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Study setting {9} | MUI | SECONDARY | In this single-center prospective, triple-blinded, two-group, randomized trial, 60 patients will be recruited and randomly assigned to one of the two groups to test the effect of a PECS II block with ropivacaine 0.5% on the postoperative opioid demand (see Consolidated Standards of Reporting Trials flow diagram (CONSORT) [Trial flow diagramThe primary outcome parameter is the overall opioid demand given as intravenous MME during the first 24 h after extubation.The secondary outcome variables are the interval until extubation, ICU discharge, data on ICU, length of hospital stay (LOS), the VAS at 2, 4, 6, 12, and 24 h after extubation, and the Overall Benefit of Analgesia Score (OBAS) at 24 h after extubation [This study will be performed in the Innsbruck Medical University Hospital. All participants will be recruited by a medical specialist team (recruiting team) at the Medical University of Innsbruck (MUI) (Investigation Site). All data will be collected by the research team consisting of physicians and healthcare researchers. The study investigators will perform data analysis. | PMC10476350 |
Eligibility criteria {10} | pain, Psychiatric disorders, myxoma, allergies, atrial septal defect | SYSTEMIC INFECTION, DIABETIC NEUROPATHY, CHRONIC RENAL DISEASE, MYXOMA, ALLERGIES, VALVULAR HEART DISEASE, CHRONIC PAIN SYNDROME | Adult patient with an American Society of Anesthesiologist (ASA) physical status I-III, aged 18–80 years, scheduled for elective minimal invasive cardiac surgery, e.g., mitral valve procedures, tricuspid valve procedures, myxoma resection, or atrial septal defect repair. All participants will undergo the usual standard medical work-up before, during, and after the procedure according to the ESC/EACTS Guidelines on Valvular Heart Disease [This includes echocardiography, spirometry, carotid artery duplex scan, cardiac MRI, and/or computed tomography, and interviews with the cardiologist, cardiac surgeon, and anesthesiologist.To be eligible for this study, patients must meet all of the following criteria:Age: 18–80 years.BMI 18–35 kg/m.Informed consent.MICSThe exclusion criteria are as follows:Known allergies to administered drugs.Severe diabetic neuropathy.LV-dysfunction (EF < 30%).Drug-opioid abuse.Patients with chronic pain syndrome.Systemic infection.Psychiatric disorders that lead to alteration in the perception and evaluation of pain.Pregnancy.Anticipated endotracheal intubation > 24 h.eGFR < 30 or chronic renal disease. | PMC10476350 |
Who will take informed consent? {26a} | Every participant must give written consent before participating in the clinical trial.An investigator will provide and obtain the informed consent form. Therein, the investigator will thoroughly inform the participant in oral and written form in an understandable manner for the patient about the character, importance, relevance, and consequences of the clinical trial. Before the participant may sign the informed consent form, there will be ample opportunity to consider participation and discuss questions with the investigators. The informed consent file must be signed and dated by the participant and the investigator and stored in the investigator site file. Nevertheless, if the participant decides not to participate any time before the intervention, he will not be included without negative impacts on the procedure. | PMC10476350 | ||
Additional consent provisions for collection and use of participant data and biological specimens {26b} | On the consent form, participants will be asked if they agree to the use of their data should they choose to withdraw from the trial. This includes their data being used for analysis as well as any future publications or presentations related to the study. Since this is a monocenter trial, the consent form will not include a section regarding data sharing permissions. This trial does not involve collecting biological specimens for storage. All necessary measures will be taken to protect the privacy and confidentiality of participants. Participants will also be provided with the contact information for the study team in case they have any questions or concerns regarding their participation in the study. | PMC10476350 | ||
The explanation for the choice of comparators {6b} | Two groups will be included. The intervention group receives PCS II block with 30 ml of ropivacaine 5 mg/ml, while the control group receives a plane PECS II block with 30 ml of sodium chloride 0.9%. All other medical interventions will be identical. | PMC10476350 | ||
Intervention description {11a} | pain | After obtaining written informed consent, all patients will be taught to assess pain using the visual analog scale (VAS; 0–100 mm). According to institutional standards, patients will be fasted for 6 h for solids and 2 h for fluids and receive oral premedication with midazolam 0.05–0.1 mg /kg if requested.Before the arrival of the patient in the operating room, a study nurse will open an opaque envelope and prepare the study medication (30 ml ropivacaine 0.5% for the intervention group and 30 ml sodium chloride 0.9% for the placebo group) according to the study randomization and hand it to the blinded anesthetist.Upon arrival at the operating room, standard monitoring (5-channel electrocardiogram, pulse oximetry (SpOA five-lumen central venous catheter will be inserted in the right subclavian or internal jugular vein, depending on the indication of a bicaval extracorporeal venous drainage for cardiopulmonary bypass. Immediately afterward, the ultrasound-guided PECS II block will be performed under aseptic conditions on the right hemithorax using the technique described by Blanco et al. [According to our institutional standards, a trans-esophageal echocardiographic probe will be inserted in all patients to control and assess cardiac function.All PECS II blocks will be performed under ultrasound guidance by five consultant anesthetists experienced in the technique ( | PMC10476350 | |
Postoperative analgesia regimen | At the end of the surgical procedures, all patients will receive a bolus of piritramide 0.1–0.2 mg/kg and will be transferred to the postoperative ICU ward. Patients will be extubated when extubation criteria are reached (normothermic, fully awakened, spontaneously breathing, hemodynamically stable with moderate vasopressor support, etc.). After extubation, VAS will be recorded by trained medical staff members and then after 2, 4, 6, 8, 12, and 24 h. If VAS exceeds a value of 30 mm at any time, an administration of piritramide will be allowed. The time interval from completing the PECS II block until the first request for opioids (VAS > 30 mm) after extubation is defined as the duration of analgesia. Opioid consumption will be assessed as an intravenous morphine milligram equivalent (MME) dose. | PMC10476350 | ||
