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Validation of PECSS | WELLS | Finally, results were validated using the independent held-out validation set. Distribution of each candidate predictor and Wells score indicator in the derivation set can be found in Table S Distribution of PECSS among patients with different PE severity grades in the derivation and validation set. Shaded areas indicate patients proportions where PE can be safely ruled out and no CTPA is needed: PECSS no higher than 4, or 4 < PECSS ≤ 6 and D-Dimer ≤ 2.5 mg/L | PMC10408070 | |
Discussion | thrombosis, right ventricular dysfunction, shock, reduced the failure, abnormal blood pressure, pain, VTE, pulmonary artery embolism, hypotension, embolism | THROMBOSIS, CARDIAC FAILURE, SHOCK, HEMODYNAMIC INSTABILITY, EMBOLISM, WELLS, PULMONARY ARTERY EMBOLISM, RIGHT VENTRICULAR DYSFUNCTION, ELEVATED BLOOD PRESSURE, PULMONARY EMBOLISM, PULMONARY HYPERTENSION | Due to the difficulties of PE diagnosis in early clinical stage and emergency medical setting [In this investigation, we developed and validated an objective and easy-to-use scoring system to safely rule out PE among patients presenting to the emergency department. The newly proposed Pulmonary Embolism Comprehensive Screening Score (PECSS) combined important clinical predictors with indicators in the Wells score and achieved excellent performances across all PE severity grades. Particularly, we found that patients with age > 65 years old, anhelation, less pain, abnormal blood pressure, in critical condition when admitted, higher levels of pro-BNP, CRP, UA, WBC, NEUT, MONO and ALT, and lower levels of HGB, ALB and creatinine were at increased risk for PE. Through a comprehensive grid searching algorithm, PECSS identified 7 clinical predictors (anhelation, abnormal blood pressure, pro-BNP > 1000 pg/mL, CRP > 30 mg/L, UA > 300 umol/L, in critical condition when admitted and age > 65 years), in addition to indicators in Wells score (VTE symptoms, no alternative diagnosis, HR > 100 beats/min, immobilication / surgery and previous PE/VTE), and assigned corresponding scores to each of the predictor. All of the clinical predictors were easy to obtain from medical records and rountine blood tests in emergency department setting.Identification of these candidate clinical predictors were supported by previous studies. Conditions such as pulmonary main embolism can lead to obstructive shock, which is a possible cause of hypotension. Elevated blood pressure can be explained by PE associated symptoms or stress [To facilitate clinical application and further improve the screening performance, we incorporated plasma level of D-Dimer, which is often elevated in the presence of acute thrombosis, with PECSS. Optimal D-Dimer cutoff values were investigated in patients with low (PECSS Screening performances of PECSS only, PECSS + D-Dimer, Wells only, Wells + D-Dimer were thoroughly compared in terms of failure rates across all PE severity grades, sensitivity, specificity, PPV and NPV. Compared to Wells only, PECSS only approach greatly reduced the failure rates in all PE severity grades (5.1% to 0, 16.5% to 2.2%, 16.0% to 0, and 9.6% to 0.5% in severe, moderate, mild and any PE, respectively). The huge improvement indicated that by including the additional seven clinical predictors chosen by variable selection and clinical meaningfulness, PECSS are able to identify patients with suspected PE risk more accurately and efficiently than Wells score. Although PECSS + D-Dimer and Wells + D-Dimer had similar performances in moderate and mild PE, PECSS + D-Dimer had three times lower failure rate in severe PE compared to Wells + D-Dimer (0.3% versus 0.9%). This is of particular clinical significance since servere PE consists of patients with pulmonary artery embolism or multiple pulmonary arteriole embolism and had the worst clinical prognosis [Admittedly, our study has several limitations. Firstly, this is a single center study and generalization of the results require validation from multi-center set. Secondly, patients who were suspected of PE but did not undergo CTPA due to hemodynamic instability were not included in out study due to the uncertainty of their PE status. This would potentially lead to bias in applying PECSS and PECSS + D-Dimer approaches in the targeted patient population. Thirdly, radiological severity instead of clinical severity (such as hypotension, pulmonary hypertension, cardiac failure, and the need for oxygen therapy) were used when defining PE severity grades. However, they do not usually correlate perfectly with each other. Further, right ventricular dysfunction was not considered in defining the PE severity grades since echocardiography was missing for a large proportion of the study population. Although CTPA has been applied in right ventricular dysfunction, its reliability and accuracy cannot be guaranteed as echocardiography [ | PMC10408070 |
Conclusions | WELLS | In conclusion, in this study we developed a new pretest probability (PECSS) that is more comprehensive and accurate than the well established Wells score for PE diagnosis, and incorporated plasma level of D-Dimer with PECSS as a clinical instrument to rule out PE among suspected patients presenting to the emergency department. Both PECSS and PECSS + D-Dimer approaches showed excellent performances in reducing PE cases that were ruled out, and the advantages over Wells score and Wells + D-Dimer approaches were more pronounced among patients with severe PE, which would usually lead to worst prognosis and highest mortality. With PECSS and D-Dimer, PE diagnosis could be operated more efficiently without overuse of CTPA. Finally, all clinical predictors in PECSS are easy to obtain from medical records and routine blood tests, making PECSS a practical tool in emergency medical setting. | PMC10408070 | |
Acknowledgements | The authors appreciate help from colleagues from Fudan University and Zhongshan Hospital with this project. | PMC10408070 | ||
Authors’ Contributions | Luojia Tang, Dong Pan and Chun Yang acquired the data. With the supervision of Xiaolei Lin, Yundi Hu performed the statistical analyses, produced the tables and figures. Luojia Tang and Yundi Hu wrote the first draft of the manuscript. Jianyong Gu and Min Min accessed and verified the underlying data.Cheng Tang and Yunchuan Huang consulted the literature. Xiaolei Lin and Chaoyang Tong were responsible for guidance and supervision.All authors contributed to revision of the manuscript, approved the final manuscript, and agreed to submit for publication. | PMC10408070 | ||
Funding | This work was supported by Science and Technology of Shanghai Committee (Grant No. 21MC1930400 and Grant No. 21ZR1405000). The funders had no role in study design, data collection, statistical analysis, results interpretation and writing of the manuscript. | PMC10408070 | ||
Availability of data and materials | Data and materials will be available from the corresponding authors upon reasonable request. | PMC10408070 | ||
