflicts of interest. S.G. served as a paid expert consultant to the Ministry of Health of Singapore in reviewing the evidence on plain or standardized packaging. V.M. submitted an expert opinion in a court case in Israel about smoking by neighbors and is co-PI on a grant funded by the Justice Ministry on reducing children’s exposure to tobacco smoke by providing parents with biomarker information. | PMC9965201 | ||
Objectives | To have confidence in one's interpretation of treatment effects assessed by comparing trial results to external controls, minimizing bias is a critical step. We sought to investigate different methods for causal inference in simulated data sets with measured and unmeasured confounders. | PMC9843888 | ||
Methods | The simulated data included three types of outcomes (continuous, binary, and time-to-event), treatment assignment, two measured baseline confounders, and one unmeasured confounding factor. Three scenarios were set to create different intensities of confounding effect (e.g., small and blocked confounding paths, medium and blocked confounding paths, and one large unblocked confounding path for scenario 1 to 3, respectively) caused by the unmeasured confounder. The methods of g-computation (GC), inverse probability of treatment weighting (IPTW), overlap weighting (OW), standardized mortality/morbidity ratio (SMR), and targeted maximum likelihood estimation (TMLE) were used to estimate average treatment effects and reduce potential biases. | PMC9843888 | ||
Results | The results with the greatest extent of biases were from the raw model that ignored all the potential confounders. In scenario 2, the unmeasured factor indirectly influenced the treatment assignment through a measured controlling factor and led to medium confounding. The methods of GC, IPTW, OW, SMR, and TMLE removed most of bias observed in average treatment effects for all three types of outcomes from the raw model. Similar results were found in scenario 1, but the results tended to be biased in scenario 3. GC had the best performance followed by OW. | PMC9843888 | ||
Conclusions | The aforesaid methods can be used for causal inference in externally controlled studies when there is no large, unblockable confounding path for an unmeasured confounder. GC and OW are the preferable approaches. | PMC9843888 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12874-023-01835-6. | PMC9843888 | ||
Keywords | PMC9843888 | |||
Introduction | ECAs | RARE DISEASES | In orphan and rare diseases, single-arm trials are common given the impracticability, if not impossibility, of randomized controlled trials [Numerous methods have been proposed to handle the potential confounders in ECAs. When individual-level data are available, frequentist approaches may estimate a causal effect using g-computation, propensity score (PS)-based weighting, PS-based stratification, PS-based matching, targeted maximum likelihood estimation (TMLE), etc. [By definition, a confounding variable must be correlated with the outcome and the treatment. The randomization aspect of many studies minimizes the correlations and hence the risk of bias due to confounding. However, when real-word data (RWD) is used to construct an ECA, the benefits of randomization are not possible, and unmeasured or unobserved predictive variables may represent unobserved confounders. Furthermore, the confounder misclassification may lead to another layer of bias when combining trial data and RWD [ | PMC9843888 |
Materials and methods | PMC9843888 | |||
Study design | We generated a treatment arm (e.g., single-arm trial) and an ECA (e.g., standard of care) in order to simulate an externally controlled study. Three types of outcomes – continuous, binary, and time-to-event endpoints were assessed between two arms. In order to emulate a biased ECA, both measured and unmeasured confounders were added to the data. For each outcome, we explored three scenarios for the relationship between unmeasured confounders and observed variables (Fig. Diagram of measured and unmeasured confoundersIn scenario 1 & 2, as shown in Fig. In scenario 3 (Fig. A set of random samples were drawn from a simulated target population for each scenario. For each generated sample, g-computation, PS-based weighting, e.g., inverse probability of treatment weighting (IPTW), standardized mortality/morbidity ratio (SMR), and overlap weighting (OW), and targeted maximum likelihood estimation (TMLE) were used to estimate treatment effects based on observed outcomes and measured confounders which were incorporated in the analytic model. | PMC9843888 | ||
Simulated dataset | We generated a data set with 20,000 individuals, which was considered as a target population. In this data set, variable From this target population, we randomly drew 3000 samples. Each sample contained 200 observations (i.e. ‘individuals’) and were randomly drawn from the target population. Also, we drew another 3000 samples with 100 individuals per sample in a similar fashion, in order to further validate our results given a different sample size. | PMC9843888 | ||
True effect | REGRESSION | For assessing the various methods that obtained estimates based on samples, the true effect of treatment in the population is needed. Population level ATEs were obtained by applying regression models to estimate marginal effects in the full dataset (n = 20,000), including both measured and unmeasured confounders in the analyses. The ATEs of | PMC9843888 | |
Methods for minimizing potential biases | This study explores g-computation, PS-based weighting, and TMLE methods that can be used to handle individual-level data for reducing potential biases in externally controlled studies. | PMC9843888 | ||
G-computation | G-computation is one of Robins’ g methods [ | PMC9843888 | ||
PS-based weighting | One of common PS-based weighting method is IPTW [ | PMC9843888 | ||
