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Background | diaphragmatic dysfunction | Few specific methods are available to reduce the risk of diaphragmatic dysfunction for patients under mechanical ventilation. The number of studies involving transcutaneous electrical stimulation of the diaphragm (TEDS) is increasing but none report results for diaphragmatic measurements, and they lack power. We hypothesised that the use of TEDS would decrease diaphragmatic dysfunction and improve respiratory muscle strength in patients in ICU. | PMC10469422 | |
Methods | diaphragm dysfunction, extubation failure, cough | We conducted a controlled trial to assess the impact of daily active electrical stimulation versus sham stimulation on the prevention of diaphragm dysfunction during the weaning process from mechanical ventilation. The evaluation was based on ultrasound measurements of diaphragm thickening fraction during spontaneous breathing trials. We also measured maximal inspiratory muscle pressure (MIP), peak cough flow (PEF) and extubation failure. | PMC10469422 | |
Results | DIAPHRAGM | Sixty-six patients were included and randomised using a 1:1 ratio. The mean number of days of mechanical ventilation was 10 ± 6.8. Diaphragm thickening fraction was > 30% at the SBT for 67% of participants in the TEDS group and 54% of the Sham group (OR1.55, 95% CI 0.47–5.1; | PMC10469422 | |
Supplementary Information | The online version contains supplementary material available at 10.1186/s13054-023-04597-1. | PMC10469422 | ||
Keywords | PMC10469422 | |||
Background | muscle weakness, involuntary muscle contractions | MUSCLE WEAKNESS | Inspiratory muscle weakness is caused by the suppression of respiratory muscle activity by sedative agents and mechanical ventilation, as well as other inflammatory mechanisms [Neuromuscular electrical stimulation can be used to maintain muscle thickness and strength and has the advantage of not requiring cooperation since it produces involuntary muscle contractions. Data are mostly available for the lower limb muscles, particularly the quadriceps [ | PMC10469422 |
Method | PMC10469422 | |||
Design and recruitment | cutaneous lesion | MUSCLE WEAKNESS, PATHOLOGY | We conducted a single centre, double-blind randomised controlled trial with intention to treat analysis in our 18 bed ICU at Le Havre Hospital in France. We recruited consecutive individuals with a diagnosis that did not involve covid-19, who were admitted to our ICU between December 2019 and July 2022. The inclusion criteria were aged > 18 years, ventilated for at least 24 h with an expected stay of more than 72 h in the unit. The patients were required to be fully independent prior to admission to the ICU. The exclusion criteria were having been hospitalised for > 72 h before ICU admission, having a pacemaker or an implantable defibrillator, a cutaneous lesion that could interfere with probes, neurological pathology with disabling muscle weakness, chronic loss of autonomy (defined by a Katz score below 6/6), BMI > 35 kg/mEthical approval was granted by the French Comité de Protection des Personnes Ile de France X (38-19). All participants or their relatives provided written informed consent for participation. This study was prospectively registered (NCT04171024) and is reported according to the CONSORT guidelines.Randomisation was performed by a computer-generated random number sequence ( | PMC10469422 |
Procedure | muscle contractions, CM | CONTRACTION, BLIND | The medical, paramedical and physiotherapist teams involved in the care and decision to wean the patient from mechanical ventilation were not aware of the participant’s group allocation. Each morning, after the daily assessment for contraindications to transcutaneous electrical stimulation and diaphragm thickness measurement, blind investigators (CM and YC) positioned the electrodes according to the ultrasound location (see Additional file The stimulation applied to the TEDS group was a bidirectional current with a frequency of 50 Hz and an impulse width of 300 ms. The intensity was set to produce a palpable contraction of the muscles under the probes [The sham stimulation was a bidirectional current with a frequency of 2 Hz and a pulse duration of 300 microseconds; this did not produce muscle contractions but created some interference with the monitoring signals to ensure blinding of the nursing staff. The sham session lasted 20 min. TEDS or SHAM stimulation was applied until the first extubation attempt.The care and weaning protocols were standard practice on the ward and were identical between participants. The physicians who decided on patient care and ventilatory weaning were not aware of the randomisation or the daily diaphragmatic ultrasound measurements. | PMC10469422 |
Measures | PMC10469422 | |||
Primary aim | diaphragmatic dysfunction | DYSFUNCTION | Every morning, between 10 and 11 a.m., we used the Philips CX 50 ultrasound machine with a linear probe (5–12 MHz) to measure diaphragm thickness. The probe was placed perpendicular to the skin in the zone of apposition between the mid-axillary or antero-axillary line, in the 8th to 11th intercostal spaces. We measured diaphragm thickness perpendicular to the direction of the fibres between the pleural and peritoneal membranes, but not including the membranes. As previously described [If the SBT failed, and the decision to extubate was delayed, the value used for the analysis was that measured on the day of the extubation. Based on the results of our meta-analysis on the predictive values of the DTF on weaning failure, we defined diaphragmatic dysfunction as a DTF < 30% and considered a DTF of 20% to indicate severe dysfunction [ | PMC10469422 |
Secondary aims | PMC10469422 | |||
Respiratory muscle evaluation | cough, CM, ® | BLIND | The blind assessors (CM and YC) monitored daily changes in end-tidal thickness of the right hemidiaphragm from the day of inclusion until extubation using a high frequency (13 MHz) linear transducer over the apposition zone to monitor diaphragm thickness. Maximum inspiratory pressure (MIP) and cough peak expiratory flow (PEF) were also measured at the beginning of the SBT. The MIP was measured using an electronic manometer with a micro-RPM® unidirectional valve. Participants were informed that MIP would be evaluated at the residual volume and were instructed accordingly. The participant was disconnected from the ventilator for a minimum of 20 s [ | PMC10469422 |
Characteristics and clinical outcomes | death, SBT failure, illness, extubation failure | EVENTS | At admission, we collected demographic data, comorbidities, primary cause of admission and severity of illness by Simplified Acute Physiology Score (SAPS 2) and Sequential Organ Failure Assessment (SOFA). Each day we collected ventilator setting, administration of neuromuscular blockers or sedative drugs and Ramsay sedation score. From the day of intubation until the first extubation or death, we counted events such as SBT failure (defined as the clinical impossibility to extubate the patient and re-establish initial ventilatory parameters), extubation and extubation failure (defined as re-intubation within 48 h or death), causes of extubation failure, tracheostomy and discharge from the ICU. Ventilator-free days were computed to 28 days. (Participants who required more than 28 days of ventilatory support or who died before 28 days were counted as 0.) | PMC10469422 |
Statistical analysis | REGRESSION | Based on the results of the studies with the most robust methodology [Baseline data for both groups were summarised using means and standard deviations for continuous variables and absolute and relative frequencies for categorical data. We performed a chained equation multiple imputation with 20 imputed datasets for missing data.The between group differences were modelled using linear regression for quantitative variables and expressed as mean differences and 95% confidence intervals. For these between group differences, a Cohen’s All statistical analyses were performed with Stata version 17.1 (StataCorp LLC, College Station, Texas, USA). | PMC10469422 | |