Declarations | PMC10408070 | |||
Ethics approval and consent to participate | We've been waived the need for informed consent by Ethics Committee of Zhongshan Hospital, Fudan University. Because the subject cannot be found in the research using human body materials or data with identifiable information, and the research project does not involve personal privacy or commercial interests. The study was retrospectively registered (No. CJ0647) and approved by Human Genetic Resources in China in April 2022. Ethical approval was received from the Medical Ethics Committee of Zhongshan Hospital (NO.B2021-839R). All methods were performed in accordance with the relevant guidelines and regulations. | PMC10408070 | ||
Consent for publication | NA. | PMC10408070 | ||
Competing interests | All authors who have taken part in this study declare that they have no competing interest to disclose. | PMC10408070 | ||
References | PMC10408070 | |||
1. Introduction | cardiovascular disease | OXIDATIVE STRESS, DISEASES, CARDIOVASCULAR DISEASE | We compared the effects of two specific resistance training (RT) exercise orders on cardiovascular risk factors. Forty-four untrained older women (>60 years) were randomly assigned to three groups: control (COCardiovascular diseases are the main cause of worldwide mortality, affecting a large part of the older population, with high prevalence in women [However, RT-related changes magnitude may be affected by the manipulation of the variables that compose training programs, which are related to intensity (e.g., perceived effort, external load, the velocity of muscle action, and rest intervals), volume (e.g., number of exercises, sets, repetitions, and frequency) and structure (e.g., exercise selection and exercise order). Considering that the exercise order may affect the intensity and volume of a training session, this variable may play a crucial role in the RT-induced adaptative responses [Nevertheless, current recommendations were mainly based on data from acute investigations [Recent studies revealed that the exercise order might also affect the volume load (repetitions × load) [Therefore, this study aimed to compare the effects of two specific exercise orders (MJ-to-SJ versus SJ-to-MJ) on cardiovascular disease risk factors. We hypothesized that the training protocol with the MJ-SJ exercise order would induce greater improvements in body fat, glucose, lipid profile, inflammatory, and oxidative stress biomarkers because of the potential higher volume load training achieved with this exercise order. | PMC9859374 |
2. Materials and Methods | PMC9859374 | |||
2.1. Experimental Design | SECONDARY | This work is part of the “Active Aging Longitudinal Study”, a research project initiated in 2012 to investigate the effects of supervised, structured, and progressive RT programs on neuromuscular, morphological, physiological, metabolic, cognitive, and behavioral outcomes in older women. The sample in the present study consisted of the 2015 annual cohort of participants from this research project. A randomized controlled trial was carried out over 16 weeks, with 12 weeks dedicated to the RT program and four weeks to assessments. Anthropometric, muscular strength, body fat measurements, and venous blood collections for biochemical analysis were performed in weeks 1–2 and 15–16 pre- and post-intervention. The training groups performed a supervised progressive RT program between weeks 3–14. The control group did not perform any exercise during this period. This investigation is a secondary analysis of the previous work published [ | PMC9859374 | |
2.2. Participants | RECRUITMENT, DYSFUNCTION | Participant recruitment was carried out through newspaper and radio advertising. A preliminary sample was selected through an interview and clinical anamnesis. All participants completed health history and physical activity questionnaires and met the following inclusion criteria: female, >60 years, physically independent, free from cardiac or orthopedic dysfunction, not receiving hormonal replacement therapy, and not performing any regular physical exercise more than once a week over the six months preceding the onset of the current experiment. A diagnostic graded exercise test with a 12-lead electrocardiogram was conducted on the sample selected for this study. The exams were reviewed by a cardiologist, and they were released without restrictions to participate in this study. Participants of training groups who did not reach adherence ≥ 85% of training sessions were excluded from the analysis.A priori sample analysis revealed that to achieve an effect size = 0.5 for muscular strength with a power of 0.8 and an alpha error = 5%, a total of 42 participants would be necessary (14 for each group). Considering a drop-out rate of approximately 25%, we recruited 54 older women who were randomly assigned to one of three conditions: a control group that did not perform any exercise (CO | PMC9859374 | |
2.3. Fat Mass and Trunk Fat | NRL 41990 | Dual-energy X-ray absorptiometry exams (DXA) were conducted in a Lunar Prodigy device, model NRL 41990 (GE Lunar, Madison, WI, USA), to determine the fat mass and trunk fat. Information on lean soft tissue was previously reported in another study [ | PMC9859374 | |
2.4. Metabolic Biomarkers | high-density lipoprotein, TG, TNF-α | STASIS | Venous blood samples were collected into one tube between 7:00 am and 9:00 am after a 12 h fast and at least 48 h since the last RT session. Five milliliters were withdrawn from a prominent superficial vein in the antecubital space using a clean venous puncture with minimal stasis and placed in a tube containing a dipotassiumethylenediaminetetra-acetic acid (EDTA) as an anticoagulant and preservative. All samples were centrifuged at 3000 rpm for 15 min, and plasma or serum aliquots were stored at −80 °C until assayed. Inter- and intra-assays coefficients of variation were <10% as determined in human plasma. Glucose, total cholesterol (TC), high-density lipoprotein (HDL-c), triglycerides (TG), and high-sensitivity C-reactive protein concentrations were determined by standard methods in a specialized laboratory at University Hospital. The LDL-c was calculated using the following equation: LDL-c = TC − (HDL-c) − (TG/5), with TG/5 = VLDL-c. The analyses were performed using a biochemical auto-analyzer system Dimension RxL Max (Siemens Healthcare Diagnostics, Malvern, PA, USA) according to established methods in the literature consistent with the manufacturer’s protocol. Interleukin-10 (IL-10), Interleukin-6 (IL-6), and TNF-α were determined by enzyme-linked immunosorbent assay (ELISA), according to the specifications of the manufacturer (R&D Systems, Minneapolis, MN, USA). Advanced oxidation protein products (AOPP) were determined in the plasma using a semiautomatic method described by Witko-Sarsat et al. [ | PMC9859374 |