TMLE | death | The TMLE method puts g-computation and PS-based weighting together, which is also considered as doubly robust estimation [Last, the estimated ATE for each outcome can be calculated as follows:The TMLE method was conducted using R package “ltmle” with the default machine learning algorithms. Since the package “ltmle” cannot directly provide hazards ratio (HR) for time-to-event outcome (where RR is the relative risk, HR is the hazard ratio, and d is the death rate for reference group (e.g., d = 0.4) [ | PMC9843888 | |
Model comparison | All statistical analyses were conducted in RStudio (version 1.4.1717) and R (version 4.0.4). In addition to the aforementioned methods, we also conducted the analysis using a raw model, which directly estimated the treatment effects without any adjustment. In order to assess these methods, we compared the true effect with the results (point estimate and 95% confidence interval) from each model, and calculated the bias, root mean squared error (RMSE) along with coverage and width of 95% confidence interval for the treatment effects. The bias was defined as the average difference between the true value (simulated) and its estimate across the simulation replicates using the original scale for the continuous outcome and the log-transformed scale for the binary and time-to-event outcomes, such as log(HR). RMSE was the square root of the mean squared error (MSE) that was the average squared difference between the true value and its estimate across the simulation replicates. Coverage was the proportion of times the 95% confidence interval of the estimate contained the true value. Width was the average difference between the upper and lower bounds of 95% confidence interval of estimate. | PMC9843888 | ||
Results | PMC9843888 | |||
Estimated ATE for binary endpoint | Similar to the results for the continuous endpoint, the mean estimated ATE (0.94) for binary endpoint from the raw model obviously deviated from the true effect (log odds ratio = 1.21) in scenario 1, and the deviation was even larger in scenario 2 & 3. As shown in Fig. Density distribution of treatment effect estimates by different methods for a binary endpoint ( | PMC9843888 | ||
Estimated ATE for time-to-event endpoint | The mean estimated ATEs for time-to-event endpoint from the raw model also considerably differed from the true effects in all scenarios (e.g., log hazard ratio = -0.65 versus -0.83 in scenario 1). The mean estimated ATEs for time-to-event endpoint from g-computation, IPTW, OW, SMR, and TMLE in scenario 1 were -0.83, -0.81, -0.86, -0.85, and -0.68, respectively, which closely approximated to the true effect except the estimate by TMLE with a conversion from RR to HR had an obvious deviation (-0.68 versus -0.83). As shown in Fig. Density distribution of treatment effect estimates by different methods for a time-to-event endpoint ( | PMC9843888 | ||
Sensitivity analysis | When the sample size was reduced from 200 to 100, we found similar results in terms of reduction in bias associated with each method, but we observed increase of variance, which led to a larger MSEs and wider confidence intervals (supplementary file S | PMC9843888 | ||
Discussion | SECONDARY | By design, both the unmeasured confounder In scenario 1 & 2, the unmeasured confounder After adding an additional relationship between Although the same predictors were used for modeling, the g-computation had the smallest RSMEs in most of settings of this simulation study (Table TMLE is a doubly robust maximum-likelihood-based approach that includes a secondary "targeting" step that optimizes the bias-variance tradeoff for the target parameter [Among the three PS-based weighting methods, OW had the best performance in this simulation. Both IPTW and SMR use the propensity score as a part of denominator for calculating the weight, but OW does not. The weight using reciprocal of propensity score could be greatly amplified when the propensity score is very small or large (e.g. 0.01 or 0.99). Therefore, OW may be less sensitive to the extreme values of propensity score, which might lead to a smaller RSME for estimating the treatment effect compared with IPTW and SMR [One of merits in this study is that we explored some scenarios which the previous studies had not investigated, such as three types of outcomes along with different confounding effects (small and blocked confounding paths, medium and blocked confounding paths, and one large unblocked confounding path) caused by an unmeasured confounder [ | PMC9843888 | |
Conclusion | In externally controlled studies, the methods of g-computation, PS-based weighting (IPTW, OW and SMR), and TMLE can be used to minimize the biases due to measured and unmeasured confounders. However, the extent of bias reduction by these methods depends on the technique used and the existence of an unblockable confounding path for an unmeasured confounder. Our findings in this simulation study suggest that g-computation and OW are the preferable alternative approaches producing relatively unbiased estimates, especially when there is no large, unblocked confounding path for an unmeasured confounder. | PMC9843888 | ||
Acknowledgements | MAY | Sai Karanam from Eliassen Group, LLC provided the R codes validation. This work was delivered as a podium presentation at ISPOR 2022, Washington, D.C., and virtual, May 15-18, and the authors thank the participants for their constructive feedback that improved the quality of the manuscript. | PMC9843888 | |
Authors’ contributions | Study concept and design: JR, PC, JC, HP & DM; Data source: JR & PC; Statistical analysis and simulation: JR, PC & JC; Manuscript draft and review: JR, PC, JC, HP & DM. The author(s) read and approved the final manuscript. | PMC9843888 | ||
Funding | This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. | PMC9843888 | ||
Availability of data and materials | The example of R codes for data simulation and analysis can be found in the supplementary file S | PMC9843888 | ||
Declarations | PMC9843888 | |||
