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Secondary outcomes | dysuria, pain | SECONDARY | The evaluation of excellent clinical response obtained at 12 h, 36 h, 48 h, and 72 h showed that the test drug was superior in pain, burning, and burning on urination from 36 to 48 h (Table Evaluation of excellent clinical response at 12 h, 26 h, 48 h, and 72 hEvaluating the time to reach the absence of symptoms according to patients’ reports, 52.41% of group 1 achieved complete resolution of pain within 72 h, and 47.59% were censored, versus 49.28% of group 2 without pain and 50.71% censored. The mean time for complete resolution of pain was 59.42 h (95% CI 56.32 h, 62.52 h) in group 1 and 64.63 h (95% CI 62.52 h, 66.74 h) in group 2, log-rank In the evaluation of sustained healing, 54.93% of group 1 had no pain after 72 h, versus 45.77% of group 2, According to the investigator's opinion, 61.3% of group 1 and 65.0% of group 2 were categorized as very much to much improved, Investigator's evaluation of dysuria according to the Clinical Global Impression scaleThe results with the PP population are also similar for secondary outcomes (data not shown).Seventy-nine percent of participants in group 1 and 87.8% of group 2 had negative urine culture at V1. At V2, 93.3% of participants in group 1 and 94.8% in group 2 had negative results; 13% of group 1 and 31.3% of group 2 with | PMC10756887 |
Safety | vomiting, pain, dizziness, headache, nausea, vomiting | EVENTS | During the trial, 40 episodes of AEs were recorded: 13 in group 1 and 27 in group 2. The AEs were mild (72.5%) or moderate (27.5%) in intensity, probably to possibly related to treatment, and all of them had complete resolution. The main AEs were nausea/feeling sick: 38.5% of group 1 and 40.7% of group 2; epigastric pain: none in group 1 and 22.2% of group 2; and vomiting: 15.4% of group 1 and 11.1% of group 2. Three participants from group 1 and 8 from group 2 were excluded from the study because of AEs; these events included nausea, vomiting, epigastric pain, dizziness, headache, and malaise. | PMC10756887 |
Acknowledgements | The authors acknowledge writing assistance from Dr. Mariana Matos M.D., a medical writer. | PMC10756887 | ||
Authors’ contribution | F. Savioli Neto, H. Hachul, M.A. Pereira, and C. Isaia Filho were investigators in this trial. They all provided substantial contributions to the design or development of the study, participated in the collection and interpretation of the data, critiqued the manuscript, and approved the final version. | PMC10756887 | ||
Funding | This study was funded by EMS S.A, SP, Brazil. | PMC10756887 | ||
Data Availability | The dataset supporting the conclusions of this article is available upon request, by contacting the corresponding author. | PMC10756887 | ||
Declarations | PMC10756887 | |||
Conflicts of interest | All authors were principal investigators of their respective research centers and received a fee for including patients in the study. | PMC10756887 | ||
References | PMC10756887 | |||
Objective | Edited by: Emre Pabuccu, Ufuk University, TürkiyeReviewed by: Hongzhan Zhang, Shenzhen Zhongshan Urological Hospital, China; Guanhua Qian, Chongqing Medical University, China; Xiushan Feng, Fujian Medical University, China†These authors have contributed equally to this workThe administration of progesterone before transfer in hormone replacement treatment (HRT) is crucial for the clinical outcomes of frozen-thawed embryo transfer (FET), but the optimal duration of progesterone remains controversial. This study aimed to investigate the effect of the duration of progesterone administration on the clinical outcomes of FET cycles. | PMC10415160 | ||
Methods | SECONDARY, EARLY PREGNANCY | This prospective cohort study included 353 artificial FET cycles conducted at a reproductive medicine center between April and October 2021. The FET cycles were stratified into four groups based on the duration of progesterone supplementation before the procedure and the embryonic development stage: group P3 (73 patients) received intramuscular progesterone for 3 days and group P4 (87 patients) for 4 days before Day 3 frozen embryo transfer, group P5 (70 patients) for 5 days and group P6 (123 patients) for 6 days before frozen blastocyst transfer. This trial was performed using one or two vitrified embryo(s) when the endometrial thickness reached 7 mm after estrogen supplementation in an artificial cycle. The primary outcome was clinical pregnancy, and secondary outcomes included biochemical pregnancy, implantation, early pregnancy loss, and live births. | PMC10415160 | |
Results | There were no significant differences in the demographic and clinical characteristics between the groups. No significant difference was observed in the clinical pregnancy rates between groups: 23/73 (31.5%) in group P3 vs 28/87 (32.2%) in group P4 ( | PMC10415160 | ||
Conclusion | There may be no significant correlation between the duration of progesterone supplementation and pregnancy outcomes in artificial FET cycles, although the clinical pregnancy rate was higher when progesterone supplementation was extended for one day before FET. | PMC10415160 | ||
Introduction | stenosis | STENOSIS | Due to recent developments in clinical practice and laboratory technology, embryo cryopreservation has become a central component of assisted reproductive technology (ART). Improved laboratory technology has contributed to an increased number of embryos available for Despite the emerging importance of the FET cycle, optimal endometrial preparation before it remains unclear. Although several randomized trials have examined the effects of different cycle regimens on FET, there is still no evidence for a single optimal endometrial priming protocol for FET cycles (In contrast to estrogen, progesterone appears to be a significant determinant of the WOI because the endometrial WOI is confined to the stenosis interval in the luteal phase (As for the lack of evidence regarding to the optimal duration of progesterone administration, there is still much more to be learned about endometrial preparation and synchronization to maximize endometrial function and receptivity, and select the best time for embryo transfer ( | PMC10415160 |
Materials and methods | PMC10415160 | |||