2.5. Dietary Intake | Food intake was assessed by the 24 h dietary recall method applied on two non-consecutive days of the week, with a photographic record taken during an interview. Dietary intake was monitored in the first two and the last two weeks of the intervention period. The homemade measurements of the nutritional values of food were converted into grams and milliliters by the online software Virtual Nutri Plus (Keeple | PMC9859374 | ||
2.6. Muscular Strength | Maximal dynamic strength was evaluated through the one-repetition maximum (1RM) test on the chest press, leg extension, and preacher curl exercises. The participants completed three attempts in each exercise for three testing sessions [ | PMC9859374 | ||
2.7. Resistance Training Program | muscle failure | Participants from both training groups (MJ-SJ and SJ-MJ) performed the same 12-week RT program with eight exercises. All participants were personally supervised by physical education professionals with substantial RT experience to help ensure consistent and safe exercise performance, carried out differing only in the exercise order. The RT sessions were performed three times per week on Mondays, Wednesdays, and Fridays during the morning hours. Participants of the MJ-SJ group performed exercises in the following order: chest press, seated row, triceps pushdown, preacher curl, horizontal leg press, leg extension, leg curl, and seated calf raise. On the other hand, participants of the SJ-MJ group performed exercises in the following order: preacher curl, triceps pushdown, seated row, chest press, seated calf raise, leg curl, leg extension, and horizontal leg press. The RT sessions consisted of 3 sets of 10–15 repetitions per exercise; if the participant reached momentary muscle failure—i.e., attempted to perform another repetition with proper technique but was unsuccessful—before the upper limit of repetitions, the load was kept the same for the next session. On the other hand, when 15 repetitions were completed in the three sets for a determined exercise, the load was adjusted by 2–10% [ | PMC9859374 | |
2.8. Statistical Analyses | One-way analysis of variance (ANOVA) was used to compare general characteristics and weekly VL. A Chi-square test was used to compare clinical characteristics. Generalized Estimating Equations (GEE) were applied for pre- to post-intervention and inter-group comparisons. When the Wald χ2 was significant, a Fisher post hoc test was employed to identify the mean differences. The ES was calculated as the post-training mean minus pre-training mean divided by the pooled standard deviation [ | PMC9859374 | ||
3. Results | Forty-four participants finalized the experimental protocol (MJ-SJ = 15, SJ-MJ = 14, and CO | PMC9859374 | ||
3.1. Volume Load | The volume load for each week and according to the group are presented in | PMC9859374 | ||
4. Discussion | muscle mass, cardiovascular disease | OXIDATIVE STRESS, CARDIOVASCULAR DISEASE, CARDIOVASCULAR DISEASES | The main findings of this study were that RT was effective for decreasing fat mass and trunk fat, as well as for improving glucose concentrations and inflammatory (IL-10, TNF-α, C-reactive protein) and oxidative stress biomarkers (AOPP and FOX), regardless of the exercise order. Our hypothesis that the MJ-SJ group would present superior responses was refuted. According to our knowledge, this is the first study comparing the effects of different exercise orders on cardiovascular disease risk factors in untrained older women. Because of this unique approach, comparisons with other studies are limited. It is worth highlighting that we found similar gains in muscular strength and muscle mass for MJ-SJ and SJ-MJ exercise orders in this same sample [Given that the MJ-SJ order could favor the accumulation of a higher volume load, we hypothesized that this order could be more efficient in improving risk factors for cardiovascular diseases. The volume load is a determining variable for the RT adaptations [For IL-6, although the effect of RT was not significant for both training groups, effect size values indicated that the decrease was of moderate magnitude. In contrast, the control group had an increase in the IL-6 concentration. As it is a pro- and anti-inflammatory cytokine, the IL-6 responses, by itself, do not allow us to state that the increase or decrease was due to corresponding to a less inflamed environment [We also observed a reduction in blood glucose and LDL-c in MJ-SJ and SJ-MJ contrasted to the control group. The lack of investigations that directly compare the effect of the exercise order on blood markers restricts us from comparing with previous findings; notwithstanding, our results are in accordance with previous studies that found favorable effects of RT on these outcomes in older women [Regarding oxidative stress, we did not observe any difference between the two exercise orders; both intervention groups improved oxidative stress biomarkers (i.e., AOPP and FOX). Few studies have investigated the RT effect—and consequently the exercise order—on oxidative stress biomarkers. From the available findings, it is possible to notice some divergences in the impact of RT on these biomarkers. For example, Ribeiro et al. [It is essential to feature the strengths of the present study. Professionals with RT experience supervised all training sessions to ensure participant safety and the proper exercise technique. The importance of supervised RT in older adults has been reported in some studies [ | PMC9859374 |
5. Conclusions | Our results suggest that 12 weeks of RT in both MJ-SJ and SJ-MJ exercise orders seem effective for improving body fat and blood biomarkers in untrained older women. Therefore, professionals and researchers can choose exercise order of preference between MJ-SJ and SJ-MJ when prescribing RT exercises focused on inducing adaptations in body fat and blood biomarkers in physically independent older women. | PMC9859374 | ||
Author Contributions | Conceptualization, C.M.T. and E.S.C.; methodology, C.M.T. and E.S.C.; formal analysis, C.M.T. and P.M.C.; investigation, C.M.T., P.M.C., M.M.D., D.S., W.K. and B.C.; resources, E.S.C.; data curation, C.M.T. and E.S.C.; writing—original draft preparation, C.M.T.; writing—review and editing, C.M.T., P.M.C., M.M.D., D.S., W.K., B.C., D.C.T., R.D., R.J.R., D.V., D.S.B., C.R.C., L.B.S. and E.S.C.; project administration, C.M.T., P.M.C. and E.S.C. All authors have read and agreed to the published version of the manuscript. | PMC9859374 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of the State University of Londrina. | PMC9859374 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9859374 | ||
Data Availability Statement | The raw data supporting the conclusions of this article will be made available by the corresponding author, without undue reservation. | PMC9859374 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC9859374 | ||
References | Weekly volume load according to training groups (MJ-SJ = 15 and SJ-MJ = 14). * Dietary intake, total strength, body fat, and blood biomarkers after the 12-week period of intervention.Note: MJ-SJ = group that performed RT in a multi-joint to single-joint order, SJ-MJ = group that performed RT in a single-joint to multi-joint order, COEffect size values of the pre- to post-intervention changes for analyzed variables.Note: MJ-SJ = group that performed RT in a multi-joint to single-joint order, SJ-MJ = group that performed RT in a single-joint to multi-joint order, CO | PMC9859374 | ||