Ethics approval and consent to participate | Ethics approval and consent to participate is not required since this study used the simulated data only. | PMC9843888 | ||
Consent for publication | Not applicable. | PMC9843888 | ||
Competing interests | The authors declare no competing interests. | PMC9843888 | ||
References | PMC9843888 | |||
Introduction and hypothesis | SUI, MUI, urinary incontinence | STRESS URINARY INCONTINENCE, URINARY INCONTINENCE | This study was aimed at investigating the long-term effectiveness of minimally invasive mid-urethral sling (MUS) surgery and at comparing the outcomes between retropubic (tension-free vaginal tape, TVT) and transobturator tape (TOT) methods in the treatment of stress urinary incontinence (SUI) and mixed urinary incontinence (MUI) with a predominant stress component in a long-term follow-up of a randomized controlled trial. | PMC10506929 |
Methods | This work is a long-term follow-up study of a previous prospective randomized trial conducted in the Department of Obstetrics and Gynecology at Oulu University Hospital between January 2004 and November 2006. The original 100 patients were randomized into the TVT ( | PMC10506929 | ||
Results | TVT | Long-term follow-up data were obtained from 34 TVT patients and 38 TOT patients. At 16 years after MUS surgery, the UISS significantly decreased from a preoperative score in the TVT (11.88 vs 5.00, | PMC10506929 | |
Conclusion | TVT, MUI | Midurethral sling surgery had good long-term outcomes in the treatment of SUI and MUI with a predominant stress component. The subjective outcomes of the TVT and TOT procedures were similar after a 16-year follow-up. | PMC10506929 | |
Supplementary information | The online version contains supplementary material available at 10.1007/s00192-023-05527-z | PMC10506929 | ||
Keywords | Open Access funding provided by University of Oulu including Oulu University Hospital. | PMC10506929 | ||
Introduction | SUI, TVT, MUI, incontinence | INCONTINENCE, STRESS URINARY INCONTINENCE, URINE LEAKAGE | Stress urinary incontinence (SUI) is defined as involuntary urine leakage during physical exertion or while sneezing or coughing, whereas urge incontinence is involuntary loss of urine associated with urgency [The first-line treatment of urinary incontinence is conservative, and it includes lifestyle modifications (weight control, cessation of smoking, etc.) and physiotherapy. However, conservative treatment is usually inadequate. Therefore, minimally invasive mid-urethral sling (MUS) operations are currently the gold standard of surgical treatment for SUI [The aims of this study were to investigate the effectiveness of minimally invasive MUS surgery at an average of 16 years’ follow-up, and to compare the subjective outcomes of TVT and TOT methods in the treatment of SUI and MUI in the long-term follow-up of a randomized controlled trial (RCT). | PMC10506929 |
Materials and methods | MUI, urinary incontinence | URINARY INCONTINENCE | This work is a 16-year follow-up study evaluating the long-term benefits of MUS surgery compared with a previous prospective randomized controlled study on 100 women suffering from SUI or MUI with a predominant stress component. The original study protocol was approved by the regional ethics committee and the present study has approval of the hospital district of Northern Ostrobothnia, Finland (124/2020). All the women underwent surgery at the Department of Obstetrics and Gynecology at Oulu University Hospital between January 2004 and November 2006 [Preoperative urinary incontinence was evaluated with two internationally standardized and validated questionnaires: the UISS and Detrusor Instability Score (DIS) [For this long-term follow-up study, we attempted to recruit all patients from the original prospective randomized study. Of the 100 patients, 3 were deceased during follow-up (3 in the TVT group and 0 in the TOT group). Patients were contacted by postal letter, or by phone if there was no response to the letter. Long-term follow-up data were collected using the same internationally standardized and validated questionnaires (UISS and DIS) as preoperatively. The effect of surgery on well-being was measured with the PGI-I questionnaire [The IBM SPSS Statistics version 28 was used for the statistical analysis. Continuous variables were calculated as means or medians with standard deviations or interquartile range, and categorical variables were calculated as frequencies. The differences in continuous variables were analyzed using an independent samples | PMC10506929 |
Discussion | bleeding, postoperative pain, incontinence, bladder and bowel perforation, TVT, gynecological incontinence, memory disorder, SUI, MUI | BLEEDING, INCONTINENCE, URINARY INCONTINENCE, COMPLICATIONS | This long-term follow-up study of a prospective RCT showed that MUS surgery, as a treatment for SUI and MUI with a predominant stress component, has a good long-term subjective outcome. Similar subjective outcomes were found for the TVT and TOT procedures. To the best of our knowledge, this is the first long-term follow-up study using a previous RCT study population with comparable study groups and to standardize the factors related to the success of the operation.This study showed good subjective outcomes after MUS surgery in a long-term follow-up. Preoperatively, most of our patients suffered from severe incontinence (UISS>8). According to the 3-month follow-up, the UISS was significantly lower than the preoperative score, showing good primary success of the MUS procedures. Even after the 16-year follow-up, the UISS remained at a significantly lower level than the preoperative score, showing good long-term success of MUS. Furthermore, no significant difference was found in the PGI-I score between the TVT and TOT groups 16 years after surgery. Dichotomizing the PGI-I score into good (1–3) and poor (4–7) outcomes, there were slightly more patients in the TOT group reporting poor outcomes than in the TVT group, although the difference was not statistically significant. However, the patients