Study design and participants | allergic reactions | ALLERGIC REACTION | This prospective study was conducted at the Reproductive Medical Center of the Affiliated Hospital of Southwest Medical University. This study included patients who underwent FET in an artificial cycle from April 2021 to October 2021 and were allocated to one of four groups as soon as the endometrial thickness reached 7 mm after estrogen supplementation. One or two embryo(s) were transferred according to Health Commission legislation. The inclusion criteria were patients aged 22−45 years and on hormone replacement cycles. The exclusion criteria included known allergic reactions to progesterone products, uptake of an experimental medicine within 30 days before study initiation, and cancellation of FET for various reasons. The cycles were stratified into four groups based on the duration of progesterone supplementation before embryo transfer and the embryonic development stage. The cycles were assigned to groups P3 or group P5 from April 2021 to June 2021. The cycles were assigned to Groups P4 and P6 from July 2021 to October 2021. Patients in groups P3 and P4 were administered intramuscular progesterone for 3 and 4 days, respectively, before frozen-thawed Day 3 cleavage-stage embryo transfer. Patients in groups P5 and P6 were separately supplemented with intramuscular progesterone for 5 and 6 days, respectively, before the frozen-thawed blastocyst transfer. This trial was performed using one or two vitrified-warmed embryo(s) when the endometrial thickness reached 7 mm after estrogen supplementation in an artificial cycle. This study was approved by the Institutional Review Board of the hospital. Written informed consent was obtained from all participants. | PMC10415160 |
Endometrial preparation and embryo transfer | PROLIFERATIVE | All cycles were performed using the same artificial protocol. Oral estradiol valerate (Progynova, BayerSchering Pharma AG, Germany) was administered on the second or third day of the menstrual cycle after verifying that the patients were in the early proliferative phase of the menstrual cycle. Typically, 3 mg of estradiol valerate was prescribed twice daily. If the endometrial thickness was <7 mm 14 days later, patients were required to comply with a step-up protocol that involved the addition of vaginal estrogen supplementation (Femoston, Abbott Healthcare Products; 1 mg once daily), to the oral administration of estradiol valerate, based on the physician’s preference and experience. Serum estradiol and progesterone levels were determined on the day before the initiation of progesterone treatment.Intramuscular progesterone (60 mg once a day) was initiated, supplemented with oral dydrogesterone (10 mg thrice a day) when the endometrial thickness was 7 mm. Embryo transfer was performed days 4, 5, 6 and 7 of progesterone exposure in groups P3, P4, P5 and P6 respectively. No more than two embryos were transferred in any FET cycles. All the embryos were thawed on the morning of the transfer. Embryos were evaluated according to the conventional classification system currently used in our IVF laboratory: number of blastomeres, degree of cytoplasmic fragmentation and the equality of blastomeres ( | PMC10415160 | |
Outcome measures | MISCARRIAGE, EARLY PREGNANCY, PREGNANCY LOSS | The independent variable of interest was the duration of progesterone exposure, defined as the number of days from the initiation of progesterone treatment to the completion of embryo transfer. To evaluate whether the duration of progesterone administration before FET affected the clinical outcomes, the primary outcome of the study was clinical pregnancy, which was defined as the presence of one or more gestational sac(s) with an embryonic pole indicating the fetal heartbeat on transvaginal ultrasound at 7 weeks of gestation. Secondary outcomes included biochemical pregnancy, rate of implantation, live births, early pregnancy loss, and miscarriage.Fourteen days after embryo transfer, having a serumβ-hCG level of >5 IU/L was considered a biochemical pregnancy. The implantation rate was determined by dividing the number of intrauterine sacs inspected using transvaginal ultrasound divided by the number of embryos transferred. Live birth was defined as the delivery of viable infant(s) at ≥24 gestational weeks. Early pregnancy loss was considered when no gestational sac was observed even after a serum β-hCG ≥ 5 mIU/mL or loss occurring after the presence of an intrauterine gestational sac was confirmed. | PMC10415160 | |
Statistical analysis | Normally distributed measurement data are presented as the “mean ± standard”; data that is not normally distributed are presented as “median (range).” The Shapiro- Wilk (SW) test was used to determine whether the continuous variables were normally distributed. Statistical comparisons between the two groups were performed using the Mann-Whitney U test. Categorical variables were described as frequencies or percentages, and comparisons between groups were performed using Pearson’s chi-squared test or Fisher’s exact test. All statistical analyses were performed using IBM SPSS Statistics for Windows (version 19.0; IBM, Corp., Armonk, NY, USA. Statistical significance was set at | PMC10415160 | ||
Results | Overall, 353 FET cycles were performed with HRT were analyzed in this study, including FET of cleavage embryos or blastocysts. All FET cycles were stratified into four groups (P3, P4, P5, and P6) according to the embryonic development stage and the duration of progesterone administration before FET. At the time of analysis, groups P3, P4, P5 and P6 were compared. | PMC10415160 | ||
Baseline characteristics | Comparison of baseline demographic and cycle characteristics based on the duration of progesterone administration before frozen-thawed Day 3 cleavage-stage embryo transfer. The baseline characteristics are presented in Baseline and cycle characteristics for frozen-thawed day 3 embryo transfer cycles.
BMI, body mass index; FSH, Follicle stimulating hormone; LH, Luteinizing hormone; E2, estrogen; PRL, prolactin; P, progesterone; AMH, anti-Müllerian hormone; AFC, antral follicle count.Baseline and cycle characteristics for frozen-thawed blastocysts transfer cycles.
BMI, body mass index; FSH, Follicle stimulating hormone; LH, Luteinizing hormone; E2, estrogen; PRL, prolactin; P, progesterone; AMH, anti-Müllerian hormone; AFC, antral follicle count. | PMC10415160 | ||
Pregnancy outcomes | Pregnancy outcomes stratified into two groups according to the duration of progesterone administration prior to frozen-thawed Day 3 cleavage-stage embryo transfer are listed in Outcomes of frozen-thawed day 3 cleavage stage embryo transfer cycles.
Outcomes of frozen-thawed blastocysts transfer cycles.
