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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...
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 ...
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 a...
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 m...
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 usin...
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 confound...
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 ...
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...
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” ca...
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 w...
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...
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...
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-likelih...
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 confound...
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 inconti...
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 (wei...
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 s...
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 follo...
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. N...
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...
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 cumulat...
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 consu...
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...
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 amendmen...
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 ...
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, surg...
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 ...
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 ...
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 co...
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 g...
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) ...
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 plac...
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 c...
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 ...
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 manusc...
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 analgesiaPostanest...
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 postpar...
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 f...
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 wo...
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...
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 co...
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 ...
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 (pr...
PMC10294407