Discussion | diaphragm dysfunction, cough | ADVERSE EFFECTS | This study is the first to compare the use of transcutaneous electrical stimulation of the diaphragm with a sham intervention on diaphragm function in intubated and ventilated patients in the ICU. We found that: (1) TEDS did not significantly decrease the risk of diaphragm dysfunction; (2) both groups had similar decreases in diaphragmatic thickness during ventilation; (3) TEDS would not result in a statistically significant improvement in inspiratory muscle strength or peak expiratory flow during cough and (4) TEDS would not optimise weaning from mechanical ventilation and extubation success rate.Limiting the adverse effects of mechanical ventilation on the diaphragm is challenging but essential because these effects lead to poor outcomes. ICU teams are seeking new methods to maintain a sufficient level of diaphragm activity while also maintaining lung-protective ventilation and avoiding excessive respiratory effort [Our study has several limitations. First, the attrition rate was greater than we had estimated. Although we included 20% more participants than required according to the sample size calculation, we had 27% missing data. However, the intention-to-treat and per-protocol analysis results did not differ and reached the same conclusions. Also, there was no difference between participants who dropped out and those who were analysed. Second, although the diaphragm thickening fraction is accepted as an indicator of diaphragm function and a predictor for extubation failure, some recent data suggest that the correlation between ultrasonography and diaphragm pressure output is unsatisfactory, is highly variable and depends on body position [Finally, the stimulation induced noise in the cardiac monitoring data, which may disturb monitoring processes by other clinicians (see Additional file | PMC10469422 |
Conclusion | diaphragm dysfunction, critically ill | CRITICALLY ILL, MUSCLE ATROPHY | This study is the first to investigate the effect of TEDS on diaphragm function in ventilated critically ill patients and to compare it with a sham intervention. TEDS did not prevent diaphragm dysfunction or muscle atrophy. Clinically important outcomes were not better with TEDS. Further studies are warranted to address these previous limitations and develop more robust and efficient stimulation approaches. | PMC10469422 |
Acknowledgements | The authors thank Johanna Robertson for translation and critical review. | PMC10469422 | ||
Take home message | diaphragm dysfunction | Transcutaneous electrical stimulation of the diaphragm in mechanically ventilated patients in ICU did not significantly decrease the risk of diaphragm dysfunction or optimise weaning from mechanical ventilation and extubation success rate. | PMC10469422 | |
Author contributions | MC, GP and YC designed the study. MC, MM, GP and YC collected data. All authors performed the analysis and interpretation of data. MC, MM, GP and YC wrote the main manuscript. All authors critically revised the manuscript for important intellectual content. RH performed the statistical analysis. | PMC10469422 | ||
Funding | Not applicable. | PMC10469422 | ||
Availability of data and materials | The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10469422 | ||
Declarations | PMC10469422 | |||
Ethics approval and consent to participate | Ethical approval was granted by the French Comité de Protection des Personnes Ile de France X (38-19). All participants or their relatives provided written informed consent for participation. | PMC10469422 | ||
Consent for publication | Not applicable. | PMC10469422 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10469422 | ||
References | PMC10469422 | |||
Taher Abofol | cognitive asymmetries | received his PhD in cognitive science from the Faculty of Data and Decision Sciences at the Technion. His research interests revolve around decision-making, learning, and behavioral economics. His main contributions are in the study of cognitive asymmetries arising from different incentive structures and individual differences in decision-making and cognitive improvement. | PMC10543786 | |
Ido Erev | EVENTS | is the Women’s Division – ATS Academic Chair in the Faculty of Data and Decision Sciences at the Technion. His research highlights a robust description-experience gap: people exhibit oversensitivity to rare events when they decide based on a description of the incentive structure, but experience reverses this bias and triggers underweighting of rare events. Comparison of alternative models favors the assumption that people tend to select the option that led to the best outcome in a small sample of similar past experiences. These observations imply that incentives are most effective when they insure that the socially desirable behavior maximizes payoff, and minimizes the probability of regret. | PMC10543786 | |
Raanan Sulitzeanu-Kenan | human behavior | is an associate professor of political science and public policy in the Federmann School of Public Policy at Hebrew University. His studies address human behavior in the contexts of public organizations, politics, and law; he has published articles in the This research provides evidence regarding the causal effect of group conformity on task performance in stable and variable environments. Drawing on studies in cultural evolution, social learning, and social psychology, we experimentally tested the hypotheses that conformity improves group performance in a stable environment (H1) and decreases performance (by hindering adaptability) in a temporally variable environment (H2). We compare the performance of individuals, low conformity groups, and high conformity groups in a four-arm randomized lab experiment ( | PMC10543786 | |
Supplementary Information | The online version contains supplementary material available at 10.1007/s12110-023-09454-2. | PMC10543786 | ||
Keywords | ROTH | What is the causal effect of conformity on the performance and adaptability of groups? Despite the number of studies devoted to conformity since Asch’s (Although these theoretical predictions have received some support from empirical studies, they provide only tentative and partial support for their key propositions. Theoretically informed cultural-evolution studies have indeed suggested that conformity is an effective strategy for social learners in stable environments (Efferson et al., Drawing on this literature, we hypothesize that conformity improves group performance in a stable environment (H1) and decreases performance in a temporally variant environment (H2). Specifically, our second hypothesis states that conformity reduces group adaptability. We utilize an experience-based decision-making task (Erev & Roth, Our findings provide support for the hypothesis that conformity decreases group performance in a temporally variable environment (H2). Although high-conformity groups performed better than low-conformity groups in the stable stage of the game, this difference was statistically insignificant; thus our findings do not support the hypothesis that conformity increases group performance in stable conditions (H1). Intragroup individual-level analyses provide further insight into the mechanisms that account for the group-level results. In the altered environment, social information becomes less influential within low-conformity group members, whereas it retains a strong impact on high-conformity group members. These results imply that low conformity within groups facilitates greater adaptability in the use of social information. When social information is useful (in a stable environment), low-conformity groups allot only slightly less weight to social information than high-conformity groups. However, faced with indications of a change in the environment, low-conformity group members tend to reduce the weight they assign to social information, whereas high-conformity groups maintain (and even slightly increase) the level of decision weight for this information, despite its poor informative quality. In the following sections, we report the experimental study conducted to test these hypotheses. | PMC10543786 | |
Experimental Design | ROTH | We utilize an experience-based decision-making task (Erev & Roth, To test our hypotheses, we employ one of the games used by Lejarraga et al. (Two hundred and forty university students participated in the study. Participants were randomly assigned to the The temporal change in the environment was simulated by implementing two stages in the clicking task, as is described in Fig.