Baseline demographics and cycle characteristics were compared between patients who achieved clinical pregnancy after frozen-thawed Day 3 cleavage-stage embryo transfer (A comparison of baseline demographic and characteristics according to whether patients achieved a clinical pregnancy after frozen day 3 cleavage embryo transfer.CI, confidence interval; OR, odds ratio.The baseline demographics and cycle characteristics were compared between patients who achieved clinical pregnancy after frozen blastocyst transfer (A comparison of baseline demographic and characteristics according to whether patients achieved a clinical pregnancy after frozen blastocyst transfer.CI, confidence interval; OR, odds ratio. | PMC10415160 | ||
Discussion | ABNORMAL MENSTRUAL CYCLE, EARLY PREGNANCY | HRT for FET cycles includes the sequential administration of exogenous estrogen and progesterone to imitate the physiological hormonal exposure of the endometrium in a normal menstrual cycle and to accurately time the transfer of the thawed embryo to the receptive endometrium (However, the hypothesis that prolonging the duration of progesterone administration could increase the pregnancy rates has not yet been confirmed (The hypothesis that prolonging the duration of progesterone administration could diminish the early pregnancy loss rate has not yet been confirmed (Based on these results, it may be concluded that enhanced flexibility would be possible when programming vitrified-warmed embryos transfer after progesterone administration, because no differences were observed between the duration of progesterone administration ≥1 day of embryonic age as far as clinical pregnancy, implantation, live birth, and early pregnancy loss rates are concerned (In addition, this study discovered that blastocysts might have higher pregnancy outcomes in FET cycles compared with that of cleavage-stage embryos (The data also displayed that the pregnancy outcome of embryos at the cleavage stage might be related to the woman’s age, while the blastocyst pregnancy outcome might be uncorrelated with it (This study had similar or different results from those of other studies, possibly due to epidemiological variables, limitations of its design, a high level of heterogeneity in the study populations, and insufficient sample size. Although this study adjusted for multiple potential confounding factors, caution should be taken when considering the results as a basis for definitive policy due to the prospective design of a single-center study with a limited sample size, as well as possible differences in research protocol and clinical performance. Consequently, confirmation of these findings in a multi-center study with a large sample size and a more rigorous research design is warranted. | PMC10415160 | |
Conclusion | In summary, although the results of this study need to be confirmed in multicenter randomized trials, they suggest that obtaining as many high-quality blastocysts as possible and programming single blastocyst transplantation deserved consideration. Although the optimal duration of progesterone supplementation remains to be clarified, it is recommended to transfer embryos on days 3 and 5 with a degree of flexibility. However, there may be different and possibly narrower WOI for the blastocyst on the sixth day of vitrification. Further research is required to optimize FET protocols and distinguish other contributing factors that may affect pregnancy outcomes after transferring frozen-thawed embryos. | PMC10415160 | ||
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. | PMC10415160 | ||
Ethics statement | The studies involving human participants were reviewed and approved by the Affiliated Hospital of Southwest Medical University Ethics Committee. The patients/participants provided their written informed consent to participate in this study. | PMC10415160 | ||
Author contributions | LL and HZ: conceptualization and writing-original draft prepatation. JH and XS: data curation DL and GH: revising the manuscript critically for important intellectual content. All authors contributed to the article and approved the submitted version. | PMC10415160 | ||
Acknowledgments | We thank the survey participants and all members involved in this study for their painstaking efforts in conducting the data collection. | PMC10415160 | ||
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. | PMC10415160 | ||
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. | PMC10415160 | ||
References | PMC10415160 | |||
ABSTRACT | PMC10134954 | |||
Background | VASODILATION | Citrulline may amplify the effects of L-arginine and nitric oxide concentration, which may augment vasodilation and blood flow, thereby enhancing aerobic exercise performance. The purpose of this randomized, double-blind, placebo-controlled crossover study was to investigate effects of L-citrulline + Glutathione on aerobic exercise performance and blood flow in well-trained men. | PMC10134954 | |
Methods | SD, PEX, Brachial artery blood flow | BLOOD | Twenty-five males (Mean ± SD; Age: 22.2 ± 2.4 yrs; Height: 177.0 ± 4.8 cm; Weight: 75.3 ± 6.9 kg) were randomly assigned to the L-citrulline + Glutathione (Setria Performance Blend: SPB; L-citrulline [2 g] + glutathione [200 mg], 6 capsules) or placebo (PL; 3.1 g cellulose, 6 capsules) group. Participants performed a maximal oxygen consumption treadmill test to determine peak velocity (PV) and returned after eight days of ingesting either PL or SPB. Three timed treadmill runs to exhaustion (TTE) were performed at 90%, 100%, and 110% PV. Brachial artery blood flow and vessel diameter were assessed using ultrasound at 1-hr prior to exercise (1hrPrEX), after each exercise bout, immediately post-exercise (immediate PEX), and 30 minutes post exercise (30minPEX) at visits 2 and 4. Blood analytes were assessed via venous blood draws at visit 1, visit 3, and 1hrPEX, immediate PEX, and 30minPEX at visits 2 and 4. After a 14-day washout, participants repeated the same procedures, ingesting the opposite treatment. Separate repeated measures ANOVAs were performed for TTE, vessel diameter, blood flow, and blood analytes. | PMC10134954 |
Results | BLOOD | Blood flow was significantly augmented 30minPEX ( | PMC10134954 | |
Conclusion | Acute ingestion of SPB after eight days may enhance blood flow, L-citrulline, and L-arginine plasma concentrations after high-intensity exercise, which may enhance performance. | PMC10134954 | ||
Clinical Trial Registration | [ | PMC10134954 | ||
KEYWORDS | PMC10134954 | |||