Criteria for discontinuing or modifying allocated interventions {11b} | hemodynamic impairment, CRF | CRF, COMPLICATIONS | We will exclude patients from participating in case of failure to detect the suitable anatomical structures for PECS II.After PECS II is performed, it is impossible to change the allocated intervention after administration. Subjects are free to leave the study at any time for any reason without consequences. Study discontinuation should be documented in the subject’s medical file and the case report form (CRF). The investigator can withdraw an issue from the study for urgent medical reasons. These may include the following criteria:Anatomical anomalies, limited visualizationAllergic reaction to the study medicationClinical complications (hemodynamic impairment, re-operation, extracorporeal membrane oxygenation (ECMO), etc.) that may lead to prolonged weaning (more than 24 h) | PMC10476350 |
Strategies to improve adherence to interventions {11c} | To improve adherence to the study protocol, the follow-up visits for the study are planned simultaneously with the standard measurements for patients in the MICS program at the Medical University of Innsbruck. Participants do not need to adhere to specific tasks. To support faculty staff, a study nurse who reviews the patient files throughout the study period will be involved. | PMC10476350 | ||
Relevant concomitant care permitted or prohibited during the trial {11d} | There is no expected interaction between the drug under investigation and concomitant medical treatments. Local prescribing information and institutional guidelines should be followed as applicable. | PMC10476350 | ||
Provisions for post-trial care {30} | injury or death | The sponsor has insurance by the legal requirements in Austria. This insurance covers damage to research participants through injury or death caused by the study. The insurance applies to the damage that becomes apparent during the study. | PMC10476350 | |
Outcomes {12} | The primary outcome parameter is the overall opioid demand given as intravenous MME during the first 24 h after extubation.Secondary outcome variables are the interval until extubation, ICU discharge, data collected in the ICU, length of hospital stay, the VAS at 2, 4, 6, 12, and 24 h after extubation, and the Overall Benefit of Analgesia Score (OBAS) at 24 h after extubation [ | PMC10476350 | ||
Participant timeline {13} | Demographic and baseline data such as age, weight, height, and ASA score are collected soon after informed consent is granted, usually the day before surgery. On the day of surgery, data that define the type of surgery and the type and size of central venous cannulation will be noted. Also, hemodynamic data such as arterial pressure, heart frequency, and blood oxygen saturation before and soon after the performance of the PECS block will be recorded. At the end of the surgery, the amount of opioids and sedatives used during the surgery will be noted. The time of ICU admission and hemodynamic data will be noted at ICU admission.All opioids and other analgesics will be noted until the extubation and after 2, 4, 6, 8, 12, and 24 h. Also, the NRS score will be assessed at the defined time points.After 24 h, the OBAS assessment will be performed, and the study participation will end. | PMC10476350 | ||
Sample size {14} | The main hypothesis of this study is that the use of PECS II blockade in patients undergoing minimally invasive cardiac surgery reduces the overall opioid demand given as morphine milligram equivalents (MME) during the first 24 h after extubation. The sample size needed to test this hypothesis was based on four previous studies [ | PMC10476350 | ||
Recruitment {15} | RECRUITMENT | The MICS program at the University Clinic of Cardiac Surgery, Medical University of Innsbruck, serves as the primary recruitment institution. | PMC10476350 | |
Assignment of interventions: allocation | PMC10476350 | |||
Sequence generation {16a} | The investigational medication (ropivacaine 0.5%) assigned to individual patients is determined by a randomized schedule with a 1:1 allocation ratio. | PMC10476350 | ||
Concealment mechanism {16b} | BLIND | The randomization process will be realized independently from the clinical investigators using opaque envelopes (fully blind randomization). For each participant enrolled in the study, one envelope will be opened by the nurse who prepares the study medication. Preparation will be performed in a separate room without the attendance of any study investigator. | PMC10476350 | |
Implementation {16c} | The randomization list will be generated using well-established software (randomization.org) for the two groups (intervention group, placebo group). Upon the arrival of the patient in the operating theatre, a study nurse will open an opaque envelope which is labeled with the patient’s identification code and prepare the study medication (30 ml ropivacaine 0.5% for the intervention group and 30 ml sodium chloride 0.9% for the placebo group) according to the study randomization and hand it to the blinded anesthetist. | PMC10476350 | ||
Assignment of interventions: blinding | PMC10476350 | |||
Who will be blinded {17a} | This study is, per definition, triple-blinded as the participants, care providers, and investigators involved in the study procedure do not know the randomization arm. All study assessments will be performed in an observer-blinded fashion. | PMC10476350 | ||
Procedure for unblinding if needed {17b} | A patient identification code will replace patient identifying data. The randomization list and the codebook will be stored digitally and only accessible to study personnel. Unblinding is possible at all times after consultation with the principal investigator. | PMC10476350 | ||
Data collection and management | PMC10476350 | |||
Plans for assessment and collection of outcomes {18a} | CRF | CRF | All investigators will be trained within the initiation visit. Training topics cover Good Clinical Practice, the study protocol, and OBAS and VAS assessment execution.The patient’s demographical data will be registered soon after the patient’s informed consent. The PECS II block will be performed by experienced anesthesiologists who have completed at least 50 procedures. All data will be collected using a paper-based CRF. The healthcare data of participants will be derived from the electronic patient file. All data will be stored for 15 years, and results will be published in scientific journals. | PMC10476350 |