Key Points | PMC10618840 | |||
Question | anxiety | Compared with standard care, can a virtual reality–based intervention with preoperative education improve preoperative anxiety in adult patients undergoing elective surgery? | PMC10618840 | |
Findings | anxiety | This randomized clinical trial of 74 adult patients undergoing elective surgery found that a virtual reality–based intervention was effective in reducing preoperative anxiety. | PMC10618840 | |
Meaning | anxiety | The findings of this study suggest that virtual reality–based interventions can improve preoperative anxiety in adult patients undergoing elective surgery, but more randomized clinical trials with larger samples are needed to further confirm its effects.This randomized clinical trial examines the effectiveness of a virtual reality (VR)–based intervention with preoperative education in reducing preoperative anxiety in adult patients undergoing elective surgery. | PMC10618840 | |
IMPORTANCE | anxiety | Preoperative anxiety is common among adult patients undergoing elective surgery and is associated with negative outcomes. Virtual reality (VR)–based interventions have been considered simpler, safer, and more effective for reducing anxiety in patients undergoing surgery than conventional care. | PMC10618840 | |
OBJECTIVE | anxiety | To examine the effectiveness of a VR-based intervention with preoperative education in reducing preoperative anxiety among adult patients undergoing elective surgery. | PMC10618840 | |
DESIGN, SETTING, AND PARTICIPANTS | An assessor-blinded prospective randomized clinical trial was conducted to recruit adult patients aged 18 years or older who were scheduled for their first elective surgery procedure under general anesthesia within the next 2 to 4 weeks at a preanesthesia assessment clinic in Hong Kong from July to December 2022. | PMC10618840 | ||
INTERVENTIONS | Participants were randomly assigned to either an intervention group (an 8-minute immersive 360° VR video tour in the operating theater via a head-mounted display console) or a control group (standard care). | PMC10618840 | ||
MAIN OUTCOMES AND MEASURES | Pain, Anxiety, anxiety, pain | SECONDARY | The primary outcome of preoperative anxiety was measured using the Amsterdam Preoperative Anxiety and Information Scale (range, 6-30; higher scores indicate greater anxiety), and the secondary outcomes (ie, stress, preparedness, and pain) were assessed by Visual Analog Scale at 3 time points: baseline at beginning of clinical session (T0), at the end of the clinical session immediately after the intervention (T1), and before the surgery (T2). Pain, satisfaction levels, and postoperative length of stay were evaluated after the surgery (T3). Simulation sickness was assessed after the intervention by use of the Simulation Sickness Questionnaire. A generalized estimating equations model was applied to compare changes in outcomes over time. | PMC10618840 |
RESULTS | anxiety | A total of 74 participants (mean [SD] age, 46.34 [14.52] years; 38 men [51.4%] and 36 women [48.6%]) were recruited and randomized to the control group (37 participants) and intervention group (37 participants). Compared with the control group, the VR-based intervention group showed significantly decreased preoperative anxiety at T1 (β, −5.46; 95% CI, −7.60 to −3.32; | PMC10618840 | |
CONCLUSIONS AND RELEVANCE | anxiety | The findings of this study suggest that a VR-based intervention is a feasible and effective way to reduce preoperative anxiety in adult patients undergoing elective surgery. Given the promising results of this study, further study in the form of large-scale, multicenter, randomized clinical trials with broader implementation is warranted. | PMC10618840 | |
TRIAL REGISTRATION | Chinese Clinical Trial Registry Identifier: | PMC10618840 | ||
Introduction | anxiety | Surgical procedures are often associated with anxiety and stress.Traditionally, pharmacological interventions have been used to manage preoperative anxiety,VR allows humans to visualize, manipulate, and interact with a computer-generated, simulated 3-dimensional image or environment through human-computer interaction.The application of VR for managing preoperative anxiety has shown more promising effects than traditional means. Four previous randomized clinical trials (RCTs) | PMC10618840 | |
Methods | This was a prospective, single-blind RCT conducted from July to December 2022. However, owing to the COVID-19 pandemic, the study was suspended after December 2022. The protocol is provided in | PMC10618840 | ||
Participants and Setting | substance abuse, vestibular dysfunction | DISORDER, PARKINSON DISEASE, MULTIPLE SCLEROSIS, MOTION SICKNESS, MUSCULAR DYSTROPHY | The study was conducted at the preanesthesia assessment clinic of a public general district hospital in Hong Kong. Patients attending the preanesthesia assessment clinic were invited to participate in the study if they met the inclusion criteria, which included (1) being at least 18 years old, (2) scheduled for their first elective surgery procedure under general anesthesia within the next 2 to 4 weeks, (4) spoke Cantonese, and (5) were grade I or II of American Society of Anesthesiologists (ASA) Physical Status Classification System. Patients were excluded if they (1) were undergoing an emergency procedure without prior preoperative assessment, (2) were cognitively impaired or unable to consent, (3) had a history of any psychological disorder, and (4) had a history of vestibular dysfunction or motion sickness, had alcohol or substance abuse, or had Parkinson disease, multiple sclerosis, or muscular dystrophy. | PMC10618840 |
Sample Size | According to a meta-analysis | PMC10618840 | ||
Recruitment Procedure | Consecutive sampling was used to recruit participants who attended the preanesthetic assessment clinic for scheduled elective surgery under general anesthesia. Participants were identified through a medical record review and were approached for eligibility by an independent research assistant. The list of interested participants was recorded and sent to the researcher for further contact. The researcher explained the study details to potential participants. After obtaining written consent from the patient, an independent outcomes assessor blinded to the group allocation collected baseline data (T0). | PMC10618840 | ||