Introduction | VASODILATION, SECONDARY | As the global sports nutrition market totaled $10.7 billion in 2020 with a projected growth of 10.9% from 2021 to 2028 [During exercise, the demand for oxygen delivery and energy substrates is elevated in the working skeletal muscle. These demands are met with an increase in vasodilation and blood flow [Nitric oxide and nitrates have been the focus of most research on vascular function and performance as they have consistently demonstrated the ability to increase blood flow and prolong time to exhaustion (TTE) [While L-citrulline combined with GSH is known to enhance the effectiveness of resistance training, it is unclear whether it improves endurance performance. The purpose of the current study was to investigate the effects of L-citrulline + GSH on aerobic exercise performance and blood flow in well-trained men. The primary aim of this study was to determine the effects of orally delivered L-citrulline + GSH (Setria Performance Blend: SPB) vs. placebo on endurance performance, and blood flow before and after exercise in aerobically fit men. We hypothesized that the SPB would improve aerobic performance, increase blood flow, and increase vessel diameter compared the placebo. The secondary aim was to identify the effects of L-citrulline + GSH supplementation on blood metabolites of L-arginine, and L-citrulline. We hypothesized that the SPB would increase plasma concentrations of L-arginine and L-citrulline compared to the placebo. | PMC10134954 | |
Materials and methods | PMC10134954 | |||
Subjects | SD, illness | RECRUITMENT | Twenty-five highly active males (Mean ± SD; Age: 22.2 ± 2.4 yrs; Height: 177.0 ± 4.8 cm; Weight: 75.3 ± 6.9 kg; VOCONSORT recruitment. The five individuals who were active in the study during the mandatory stay at home orders issued in March 2019 in response to COVID-19 were stopped due to the university halt in research, not due to illness.Anthropometric and descriptive characteristics of study participants (Data are presented at mean ± standard deviation (SD). | PMC10134954 |
Experimental design | CAVITY | This study employed a randomized, double-blind, placebo-controlled, crossover design. Participants were asked to abstain from food and caloric beverages (12hrs), caffeine (12hrs), alcohol (24hrs), and physical activity (24hrs) prior to the baseline visit. Prior to the exercise testing sessions, participants were asked to abstain from food caloric beverages (4hrs), caffeine (12hrs), alcohol (24hrs), and physical activity (24hrs). Participants were instructed to refrain from using antibacterial mouthwash, chewing gum, and brushing their teeth on the morning of laboratory visits, as these factors may have modulated the conversion of nitrate to nitrite by influencing nitrate reductase enzymes in the oral cavity [Experimental Design Figure [1hrPrEX- 1 hour prior to exercise; *time to exhaustion order was randomized per participant]. | PMC10134954 | |
Maximal oxygen consumption (VO | To determine VO | PMC10134954 | ||
Body composition | stature, FM | Body composition was assessed via whole-body dual-energy x-ray absorptiometry scans (DXA; GE Lunar iDXA, GE Medical Systems Ultrasound & Primary Care Diagnostics, Madison, WI, USA) to characterize the stature of the sample. Participants were placed in the center of the scanning table after removing shoes and any clothing or jewelry containing metal or hard plastic. Participants were instructed to minimize movement during the scan, which was used to estimate lean mass (LM), fat mass (FM), and body fat percentage (BF%). Regions-of-interest from the default software (enCORE Software version 16) were adjusted by a trained technician. DXA test-retest reliability from this laboratory for individuals of similar stature included an ICC = 0.98 and SEM = 0.85 kg for FM, ICC = 0.99 and SEM = 1.07 kg for LM, and ICC = 0.96 and SEM = 1.279% for %fat. | PMC10134954 | |
Supplementation | Participants were provided an opaque bottle in a randomized order with half of the participants initially assigned to the Setria Performance Blend [SPB; L-citrulline (2 g) + glutathione (200 mg); Kyowa Hakko Bio, Tokyo, Japan] and the other half a placebo (PL; 3.1 g cellulose). Participants ingested their assigned treatment seven consecutive days prior to the first exercise visit (visit 2) and took the eighth dose at the laboratory. After a 14-day washout period, another baseline blood draw as obtained (visit 3), and participants began ingestion of the alternative treatment prior to the second exercise visit (visit 4). Utilizing a random allocation software, participants were randomly assigned treatment order in blocks of four to ensure equally balanced groups. Treatments were packaged in separate opaque bottles and blinded as treatment A and treatment B by the sponsor; both treatments were identical in appearance and taste. Participants were instructed to ingest six capsules of the assigned treatment once per day one hour prior to exercise for seven days. On day eight, participants were instructed to bring the treatment to the exercise visit where the eighth dose was consumed an hour before the exercise test (visits 2 and 4). Treatment consumption was separated by a minimum of a fourteen-day washout period, based on a half-life of ≤8 hours for both nitrate and L-citrulline [ | PMC10134954 | ||
High-speed running | fatigue | During the two exercise testing visits (visits 2 and 4) following the week-long supplementation regimens, participants arrived at the lab, ingested the final dose of the appropriate supplement, and waited 60 minutes before completing three separate treadmill runs to volitional fatigue at 90%, 100%, and 110% of the peak treadmill speed that was determined by PV from the VO | PMC10134954 | |
Brachial blood flow | Brightness-mode ultrasound (Logiq-e, GE Healthcare, Chicago, IL) was used to assess vessel diameter and blood flow through the brachial artery as previously described [ | PMC10134954 | ||
Blood analytes | PEX | A 5 ml venous blood sample was obtained from the antecubital region of the arm at visit 1, prior to VO2max, midpoint of the study (visit 3), and during visits 2 and 4 1hrPrEX, immediately post exercise (immediate PEX), and 30minPEX using one SST tube for each blood draw ( | PMC10134954 | |
Statistical analyses | BLOOD | If a participant was missing data for two or more visits, they were excluded from the initial analysis. The data of subjects whose capsule intake rate was 80 to 120% were used for analysis, but data of those who exceeded or fell below the range were excluded from the initial analysis (Time to exhaustion values were evaluated using a series of separate repeated measures analyses of variance (ANOVAs) for treatment (SBP vs. PL) by TTE bout (90%, 100%, and 110%). Blood flow and vessel diameter variables were evaluated using separate repeated measures ANOVAs for each time point (1hrPrEX, 90%, 100%, 110%, and 30minPEX) between treatments; blood analyte variables were evaluated using a similar approach. Analyses were performed using SPSS (Version 26.0; IBM, Somers, NY, USA) with statistical significance set | PMC10134954 | |
Results | Demographic and body composition values are presented in | PMC10134954 | ||