with poor subjective outcomes according to the PGI-I score had a higher age and BMI, which could explain the slight difference between the TVT and TOT groups. Our findings are comparable with those of previous studies, which showed that MUS surgery has good long-term effectiveness in the treatment of SUI [To our knowledge, there are only a limited number of studies comparing the outcomes of retropubic and transobturator MUS techniques. The present study showed no difference in the subjective outcomes between the TVT and TOT procedures in a long-term follow-up when the confounding factors related to operation success, such as the patients’ characteristics and the surgeons’ experience, were considered. We found that in a 16-year follow-up, the severity of urinary incontinence, pelvic floor function, and postoperative improvement according to validated questionnaire scores were similar in the TVT and TOT groups. These results are in accordance with those of several other studies demonstrating equal long-term effectiveness between TVT and TOT procedures [The TVT procedure was the first minimally invasive MUS operation to be used effectively to treat SUI. The TVT route can expose patients to rare but, nonetheless, severe complications (bladder and bowel perforation, severe bleeding), which can be avoided using the TOT route [Long-term follow-up with a high response rate (72%) and a prospective randomized controlled design are the strengths of this study. This study is the first long-term study to be based on a previous RCT with minimal differences in the baseline characteristics (i.e., a slightly higher BMI in the TOT group). Validated questionnaires were used to assess the subjective cure, which is the main focus of gynecological incontinence surgery. Furthermore, the procedures were performed by one experienced surgeon, reducing the bias of a learning curve effect on the clinical outcome. This study also has some limitations. The number of patients in the study was quite small, and the limited number of cases could underestimate the statistically significant differences between the study groups. Furthermore, despite the high response rate, missing data may lead to a slight bias, whereas nonresponders were older, they had more severe incontinence and the immediate success of MUS was lower, which may have had a slight effect on the evaluation of the long-term outcome. Although we were able to analyze the subjective cure rate using a validated questionnaire, the lack of assessment of postoperative pain and an objective cure rate can be considered limitations. Moreover, the PFDI-20 questionnaire is aimed at investigating pelvic floor problems, not at purely assessing difficulties in urinary incontinence. We did not have complete information about the patients’ general state of health, and the subjective symptom assessment could not have been completely reliable in all study cases, especially among the elderly and/or patients with memory disorder. Although we were able to standardize the experience of the surgeon, it makes the results less generalizable, and it is possible that the one surgeon favored or had more expertise in one method than in the other. Last, our data were limited in evaluating the need for re-operation and the number of complications related to different surgical methods.Midurethral sling surgery is a minimally invasive and effective treatment for SUI when conservative treatment does not provide sufficient symptom relief. Initially, the focus was on the TVT method, but complications after TVT led to the development of TOT methods. However, owing to a lack of evidence for their effectiveness and long-term follow-up data, there has been uncertainty about the superiority of one of these two methods over the other. Our prospective follow-up of an RCT shows that TVT and TOT procedures are equally effective in terms of the subjective cure rate in a long-term follow-up when the factors related to MUS surgery success are standardized. Despite the limited sample of women presented in this long-term follow up, this study provides insightful data that could also be useful in future meta-analyses. Further studies are needed in terms of complications and need for reoperations related to different MUS techniques. Considering these results, we recommend choosing the method in accordance with the surgeon’s best experience. | PMC10506929 |
Authors’ contributions | TVT | H. Salo: project development, data collection, data analysis, manuscript writing; H. Sova: project development, data analysis, manuscript writing; J. Laru: project development, manuscript writing; A. Talvensaari-Mattila: project development, manuscript writing; T. Piltonen: project development, manuscript writing; V. Nyyssönen: project development, data collection; M. Santala: surgical treatment TVT and TOT; S. Koivurova: project development, manuscript writing; H. Rossi: project development, data analysis, manuscript writing. | PMC10506929 | |
Funding | Open Access funding provided by University of Oulu including Oulu University Hospital. H. Salo has received a research grant from the Finnish Society of Gynecological Surgery. | PMC10506929 | ||
Ethics declaration | PMC10506929 | |||
Conflicts of interest | None. | PMC10506929 | ||
References | PMC10506929 | |||
Background | postoperative pain, colorectal cancer, pain | COLORECTAL CANCER | Although laparoscopic surgery provides earlier recovery, less morbidity and hospital stay, however, severe pain is still a problem after it. Duloxetine has been recently used in postoperative pain management. We tested perioperative duloxetine to evaluate its effect on patients undergoing laparoscopic colorectal cancer surgery. | PMC10186677 |
Methods | ADVERSE EFFECTS | Sixty patients were enrolled in this study divided into two equal groups; duloxetine group each patient received an oral duloxetine capsule (60 mg) 1st dose at night before surgery, the 2nd dose 1 h preoperative, and the 3rd dose 24 h postoperative. Placebo group received placebo capsules at the same times. The cumulative morphine consumption in 48 h, postoperative VAS score, quality of recovery (QoR-40 score), sedation, and adverse effects were evaluated. | PMC10186677 | |