Randomization and Blinding | RECRUITMENT | The randomization procedure was performed by a research assistant who was not involved in the recruitment, enrollment, and treatment process. Participants were randomly assigned at a 1:1 ratio to either the VR-based intervention group or the control group using block randomization (block size, 4). The research assistant who performed randomization prepared opaque, sealed envelopes numbered sequentially to conceal the allocation sequences and delivered them to participants to inform allocation results.Because of the nature of the intervention, only the outcome assessor was blinded to the group allocation. The participants and interventionists could not be blinded. Nevertheless, the participants were instructed not to reveal their group allocation to the outcome assessor at the time of outcome assessment and were asked not to share details about the intervention with others. | PMC10618840 | |
Control Group | Participants in the control group received standard care in the preanesthetic assessment clinic. Routine preoperative information was provided to participants in the control group by the perioperative nurses in the clinic. | PMC10618840 | ||
Intervention Group | infection, HMD | INFECTION | In addition to standard care, participants in the intervention group received a VR-based intervention. The VR-based intervention consisted of a VR video created with a high-quality 360° camera at a resolution of 5760 × 2880 pixels a 30 frames-per-second format with 360° directional sound. The VR video included a virtual tour simulating the entire journey of the perioperative process, from entering the operating theater to being transferred to the recovery area, including introduction, reception, induction, operating theater, postanesthesia care unit, and ending (eFigure 1 in The participants in the intervention group were provided with a VR console (Oculus Quest 2; Meta) in a separate room within the clinic during their visit to watch the VR video. Supporting staff assisted the participants in using the device whenever necessary. The console is an all-in-one, high-quality, standalone HMD VR console that operates without the need for computer or device attachment. It has a screen resolution of 1832 × 1920 pixels, a refresh rate of 90 Hz, integrated speakers and microphone, 2 to 3 hours of battery life, and adjustable interpupillary distance with 3 settings for 58 mm, 63 mm, and 68 mm. An additional accessory, the Elite Strap, was applied to the console to enhance its wearability, head support, and comfort. After consulting with the hospital’s senior nursing officer of infection control unit, infection control measures were taken by applying disposable eye mask covers and using alcohol wipes for disinfection after use. Screen captures of the VR video are shown in eFigure 1 in | PMC10618840 |
Intervention Fidelity | HMD | Five nursing staff members at the preanesthetics assessment clinic received 30 minutes of training on how to operate the HMD console. The training included instructions on setting up the devices, adjusting the interpupillary distance on the HMD consoles, troubleshooting potential issues, and separating participants into control and intervention groups. A standardized procedure for implementing the VR-based intervention was developed to ensure the nurses’ adherence to the study protocol. | PMC10618840 | |
Outcome Measures | PMC10618840 | |||
Primary Outcome: Preoperative Anxiety | Anxiety, anxiety | Preoperative anxiety was measured using the Amsterdam Preoperative Anxiety and Information Scale (APAIS). | PMC10618840 | |
Secondary Outcomes | pain | SECONDARY | The secondary outcomes included pain at rest (measured using the Visual Analog Scale [VAS] to assess the subjective pain | PMC10618840 |
Data Collection | ADVERSE EVENTS | The participants’ sociodemographic (age, sex, marital status, living arrangement [living alone or not], and educational level) and clinical (current medication regimen and medical history) data were collected by the blinded outcome assessor at the beginning of the preanesthetic assessment clinic session (T0, baseline), close to the end of the clinical session immediately after the intervention (T1, postintervention), before transference to the operation theater (at ward) or after admission to the operation theater (at the reception area) (T2), and between 24 and 48 hours after the surgery (T3). If any psychosomatic discomfort reaction was observed in participants, the intervention would be terminated, and corresponding support would be provided to help them relax. Any adverse events were reported to the institutional review board of the Chinese University of Hong Kong. | PMC10618840 | |
Statistical Analysis | SPSS statistical software version 29.0 (IBM) was used for data analysis. The demographic characteristics and baseline outcome measures were summarized by frequency, percentage, mean (SD), and range. Normal Q-Q plots of skewness and kurtosis of data were used to assess continuous variables’ normality. Normality was further evaluated by using the Shapiro-Wilk test to determine the skewness and kurtosis of the data sets. The χ | PMC10618840 | ||
Results | PMC10618840 | |||
Characteristics of Participants | ADVERSE EVENTS | A total of 157 participants were assessed for eligibility. Of these, 74 participants (47.1%) agreed to participate and provided written consent (mean [SD] age, 46.34 [14.52] years; 38 men [51.4%] and 36 women [48.6%]); 37 participants each were randomized to the intervention and control groups. All participants in both the intervention and control groups completed the interventions and follow-up assessments at the end of the clinic session, except for 1 participant in the control group who was discharged before data collection. No major adverse events were reported. Therefore, the overall attrition rate at T1 and T2 was 0%, and the attrition rate was 0% in the intervention group and 2.7% in the control group. The | PMC10618840 | |
Participant Enrollment Flowchart | T1 refers to the end of the clinical session immediately after the intervention, T2 refers to the time before transference to the operation theater or after admission to the operation theater and before the surgery, and T3 refers to 24 to 48 hours after the surgery. | PMC10618840 | ||
Sociodemographic Characteristics of the Participants | PMC10618840 | |||
Comparison of Outcomes Scores Between Study Groups at 3 Time Points | Abbreviation: NA, not applicable.T1 is after the intervention. T2 is the time before transference to the operation theater (at ward) or after admission to operation theater (at the reception area). T3 is between 24 and 48 hours after the surgery.Data between groups were compared with independent Data between groups were compared with Mann-Whitney | PMC10618840 | ||
Changes in the Outcomes Between Study Groups Across Time Using Generalized Estimating Equation Model (N = 74) | pain | Group refers to the group differences at baseline between the intervention and control groups. Group*T1 refers to additional score changes of the variables in the intervention group compared with those in the control group at T1. Group*T2 refers to additional score changes of the variables in the intervention group compared with those in the control group at T2. T1 is close to the end of the clinical session (postintervention), and T2 is before transference to the operation theater (at ward) or after admission to operation theater (at the reception area).β refers to the group-by-time interaction terms and represents the difference in mean changes in an outcome at a specific time point with respect to the baseline (T0) between the intervention and control groups (mean change in intervention group minus mean change in control group).Changes in pain scores were also examined at T3 (after operation) between groups (T3, 62.86; 95% CI, 57.36 to 68.37; | PMC10618840 | |