High-speed running | SE, SPB= | There was no significant treatment effect on TTE at 90% [Mean Difference (MD; SPB-PL) ± Standard Error (SE): −32.6 ± 16.3 sec; Individual responses and mean for vessel diameter (A-C) responses for compliant participants (High-speed running data per treatment group.Data are presented as mean ± standard error (SE) and mean difference (MD) ± SE. SPB= active; PL= placebo; sec = seconds; TTE = time to exhaustion. | PMC10134954 | |
BrachiaL vessel diameter and blood flow | PMC10134954 | |||
Blood flow | There was no significant treatment effect on blood flow at 1hrPrEX (Mean ± standard deviation for blood flow across time points for compliant participants. *Indicates statistical significance between time points. | PMC10134954 | ||
Blood analytes | PMC10134954 | |||
Arginine | PEX | There was a significant difference between L-arginine concentration at baseline visits [(visit 1; 123.6 ± 22.5 nmol/L) vs. (visit 3; 134.8 ± 27.8 nmol/L; Comparison of blood analytes per treatment group.PrEX = prior to exercise; PEX = post exercise; MD = mean difference; *indicates significant difference between treatments ( | PMC10134954 | |
L-citrulline | There was no significant difference between L-citrulline concentration at baseline visits [(visit 1; 33.9 ± 8.5 nmol/L) vs. (visit 3; 33.8 ± 7.7 nmol/L; | PMC10134954 | ||
Discussion | VASODILATION | Endurance performance largely depends on increased oxygenation and blood flow to skeletal muscle [NO-related supplements are growing in popularity; however, to date there is a lack of consensus regarding the effects of L-citrulline and L-arginine on aerobic exercise performance [Due to the role of NO in vasodilation and improvements in blood circulation, many studies have investigated the mechanisms of NO-related supplements on aerobic exercise performance [In addition to vasodilation, NO promotes increases in blood flow enhancing nutrient, hormone, and oxygen delivery to exercising muscles [Nitrates and nitrites have consistently been used as indicators of NO status, as a result of the rapid metabolism of L-arginine and L-citrulline [Previous research in recreationally trained individuals has demonstrated that L-citrulline supplementation may improve aerobic performance markers such as TTE and aerobic capacity [ | PMC10134954 | |
Conclusion | In conclusion, L-citrulline + GSH supplementation did not enhance TTE in aerobically trained men. Although SPB supplementation did not translate to improved performance, there was a significant increase in blood flow at 30 minutes following exercise. Increased blood flow after exercise may promote exercise recovery due to augmented nutrient, hormone, and oxygen delivery. In agreement with previous reports of increased L-arginine from oral L-citrulline supplementation [ | PMC10134954 | ||
Disclosure statement | The authors have no conflicts of interest. AS-R designed the study. HC, CG, LG, and AS-R collected the data and contributed to manuscript preparation. HC and AS-R analyzed and interpreted the data. All authors reviewed and approved the final manuscript. | PMC10134954 | ||
References | PMC10134954 | |||
Background | CERVICAL CANCER | The long-term prognosis of minimally invasive surgery and open surgery for early cervical cancer is controversial. This study mainly discusses the feasibility and effectiveness of the endocutter in radical laparoscopic hysterectomy for early cervical cancer. | PMC10239128 | |
Methods | CERVICAL CANCER, RECURRENCE, COMPLICATIONS, SECONDARY | A single-center, prospective, randomized controlled trial of modified radical laparoscopic hysterectomy on patients with FIGO stage IA1 (lymphovascular invasion), IA2, and IB1 cervical cancer, between January 2020 and July 2021. Patients were randomly assigned into laparoscopic radical hysterectomy (LRH) and open radical hysterectomy (ORH) groups. The ORH group used right-angle sealing forceps for vaginal stump closure, whereas the LRH group used endoscopic staplers. The primary outcomes included the evaluation of the patient’s perioperative indicators, as well as short- and long-term complications. Recurrence and overall survival were considered secondary outcomes. | PMC10239128 | |
Results | As of July 2021, 17 patients were enrolled in the laparoscopic surgery group and 17 in the open surgery group. The hospitalization time of the laparoscopic group was significantly shorter than those of the open group (15 min vs. 9 min, | PMC10239128 | ||
Conclusions | early-stage cervical cancer | Modified LRH with endocutter closure of the vaginal stump is an effective approach and not inferior to ORH in treating patients with early-stage cervical cancer. | PMC10239128 | |
Trial registration | ChiCTR2000030160, date of registration February 26, 2020 ( | PMC10239128 | ||
Keywords | PMC10239128 | |||
Background | cancer, death | CANCER, CERVICAL CANCER, CERVICAL CANCER | Cervical cancer incidence and mortality rates rank fourth among women’s cancer globally. The annual cervical cancer occurrence in 2020 was estimated to be more than 600,000 new cases, with a corresponding death toll of 340,000 patients [To this end, we used an observational, randomized controlled trial design to compare the clinical outcomes of modified laparoscopic radical hysterectomy and open radical hysterectomy. In addition, the study aimed to investigate the feasibility and safety of using an endoscopic stapler device to treat patients with | PMC10239128 |
Materials and methods | PMC10239128 | |||
Trial design | CERVICAL CANCER | This study was a single-center, phase 2, randomized controlled trial registered under Chinese clinical trial number ChiCTR2000030160. Data was gathered from patients with FIGO (2018) stage IA1 (lymphovascular invasion), IA2, and IB1 cervical cancer at Zhongda Hospital of Southeast University in Nanjing, China, between March 2020 and July 2021. The institutional review board evaluated and approved relevant medical ethics issues (ethical approval number 2020ZDSYLL106-Y01). The study design flowchart is shown in Fig. Laparoscopic vaginal stump closure using the endocutter | PMC10239128 | |
Sample size | The sample size was calculated according to the method specified in the previous study [ | PMC10239128 | ||