The experience-based task. The left panel presents the expected value of the two buttons throughout the game. Up to round 60 the higher paying button is A (blue), whereas from round 61 onward, the dominant button is B (orange). The right panel presents the probability of obtaining a positive (+ 7; solid lines) and a negative (− 5; dashed lines) payoff, in each of the two buttons across the 100 rounds | PMC10543786 | |
Procedure | Participants assigned to the individual condition were provided with asocial information only in the form of their payoff for each decision round. In the two group conditions, participants were provided with both asocial information (decision payoff) and implicit social information. They inferred the latter from whether their individual choice was a minority opinion or aligned with the majority in each round, based on whether it mismatched or matched the group’s choice, respectively.All participants performed the experiment individually on their own computer terminal. In the individual condition, participants read the following instructions:
You will play a game of 100 rounds. In each round, you will be asked to choose one of two money machines. When you click on the machine, you will win or lose points. Your payoff at each round will be determined based on your choice and the probability of winning, which may change during the game. At the end of each round, you will see your payoff and the forgone payoff had you chosen the other machine. If you have any questions, please ask the experimenter. Please press start when you are ready.In the two group conditions, we deviate from the design of Lejarraga et al. (The instructions of the low conformity (LoConf) group condition were as follows:
You are part of a group of three players. You will play a game of 100 rounds. In each round, you will be asked to choose one of two money machines. When you click on the machine, you will win or lose points. Your payoff at each round will be determined according to your choice and the other players’ choices and to the probability of winning, which may be changed during the game. At the end of each round, you will see your payoff and the forgone payoff had the group chosen the other machine. If you have any questions, please ask the experimenter. Please press start when you are ready.The LoConf game has multiple Nash equilibria.In the high-conformity (HiConf) group condition, the procedure and instructions are the same as for the low-conformity (LoConf) group condition, with one difference: the payoff for each player is also affected by whether their individual choice aligns with the majority choice. In the case of a minority opinion, two points are deducted from the dissenting participant’s payoff, whereas each majority participant receives an additional point.When players cannot know with certainty which button maximizes their payoff, behavior in the present game is likely to depend on the way the players have adapted to past experiences. As noted above, the common assumptions in cultural evolution predict that conformity facilitates efficiency in a stable environment but may impair maximization in a dynamic environment. The following experiment is designed to evaluate the robustness of these predictions.Beyond its direct effect on players’ potential payoff, this novel treatment of conformity is intended to draw their attention to social information—specifically, whether the player’s opinion aligns with or differs from the majority. We therefore test the efficacy of this treatment at both the group and individual levels. At the group level, we estimate the prevalence of minority opinions within group decisions across the two group conditions. At the individual level, we assess whether the treatment increases players’ propensity to change their choices after finding themselves in a minority opinion, controlling for the monetary payoff. These analyses are reported in the “Results.”Cultural-evolutionary theory identifies several important considerations in designing experimental studies of conformity. First, not all forms of social learning constitute conformity. Social learning is defined as the acquisition of behavior through observation or interaction with other individuals (Aplin et al., The design of this study addresses these considerations. First, given that conformity leads to the homogenization of group behavior, we evaluate the efficacy of our conformity treatment by comparing the proportion of minority decisions [i.e., 1 – The two group conditions provide the comparisons required to test our main hypotheses in both the stable and variable stages of the game. In order to address the alternative claim made by Lejarraga et al. (The instructions in all conditions informed the participants that a change in the probability of gaining the positive payoff is possible, without indicating how prevalent the change would be, nor when in the sequence of trials it would occur. Our goal was that participants would not assume a static environment. In all three conditions, payoffs in points were converted to monetary sums. In the group conditions, all three members received full compensation; thus group members had the same economic incentives as individual participants. The mean total individual compensation was equivalent to US $9.70. | PMC10543786 | ||
Statistical Analysis | To identify the effect of conformity on performance in a temporally varying environment, we estimate the interaction effect of change and conformity on performance. Equation 1 presents this relationship:
where | PMC10543786 | ||
Results | PMC10543786 | |||
Assessing the Validity and Efficacy of the Conformity Treatment | We begin by assessing the validity and efficacy of our conformity treatment. To assess the efficacy of the conformity treatment at the group level, we compare the propensity for minority opinions within group decisions in the LoConf group and HiConf group conditions. The proportion of group decisions involving the minority opinion was overall higher among the LoConf group condition (61.5%) than the HiConf group condition (37.72%; To assess whether the conformity treatment serves as a priming mechanism that draws attention to social information, we estimate its effect on the individual = level propensity to change a player’s choices after finding themselves in a minority opinion, controlling for the monetary payoff. Table | PMC10543786 | ||
Descriptive Results | Figure
The probability of choosing the maximizing choice before and after the change (round = 61) and across conditions (blue: individual; red: LoConf group; green: HiConf group). The vertical dashed red line indicates the point of change in the gameTable
Average probabilities of correct choice | PMC10543786 | ||
Generalized Estimating Equation Results | To formally estimate the varying effect of environmental change on performance across group conformity levels, we conducted a set of generalized estimating equation (GEE) analyses, reported in Table
Generalized estimation equation (GEE) analyses of group performanceCoefficients represent logit estimates. Group clustered standard errors in parentheses; *** Models 2–4 fit Eq. 1 to the data, including the stable stage and the 20, 30, and full 40 rounds after the change, respectively. These separate analyses allow us to address the fact that as time elapses since the change, the game reverts to a new stable state. The coefficients of the interaction between change and conformity level are presented first (in bold). All three estimates are negative and statistically significant, suggesting that the negative effect of change on performance is greater for HiConf groups than for LoConf groups (the reference category). In contrast, the coefficients of the interaction between individuals and LoConf groups (Change × Individual) are small and statistically insignificant, suggesting that the effect of change on the performance of individuals and LoConf groups is not significantly different.Note that the GEE results indicate no significant differences between the performance of LoConf and HiConf groups in the stable stage of the game (rounds 1–61), given the insignificant coefficients of Figure