Plans to promote participant retention and complete follow-up {18b} | After enrollment and randomization, the investigators will make every reasonable effort to follow the study subject throughout the entire study period. Subjects are free to discontinue their study participation at any time. Participant retention will be increased by implementing study visits into routine clinical postoperative care. | PMC10476350 | ||
Data management {19} | CRF | CRF | An independent internal monitor (Tirol Kliniken) will provide the monitoring and quality assurance of the study. The study team will process data entry from paper based CRF into statistical software. Programmed checks make data validation of range, validity, and consistency. If necessary, queries are made by the study software or an authorized person. Based on the questions, the investigator can check and clarify discrepancies.After recording all entries and clarifying all queries, the database will be closed after the study. This performance must be documented. All data will be handled confidentially, and research data will be coded using a unique patient identification number. To reproduce the study findings and help future users understand and reuse the data, all changes made to the raw data and all steps taken in the analysis will be documented. The database files will be kept for 15 years after the study has ended. | PMC10476350 |
Confidentiality {27} | All local legal requirements regarding data protection will be adhered to. All study findings and documents will be regarded as confidential. The Investigator and research team members must not disclose any information without prior written approval from the Sponsor.The pseudonymity of patients participating must be maintained. The patients will be recognized on CRFs and other documents by age and identification number throughout documentation and evaluation. Records that identify the patient personally (e.g., the signed informed consent) must be maintained in confidence by the investigator. The patients will be told that all study findings will be stored on a computer and handled in the strictest confidence. | PMC10476350 | ||
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} | Not applicable; no biological specimens will be collected for this study. | PMC10476350 | ||
Statistical methods | PMC10476350 | |||
Statistical methods for primary and secondary outcomes {20a} | Data will be entered into electronic case record files (eCRF; RedCap®, Nashville, TN). R 4.2 (The R Project for Statistical Computing, Vienna, Austria) will be used for statistical analysis. The normality of data will be assessed using graphical and inferential tests. Median/interquartile range or mean/standard deviation will be used to summarize and evaluate continuous data and count/percent for categorical data. Student’s | PMC10476350 | ||
Interim analyses {21b} | This study can be classified as low risk; no interim analyses will be conducted during this trial. | PMC10476350 | ||
Methods for additional analyses (e.g., subgroup analyses) {20b} | No subgroup analysis is planned, justified by the sample size and the pragmatic study design.We anticipated that there would be meaningful differences in treatment effects across subgroups of participants. | PMC10476350 | ||
Sample size | Our study was designed to detect an effect of the PECS II block on 24 h postoperative opioid demand. As patients undergoing minimal invasive mitral valve surgery tend to be quite a homogenous population, to our understanding, conducting subgroup analyses would not have added much value to our study. Also, conducting subgroup analyses would have reduced our statistical power. Therefore, we were concerned that subgroup analyses would not yield meaningful results. | PMC10476350 | ||
Methods in analysis to handle protocol non-adherence and any statistical forms to handle missing data {20c} | PMC10476350 | |||
Per-protocol population | bleeding | BLEEDING, HEMODYNAMIC INSTABILITY, COMPLICATIONS, SECONDARY | The per-protocol-population will include all patients who received intervention or sham intervention (placebo) and surgery without major protocol deviations. Significant protocol deviations or complications (hemodynamic instability, prolonged intubation, reintubation, bleeding, reoperation) and subsequent failure to obtain primary and secondary outcome data will be documented before the database lock. | PMC10476350 |
Intention-to-treat population | The intention-to-treat population will consist of all patients who were enrolled in the study and gave informed consent, but data is missing due to the abovementioned factors. This population will be analyzed in a separate ITT cohort. In case of withdrawals and missing data, the last observation carried forward (LOCF) procedure will be applied where appropriate. | PMC10476350 | ||
Plans to give access to the complete protocol, participant-level data, and statistical code {31c} | The entire protocol of the study will be published together with a manuscript on the clinical trial results. The datasets analyzed during the current study and the statistical code will be available from the corresponding author upon reasonable request. It will only be accessible to personnel directly involved in the study. | PMC10476350 | ||
Oversight and monitoring | PMC10476350 | |||
Composition of the coordinating center and trial steering committee {5d} | This is an investigator-initiated, single-center trial, run by a small study team that can be seen as the trial steering committee. Organizational support will be provided by the Competence Centre for Clinical Trials, Medical University of Innsbruck (KKS). The study team meets on a daily basis, to review routine clinical cases. Study-related topics will be discussed during this daily meeting as appropriate. The KKS will provide consultancy during the study initiation and closure phases, as well as on demand. | PMC10476350 | ||
Composition of the data monitoring committee, its role and reporting structure {21a} | An independent local monitor (Tirol Kliniken) will check trial quality repeatedly (at least every 6 months) and check at least 10% of the signed informed consent files (ICF). Complete data of the first five participants will be reviewed, including inclusion and exclusion criteria. The study has a low risk; therefore, there is no need for data safety monitoring board. | PMC10476350 | ||