Results | Duloxetine group had lower VAS scores compared to placebo group, (3 ± 0.69) VS. (4.17 ± 0.83), (2.5 ± 0.6) VS. (4.3 ± 0.9), (2.2 ± 0.7) VS. (3.9 ± 0.6), (1.6 ± 0.7) VS. (3.6 ± 0.8), (1.1 ± 0.8) VS. (3.7 ± 0.7), (0.7 ± 0.7) VS. (3.5 ± 0.8), (0.6 ± 0.7) VS. (3.5 ± 0.8) respectively, P ˂0.01. The cumulative morphine consumption was significantly reduced in the Duloxetine group compared to the placebo group (4.6 ± 2.9 vs. 11.3 ± 1.7 mg), P < 0.01. The total QoR-40 score for duloxetine group was (180.8 ± 4.5) vs. (156 ± 5.9) in placebo group ( | PMC10186677 | ||
Conclusions | Perioperative duloxetine had reduced postoperative pain, decreased opioid consumption, and improved the quality of recovery in patients undergoing laparoscopic colorectal surgery. | PMC10186677 | ||
Keywords | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). | PMC10186677 | ||
Introduction | colorectal cancer, major depression, postoperative pain, CRC, anxiety, cancer, pain, chronic pain | CANCER, COLORECTAL CANCER, CHRONIC PAIN, ADVERSE EFFECTS | GLOBOCAN 2018 reported that colorectal cancer (CRC) is the third most deadly and fourth-most common cancer worldwide [Multi-modal analgesia is advocated for perioperative pain management, to reduce opioid use and its associated adverse effects [Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) commonly prescribed for the treatment of major depression and anxiety; it has also been used in the treatment of chronic pain conditions [We hypothesized that the incorporation of perioperative oral duloxetine doses would produce a reduction in postoperative pain intensity, opioid consumption, and quality of recovery for patients subjected to colorectal surgery. | PMC10186677 |
Patients and methods | PMC10186677 | |||
Ethics approval and consent for participation | Cancer | CANCER | This study is a prospective, randomized, double-blinded, placebo-controlled trial. It was done after obtaining approval from both the local ethics committee and the Institutional Review Board (IRB) from the South Egypt Cancer Institute, Assuit University, Assuit, Egypt and strictly followed the regulations and amendments of Helsinki Declaration. Informed written consent was obtained from all patients. The study was recorded at Clinical trials, identifier: NCT04294953 at 4/3/2020, and conducted according to the Consolidated Standards of Reporting Trials (CONSORT) statement. | PMC10186677 |
Participants | allergy, pain, psychiatric, abnormal liver or renal function, cancer colon | ALLERGY, DISORDERS, CANCER COLONS | The inclusion criteria were: adult patients with ASA I-III, aged 18–65 years and, scheduled for laparoscopic colorectal surgery for cancer colon. The exclusion criteria were: Patients that have an allergy to the study drug, abnormal liver or renal function tests, a chronic opioid user (> 3 months), being on gabapentin or pregabalin (> 3 months), antidepressant drugs, patients with psychiatric disorders, pregnant females, unable to express their pain or patient refusal. | PMC10186677 |
Outcome | pain | SECONDARY | The primary aim of our study is to evaluate the efficacy of perioperative duloxetine on postoperative morphine consumption after colorectal surgery. The secondary aims include its effect on VAS pain scores and postoperative quality of recovery. | PMC10186677 |
Randomization and blinding | Sixty patients were randomized by the use of a computer-generated table of random numbers in a 1:1 ratio into 2 groups and concealed in an opaque and sealed envelope. | PMC10186677 | ||
Duloxetine group | Each patient received an oral duloxetine capsule of 60 mg 12 h before surgery, the 2nd dose of 60 mg 1 h preoperative and, the 3rd dose of 60 mg 24 h postoperative. | PMC10186677 | ||
Placebo group | pain | Each patient received a placebo capsule at the same scheduled times. The placebo capsule was prepared by the hospital pharmacy to ensure that active duloxetine and placebo capsules were identical.The patient’s follow-up was conducted by an anaesthesia resident blinded to the study. The attending anaesthesiologist, surgeon and data-collecting person were unaware of the patient assignment.All patients were instructed on how to evaluate their pain using VAS (Visual Analog Scale) [ | PMC10186677 | |
Procedures | Anesthesia | The anaesthetic protocol was standardized for all patients. Basic monitoring (pulse oximeter, electrocardiogram, non-invasive arterial blood pressure, and end-tidal Co2) was attached. IV access was inserted and 500 ml of normal saline was given preoperative. Anesthesia was induced with fentanyl (Fentanyl Hamein, Sunny Pharmaceutical, Germany) 2 µg/kg, propofol (Propofol 1%, Fresenius Kabi, Deutschland) 1–2 mg/kg, lidocaine 1.5 mg/kg and rocuronium (Esmerone, Organon, The Netherlands) 0.5 mg/kg was administered to facilitate endotracheal intubation. Anesthesia and muscle relaxant were maintained by isoflurane 1 to 1.5 MAC (minimum alveolar concentration) in a 50% oxygen/air mixture and rocuronium 0.15 mg/kg respectively. Additional intraoperative analgesia consisting of IV boluses of 25 µg fentanyl was given as determined by fluctuation in vital signs (increasesd in heart rate > 20% above the basal value). At the end of the surgery, a dose of paracetamol 1 gm/100 ml IV was given to all patients before extubation. Intravenous neostigmine (0.05 mg/kg) and atropine (0.01 mg/kg) were administered to reverse muscle relaxants.After extubation, patients were transferred to the post-anesthesia care unit (PACU), where a standard analgesic regimen of paracetamol 1 g was given intravenously every 8 h. to all patients. In addition, an intravenous PCA morphine bolus of 3 mg without background infusion and a lockout period of 15 min were given upon patient’s request during the follow up period. | PMC10186677 | |