Mean performance across conditions throughout the game. GEE estimates for 10 sets of 10 rounds (CI = 1SE) | PMC10543786 | ||
Individual Level Within-Group Mechanism | EVENT | In order to obtain a better understanding of the group-level results, we conducted a set of (within-group) individual-level analyses, to estimate the role of social information—holding a minority opinion—in determining the decisions of group members: namely, whether they change their choice in the subsequent round. Following the advice of Morgan and Laland (Table GEE estimation of group members’ choice changeLogit estimates with group clustered standard errors in parentheses; ***
(Both social and asocial information were found to predict an individual’s likelihood of changing their subsequent choice, but these effects vary across group conditions and stages of the game. In the stable stage (rounds 1–60: Model 5), social information (holding a minority opinion) increases the likelihood of changing one’s subsequent choice. This effect is smaller and marginally significant in the LoConf group condition (In both stages of the game, asocial information (receiving a higher payoff) decreased the propensity of players to change their subsequent choice, as expected. This effect was identified only when players’ choices aligned with the group. Instead of a reversed effect in the event of being in the minority, the effect became small and statistically insignificant. This pattern was similar for both group conditions and did not significantly alter across the two stages of the game. Furthermore, the effect of asocial information on majority group members was not significantly different from its effect on players in the individual condition. These results are depicted in Fig. These findings provide an individual-level account for the varying group-level adaptability under high and low conformity. Whereas asocial information in our setting is a noisy yet unbiased signal that facilitates learning and adaptation, social information is based on accumulated learning and therefore reflects Given this varying utility of social information in stable and altered environments, the finding that social information becomes less influential among members of LoConf groups when the environment changes, whereas it increases its influence among members of HiConf groups (Fig. | PMC10543786 | |
Discussion | This research provides evidence regarding the causal effect of conformity on group performance in stable and variable environments. Drawing on studies in the evolution of culture and the social transmission of information (Boyd & Richerson, Our experimental design builds on the works of Rakow and Miler (The results do not provide support for the hypothesis that conformity increases group performance in stable conditions (H1). High conformity groups did perform better in this stage, but the current analysis does not permit rejecting the null hypothesis (Individual-level analyses within groups provide further insights into the mechanisms that account for the group-level results. In a stable environment both asocial (payoff) and social (minority/majority opinion) information appear to influence behavior. Notably, the two appear to exert a similar influence on the choices of individuals in the two group conditions (social influence is more influential on members of high conformity groups, but this difference is statistically insignificant at this stage of the game: Specifically, the individual-level analyses suggest that low conformity within groups facilitates greater adaptability in the use of social information. When social information is useful (stable environment), low conformity groups allot similar (though somewhat lower) weight to social information as high-conformity groups. However, faced with indications of a change in the environment, low-conformity group members tend to allocate less weight to social information, whereas high-conformity groups maintain the same level of decision weight for this information.To the best of our knowledge, these findings are the first to provide human behavioral evidence for the causal effect of conformity on the performance and adaptability of groups. These findings support evolutionary models of social transmission of information (Boyd & Richerson, The results of this research correspond to the findings of Lejarraga et al. ( | PMC10543786 | ||
Acknowledgements | We are grateful to Reut Blaywais, Yuval Berger, Itamar Faran, Micha Mandel, Sarah Roost, and Omer Yair for helpful suggestions and comments on previous versions of this article. | PMC10543786 | ||
Declarations | PMC10543786 | |||
Conflict of Interest | The authors declare that they have no conflict of interest. | PMC10543786 | ||
References | PMC10543786 | |||
Subject terms | autism | Early supports to enhance social development in children with autism are widely promoted. While oxytocin has a crucial role in mammalian social development, its potential role as a medication to enhance social development in humans remains unclear. We investigated the efficacy, tolerability, and safety of intranasal oxytocin in young children with autism using a double-blind, randomized, placebo-controlled, clinical trial, following a placebo lead-in phase. A total of 87 children (aged between 3 and 12 years) with autism received 16 International Units (IU) of oxytocin (Trial registration | PMC9607840 | |
Introduction | lifelong social behavior, impairments in social communication, Autism spectrum disorder, repetitive behaviors, autism | RECRUITMENT | Autism spectrum disorder (autism) is a neurodevelopmental condition characterized in the DSM-V by impairments in social communication and interaction, and the presence of stereotypical and repetitive behaviors [Oxytocin is a crucial regulatory hormone to both early life social learning and lifelong social behavior [This present study investigated the efficacy, tolerability, and safety of intranasally-administered oxytocin to improve social interaction difficulties in young autistic children. This study included a placebo lead-in phase to evaluate response to drug to characterize potential responders and focused recruitment at a younger age than most clinical trials. We predicted that oxytocin nasal spray would be both safe and tolerable for this cohort of young autistic children. We further predicted that oxytocin would improve caregiver-reported social responsiveness, and a clinician rating of improvement in social behavior in young children with autism, and that this effect would be largest in younger children. | PMC9607840 |
Materials and methods | PMC9607840 | |||
Study design | RECRUITMENT, BRAIN | Patients were enrolled in a double-blind, randomized controlled, placebo lead-in, multi-site trial of oxytocin nasal spray and an identical placebo across four assessment time points (wk 0 baseline, wk 3 post-placebo lead in, wk 15 post randomized treatment, wk 27 follow-up assessment). The study was conducted at the Brain & Mind Center (BMC), University of Sydney, and the Telethon Kids Institute (TKI), Western Australia. Ethical approval was provided by the University of Sydney Human Research Ethics Committee (2013/502). The trial was pre-registered prior to recruitment with the Australian Clinical Trials Registry (ACTRN12617000441314). Informed consent from caregivers was obtained for each participant. | PMC9607840 | |