Adverse event reporting and harms {22} | ADVERSE EVENTS, ADVERSE EVENT | Although serious adverse events are not to be expected, the sponsor and the principal investigator will suspend the study if there is reasonable doubt that the continuation of the survey will compromise the safety and well-being of participants. In this case, the local ethics committee will be informed immediately, and the study will remain suspended pending a favorable decision from the local ethics committee.Adverse events will be noted, and serious adverse events will also be reported to the local ethics committee. | PMC10476350 | |
Frequency and plans for auditing trial conduct {23} | CRF | CRF | For quality assurance, monitoring audits will be performed. An independent local monitor will perform the monitoring.Monitoring visits will be conducted to review study plan compliance, compare CRFs and individual patients’ medical records, perform an accounting of study material, and ensure that the study is conducted according to applicable regulatory requirements. CRF entries will be verified with source documentation. Monitoring visits will be performed repeatedly for at least all 6 months and check at least 10% of the signed ICFs. | PMC10476350 |
Plans for communicating significant protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25} | After the protocol has been submitted to the ethics committee (EC), any substantial change will require a formal amendment. The amendment must be signed by all of the signatories to the original protocol. Once the study has started, amendments should be made only in exceptional cases. The ethics committees must be informed of all amendments. Approval must be sought for ethical aspects and obtained from the competent authorities | PMC10476350 | ||
Dissemination plans {31a} | For all publications, the data protection of the subjects will be maintained. This includes a presentation at national and international conferences and publications in scientific journals. The study data are the property of the Medical University of Innsbruck. The data from the whole trial can be published separately. There are no publication restrictions, and the trial results will be accessible to the public. | PMC10476350 | ||
Discussion | Acute postoperative pain, pectoral muscle resection | CHRONIC PAIN, SECONDARY | This study will assess the opioid demand during the first 24 h after extubation following MICS. The available evidence on using local anesthetics in major cardiac surgery is scarce [The secondary endpoints assess the evolution of VAS during the first 24 h, namely 2, 4, 6, 8, 12, and 24 h after extubation. Also, the OBAS after 24 h will be assessed, giving a more subjective evaluation of the analgesia and its subjective benefit [Acute postoperative pain and the development of chronic pain are significant issues in cardiac surgery [With the upcoming less invasive surgical approaches, such as MICS, where two or three small thoracotomies replace open surgery access, an increased interest in ERAS pathways arose in cardiac surgery [Over the last decade, several ultrasound-guided truncal fascial plane blocks have been latter block has shown to provide good analgesia to the anterolateral chest wall for modified mastectomy, including axilla dissection and pectoral muscle resection [Given the strict unilateral right approach of MICS, the PECS II block could be an exciting addition to multimodal analgesia. And as central venous catheters are usually placed on the right side, the ultrasound-guided PECS II block does not require further positioning, washing, and covering of the patient, thereby adding an essential advantage in time and logistics compared to other regional anesthesia techniques.This study was designed to clarify if a PECS II block could efficiently reduce opioids in patients undergoing unilateral MICS. This study’s results may support anesthesiologists in choosing strategies for multimodal analgesia. | PMC10476350 |
Trial status | Protocol version 1.4, effective date: 21 January 2022. First patient first visit (FPFV): 08 February 2022. Currently, 36 of 50 participants are included, date: 11 October 2022. Last patient last visit (LPLV) is expected in April 2023. | PMC10476350 | ||
Acknowledgements | Not applicable. | PMC10476350 | ||
Authors’ contributions {31b} | NB | EH: Conception and design of the study, study investigation, drafting the article, final approval. OS: Conception and design of the study, study investigation, drafting the article, final approval. FN: Study investigation, drafting the article, final approval. AF: Study investigation, drafting the article, final approval. NB: Study investigation, drafting the article, final approval. PM: Conception and design of the study, drafting the article, final approval. JH: Study investigation, drafting the article, final approval. LG: Conception and design of the study, study investigation, drafting the article, final approval. | PMC10476350 | |
Funding {4} | The PECS MICS trial is investigator-initiated at the Medical University of Innsbruck, Austria. | PMC10476350 | ||
Availability of data and materials {29} | The datasets analyzed during the current study are available from the principal investigator or the corresponding author on reasonable request and are otherwise only accessible to the study collaborators. | PMC10476350 | ||
Declarations | PMC10476350 | |||
Ethics approval and consent to participate {24} | der Medizinischen Universität Innsbruck-Austria | This trial was approved by the local ethical committee (Ethiokkommission der Medizinischen Universität Innsbruck-Austria) (EK Nr:1332/2022, date 17 January 2022) from the local Ethical Committee (Ethiokkommission der Medizinischen Universität Innsbruck-Austria). | PMC10476350 | |
Consent for publication {32} | Not applicable. | PMC10476350 | ||
Competing interests {28} | The authors declare no competing interests. | PMC10476350 | ||
References | PMC10476350 | |||