Outcome assessments and data collection | Pain | In the PACU, the following parameters were assessed: (1) the cumulative morphine consumption in the first 48 h (as a primary outcome). (2) Pain intensity was evaluated by VAS at time intervals 0–2 h, 2–4 h, 4–8 h, 8–12 h, 12–24 h, 24–36 h, and 36–48 h. (3) Also, the quality of recovery − 40 scoring system (QoR-40) was recorded by the anesthesia resident 48 h after the surgery. (4) Postoperative sedation was assessed at 0–2, 2–4, 4–6, 6–12, 12–24, and 24–48, using a Modified Observer’s Assessment of Alertness | PMC10186677 | |
Statistical analysis | PMC10186677 | |||
Sample size calculation | The sample size was calculated using the G* power program. Based on a previous study [ | PMC10186677 | ||
Statistical analysis | SD, pain | IBM-SPSS 24.0 (IBM-SPSS Inc., Chicago, IL, USA) was used for data verification, coding by the researcher and analysis. The normality of data distribution among the studied groups was tested with the Shapiro-Wilk and Kolmogorov-Smirnov tests. Normally distributed continuous data were reported as means ± (SD) and were compared with 2-sided independent t-tests for equal variances. Non- Normally distributed interval data and ordinal data were reported as medians (interquartile range [IQR]) and were compared using the T-test. Categorical variables are presented as counts (percentages) and were evaluated with the Fisher exact test. Nonparametric correlations using the Spearman rho correlation coefficient between the global QoR-40 and “both opioid consumption and the pain subcomponent of the QoR-40” were performed. The level of rejection of the null hypothesis, using the T-test was set at P value < 0.05 for the postoperative cumulative 48 h morphine consumption. | PMC10186677 | |
Results | PMC10186677 | |||
Patients characteristics | cancer colon | CANCER COLONS | Sixty-six patients were assessed for eligibility to participate in the study. Four patients were inoperable and two patients refused to participate. A final sixty patients were scheduled for laparoscopic colorectal surgery for cancer colon completed this study and equally distributed in two groups (n = 30 patient per group) as shown in flow diagram (Fig.
Flow diagram of the study participants
Demographic data and patient’s characteristicsData were represented as mean, standard deviation, number and percentage
| PMC10186677 |
Study endpoints | PMC10186677 | |||
Primary outcome | pain | The duloxetine group had significantly lower pain scores represented by VAS score in the first 48 postoperative hours than the placebo group at all-time intervals: 0–2, 2–4, 4–8, 8–12, 12–24, 24–36 and,36–48, Mean and standard deviation (mean ± SD) (3 ± 0.69) vs. (4.17 ± 0.83), (2.5 ± 0.6) vs. (4.3 ± 0.9), (2.2 ± 0.7) vs. (3.9 ± 0.6), (1.6 ± 0.7) vs. (3.6 ± 0.8), (1.1 ± 0.8) vs.(3.7 ± 0.7), (0.7 ± 0.7) vs. (3.5 ± 0.8), (0.6 ± 0.7) vs. (3.5 ± 0.8) respectively, P value ˂0.01 (Table
Post-operative VAS score in 48 h, intraoperative fentanyl consumption, and post-operative total morphine consumption in 48 hData were represented as mean, standard deviation, mean difference and 95% confidence interval of the difference | PMC10186677 | |
Secondary outcome | bradycardia, headache, nausea, vomiting | Total intraoperative fentanyl consumption was decreased in the duloxetine group compared to the placebo group, mean and standard deviation (mean ± SD) (25.33 ± 26.20) vs. (74.16 ± 27.45), P value ˂0.01 (Table The cumulative 48 h morphine consumption was significantly reduced in the Duloxetine group compared to the placebo group, (mean ± SD) (4.6 ± 2.9 mg vs. 11.3 ± 1.7 mg), P < 0.01 (Table Subjects in the duloxetine group had better postoperative quality of recovery than the placebo group. The mean and standard deviation (mean ± SD) of total QoR-40 score for the duloxetine group was (180.8 ± 4.5) compared to (156 ± 5.9) in the placebo group (
Quality of recovery (QOR) questionnaireData were represented as mean, standard deviation, mean difference and 95% confidence interval of the differencePatients in the Duloxetine group appeared to be more sedated in all the 48 h postoperatively in comparison to the placebo group. Median (IQR) of Modified Observer’s Assessment of Alertness
Post-operative sedation score by Modified Observer’s Assessment of Alertness Data were represented as median (IQR).Concerning the postoperative side effects during the first 48 h, where number and percentage of nausea, vomiting, bradycardia and headache were more in the duloxetine group than the placebo group, 6 (20%) vs. 2 (6.6%), 5 (16.6%) vs. 2 (6.6%), 1 (3.3%) vs. 0 and, 3 (10%) vs. 1 (3.3%) respectively; howerver they did not reach the statistical significance level (Table
Post-operative side effectsData were represented as number and percentage (%) | PMC10186677 | |
Discussion | postoperative pain, bradycardia, cancer, pain, headache, nausea, vomiting | ADVERSE EFFECTS, CANCER | The present trial had shown that patients subjected to laparoscopic colorectal surgery who administered three perioperative duloxetine, 60 mg 12 h preoperative, a second dose one hour preoperative, and a third dose 24 h postoperative, had a significant lower postoperative morphine consumption, intraoperative fentanyl consumption, a significant decreased postoperative pain and better quality of recovery for 48 h postoperatively. The adverse effects including nausea, vomiting, bradycardia, and headache were higher in the duloxetine group compared with the placebo group; however they did not reach the statistical significant level.The unique criteria of our study that administered three perioperative doses of duloxetine instead of single or twice doses as in previous studies, more over we assess the perioperative duloxetine on the QoR. Furthermore, the nature of pain in laparoscopic surgery is different from open surgery.Unlike postoperative pain after open surgery, which is most of somatic origin, postoperative pain after laparoscopic surgery consists of both somatic and