Participants | Autism, Autism Spectrum Disorder, DSM-5, autism | Children aged between 3 and 12 years of age who met DSM-5 criteria for Autism Spectrum Disorder were recruited. Children aged between 3–12 were recruited to the BMC, while children aged 3–6 were recruited to TKI. This decision was based on available funding provided to each site. Participants were recruited through advertisements and specialist networks. To confirm eligibility, caregivers of participants initially completed a telephone screening assessment to determine whether their child had received a previous diagnosis associated with autism and were not likely to meet noted exclusion criteria.Participants then completed screening assessments, the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) [ | PMC9607840 | |
Medication | Pfeiffer | PFEIFFER | Oxytocin nasal spray consisted of 8IU each spray per nostril morning and night; 32IU per day). The placebo spray included all of the same ingredients except oxytocin. All sprays contained sorbitol (2%), glycerol (2%), benzyl alcohol as preservative, and distilled water, within an amber 8 ml glass nasal spray with metered Pfeiffer pump spray bottle. Drug kits were manufactured by PCI Pharma Services. We followed guidelines outlined by both Guastella et al., 2013 [ | PMC9607840 |
Assessment schedule | A schedule of assessments conducted at each visit is provided in Supplementary Table | PMC9607840 | ||
Medication schedule and adverse event reporting | ADVERSE EVENTS | Instructions were provided to caregivers on site during drug allocation visits (Wk 0 and 3) consistent with our previous published guidelines [Monitoring of potential adverse events was by telephone during mid-intervention for the treatment phase (i.e., wk 9) and at treatment completion (wk 15). Caregivers (and the child when appropriate) were asked open-ended questions about adverse events or side effects that had occurred during the treatment period. Caregivers were also asked to complete a daily diary reporting any side effects of nasal spray administration. This diary was also used to evaluate treatment compliance and was reviewed during Visit 3. Serious adverse events were reported to the local institutional review board. | PMC9607840 | |
Primary and secondary outcome measures | PMC9607840 | |||
Primary outcomes | The first primary outcome measure was the caregiver-completed Social Responsiveness Scale, Second Edition (SRS-2) [ | PMC9607840 | ||
Secondary outcomes | Repetitive Behavior Scale-Revised | Secondary caregiver-completed outcomes measures included the Repetitive Behavior Scale-Revised (RBS-R) [ | PMC9607840 | |
Statistical analyses | SECONDARY, SENSITIVITY | Data were managed using REDCap [Within the participants who were included in the modified intention-to-treat analysis (Analysis of primary and secondary outcomes were conducted on the modified intention-to-treat population and were based on a 2 (Drug; Oxytocin, Placebo) x 4 (Time; baseline wk 0, post-placebo lead in wk 3, post randomized treatment wk 15, follow-up assessment wk 27) x 2 (age group; 3–5 years, 6–12 years) mixed-design ANOVA. Age was entered as a pre-planned factor and our Data Safety Monitoring Board (DSMB) requested that we only recruit for the younger age group following interim analysis. Site was considered as an additional factor but was removed from models due to lack of significance. Greenhouse-Geisser corrections were applied when assumptions of sphericity were violated. For the CGI only, a 2 (Drug; Oxytocin, Placebo) x 3 (Time; post-placebo lead in wk 3, post randomized treatment wk 15, follow-up assessment wk 27) x 2 (age group; 3–5 years, 6–12 years) mixed-design ANCOVA was conducted on improvement scores, with baseline (wk 0) severity scores included as a covariate.To unpack interaction effects, planned simple contrasts were used, comparing each timepoint to study baseline (Visit 1). For contrasts that reached statistical significance, the sample was first split by age (3–5 years; 6–12 years) and repeated measures ANOVAs were used to compare scores between treatment conditions (oxytocin, placebo). Where appropriate, effect sizes (Cohen’s Sensitivity analyses of the primary outcome included group differences in SRS-2 Total Raw scores (i) separately in the subgroups of participants with a baseline SRS-2 Total Raw score at or above the sample median or with a baseline SRS-2 Total Raw score below the sample median, and (ii) in the per-protocol population (defined as all participants who completed the trial and had SRS-2 data available at each timepoint).Clinical changes were also evaluated for individual participants using the Reliable Change Index (RCI) [Analyses on treatment guess were conducted on participants with available treatment guess data at Visit 3. Chi-square tests were used to compare the proportion of treatment guesses between the oxytocin and placebo conditions. Safety analyses included all participants who were randomized to oxytocin or placebo ( | PMC9607840 | |
Results | PMC9607840 | |||
Participants | Participants were recruited to each site between April 2017 and February 2020. Caregivers of 331 children expressed interest in this trial. Due to logistical reasons and restraints, the time period for being enrolled in this trial was limited, which impacted on our ability to assess large numbers of participants for eligibility. Further, the broad inclusion criteria meant that there was a high conversion rate from eligibility assessment to study enrollment. In total, 121 children were assessed for eligibility and 103 invited to participate (See Consort Diagram in Fig. CONSORT diagram of study participants by randomization schedule. | PMC9607840 | ||
Primary outcomes | PMC9607840 | |||
Primary outcome 1 – social responsiveness scale (SRS-2) total score | For SRS-2 Total scores, there was no main effect of treatment condition ( | PMC9607840 | ||
Plotting mean scores on the primary outcome measure (Social Responsiveness Scale-2) separately for younger and older children. | Error bars represent 95% confidence intervals.To further break down this interaction, we used individual repeated measures ANOVAs to look at differences between visits (V1 and V3, V1 and V4) between the oxytocin and placebo conditions separately for each age group. Considering first the 3–5 year age group, there was a significant difference in SRS-2 total scores from V1 to V3; such that participants in the oxytocin condition demonstrated a larger change in scores from baseline to post-treatment (indicating improvement) relative to those in the placebo condition, | PMC9607840 | ||
Primary outcome 2 – clinician global impression–improvement | Considering the second primary outcome, the CGI, there were no significant main effects for time or treatment condition on overall improvement (There was no significant three-way interaction between time, treatment condition and age group on the CGI for overall improvement ( | PMC9607840 | ||
Secondary outcomes | SECONDARY | Overall, there were no significant effects of treatment condition, or interactions between treatment condition, time and age group across the duration of the trial for any total scores of secondary outcomes. | PMC9607840 | |
Clinical data | Figure | PMC9607840 | ||
SRS-2 Total scores at Visit 1 (Baseline) and Visit 3 (Post-treatment). | The solid diagonal line represents ‘line of no change’ and the dotted lines represent upper and lower Reliable Change Index (RCI) confidence limits. Test-retest reliability = 0.84; s.d. for baseline = 25.47.Inspection of the figure shows that, within the younger age group, 94.4% (17/18) of participants fell at or on the improvement size of the ‘line of no change’ (i.e., RCI = 0) after oxytocin and 38.5% (5/13) of participants fell at or on the improvement size of the ‘line of no change’ (i.e., RCI = 0) after placebo. 27.8% (5/18) participants showed clinically significant improvement after oxytocin, while 15.4% (2/13) showed clinically significant improvement after placebo. No participants showed clinically significant deterioration after oxytocin or placebo.Within the older age group, 70.4% (19/27) of participants fell at or on the improvement size of the ‘line of no change’ (i.e., RCI = 0) after oxytocin. 82.8% (24/29) of participants fell at or on the improvement size of the ‘line of no change’ (i.e., RCI = 0) after placebo. A total of 18.5% (5/27) participants showed clinically significant improvement after oxytocin, while 31.0% (9/29) showed clinically significant improvement after placebo. 3.7% (1/27) participants showed clinically significant deterioration after oxytocin, while no participants showed clinically significant deterioration after placebo. | PMC9607840 | ||