Subject terms | RPE | This study investigates the effect of the consumption of caffeinated chewing gum on the performance of Romanian deadlift on the flywheel training device. A total of 19 participants completed a randomized, cross-over, single-blind experiment with food-grade caffeinated chewing gum trial (CAF) or placebo trail (PL). Gum were chewed for 10 min and rest for 15 min prior to the Romanian deadlift test using the inertial resistance training machine. 5 sets of 6 Romanian deadlifts were performed, with a 3-min rest between sets, followed by a 7-day washout period before the next set of trials. The average power, average force, total peak power, peak concentric power, peak eccentric power, heart rate, and rating of perceived exertion (RPE) for each trials were analyzed using paired-T test. Compared to placebo, caffeinated chewing gum trial enhanced peak concentric power ( | PMC10716112 | |
Introduction | In recent years, resistance training has become increasingly popular. Training methods typically involve lifting some sort of weight, such as barbells, dumbbells, and pulleys. This type of training focuses primarily on counteracting the force of gravity. In contrast, flywheel training, also known as inertial training, uses the inertia of the flywheel to provide resistance during the concentric (muscle shortening) and eccentric (muscle lengthening) phases of movement. Recent literature using inertial flywheel resistance training has shown that strength, power and performance, such as the vertical jump and the first 5 m of the sprint test, are usually significantly improved after 4–8 weeks of flywheel trainingCaffeine consumption is widespread, with approximately 90% of adults consuming some form of caffeine in their diet and approximately 30–60% of athletes consuming caffeine as a sports supplementHowever, it is still unclear whether caffeinated chewing gum supplementation can improve the performance of the Romanian deadlift on a flywheel. Therefore, the aim of this study was to investigate the effect of a caffeinated chewing gum supplementation on the performance of the Romanian deadlift on a flywheel training device. | PMC10716112 | ||
Materials and methods | PMC10716112 | |||
Experimental design | SECONDARY | The study was a randomized, crossover, single-blind study design in which participants were randomized to ingest a caffeinated chewing gum trial (CAF) and a placebo gum trial (PL) 7 days apart, 10 min before performing the Romanian deadlift on a flywheel training device, CONSORT diagram and study design as shown in Fig. CONSORT diagram and study design.The participants made three visits to the laboratory. During the first visit, participants were familiarized with the exercise tests and the maximum resistance was determined. Following the familiarization visit, participants were randomized in a counterbalanced fashion to two main conditions, PL and CAF. The primary outcome was the performance of the Romanian deadlift on a flywheel training device, and the secondary outcomes were heart rate and RPE. | PMC10716112 | |
Participants | All 19 participants (age 22.5 (3.5) years; height 176.2 (6.5) cm; body mass 78.8 (13.2) kg; habitual caffeine intake: 62.55 (94.01) mg/day). A priori power analysis, using an expected effect size (f) of 0.55 for peak eccentric power on the Romanian deadlift test, an α of 0.05, a statistical power of 0.80All participants were interviewed verbally about their exercise habits over the previous 6 months. They were instructed to avoid caffeine-containing foods such as coffee, energy drinks, tea and chocolate for 24 h prior to the formal experiment. Excessive exercise training was prohibited for 72 h prior to the study. All potential problems that participants may encounter during the experiment were explained before the study began and the procedure was fully explained. Participants were asked to complete an informed consent form. This study was approved by the Institutional Review Board of Jen-Ai Hospital—Dali Branch (111-09) and registered in the ClinicalTrials.gov (Date: 22/02/2022; ID “NCT05900349”; | PMC10716112 | ||
Experimental protocol | Experimental protocol was shown on Fig. Experimental protocol.On the day before the first formal experiment, the participants' dietary intake was recorded, and they were asked to replicate the same diet before the next experiment. Participants were also instructed to avoid consuming caffeinated foods for 24 h before the formal experiment and to refrain from excessive exercise training for 72 h.On the day of the experiment, the participants arrived at the laboratory in the afternoon, following their regular training schedule. After a 5-min warm-up on a bicycle ergometer, they chewed either food-grade caffeinated chewing gum (200 mg per serving) or a placebo gum for 5 min. After a 10-min rest period, participants performed a set of 6 repetitions and 5 sets of Romanian Deadlift (RDL) exercises using the non-gravity-dependent flywheel inertial device (K-Box 4, Exxentric®, Stockholm, Sweden). There was a 3-min rest period between sets. The Exxentric kMeter (© Exxentric AB, Sweden), connected to its application via Bluetooth, was used in each RDL test to record average power (W), average force (N), peak concentric power (W), peak eccentric power (W) and total work (KJ). This device had been used in other studies and had demonstrated good reliability and validity in measuring various performance indicatorsAfter completion of the first experiment, participants had a 7-day rest and washout period before proceeding to the next set of experiments. All trials were completed within one month, followed by analysis of the experimental results. | PMC10716112 | ||
Statistical analysis | RPE | The Shapiro–Wilk test was conducted to test the normality of the data. Two-way ANOVA was used to compare the differences in heart rate, RPE and other measures between the CAF trial and the PL trial before and after the Romanian deadlift inertia resistance training test. We represent standard deviations in parentheses [i.e., mean (SD)] | PMC10716112 | |
Ethics approval and consent to participate | This study was approved by the Institutional Review Board of Jen-Ai Hospital (111-09) in Taiwan. | PMC10716112 | ||
Results | All 19 participants completed the test sessions and were included in the analysis. According to the pre-test dietary questionnaire, the participants had an average daily caffeine intake of 62.55 (94.01) mg. The absolute dose of caffeine given in this experiment was 200 mg, and after weight calculation, the caffeine intake of each participants was 2.75 (0.53) mg/kg. Based on the pre-test results, the flywheel resistance during the RDL exercise was 0.06 (0.02) kg/mComparison of peak concentric power (Fig. Peak concentric and eccentric power. The peak concentric power (Figure The average power (Participants' heart rates were monitored and RPE levels were assessed (Fig. Comparison of heart rate and rating of perceived exertion between the CAF and PL trials. | PMC10716112 | ||