Effects of VR-Based Intervention on Secondary Outcomes | Participants in the VR-based intervention group reported significant decreases in stress levels compared with the control group at T1 (β, −10.68; 95% CI, −16.00 to −5.36; | PMC10618840 | ||
Discussion | anxiety, pain | This RCT is one of the few to investigate the effects of a VR-based intervention in reducing preoperative anxiety among adult patients undergoing elective surgery in a preanesthetic assessment clinic setting. The results provide promising evidence that the VR-based intervention can effectively improve preoperative anxiety, stress, preparedness, and pain in adult patients undergoing elective surgery.A significant reduction in preoperative anxiety was observed by adopting the VR-based intervention in a preanesthetic assessment clinic. These results align with those of prior related studies.Another possible reason for the significant reduction in preoperative anxiety among participants in the VR-based group could be the information guidance they received about their anesthesia and surgical procedures. Previous studies have shown that providing preoperative information to patients, including the journey to the operating theater for surgery, effectively decreases preoperative anxiety.The results of this study revealed that participants in the VR-based intervention group experienced significantly less stress and better preparedness compared with the control group. These findings are consistent with those of similar studies.The participants’ satisfaction level toward the preoperative services was significantly higher in the intervention group than in the control group. Previous studies have also found positive results when applying VR interventions before and during surgeryThis study found no significant effects of the VR-based intervention on pain levels. These results differ from those of a previous meta-analysis.Similar to previous studies, | PMC10618840 | |
Strengths and Limitations | anxiety | RECRUITMENT | There are several strengths of this study. First, it adopted an RCT design, which is considered the criterion standard for evaluating the cause-and-effect relationships between interventions and outcomes. Second, to our knowledge, it was the first study to investigate VR-based interventions in a preanesthetic assessment clinic setting, providing valuable insights into its potential as a nonpharmacological approach to reducing preoperative anxiety and improving outcomes in adult patients undergoing elective surgery.There are also some limitations to be considered. First, because the 0.64 effect estimator corresponded to the standardized mean difference for different scales to measure preoperative anxiety in the previous meta-analysis and although it was adopted for sample size calculation, this could not precisely imply that a score reduction of at least 0.64 on the APAIS indicates a relevant reduction in anxiety. Furthermore, the study was conducted during the COVID-19 pandemic, and up to 50% of elective surgical procedures had been canceled or deferred. Therefore, only 74 participants were recruited, and the power of the intervention may be limited. Second, this study was conducted in a single preanesthetic assessment clinic, and the standard of care and provision of service may vary among different clinics. Also, the recruitment of mostly young participants with ASA grade I status for relatively low-risk, short duration, or less-pain-induced surgical procedures may limit the generalizability of the findings to patients aged more than 80 and 90 years or patients with higher ASA risk. Patients in different assessment clinics for different types of surgical procedures should be investigated in future studies. Third, owing to the nature of the intervention, the allocation of intervention was unable to be concealed from the participants, and those in the intervention group may have been more susceptible to performance bias by subjectively providing more positive self-reports that aligned with the perceived goals of their assigned intervention during the outcome measurement. | PMC10618840 |
Conclusions | anxiety | In conclusion, the findings of this trial indicate that VR-based interventions can be effective in reducing preoperative anxiety and stress levels, as well as promoting preparedness and service satisfaction in adult patients undergoing elective surgery. However, more RCTs with larger samples are needed to further confirm their effects and improve external validity. Findings from this study support research to explore the role of VR technology in other nursing care and health service settings to help manage preoperative anxiety. | PMC10618840 | |
Purpose | endometriosis | ENDOMETRIOSIS, OXIDATIVE STRESS, EARLY PREGNANCY | Edited by: Achmad Kemal Harzif, University of Indonesia, IndonesiaReviewed by: Seido Takae, St. Marianna University School of Medicine, Japan; Xiufeng Ling, Nanjing Medical University, China†ORCID: Fardin Amidi, This article was submitted to Reproduction, a section of the journal Frontiers in EndocrinologyIn a randomized, triple-blind, placebo-controlled clinical trial (RCT) including 50 infertile women with endometriosis candidate for assisted reproductive techniques (ART), we studied the effect of Astaxanthin (AST) on pro-inflammatory cytokines, oxidative stress (OS) markers, and early pregnancy outcomes. | PMC10067663 |
Methods | endometriosis, TNF-α | ENDOMETRIOSIS | Before and after 12 weeks of AST treatment (6 mg per day), blood serum and follicular fluid (FF) samples were collected from 50 infertile women with endometriosis stage III/IV undergoing ART. Pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and OS markers (malondialdehyde [MDA], superoxide dismutase [SOD], catalase [CAT], and total antioxidant capacity [TAC]) were measured in the serum and FF. ART outcomes were also compared between the groups. | PMC10067663 |
Results | ± | Increased serum levels of TAC (398.661 ± 57.686 | PMC10067663 | |
Conclusion | inflammation, endometriosis, OS | INFLAMMATION, ENDOMETRIOSIS | AST pretreatment can modulate inflammation and OS in endometriosis-induced infertile patients. ART outcomes also improved after 12 weeks of AST therapy. Our results suggest that AST can be a potential therapeutic target for infertile patients with endometriosis undergoing ART. | PMC10067663 |