visceral elements [The improved postoperative analgesia, reduction of opioid consumption and pain intensity reported in our study is in concordance with Castro-Alves and his collegues [Moreover, in our previous [It is reasonable that if an analgesic could also provide emotional stability, it would be a better adjunct for postoperative recovery. One of the most important findings in our study was the better postoperative quality of recovery, as represented by the total score of 180.8 ± 4.5 in patients who received duloxetine compared with those who received a placebo capsule 156 ± 5.9. It specifically improved the five domains: physical comfort, independence, emotional, psychological, and pain in the quality of recovery score. This improvement in QOR is not only due to less opioid consumption and lower VAS scores but also due to a favorable effect on emotional and psychological status which are of utmost importance in cancer patients undergoing surgery.Nasr’s Also, in accordance with our study, a meta-analysis conducted by Zorrilla and partners [In contrast to our study, Erdmann and his collegues [Dose selection in this trial was inspired by our previous study [It has been proposed that duloxetine exerts its analgesic action through three different processes and locations. The dorsal horn of the spinal cord dopamine, NE, and serotonin levels are raised as a result of its action. These monoamines stimulate the spinal cord’s 5-HT | PMC10186677 |
Study limitations | chronic pain | CHRONIC PAIN | Follow up period was only 48 h postoperatively; we could not report the effect of duloxetine on chronic pain management. We did not report the effect of duloxetine on the hospital stay period or the intestinal recovery. In further studies, the third group with two doses of Duloxetine group could be added to detect the effect of the dose on the side effects. | PMC10186677 |
Acknowledgements | Not applicable. | PMC10186677 | ||
Author contributions | HAE | RECRUITMENT | DFH: Statistical analysis and writing of manuscript and revision; MAM: Study design; HAE: Study design; MIA: Patient recruitment, the conduct of the study, data collection; NAE: Data entry and Statistical analysis; SMK: Conduct of study, writing of manuscript and revision. All authors read and approved the final manuscript. | PMC10186677 |
Funding | The Authors certify that no funding has been received for the conduct of this study.Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). | PMC10186677 | ||
Data Availability | The database is closed and there is no public access. However, permission to access and use the database can be obtained if necessary by request to the corresponding author. | PMC10186677 | ||
Declarations | PMC10186677 | |||
Ethics approval and consent for participation | Cancer | CANCER | It was done after obtaining approval from both the local ethics committee and the Institutional Review Board (IRB) from the South Egypt Cancer Institute, Assuit University, Assuit, Egypt and strictly followed the regulations and amendments of Helsinki Declaration. Informed written consent was obtained from all patients. | PMC10186677 |
Consent for publication | Not applicable. | PMC10186677 | ||
Competing interests | The authors have no conflicts of interest related to this article. | PMC10186677 | ||
Abbreviations | American Socity of Anesthesiology physical status classificationConfident intervalColorectal cancerInstitutional Review Board.Interquartil rangeModified Observer’s Assessment of Altreness/ Sedation ScaleNon steroidal antiinflammatory drugsSeretonin-norepinephrine reuptake inhibitor.Patient controlled analgesiaPostanesthesia care unitThe Quality of Recovery − 40 scoring systemVisual Analog Scale5 Hydroxy-tryptamine | PMC10186677 | ||
References | PMC10186677 | |||
Background | depression, depressive symptoms | Although many conventional healthcare services to prevent postpartum depression are provided face-to-face, physical and psychosocial barriers remain. These barriers may be overcome by using mobile health services (mHealth). To examine the effectiveness of mHealth professional consultation services in preventing postpartum depressive symptoms in real-world settings, we conducted this randomized controlled trial in Japan, where universal free face-to-face perinatal care is available. | PMC10294407 | |
Methods | This study included 734 pregnant women living in Yokohama city who could communicate in Japanese, recruited at public offices and childcare support facilities. The participants were randomized to the mHealth group (intervention, | PMC10294407 | ||
Results | Most women completed all questionnaires ( | PMC10294407 | ||
Conclusions | depressive symptoms | Local government-funded mHealth consultation services have a preventive effect on postpartum depressive symptoms, removing physical and psychological barriers to healthcare access in real-world settings. | PMC10294407 | |
Trial registration | UMIN-CTR identifier: UMIN000041611. Registered 31 August 2021. | PMC10294407 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12916-023-02918-3. | PMC10294407 | ||
Keywords | PMC10294407 | |||
Background | depression, Depression | DISORDER | Depression during the perinatal period is a common disorder in many countries and an estimated global prevalence of postpartum depression (PPD) is 17.7% [Although screening and preventive interventions for depression during the perinatal period have been recommended and implemented [Using mobile wireless technologies for public health (i.e., “mHealth” [To the best of our knowledge, no intervention study has been conducted on the effectiveness of mHealth consultation services in preventing PPD [ | PMC10294407 |
Methods | PMC10294407 | |||