Treatment guess | At Visit 3 (post-treatment) caregivers were asked to guess whether their child had received oxytocin or placebo for the duration of the treatment (see Table Treatment Guesses in whole sample ( | PMC9607840 | ||
Discussion | autistic, autism | ADVERSE EVENTS | The results of this study showed there was no overall benefit of oxytocin treatment for children with autism. Despite this, there was some evidence to suggest that younger children showed greater improvements on social responsiveness at the end of oxytocin treatment, in comparison to placebo. There was no evidence of any benefit from oxytocin treatment to older autistic children, nor was there evidence that observed benefit in the younger age group was maintained following treatment discontinuation. In regards to placebo treatment, this study showed consistent, small to moderate effect sizes of improvement from placebo treatment across measures during the placebo lead-in phase. These effects dissipated during the second phase of placebo treatment (i.e., from Visit 2 to Visit 3 in the placebo group) to support the effectiveness of the placebo washout. In terms of safety, oxytocin nasal spray was well tolerated. There were no serious adverse events linked to oxytocin administration. Interestingly, a greater number of placebo-administered participants reported adverse events in comparison to oxytocin.While some studies have suggested benefits of oxytocin to younger children [Previous studies have also highlighted the potential of placebo-based responses to provide therapeutic outcomes across many clinical conditions [While the safety of oxytocin treatment for children has been debated [We note limitations of the current study, including a moderate sample size, the inclusion of participants on other psychotropic medications that were stabilized before drug assignment, and reliance on a caregiver and clinician reports as outcome measures. The development of sensitive observational and other markers of change for use in autism clinical trials remains an ongoing priority [In conclusion, the results of this study showed that younger children may benefit from oxytocin nasal spray in comparison to placebo, as indicated by change on caregiver-rated social responsiveness. Oxytocin treatment was found to be well tolerated, with more adverse events reported in the placebo condition. There was evidence of a moderately sized placebo effect across measures in the trial. This study provides one of the first studies in the autism field to demonstrate the benefit of a placebo lead-in phase for clinical trials. There is now a pressing need to conduct larger studies that can definitively test whether younger children benefit from oxytocin, to better disentangle placebo-based effects, and to determine whether oxytocin can be used to enhance social learning circuits. There is also a great need to identify biological pathways underpinning oxytocin uptake, and to identify objective markers of treatment response, in order to better understand how oxytocin may be appropriately used. | PMC9607840 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41380-022-01845-8. | PMC9607840 | ||
Acknowledgements | We would like to thank the staff and students who assisted in the collection of data and the children and families who gave their time to the completion of this research. We thank statistician Caro Badcock for the independent statistical plans, data monitoring, and review of all conducted analysis. We also thank the data safety monitoring board. | PMC9607840 | ||
Author contributions | Authors AJG, AJOW, IBH, and SGG were involved in the conception and the design of the study, authors AJG, AJOW, YJS, SGG, and IBH were involved in the development of the initial protocol and ethics submission, authors AJG, AJOW YJS, RT, IP, JG, MMD, ZA, JW, EET, and IBH collected trial data, authors AJG and KAB analysed and reviewed final trial data with the independent statistician and wrote the first draft of the manuscript. All authors provided edit and review of the manuscript and approved submission of the final manuscript. | PMC9607840 | ||
Funding | This study was supported by the National Health and Medical Research Council (1043664) and the Bupa Health Foundation independent research grants program. Open Access funding enabled and organized by CAUL and its Member Institutions. | PMC9607840 | ||
Competing interests | depression, Psychosis, anxiety | BRAIN | Author AJG has received contracted funding for his team to conduct sponsored clinical trials. He has not received personal financial benefits from this contracted work. Professor Ian Hickie was an inaugural Commissioner on Australia’s National Mental Health Commission (2012-18). He is the Co-Director, Health and Policy at the Brain and Mind Center (BMC) University of Sydney, Australia. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. Professor Hickie has previously led community-based and pharmaceutical industry-supported (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca) projects focused on the identification and better management of anxiety and depression. He was a member of the Medical Advisory Panel for Medibank Private until October 2017, a Board Member of Psychosis Australia Trust and a member of Veterans Mental Health Clinical Reference group. He is the Chief Scientific Advisor to, and a 5% equity shareholder in, InnoWell Pty Ltd. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M Australian Government-funded Project Synergy (2017- 20; a three-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. | PMC9607840 |
References | PMC9607840 | |||
Introduction: | deaths | ACUTE PANCREATITIS, DISEASE, ACUTE PANCREATITIS, COMPLICATIONS | Acute pancreatitis is a high-incidence benign disease. In 2009, it was the second highest cause of total hospital stays, the largest contributor to aggregate costs (approximately US$ 7000.00 per hospitalization), and the fifth leading cause of in-hospital deaths in the United States. Although almost 80% of acute pancreatitis cases are mild (usually requiring short-term hospitalization and without further complications), severe cases can be quite challenging.Classifications, scores, and radiological criteria have been developed to predict disease severity and outcome accurately; however, in-hospital care remains of widespread use, regardless of disease severity. A recent Turkish study reported that mild acute pancreatitis can be effectively and safely managed with home monitoring. Although the optimal timing for oral refeeding remains controversial and could cast some doubt on the feasibility of home monitoring, some guidelines already advocate for starting it within 24 hours.The present clinical trial aims to assess whether home monitoring is effective, safe and non-inferior to hospitalization for managing mild acute pancreatitis. | PMC10194650 |
Methods: | ACUTE PANCREATITIS | This will be a multicenter open-label randomized (1:1) controlled clinical trial to assess the efficacy and safety of home monitoring compared to in-hospital care for mild acute pancreatitis. All patients coming to the emergency department with suspected acute pancreatitis will be screened for enrollment. The main variable will be treatment failure (Yes/No) within the first 7 days after randomization. | PMC10194650 | |