Introduction | Janus kinase-2/signal transducer, endometriosis, pelvic pain, infertility | ENDOMETRIOSIS, ENDOMETRIOSIS, DEGENERATION, CAVITY, INFLAMMATORY DISEASE, INFLAMMATORY RESPONSE | Endometriosis, the presence of endometrial-like tissue (glands and stroma) outside the uterine cavity, is a chronic estrogen-dependent inflammatory disease affecting approximately 10-15% of reproductive-age women and 35–50% of women with pelvic pain and/or infertility worldwide (A complex network of molecular, cellular, and hormonal factors could help unravel the underlying pathogenic mechanism for declined reproductive outcomes of endometriosis patients (The assisted reproductive technique (ART) is the main treatment option for endometriosis-induced infertility (Astaxanthin (dihydroxy-4,4′-dione- β,β′-carotene: AST), called the king of antioxidants, is a red-orange, lipid-soluble xanthophyll photo-pigmented ketocarotenoid isolated from the alga AST targets several molecules and pathways, including phosphoinositide 3-kinases (PI3K)/Akt and Janus kinase-2/signal transducer and activator of transcription-3 (JAK2/STAT3) signaling pathways, NF-κB family, mitogen-activated protein kinases (MAPKs), nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1), and peroxisome proliferator-activated receptor gamma (PPARγ) to efficiently modulate the dynamic oxidant: antioxidant equilibrium (Furthermore, AST suppresses the expression of scavenger receptors, controlled by NF−κB, the main mediator of the inflammatory response through inhibiting IκB-α degeneration and the NF-κB nuclear translocation (Fertility-enhancing properties of AST have been established in various | PMC10067663 |
Materials and methods | PMC10067663 | |||
Patient enrollment and study design | endometriosis, Endometriosis | ENDOMETRIOSIS, ENDOMETRIOSIS | This was a prospective, parallel, randomized, triple-blind, placebo-controlled clinical trial (RCT) with a 1:1 ratio. We enrolled 50 infertile endometriosis patients presenting for ART at Omid Fertility Clinic, Tehran, Iran, between December 2021 and September 2022. Endometriosis patients classified as moderate (stage III) or severe (stage IV) according to the American Society of Reproductive Medicine criteria, 1997 ( | PMC10067663 |
Treatment randomization and blinding | Eligible patients were randomly assigned to the AST or placebo groups (1:1) using the balanced block randomization method within a block size of 4 by an independent statistician. This trial was a triple-blind study. All patients, researchers, statisticians, embryologists, and laboratory personnel were blinded to the individual treatment allocation. The Consolidated Standards of Reporting Trials (CONSORT) diagram (Patient enrolment and CONSORT diagram. | PMC10067663 | ||
Trial procedures | endometriosis | ENDOMETRIOSIS | All infertile endometriosis patients candidate for ICSI protocol who visited Omid Fertility Clinic and met the inclusion criteria were recruited. Before and alongside the routine gonadotropin-releasing hormone (GnRH) antagonist ovarian stimulation protocol, 6 mg daily of oral AST or placebo capsules (AstaReal | PMC10067663 |
Blood and FF collection and biochemical measurements | ENDOMETRIOSIS | Sample collections were carried out following the guidelines suggested by the World Endometriosis Research Foundation (OS markers and cytokines were measured in duplicate, in a blinded manner, in pairs (pre/post-intervention) simultaneously, and in the same analytical run to reduce systematic error and inter-assay variations. Measurements of serum and FF levels of OS markers were performed using the human enzyme-linked immunosorbent assay (ELISA) kits (Zellbio, GmbH, Germany), according to the manufacturer’s instructions. The kit sensitivity was 0.5 U/mL for CAT, 1 U/mL for SOD, 0.1 µM for MDA, and 0.1 mM for TAC detection. A microplate reader (BioTek, Winooski, USA) was used to measure absorbance at wavelengths specific to each marker. Pro-inflammatory cytokine concentrations were determined in serum and FF by high sensitivity human ELISA system using commercially available human kits (Karmania Pars Gene company; KPG, Iran), following the manufacturer’s instruction. The kit sensitivity was 2 pg/mL, and the absorbance was measured at 420 nm | PMC10067663 | |
COS protocol | endometriosis | ENDOMETRIOSIS | The GnRH antagonistic protocol combined with the whole embryo freezing strategy is more efficient for ovulation induction in the Iranian endometriosis population. Thus, patients were submitted to a flexible antagonist protocol. Recombinant follicle-stimulating hormone (rFSH) (150–300 IU/day, Gonal-F | PMC10067663 |
ART outcomes | Two hours following OPU, hyaluronidase enzyme (SigmaReproductive outcomes, including the number of oocytes retrieved, the number of MII oocytes, oocyte maturity rate (the number of normal MII oocytes per the total number of normal oocytes retrieved, expressed as a percentage ( | PMC10067663 | ||
Sample size and statistical analysis | The serum level of TAC was the primary outcome. According to Choi et al.’s study ( | PMC10067663 | ||
Ethical approval | The trial was approved by the Deputy of the Research and Ethics Committee of TUMS (approval date: 2021, December 19; code: IR.TUMS.MEDICINE.REC.1400.1085) and conducted following the Declaration of Helsinki, the International Council for Harmonisation Guidelines for Good Clinical Practice and applicable regulatory requirements. The study protocol was also registered in the Iranian Registry of Clinical Trials (registration code: IRCT20220625055274N1). Here we present a part of the RCT registered in the IRCT. All participants signed written informed consent to use the capsules and provide serum and discarded follicular fluid (FF) samples collected during OPU for research purposes. Before obtaining informed consent, the researchers explained the antioxidant properties, effects, and consumption instructions. | PMC10067663 | ||
Results | PMC10067663 | |||
Baseline characteristics | MAY | As depicted in the CONSORT flowchart, a total of 57 patients were randomized and exposed, of whom 50 (25 in each group) were enrolled and treated from December 2021 to May 2022 (Demographic characteristics, clinical data, and endocrine profile of the participants.AST, Astaxanthin group; BMI, Body Mass Index [weight (kg)/height (m2)]; AMH, Anti-müllerian Hormone; FSH, Follicle-stimulating Hormone; LH, Luteinizing Hormone; E2, Estradiol; P, Progesterone. Data are presented as mean ± SD. A P-value less than 0.05 is considered significant. | PMC10067663 | |
Serum and FF antioxidants and OS profile | tumor necrosis | TUMOR NECROSIS | Pre- and post-intervention concentrations of OS markers and cytokine levels results are shown in OS markers and cytokine levels in two groups.AST, Astaxanthin group; MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; TAC, total antioxidant capacity; IL-1β, interleukin 1β; IL-6, interleukin 6; TNF-α, tumor necrosis factor-α. Data are presented as mean ± SD. A P-value less than 0.05 is considered significant (*P < 0.05, ***P < 0.001, and ****P < 0.0001). | PMC10067663 |
Serum and FF cytokine parameters | TNF-α | Among cytokine parameters, significantly lower serum levels of IL-1β (4.515 ± 0.907 vs. 6.8760 ± 0.8478; P = 0.000) and TNF-α (2.520 ± 0.525 vs. 2.968 ± 0.548; P = 0.038) were observed after AST treatment ( | PMC10067663 | |