Discussion | RPE | The main findings of this study were that caffeine ingestion via caffeinated chewing gum significantly improved the performance of the Romanian deadlift on the flywheel exercise compared to placebo in peak concentric power, peak eccentric power, average power and total work. However, there were no significant differences between the two trials in average force, RPE and heart rate.In previous studies, caffeine was mainly ingested in the form of capsules, which took approximately 45–60 min to reach high concentrations in the bloodLopes-Silva has demonstrated that caffeine intake can improve intermittent upper body strength endurance performance in combat sports athletesIn the recent literature, only one study was found in which inertial flywheel resistance performance was measured with 6 mg/kg caffeine supplementation, and the study found significant improvements in total mean and peak power, and centripetal and centrifugal mean and peak powerEven though, the effect of caffeinated chewing gum on the performance of the Romanian deadlift on a flywheel is still unclear. The flywheel training device is a method specifically designed for eccentric training | PMC10716112 | |
Strength and limitations | This trial used a rigorous two-arm crossover randomized controlled design. All outcomes were measured by Exxentric kMeter (© Exxentric AB, Sweden) to ensure reliabilityThis study provides new evidence on the potential benefits of using caffeinated chewing gum to enhance physical performance. However, it is important to note that the field is still in its infancy and our understanding is largely based on limited research. Therefore, there is an urgent need for larger clinical trials to robustly determine the efficacy and safety of caffeinated chewing gum in improving physical performance. Future research should focus on different doses, timing of ingestion, and interactions of caffeine with different physical activities. Finally, we used absolute rather than relative doses of caffeine due to logistical constraints associated with individual chewing gum formulations. This approach may not accurately reflect real-world situations where caffeine intake may vary according to personal response. | PMC10716112 | ||
Acknowledgements | Thanks for National Taiwan University of Sport, National Science and Technology Council and China medical university hospital to provide the equipment and necessary assistance for this study. | PMC10716112 | ||
Author contributions | S.-H.W. | C.-C.H. and S.-H.W. assisted the data analysis and manuscript preparation. Y.-C.H., S.-Y.Y. assisted the experimental design and manuscript preparation. C.-H.C. carried out the experiment, data analysis and assisted the manuscript preparation. | PMC10716112 | |
Funding | This study was not funded by any organization. The publication fees were funded by China medical university hospital. | PMC10716112 | ||
Data availability | All relevant materials are presented in the present manuscript. | PMC10716112 | ||
Competing interests | The authors declare no competing interests. | PMC10716112 | ||
References | PMC10716112 | |||
Introduction | adrenal tumors, prednisoloneEndothelial dysfunction, adrenal incidentalomas, hypertension, benign nonfunctioning adrenal adenomas, Adrenal incidentalomas | ADRENAL INCIDENTALOMA, ADRENAL TUMORS, EVENTS, ATHEROSCLEROSIS, HYPERTENSION, PATHOGENESIS, ADRENAL INCIDENTALOMAS | Adrenal incidentalomas are adrenal tumors that are detected unexpectedly during imaging procedures conducted for unrelated reasons. Most of the adrenal incidentalomas are classified as benign nonfunctioning adrenal adenomas (NFA), and patients with NFA which have lower rates of cardiovascular events and mortality than those in patients with autonomous cortisol secretionAdministration of glucocorticoids for more than three months causes cardiovascular events, even with less than 7.5 mg of prednisoloneEndothelial dysfunction represents an initial stage in the pathogenesis and advancement of atherosclerosis, leading to increased cardiovascular complicationsThe purpose of this study was to evaluate vascular function in patients with NFA who have hypertension and/or DM and the effects of administration of overnight 1 mg dexamethasone on vascular function in those patients. | PMC10684497 |
Results | PMC10684497 | |||
Study protocol 1 | PMC10684497 | |||
Baseline clinical characteristics | hypertension | HYPERTENSION | The baseline clinical characteristics of the 272 control patients with hypertension and/or DM and 22 patients with NFA who had hypertension and/or DM are summarized in Supplemental Table Moreover, we assessed vascular function in patients with NFA who had hypertension and/or DM using propensity score matching to create matched pairs between control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM. In propensity score-matched pairs of control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM, the clinical characteristics of matched pairs of 22 control patients with hypertension and/or DM and 22 patients with NFA who had hypertension and/or DM are summarized in Table Clinical Characteristics of Propensity Score-matched Pairs of Subjects in Protocol 1.N/A indicates not applicable.Results are presented as means ± SD for continuous variables and percentages for categorical variables. | PMC10684497 |
Vascular function in patients without adrenal incidentalomas and patients with NFA | hypertension | HYPERTENSION | There were no significant differences in FMD and NID between control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM (3.4 ± 2.8% vs. 2.9 ± 1.9% and 11.5 ± 5.7% vs. 11.4 ± 4.3%, P = 0.46, and P = 0.99, respectively) (Supplemental Table In propensity score-matched pairs of control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM, there were no significant differences in FMD and NID between control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM (3.5 ± 3.3% vs. 2.9 ± 1.9% and 11.0 ± 4.5% vs. 11.4 ± 4.3%, P = 0.50 and P = 0.70, respectively) (Table | PMC10684497 |
Study protocol 2 | PMC10684497 | |||