Discussion: | ACUTE PANCREATITIS, DISEASE, ACUTE PANCREATITIS | Acute pancreatitis implies a high economic burden in healthcare systems worldwide. Recent evidence suggests that mild disease can be safely and effectively treated with home monitoring. This approach may produce considerable cost savings and positively impact patients’ quality of life. We expect the results to show that home monitoring is effective and not inferior to hospitalization for managing mild acute pancreatitis and that the economic costs are lower, kickstarting similar trials throughout the world, optimizing the use of limited healthcare budgets, and improving patients’ quality of life. | PMC10194650 | |
1. Introduction | PMC10194650 | |||
1.1. Background | nonalcoholic | ACUTE PANCREATITIS, DISEASE, ACUTE PANCREATITIS, COMPLICATIONS | Acute pancreatitis (AP) is a high-incidence benign disease. In the United States, the estimated annual incidence ranges from 110 to 140 cases/100,000 peopleSevere AP can be quite challenging, usually requiring long-term hospitalizations, intensive care, and/or surgical treatment. Fortunately, almost 80% of APs are mild, usually requiring short-term hospitalization (approximately 5 days) without further complications. Different trustworthy criteria, such as the Atlanta classification, Ranson score, and the Bedside Index for Severity in Acute Pancreatitis (BISAP) score, have been developed to predict disease severity and outcome.Recently, a Turkish pilot study reported that patients with mild nonalcoholic AP could be safely monitored at home when undergoing regular visits by a nurse under physician oversight.Accordingly, we designed the present clinical trial to assess whether home monitoring is effective, safe and non-inferior to hospitalization for managing mild AP. | PMC10194650 |
1.2. Working hypotheses and objectives | AP-related complications | SECONDARY | The current study protocol has 2 working hypotheses:home monitoring is effective and safe for managing mild AP.home monitoring is not inferior to hospitalization for managing mild AP.Our main objective is to assess the efficacy of home monitoring compared to in-hospital care for mild AP.Our secondary objectives are:To assess the safety of home monitoring by estimating the incidence of AP-related complications during the first 30 days after diagnosis.To study the readmission rate during the first 30 days after diagnosis.To estimate the incidence of mortality at 30 days.To assess the quality of life (QoL).To study treatment-related costs. | PMC10194650 |
2. Methods | PMC10194650 | |||
2.1. Study design | nausea or, pain, vomits, abdominal pain | ACUTE PANCREATITIS | This will be a multicenter open-label pilot randomized controlled clinical trial to assess the safety, efficacy, and non-inferiority of home monitoring compared to in-hospital care for mild AP. Patients will be randomly assigned (1:1) to either the home monitoring (experimental) group or the in-hospital (control) group (see Fig. Study Flowchart. ER = emergency room. *Patients requiring admission periods longer than 72 hours will be visited in the outpatient clinic 5–7 days after discharge.All patients with abdominal pain and clinical suspicion of acute pancreatitis will be initially evaluated by each center’s emergency room (ER) specialist physician. Once the diagnosis of mild AP is confirmed (Time 0), we will follow the 2012 Revised Atlanta Classification CriteriaSupportive care in the ER at Time 0 will consist of intravenous administration of fluid therapy, analgesia with acetaminophen 1 g/8 h interchanged with dipyrone 575 mg/8 h (or Dexketoprofen 25 mg/8 h, if allergies/intolerance); antiemetic treatment with Ondansetron 4 mg/8 h; gastroprotective treatment with Omeprazole 20 mg/24 h. After 12 hours in the ER (Time 1), patients will be reassessed for severity and, if adequate pain control (Visual Analogue Scale [VAS] ≤ 3) and no nausea or vomits, we will assess oral feeding tolerance.After 15 hours and before 24 hours after Time 0 (Time 2), patients still presenting VAS ≤ 3 and adequate oral feeding tolerance will be fully informed about the study, provided with the information sheet and invited to participate. If they accept, we will ask them to sign the written informed consent. Afterward, we will perform the randomization, and patients will be informed of their assigned study group. | PMC10194650 |
2.2. Settings | This multicenter study will be carried out at the following medical centers:Hospital Univeritari de Bellvitge;Consorci Corporació Sanitària Parc Taulí de Sabadell;Hospital Sant Joan Despí Moises Broggi—Consorci Sanitari Integral;Hospital de Viladecans;Hospital Hospital de Igualada - Consorci Sanitari de l’Anoia;Hospital Fundació Sant Joan de Déu de Martorell;Hospital Germans Trias i Pujol de Badalona;Hospital de Terrassa;Hospital Universitari Vall d’Hebron;Hospital de la Santa Creu i Sant Pau. | PMC10194650 | ||
2.3. Eligibility criteria | Patients who meet all inclusion criteria and none of the exclusion criteria will be included in the RHINO-trial. | PMC10194650 | ||
2.3.1. Inclusion criteria. | vomiting, AP-related complications, pain | SYSTEMIC INFLAMMATORY RESPONSE, BLOOD | Adult patients (≥18 and ≤80 years of age);Both sexes;Diagnosed with mild AP by at least 2 of the following 3 criteria:Abdominal pain;Plasma/urine amylase or lipase levels ≥ 3× upper limit of normal;Imaging tests (Abdominal ultrasound/ computerized tomography scan) showing signs of AP.Lack of potential severity criteria (at randomization), i.e., presenting none of the following:Systemic inflammatory response syndromePlasma C-reactive Protein levels ≥ 150 mg/dL;Marked increase in the White Blood Cell Count;Coagulopathy (INR > 1.4);Hematocrit > 44%;Blood Creatinine > 170 µmol/L;BISAP score > 2.Satisfactory pain control (VAS ≤ 3) after 12 hours of treatment in the ER;Satisfactory oral feeding tolerance (i.e., no repeated vomiting episodes);Lack of evidence of AP-related complications (systemic or local) in the imaging tests;Adequate cognitive capacity to follow medical orders;Patients meeting each center’s logistic homecare criteria;Patients who give their written informed consent. | PMC10194650 |
2.3.2. Exclusion criteria. | chronic pulmonary disease, cirrhosis, chronic kidney disease, pancreatic disease | ACUTE MYOCARDIAL INFARCTION, HYPERBILIRUBINEMIA, CIRRHOSIS, PANCREATIC DISEASE, CHRONIC PULMONARY DISEASE | Past medical history of pancreatic disease such as:Known or Recurrent AP (>3 flare-ups/year).Previous AP flare-up within 1 month.AP after endoscopic retrograde cholangiopancreatography.Hyperbilirubinemia > 3× upper limit of normal.Past medical history of acute myocardial infarction, cirrhosis, chronic kidney disease, and/or chronic pulmonary disease.Body mass index ≥ 35 kg/mPatients who refuse to participate in the trial. | PMC10194650 |
2.4. Interventions and criteria for discontinuing allocated interventions | PMC10194650 | |||
2.4.1. Home monitoring group. | COMPLICATIONS | Patients randomized to this group will be discharged and monitored through homecare. They will be prescribed an easy-digestion diet plan and oral analgesics. A face-to-face visit will be performed for all patients 24 hours after randomization (Time 3) by both a nurse and a physician from the Homecare Department. If they deem necessary, face-to-face visits will be performed again 48 and 72 hours after randomization. Otherwise, these visits will be conducted through a phone call.Patients will be handed the Should the homecare team suspect any complications, patients will be referred to the hospital for a full evaluation. The last face-to-face study visit (Time 4) will be performed at the outpatient clinic for all participants 5 to 7 days after randomization. During this visit, patients will be asked to fulfill the EuroQoL questionnaire for health-related QoL (HRQoL) assessment. A phone call visit will be performed at 15 (± 3) days (Time 5) and 30 (± 3) days (Time 6) for all patients for overall assessment. | PMC10194650 | |