Comparison of ovarian stimulation parameters and ART outcomes | ± | Comparing ovarian stimulation parameters and ART outcomes, the number of oocytes retrieved (14.60 ± 7.79 vs. 9.84 ± 6.44; P = 0.043), the number of MII oocytes (10.48 ± 6.665 vs. 6.72 ± 4.3; P = 0.041), and high-quality embryos (4.52 ± 2.41 vs. 2.72 ± 2.40; P = 0.024) improved significantly after AST therapy. The number of transferred embryos was similar in the two groups (2.24 ± 0.43 vs. 2.04 ± 0.73; P = 0.203). The fertilization rate (P = 0.382) and multiple pregnancy rate (P = 0.741) were also similar (ART outcomes between AST and placebo groups.AST, Astaxanthin group; Oocyte maturity rate, number of MII oocytes/ number of oocytes retrieved × 100; Fertilization rate, number of fertilized oocytes/ numbers of injected MII oocytes × 100; high-quality embryos, grade A/B cleavage embryos; Fertilization rate, number of injected oocytes with 2 pronuclei (2 PN) and 2 polar bodies (2 PBs) 16-18 h post-insemination/ number of MII oocytes injected ×100. Data are presented as mean ± SD. A P-value less than 0.05 is considered significant (*P < 0.05). | PMC10067663 | |
Correlation analysis | tumor necrosis | TUMOR NECROSIS | Finally, as shown in Correlations between OS markers and ART outcomes.MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; TAC, total antioxidant capacity; MII rate (oocyte maturity rate), number of MII oocytes/ number of oocytes retrieved × 100; Fertilization rate, number of fertilized oocytes/ numbers of injected MII oocytes × 100; High-quality embryos, grade A/B cleavage embryos; Chemical pregnancies, pregnancies with a positive serum β-hCG; Clinical pregnancies, pregnancies with a definitive clinical sign. rCorrelations between pro-inflammatory cytokines and ART outcomes.IL-1β, interleukin 1β; IL-6, interleukin IL-6; TNF-α, tumor necrosis factor-α. MII rate (oocyte maturity rate), number of MII oocytes/ number of oocytes retrieved × 100; Fertilization rate, number of fertilized oocytes/ numbers of injected MII oocytes × 100; High-quality embryos, grade A/B cleavage embryos; Chemical pregnancies, pregnancies with a positive serum β-hCG; Clinical pregnancies, pregnancies with a definitive clinical sign. r | PMC10067663 |
Discussion | inflammation, endometriosis-associated infertility, PCOS, endometriosis | LATE PREGNANCY, ENDOMETRIOSIS, INFLAMMATION, UNEXPLAINED INFERTILITY, PATHOPHYSIOLOGY | Since OS and inflammation are interrelated and involved in the pathophysiology of endometriosis-associated infertility, in a randomized, triple-blind, placebo-controlled clinical trial on 50 infertile endometriosis patients candidate for ART, we investigated the antioxidative, anti-inflammatory, and fertility-enhancing effects of AST supplementation. We indicated that a 12-week supplementation with 6 mg/day of AST could effectively alleviate OS and inflammation and enhance ART outcomes.This trial showed that women using AST for 12 weeks achieved significantly higher serum levels of TAC and SOD. Serum MDA was also decreased significantly following antioxidant treatment. At the same time, the concentration of CAT remained unchanged after AST administration. However, no significant changes were detected in the CAT levels. This is consistent with published RCTs performed in Korea (A statistically significant decrease was observed in the FF TNF-α and IL-6 levels between the AST and the placebo group. However, dietary AST did not affect OS markers in the FF of endometriosis patients. Although AST supplementation led to a higher TAC level, it was not statistically significant. A previous study on PCOS patients undergoing ART (Significantly lower serum levels of IL-1β and TNF-α, but no considerable changes in serum IL-6, were observed following the intervention. In an RCT by Park et al. (2010) (Endometrial explants potentially expose the developing follicle, the oocyte, sperm, and embryos to high levels of ROS generated by inflammation. The damage to gametes and embryos can be prevented by antioxidant supplementation (Correlation analysis showed that serum IL-1β correlated negatively with fertilization rate. Nevertheless, increased IL-1β concentrations have been previously reported to be beneficial as high IL-1β in patients presenting male or unexplained infertility correlated with higher fertilization, implantation, and pregnancy rates (To the best of our knowledge, this is the first randomized, triple-blind, placebo-controlled clinical trial evaluating the effect of AST supplementation on OS markers, inflammatory cytokines, and ART outcomes in infertile endometriosis patients. Furthermore, a homogenous study population from the whole country undergoing uniform treatment practices was included. It is important to note, however, that our study had some limitations. Our study only includes patients undergoing assisted reproduction, so the results may not be generalizable to the entire endometriosis patient population. A larger sample size is required to analyze pregnancy outcomes. Besides, time constraints prevented us from evaluating late pregnancy outcomes, including live birth rate, the most relevant standard of success in ART. In addition, our analysis was limited to frozen ICSI cycles without assessing pregnancy outcomes in fresh cycles. | PMC10067663 |
Conclusion | endometriosis | OXIDATIVE STRESS, ENDOMETRIOSIS | In conclusion, AST administration could be a promising supplement to combat the oxidative stress and inflammatory reaction associated with endometriosis. This pharmacological agent may also enhance oocyte and embryo quality in endometriosis patients presenting to ART clinics. | PMC10067663 |
Data availability statement | The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author. | PMC10067663 | ||
Ethics statement | The trial was approved by the Deputy of the Research and Ethics Committee of TUMS (approval date: 2021, December 19; code: IR.TUMS.MEDICINE.REC.1400.1085). The patients/participants provided their written informed consent to participate in this study. | PMC10067663 | ||
Author contributions | FA and AA designed the experiments and contributed reagents/materials/analysis tools. SR collected the data and performed the experiments. SN performed the statistical analysis, critically appraised the data, and reviewed the manuscript. SR and MS wrote the first draft of the manuscript. MK and AM contributed to manuscript revision and editing. All authors contributed to the article and approved the submitted version. | PMC10067663 | ||
Acknowledgments | We would like to thank the peer reviewers for their time and effort in reviewing the manuscript. | PMC10067663 | ||
Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10067663 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10067663 | ||
References | PMC10067663 | |||
2. Results | PMC10177844 | |||
2.1. Participant Flow Chart | As shown in | PMC10177844 | ||
2.2. Characteristics of Participants | As shown in | PMC10177844 |
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