Baseline clinical characteristics | The baseline clinical characteristics of the 320 control patients and 18 patients with NFA are summarized in Supplemental Table Moreover, we assessed vascular function in patients with NFA using propensity score matching to create matched pairs between control patients and patients with NFA. In propensity score-matched pairs of control patients and patients with NFA, the clinical characteristics of matched pairs of 18 control patients and 18 patients with NFA are summarized in Table Clinical Characteristics of Propensity Score-matched Pairs of Subjects in Protocol 2.N/A indicates not applicable.Results are presented as means ± SD for continuous variables and percentages for categorical variables. | PMC10684497 | ||
Discussion | DM, hypertension, cerebral infarct, Cushing’s syndrome | VASODILATION, HYPERTENSION, CEREBRAL INFARCT | In the present study, we demonstrated that there were no significant differences in FMD and NID between control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM even after adjustment for cardiovascular risk factors. Overnight 1 mg dexamethasone increased FMD and NID in patients with NFA. Increases in FMD after overnight 1 mg dexamethasone were inversely correlated with changes in morning plasma levels of cortisol. This is the first study to assess the impacts of overnight 1 mg dexamethasone on vascular function.The prevalences of hypertension and DM are higher in patients with NFA than in healthy subjects. Androulakis et al.It is well established that there is a relationship of chronic glucocorticoid excess, including Cushing’s syndrome, mild autonomous cortisol secretion and iatrogenic Cushing’s syndrome, with increased incidence of cardiovascular diseaseGlucocorticoids can impact vascular reactivity by regulating either vasoconstriction or vasodilation. In the present study, changes in FMD after 1 mg dexamethasone inversely correlated with changes in morning plasma levels of cortisol, whereas there were no significant relationships between changes in FMD and changes in morning plasma levels of ACTH, blood pressure, and heart rate. These findings suggest that glucocorticoids directly affect vasodilation. Corticosteroids rapidly activate endothelial nitric oxide synthase via a non-transcriptional mechanism involving the glucocorticoid receptor and the PI3K/Akt pathway, leading to increased cerebral blood flow, reduced cerebral infarct size, and diminished vascular inflammationThis study has some limitations. First, the present study included a limited sample size of patients with NFA. However, overnight 1 mg dexamethasone improved vascular function in patients with NFA, even though the number of patients was small, and the sample size is statistically adequate to detect a 2.0% difference before and after administration of 1 mg dexamethasone. Further study is required to validate these findings in larger clinical trials. Second, in the present study, the overnight 1 mg dexamethasone suppression test was only performed for patients with NFA. It is unclear whether similar results apply to healthy subjects or patients without NFA. However, there were no significant differences in vascular function between control patients and patients with NFA. Therefore, similar results may apply to patients without NFA. Future studies are needed to confirm these findings in healthy subjects or patients without NFA. | PMC10684497 |
Conclusions | hypertension | HYPERTENSION | There were no significant differences in vascular function between control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM even after adjustment for cardiovascular risk factors. In patients with NFA, administration of overnight 1 mg dexamethasone is associated with increases in FMD and NID. Acute decreases in circulating levels of cortisol under the condition of normal adrenal function may cause acute improvements in FMD and NID. | PMC10684497 |
Methods | PMC10684497 | |||
Study protocol 1: vascular function in patients without adrenal incidentalomas and patients with NFA | cancer, Cushing’s syndrome, adrenal incidentalomas, Hypertension, hypertensive, nonfunctioning adrenal incidentalomas, hypertension | ADRENAL INCIDENTALOMA, CANCER, RENAL DISEASE, HYPERTENSION, HYPERTENSION, SECONDARY HYPERTENSION | This study was a single-center and prospective cohort study. Between August 2007 and August 2022, a total of 2657 subjects were recruited for vascular function measurements from individuals who attended the outpatient clinic at Hiroshima University Hospital. Of the 2657 subjects, 1105 subjects without computed tomography scans, 790 subjects with secondary hypertension, 399 subjects with cancer, four subjects with severe renal disease, 11 subjects with adrenal incidentalomas who did not receive detailed examinations, and 55 subjects without hypertension and/or DM were excluded. Finally, 22 patients with NFA who had hypertension and/or DM and 272 patients without adrenal incidentalomas who had hypertension and/or DM were enrolled in this study (Supplemental Figure S2).Subclinical Cushing’s syndrome was defined according to the report of the guidelines for diagnostic criteria of adrenal subclinical Cushing’s syndrome: the Japan Endocrine Society 2018. Briefly, the criteria for diagnosis of adrenal subclinical Cushing’s syndrome include the presence of an adrenal mass, lack of characteristic features of Cushing’s syndrome, and normal basal serum cortisol levels. In addition, plasma levels of cortisol after a 1 mg dexamethasone suppression test were used to identify nonfunctioning adrenal incidentalomas (< 1.8 μg/dL), intermediate phenotype adrenal incidentalomas (1.8–5.0 μg/dL), and subclinical Cushing’s syndrome (≥ 5 μg/dL). Hypertension was defined as systolic blood pressure of more than140 mm Hg and/or diastolic blood pressure of more than 90 mm Hg measured in a sitting position on at least three different occasions in the outpatient clinic of Hiroshima University Hospital. Secondary hypertensive patients were excluded from the study as previously reportedSubjects fasted overnight for at least 12 h before the study. The subjects were kept in the supine position in a quiet, dark, air-conditioned room (constant temperature of 22 °C–25 °C) throughout the study. FMD, and NID were measured after maintaining the supine position for thirty minutes. The observers were blinded to the purposes of the study and the clinical status of the subjects. All methods were carried out in accordance with the Declaration of Helsinki, and relevant guidelines and regulations. The Ethics Review Board of Hiroshima University approved the study protocol. All participants in the study provided written informed consent. | PMC10684497 |