2.4.2. In-hospital group. | a lithiasic pancreatitis | Patients randomized to this group will be admitted under the care of physicians from the Digestive and General Surgery Department or the Gastroenterology Department. Patients will be visited daily during admission and will be discharged according to their clinical evolution; however, they will remain at in-hospital care for at least 24 hours, as per standard clinical practice. They will initially receive liquid diet and intravenous analgesia; blood tests will be performed at 24 hours after randomization. Oral feeding progression will be performed according to individual tolerance.Patients will be handed the After the Outpatient Clinic visit, all patients diagnosed with a lithiasic pancreatitis (regardless of their randomized study group) will undergo evaluation for scheduling a cholecystectomy. | PMC10194650 | |
2.4.3. Criteria for discontinuing allocated interventions. | Patients allocated to the home monitoring group will be discontinued if their clinical status worsens and they require further admission. We will also discontinue patients who request to be withdrawn from the study and those who fail to comply with study-related procedures. | PMC10194650 | ||
2.7. Sample size | ADVERSE EVENTS | Previously published dataAn interim analysis (for safety purposes) will be performed when half the estimated sample size is included. A detailed report of all recorded adverse events will be provided to the Data Safety Monitoring Committee (DSMC). | PMC10194650 | |
2.8. Recruitment | Patients coming to the ER with suspected AP will be screened for enrollment. A study team member will evaluate them in the ER following the steps detailed in Figure | PMC10194650 | ||
2.9. Allocation (sequence generation, concealment, implementation) and blinding | Patients will be randomly allocated to either the experimental or the control group following a parallel group design and a 1:1 allocation ratio. A total of 308 opaque envelopes (154 for the experimental group and 154 for the control group) will be prepared prior to the study start. The envelopes will be stored in a secure vault and will be randomly opened by the time of the randomization.Since this is an open-label study, blinding (masking) is not applicable. | PMC10194650 | ||
2.10. Data collection plan | pain, illness, anxiety/depression, Comorbidity | Patients’ data will be gathered through clinical interview, clinical examination, and by reviewing the electronic medical records and the Participant Diary (provided to each participant after randomization).We will gather information on:Baseline characteristics: age, sex, recruiting hospital, body mass index, and the ASA score (American Society of Anesthesiologists’ classification scale of overall physical health).AP etiology.Symptoms presented and their onset date.ER discharge date (Home Monitoring Group).Hospital admission and discharge dates (In-Hospital Group).BISAP score and Charlson Comorbidity Index at diagnosis.Clinical data: Vital signs; VAS score; oral feeding tolerance.Laboratory and Imaging data.ER attendance and/or hospital readmission during the first 30 days after diagnosis.Mortality at 30 days after the diagnosis and new AP episode during the 30-day follow-up.EuroQoL in the outpatient clinic visit.Adverse EventsThe BISAP score is a prognostic scoring system for early identification of patients at risk for in-hospital mortality.The Charlson Comorbidity Index consists of 19 items displaying different clinical weights on the basis of the adjusted risk of one-year mortality, controlling for severity of illness and age. It has been shown to accurately relate with the 10-year life expectancy.The pain VAS is a self-reported scale consisting of a horizontal or vertical line, usually 10 centimeters long (100 mm) anchored at the extremes by 2 verbal descriptors referring to the pain status. An introductory question (with or without a time recall period) asks the patient to tick the line on the point that best refers to his/her pain.The EuroQoL questionnaire is a widely used instrument to measure health-related QoL. We will use the EQ-5D-3L version, which essentially consists of 2 pages: the EQ-5D descriptive system and the EQ-5D visual analogue scale (EQ-VAS). The EQ-5D-3L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems (labeled 1–3). The EQ-VAS records the respondent’s self-rated health on a vertical VAS where the endpoints are labeled “The best health you can imagine” and “The worst health you can imagine.” | PMC10194650 | |
2.11. Plans to promote participant retention and complete follow-up | EVENT | Follow-up will be performed either at homecare or during hospital admission. Notably, patients will be required to attend to the outpatient clinic 5 to 7 days after being discharged from the emergency department (as a safety measure); however, we do not think this will imply a considerable extra-effort that would prevent patients to complete follow-up. In each medical follow-up visit (be it face-to-face or by phone), the clinical investigator in charge will remind the patients of the importance of correctly following the study procedures and encourage them to carry on in the clinical trial.Protocol deviations will be documented and explained in detail by the study team. In the event of a “serious” protocol violation, the monitoring team will record all protocol breaches/deviations. The sponsor will review all protocol deviations and assess whether they represent a “serious” violation according to Good Clinical Practice guidelines. The sponsor will inform the IRB of any protocol breach/deviation that could impact on patient safety and on data integrity. | PMC10194650 | |
2.12. Data management | An electronic case report form (eCRF), based on REDCap platform (REDCap Consortium), will be created Before closing the database for analysis, the data manager and the principal investigator will check the completeness and accuracy of the recorded data. | PMC10194650 | ||
2.13. Statistical methods | Considering this is a pilot study, analyses will be primarily performed in the per protocol population; however, we will also perform intention-to-treat analyses whenever feasible. We will perform a general descriptive analysis of all study variables. The results will be expressed as means (standard deviation [SD]) or medians (range) for the quantitative variables and as absolute and relative frequencies for the categorical variables.We will use Pearson’s χ | PMC10194650 | ||
2.14. Data monitoring, description of any interim analyses and stopping guideline | A DSMC will be created As mentioned before, an interim analysis (for safety purposes) will be performed when half the estimated sample size is included. | PMC10194650 | ||
2.15. Harms | ADVERSE EVENTS, ADVERSE EVENT | Adverse events recorded during the study will be coded according to the latest available version of the MedDRA dictionary and will be described using absolute and relative frequencies by study group, according to severity and its causal relation with treatment.Serious adverse events will be described by study group and the 95% CI of the difference between both groups will be calculated. | PMC10194650 | |
2.16. Auditing | The Investigator shall allow direct access to trial data and documents for monitoring, audits and/or inspections by competent regulatory or health authorities. As such, eCRFs, source records and other trial-related documentation must be kept current, complete, and accurate at all times. | PMC10194650 |
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