Trial conduct and oversight | tumor, vascular tumor thrombus, squamous cell carcinoma, adenocarcinoma, bladder dysfunction | TUMOR, RECURRENCE, RECURRENCE, ADENOSQUAMOUS CARCINOMA, COMPLICATIONS, KIDNEY DYSFUNCTION, SECONDARY, ENDOMETRIOID ADENOCARCINOMA, BLADDER DYSFUNCTION | Patients who met the following criteria were included in the study: (1) FIGO2018 stage IA1 (with vascular tumor thrombus), IA2, IB1; (2) the largest tumor diameter < 2 cm (MRI evaluation or pathological evaluation after conization < 2 cm); (3) histological types: squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma, except endometrioid adenocarcinoma; (4) patients with appropriate bone marrow hematopoietic function and renal function; (5) liver function: ((1) white blood cell count > 3.0 × 10Patients with the following conditions were excluded: (1) mental illness; (2) heart, liver, or kidney dysfunction; (3) bladder dysfunction before the operation or patients with other serious complications who could not bear the risk of surgery; (4) patients who had received radiotherapy or chemotherapy; (5) pregnant patients; (6) lost to follow-up; (7) tumor diameter ≥ 2 cm; imaging evaluation showing that the cervical tumor invades the outer 1/3 of the stroma or involves the lower uterine segment; (8) patients with FIGO stage IB2 and above; (9) patients whose medical compliance and geographic location could not guarantee sufficient follow-up; (10) patients with surgical contraindications; (11) BMI ≥ 35.After signing a written consent, patients were randomly assigned by a network-based computer randomization program into the laparoscopy group and the laparotomy group at a ratio of 1:1. Masking was impossible because of the nature of the treatment.All patients underwent extensive hysterectomy and pelvic lymph node dissection (with or without bilateral adnexectomy). The primary study objective was to compare the clinical outcomes between the laparoscopic group that used the endocutter stapler for vaginal stump closure and the laparotomy group that used right-angled forceps to close the vaginal stump. The primary outcomes of interest included the patients’ perioperative observation indicators and short- and long-term period complications. Recurrence and overall survival were considered secondary outcomes. The primary endpoint is 4.5 years of post-operative DFS (the time interval from the surgery date to the first recurrence). | PMC10239128 |
Surgical procedure | METASTASIS, STERILE, CAVITY, STAGGERED, VAGINA, PERITONEAL DISSEMINATION | Following the induction of general anesthesia, the patient was placed in the lithotomy position, then disinfected and draped before access into the abdominal cavity was obtained.The laparoscopic group had four surgical incisions on the patient’s abdominal wall: (1) a 10-mm camera port in the umbilicus, (2) a 5-mm port at the McBurney’s point on the right side, (3) an identical 12-mm working port on the left lateral lower quadrant, and (4) a 5-mm port parallel to the left mid-clavicular line 2 cm laterally at the level of the umbilicus. Abdominal pressure was set to 12 mmHg. The patients were adjusted to approximately 30° of Trendelenburg position. After entering the abdominal cavity, we carefully explored the pelvic and abdominal cavities to rule out peritoneal dissemination or distant metastasis. We adopted the no-lifting technique described in earlier investigations [Subsequently, pelvic lymphadenectomy was performed, and para-aortic lymph node dissection was performed where necessary. Pelvic lymph nodes were resected en bloc according to the order of common iliac → external iliac → deep inguinal → obturator → internal iliac vessels. After dissecting one side of the lymph nodes, it was bagged and sealed in time. The wound was repeatedly rinsed with sterile water for injection, and the contralateral lymph nodes were treated similarly.Following the radical hysterectomy, the Ethicon Johnson & Johnson Echelon Flex Powered Plus Long Articulating Endoscopic Linear Cutter (Endocutter) with two rows of triple staggered titanium staples were inserted through the 12 mm trocar port. The angle between the jaws of the endocutter and the vagina’s longitudinal axis was adjusted to 90°, and then about 3 cm of the upper part of the vagina was closed after ensuring there was no abnormal tissue in the jaws except for the vaginal tissue. After the endocutter is fired, the device’s staples are released, and the vaginal stumps are sewn together on both sides while simultaneously cutting the vaginal wall (Fig. In the ORH group, the patient was placed in the lithotomy position following induction of general anesthesia. A mid-line incision of 20 cm was made on the lower abdomen, and the rest of the procedure was carried out as stated in a previous detailed report [ | PMC10239128 | |
Observation indicators | tumor, bleeding, dehiscence, major organ damage, hernia, vascular injury, infection | INTRAOPERATIVE COMPLICATIONS, TUMOR, BLEEDING, RECURRENCE, DEHISCENCE, INTRAOPERATIVE COMPLICATIONS, URETER, INFECTION, COMPLICATIONS | The patient’s general clinical and pathological information, such as age, body mass index, ECOG score, tumor grade, and pathological type, were recorded. Perioperative indexes include operation time (minutes), hospital stay (days), intraoperative complications (bleeding, major organ damage), intraoperative blood transfusion, lymphatic dissection, and the time to removal of the urinary catheter and drainage tube as well as the time spent dealing with the vaginal stump during the operation was recorded. Patients had regular follow-ups of their clinical condition, short-term post-operative indexes, post-operative complications, and pelvic lavage fluid cytopathology results were reviewed. Intraoperative complications, including bowel, bladder, ureter, nerve, or vascular injury, were considered short-term post-operative indexes. Early post-operative complications refer to vaginal stump infection and dehiscence within four weeks after surgery; long-term post-operative complications refer to incisional hernia and vaginal stump recurrence after 6 months. | PMC10239128 |
Statistical methods | The SPSS 22.0 software was used for the statistical analysis. Continuous data were analyzed using a | PMC10239128 | ||
Discussion | Cancer, tumor, cancer, early-stage cervical cancer, tumors, bipolar coagulation | TUMOR, CANCER, UTERUS, MALIGNANCIES, CERVICAL CANCER, CAVITY, CERVICAL LESION, TUMORS, VAGINA, EXTRAVASATION, SPILLAGE, CANCER | The use of LRH for cervical cancer was first reported in 1992 [The main principles of tumor surgery include the prevention of possible tumor extravasation; however, cervical cancer itself possesses the characteristic of spreading outward and toward the vagina, which can complicate surgery. The findings of the 2018 LACC trial [Moreover, it is believed that cancer cells can detach from the tumor surface during surgery for cervical malignancies and contaminate the carbon dioxide-filled peritoneal cavity. In a study by Kong et al. [Furthermore, during intraabdominal vaginotomy, the last step during LRH, intra-abdominal exposure to the tumor while separating the vagina could easily cause abdominal and pelvic dissemination and increase the risk of tumor spillage. In order to avoid the direct exposure of tumor tissue to the abdominal cavity, open surgery often uses preoperative vaginal fornix clamping, but laparoscopic radical hysterectomy cannot routinely