Study protocol 2: impacts of overnight 1 mg dexamethasone on vascular function in patients with NFA | adrenal incidentalomas, Cushing’s syndrome | PRIMARY ALDOSTERONISM, ADRENAL INCIDENTALOMA | Between November 2020 and August 2022, a total of 28 consecutive patients with adrenal incidentalomas were recruited for vascular function measurements from patients who attended the outpatient clinic at Hiroshima University Hospital. Ten of the 28 patients with adrenal incidentalomas, including five patients with subclinical Cushing’s syndrome three patients with Cushing’s syndrome, and two patients with primary aldosteronism, were excluded. Finally, 18 patients with NFA were enrolled in this study. FMD and NID were measured in the morning before and after administration of 1 mg of dexamethasone at 2300 h as a dexamethasone suppression test for all patients. | PMC10684497 |
Measurements of FMD and NID | artery transducer | VASODILATION, REACTIVE HYPEREMIA | FMD was measured in vascular response to reactive hyperemia in the brachial artery as endothelium-dependent vasodilation. A high-resolution linear artery transducer was coupled to computer-assisted analysis software (UNEXEF18G, UNEX Co, Nagoya, Japan) that used an automated edge detection system for measurement of brachial artery diameter | PMC10684497 |
Statistical analysis | DM, adrenal incidentalomas, hypertension | ADRENAL INCIDENTALOMA, CORONARY HEART DISEASE, REGRESSION, HYPERTENSION, DYSLIPIDEMIA | Results are summarized as means ± SD for continuous variables and percentages for categorical variables. Statistical significance was a probability value of < 0.05. The comparison of continuous variables was conducted using ANOVA with Tukey’s post hoc test. The comparison of categorical variables between groups was conducted using a chi-square test. The associations between variables were assessed by using Spearman’s correlation coefficients. Changes in parameters after administration of 1 mg dexamethasone were evaluated using the paired t-test. To create a matched cohort of patients with NFA who had hypertension and/or DM and patients without adrenal incidentalomas with hypertension and/or DM in protocol 1, a propensity score was computed for each patient by using logistic regression analysis to determine the probability of baseline clinical variables including age, sex, body mass index, hypertension, dyslipidemia, DM, current smokers, and precious coronary heart disease. To create a matched cohort of patients with NFA and patients without adrenal incidentalomas in protocol 2, a propensity score was computed for each patient by using logistic regression analysis to determine the probability of baseline clinical variables including age, sex, body mass index, hypertension, dyslipidemia, DM, current smokers and precious coronary heart disease. One-to-one propensity-score matching analyses were used to create matched pairs to investigate the associations of NFA with vascular function. With these propensity scores, two well-matched groups based on clinical characteristics were created with a caliper size specification (0.25 × SD of propensity score) for comparison of vascular function. Propensity-score matching analyses were used to reduce the effects of selection bias. To detect a 2.0% difference before and after administration of 1 mg dexamethasone with α of 0.05 and power 0.90, the total sample size requirement would exceed 14. We performed multiple imputations for incomplete data, since multiple imputations of missing data have been recommended to avoid potential bias in full case analysis due to missing values. The data were processed using JMP pro version 15 (SAS Institute. Cary, NC). | PMC10684497 |
Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-48295-y. | PMC10684497 | ||
Acknowledgements | We thank Megumi Wakisaka, Ki-ichiro Kawano, and Satoko Michiyama for their excellent secretarial assistance. | PMC10684497 | ||
Author contributions | S.K. and Y.H. contributed to the study design. S.K., T.M., M.K., A.M., T.Y., T.H., Y.N, C.G., F.M.Y., and A.N. performed the data collection. S.K. performed statistical analyses after discussion with all authors. S.K., Y.H. contributed to the writing of the manuscript. Y.N. revised the article critically for important intellectual content. All authors contributed to inter-pretation of data and review of the manuscript, and approved this manuscript for submission. All authors have read and agreed to the published version of the manuscript. | PMC10684497 | ||
Funding | This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (18590815 and 21590898 to Higashi). | PMC10684497 | ||
Data availability | The data presented in this study are available on request from the corresponding author. | PMC10684497 | ||
Competing interests | The authors declare no competing interests. | PMC10684497 | ||
References | PMC10684497 | |||
Key Points | PMC10485729 | |||
Question | Does cognitive training for working memory in children born very preterm improve visuospatial processing? | PMC10485729 | ||
Findings | In this multicenter, open label randomized clinical trial of 169 children aged 5½ to 6 years who were born very preterm, a cognitive training program showed no long-term efficacy for visuospatial processing. | PMC10485729 | ||
Meaning | memory disorders | The study found that a cognitive training program had no benefit for improving visuospatial processing among children born very preterm who had working memory disorders. | PMC10485729 | |
Importance | term-born | Compared with term-born peers, children born very preterm generally perform poorly in executive functions, particularly in working memory and inhibition. By taking advantage of neuroplasticity, computerized cognitive training of working memory in those children could improve visuospatial processing by boosting visual inhibition via working memory. | PMC10485729 | |
Objective | cognitive working memory, memory impairment | To evaluate the long-term effect of cognitive working memory training on visuospatial processing in children aged 5½ to 6 years born very preterm who have working memory impairment. | PMC10485729 | |
Design, Setting, and Participants | This multicenter (18 French university hospitals), open-label randomized clinical trial with 2 parallel groups (EPIREMED) was conducted from November 2016 to April 2018, with the last follow-up during August 2019. Eligible children from the EPIPAGE 2 cohort were aged 5½ to 6 years, were born between 24 and 34 weeks’ gestation, and had a global intelligence quotient greater than 70 and a working memory index less than 85. Data were analyzed from February to December 2020. | PMC10485729 |
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