Trial design and participants | RECRUITMENT, EARLY PREGNANCY | We conducted a trial in Yokohama, an urban city with the largest population size (about 3.8 million) among all municipalities in Japan, where conventional free face-to-face perinatal care services for all mothers were implemented. We enrolled participants from September 1, 2020–March 7, 2021. Initially, we recruited women in the first trimester who came to a public ward office to register their pregnancy status at the Kohoku ward. In November 2020, because of the small sample size, we expanded the target population—from women in their early pregnancy to all pregnant women—and added several recruitment methods, such as announcements on the official website, recruiting in the mother preparation classes, and distributing leaflets at public childcare support facilities and local clinics. In January 2021, we expanded the recruitment field from Kohoku ward to all wards of Yokohama city. The details of the protocol are described in Additional file | PMC10294407 | |
Randomization and masking | Participants were randomly assigned (1:1 allocation) to either the mHealth or usual care group. We used a simple randomization computer algorithm without any options, aiming to balance the baseline characteristics. After the submission of participation agreement forms, assignment information was immediately provided to the women via the website. Owing to our study design, the participants and service providers were aware of the assignment. The data collector and analyst were blinded to the group assignments until the primary analyses were completed. | PMC10294407 | ||
Intervention | depression | The intervention was mHealth consultation services provided by Kids Public, Inc. The service provider had developed and offered mHealth consultation services in other regions but never investigated the effectiveness of their services in preventing depression before this study. Participants in the mHealth group could consult healthcare professionals free of charge using their mobile device without restrictions on the frequency, from the time of assignment until four months after childbirth, funded by the City of Yokohama. The service included general consultation and emotional support related to pregnancy and childcare and did not provide formal medical diagnosis or prescription. This service was delivered through the LINE platform—the most popular mobile social network service (used by over 95% of women of childbearing age in Japan) [Participants assigned to the usual care group were not provided with the mHealth consultation services. Instead, they were offered access to a website created by a research team where they could easily access information on pregnancy and childcare provided by the City of Yokohama or other public organizations, such as national hospitals. | PMC10294407 | |
Outcomes measures | Depression, depressive symptoms | SECONDARY | The primary outcome was the risk of elevated postpartum depressive symptoms, which was assessed using the Japanese version of the Edinburgh Postnatal Depression Scale (EPDS) [The secondary outcomes were self-efficacy, loneliness, perceived barriers to healthcare access, and the use of medical facilities. Self-efficacy was assessed using a parenting self-efficacy scale for mothers with infants [We collected data using a research website and a web-based self-report questionnaire made using Google Forms at baseline and three months after childbirth. We collected personal information, including email address, age, parity, and family structure as baseline data when the participants enrolled on the research website. After the assignment, the research team sent an email to the participants asking them to answer an online questionnaire to collect additional baseline data, including sociodemographic data (trimester, household income, and education level), EPDS, and any past mental health problems. We confirmed childbirth days using birth registrations from the City of Yokohama. If we could not confirm the childbirth day from the public registration, we directly asked the participants about their child’s birthday by email. Three months after childbirth, we sent the participants an email, asking them to answer a second online questionnaire to assess the outcomes. Participants assigned to the usual care group received 500 JPY (approximately four USD) vouchers when they answered the baseline questionnaire after the assignment. All participants received 1,500 JPY (approximately 11 USD) vouchers when they answered the questionnaire three months after childbirth. | PMC10294407 |
Statistical analysis | depressive symptoms | The target sample size was 720 pregnant women, with 360 in each group, to detect an absolute difference of 7% in the risk of elevated postpartum depressive symptoms three months after childbirth between the groups. This calculation was based on the preliminary data of mothers using mHealth services in Yokohama city (proportion of EPDS ≥ 9 before and after using mHealth services; 11% and 4%, respectively), with 80% power and 5% two-sided significance level, assuming 30% attrition rate referring to other internet-based research in Japan [To examine the heterogeneity in the intervention effects across sociodemographic backgrounds, we conducted subgroup analyses by age (< 35 years or older), parity (primipara or multipara), income (tertile among participants), education (< 16 years or longer), elevated depressive symptoms at participation (EPDS score < 13 or ≥ 13), and past mental health problems. As we expanded the participants from those in the first trimester to all those pregnant, we conducted an additional subgroup analysis of trimesters (first trimester vs. second and third trimesters) besides the prespecified subgroups.As a sensitivity analysis, we conducted an all-case analysis with multiple imputations to handle missing data, using the same model as the primary analysis [To estimate the complier-average causal effect of mHealth use, we compared women according to their actual usage of mHealth based on consultation records using random allocation as an instrumental variable, while accounting for potential selection biases after randomization [ | PMC10294407 |
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