replicate this step. It can be achieved by creating vaginal cuffs or closing vaginal cuffs by suture or permanent tie. Yuan et al. [Therefore, we modified our laparoscopic surgery as follows: (1) instead of using a uterine manipulator, we used transuterine suspension sutures, which ensured that the angle and position of the uterus could be adjusted for complete exposure of the surgical field of view without squeezing or destroying the tumor. (2) In this trial, cutting and closing the vagina with the endocutter instead of the traditional way of closure allowed for a more straightforward procedure, with enough room for complete vaginal wall and cervical lesion resection. At the same time, it ensured the safety of the vaginal resection margin and reduced the spillage of intraperitoneal tumors. Compared with the previous vaginal suture methods, the endocutter closes the vaginal vault more evenly and tightly, and the closure is superior. (3) The complete resection (tumor-free) principle was strictly implemented in this trial. Previous studies have identified an association between positive vaginal excision margins and an increased risk of early-stage cervical cancer recurrence along residual vaginal tissue [The vaginal stump treatment time in the laparotomy group was significantly shorter than in the laparoscopic group. This may be related to the limitation of the laparoscopic technique itself; time is saved when using the right-angle sealing forceps compared with the endocutter device. It takes more time to follow the principle of complete resection when working under a limited field of view, and it also requires more time to extract the specimen from the vagina than direct extraction during laparotomy. However, this study found no significant difference in the total operation time between the two groups, suggesting that time spent before the treatment of the vaginal stump during the initial steps of the laparoscopic procedure can be optimized. Steps such as skin incision are relatively faster than in laparotomy; laparoscopic pelvic lymph node dissection time is shorter than open radical hysterectomy, mainly because laparoscopy has a high resolution and provides more accurate anatomy exposure, and more energy devices such as bipolar coagulation used for hemostasis are less time-consuming.From a subjective point of view, the study guaranteed the quality of the operations. The trial facility is a quality control pilot unit of the National Cancer Center and is one of China’s top 50 tertiary hospitals. The patients used in the trial were strictly screened, and the surgical staff involved have all passed strict certification procedures; they have rich experience, and all operations were completed independently. This study also has the benefit of using a prospective randomized controlled design to assess short-term clinical outcomes and the efficacy of a modified minimally invasive radical hysterectomy. These findings will help plan and design subsequent studies on the safety and efficacy of early-stage cervical cancer surgical treatment. | PMC10239128 |
Limitations | tumor, early-stage cervical cancer | TUMOR, METASTATIC DISEASE | This study has shortcomings; when a negative washing cytology result is obtained, although it is technically tumor-free, it does not mean that the prognosis of the tumor is good, and there may be unexpected metastatic disease. At this time, it should be interpreted carefully in conjunction with the pathological results. In addition, using the endocutter can increase potential surgical costs. Although the sample size of this report is still small and the follow-up time is short, further long-term follow-up data will be supplemented in the future as this trial is still ongoing at the time of this report. Nevertheless, the findings strengthen our confidence in the continued use of MIS for patients with early-stage cervical cancer. | PMC10239128 |
Authors’ contributions | All the authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by X.L. and Y.S.. The first draft of the manuscript was written by X.L., and all the authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript. | PMC10239128 | ||
Funding | The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. | PMC10239128 | ||
Availability of data and materials | The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. | PMC10239128 | ||
Declarations | PMC10239128 | |||
Ethics approval and consent to participate | MAY | The study was approved by the Institutional Research Ethics Committee of Zhongda Hospital of Southeast University (number: 2020ZDSYLL106-Y01) obtained on May 28, 2020. | PMC10239128 | |
Competing interests | The authors declare no competing interests. | PMC10239128 | ||
References | PMC10239128 | |||
Background | pulmonary embolism, Pulmonary embolism, cardiovascular disease | PULMONARY EMBOLISM, PULMONARY EMBOLISM, CARDIOVASCULAR DISEASE | Pulmonary embolism is a severe cardiovascular disease and can be life-threatening if left untreated. However, the detection rate of pulmonary embolism using existing pretest probability scores remained relatively low and clinical rule out often relied on excessive use of computed tomographic pulmonary angiography. | PMC10408070 |
Methods | pulmonary embolism, Pulmonary embolism | PULMONARY EMBOLISM, PULMONARY EMBOLISM, WELLS, REGRESSION, PULMONARY EMBOLISM | We retrospectively collected data from pulmonary embolism suspected patients in Zhongshan Hospital from July 2018 to October 2022. Pulmonary embolism diagnosis and severity grades were confirmed by computed tomographic pulmonary angiography. Patients were randomly divided into derivation and validation set. To construct the Pulmonary Embolism Comprehensive Screening Score (PECSS), we first screened for candidate clinical predictors using univariate logistic regression models. These predictors were then included in a searching algorithm with indicators of Wells score, where a series of points were assigned to each predictor. Optimal D-Dimer cutoff values were investigated and incorporated with PECSS to rule out pulmonary embolism. | PMC10408070 |
Results | pulmonary embolism | PULMONARY EMBOLISM, WELLS | In addition to Wells score, PECSS identified seven clinical predictors (anhelation, abnormal blood pressure, in critical condition when admitted, age > 65 years and high levels of pro-BNP, CRP and UA,) strongly associated with pulmonary embolism. Patients can be safely ruled out of pulmonary embolism if PECSS ≤ 4, or if 4 < PECSS ≤ 6 and D-Dimer ≤ 2.5 mg/L. Comparing with Wells approach, PECSS achieved lower failure rates across all pulmonary embolism severity grades. These findings were validated in the held-out validation set. | PMC10408070 |
Conclusions | WELLS | Compared to Wells score, PECSS approaches achieved lower failure rates and better compromise between sensitivity and specificity. Calculation of PECSS is easy and all predictors are readily available upon emergency department admission, making it widely applicable in clinical settings. | PMC10408070 | |
Trail registration | 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). | PMC10408070 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12890-023-02580-8. | PMC10408070 | ||
Keywords | PMC10408070 | |||
Background | Pulmonary embolism, cardiovascular illness, venous thromboembolism | PULMONARY EMBOLISM, WELLS | Pulmonary embolism (PE) is a common severe cardiovascular illness andcan be life-threatening if left untreated [Commonly used clinical pretest probability, such as Wells score and Geneva score, combines clinical symptoms with predisposing risk factors of venous thromboembolism and classifies patients with suspected PE into distinct risk categories [In this investigation, we aim to develop a comprehensive PE pretest score that incorporates clinical indications in Wells score and other important clinical predictors to guide clinicians in assessing PE risk with improved screening performances. The proposed PE Comprehensive Screening Score (PECSS) is designed to optimize the rule out performance among patients with severe PE and to achieve excellent operating characteristics among patients with moderate and mild PE. PE severity grades were evaluated based on CTPA and validation of PECSS was conducted in an independent held-out data set. | PMC10408070 |
Methods | PMC10408070 | |||
Data collection | We retrospectively collected data from patients presenting to the emergency department of Zhongshan Hospital (affiliated to Fudan University) from July 2018 to October 2022. Patients were included if they were 18 years and older, were suspected of PE or could not be ruled out of PE by the attending physicians. Patients were excluded if they did not have PE status or severity confirmed by CTPA, had missing D-Dimer values and were pregnant. Electronic medical records, CTPA, laboratory tests results and vital signs were collected and reviewed. | PMC10408070 | ||
PE severity grade | embolism, pulmonary artery branch embolism, pulmonary artery embolism | PULMONARY ARTERY EMBOLISM, EMBOLISM | The severity grade of PE was determined based on CTPA. PE was divided into 4 severity grade categories: 1) severe PE, which was defined as the pulmonary artery embolism or multiple pulmonary arteriole embolism; 2) moderate PE, defined as pulmonary artery branch embolism; 3) mild PE, defined as single pulmonary arteriole embolism; 4) no PE. | PMC10408070 |
Study design | Patients meeting the inclusion and exclusion criteria were randomly divided into the derivation (80%) and validation (20%) set according to the stratified randomization scheme such that the distribution of PE severity grades were similar in the two data sets. Derivation set was used to construct the new screening approach and compare it to existing approaches, while the validation set was used to validate the findings. The primary endpoint was failure rate in patients with severe PE, which was defined as the proportion of PE cases failed to be ruled out in patients with severe PE. Secondary endpoints include failure rate in moderate, mild and total PE, defined as the proportion of PE cases failed to be ruled out in patients with moderate, mild and any PE, respectively. In addition, we also evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) associated with each screening approach. | PMC10408070 | ||
Statistical analysis | REGRESSION, SENSITIVITY, WELLS | Statistical analysis was performed using R statistical software version 4.0.3. Continuous characteristics were described using mean To construct the PE comprehensive screening score (PECSS), we first screened all 26 clinical predictors that were suspected to be associated with PE according to clinical consensus. Among all these predictors, Lactic Acid, Aspartate Transaminase and Lactic Dehydrogenase had missing proportions higher than 30% and were therefore dropped from the following analyses. Next, univariate association with PE status (PE vs no PE) of each predictor was assessed using univariate logistic regression model, and predictors with P values smaller than 0.05 were selected as candidate variables in models constructing PECSS. Candidate variables selected by univariate logistic regression models were then included in a searching algorithm, where a series of points were assigned to each predictor and the total points were added to the Wells score to construct PECSS. To facilitate clinical practice and in line with total Wells score, we considered 0, 0.5, 1.0 and 1.5 points for each candidate variable so that higher scores indicate higher probability of PE. Finally, optimal PECSS cutoffs and optimal D-Dimer cutoffs within each PECSS stratum were determined to minimize the failure rate in patients with severe PE.Screening performances of PECSS, PECSS + D-Dimer and PECSS + PERC were evaluated and compared to Wells score, Wells score + D-Dimer and Wells score + PERC. Failure rates among patients with severe, moderate, mild and any PE were compared under these scoring systems, respectively. Sensitivity, specificity, PPV and NPV were also calculated for each screening approach. | PMC10408070 | |
Results | PMC10408070 | |||
Patient characteristics | A total of 4867 patients presenting to the emergency department of Zhongshan Hospital from July 2018 to October 2022 met the inclusion criteria and were included in the study. Among them, 519 could not be confirmed of PE status by CTPA, 1102 had high missing proportions of important predictors, 6 were pregnant and these patients were thus excluded from the study. Among 3240 patients included in the analysis, 2555 were randomly assigned to the derivation set and the remaining 685 patients were allocated to the validation set (Fig. Study workflow. The workflow of excluding patients passing the exclusion criteriaPatient characteristics in the derivation and validation setData are n (%), median (IQR), or mean (SD). Patients were randomly divided into the derivation and validation set using a stratified randomization scheme. P values were obtained using student t test for normally distributed variables, Wilcoxon rank sum test for skewed distributed variables and Chi-square (or Fisher’s exact) test for categorical variables | PMC10408070 | ||
Candidate predictors for PECSS | pain | REGRESSION, BLOOD | Using data from 2555 patients in the derivation set, we assessed the association strength with PE status for each clinical predictor. Univariate logistic regression showed that age above 65 years old, low hemoglobin, high white blood cell, neutrophil and monocyte, high C-reaction protein, abnormal blood pressure, high N-terminal (NT)-pro hormone BNP, low blood albumin and high blood Alanine transaminase, low blood Creatinine, high blood Uric Acid, presence of anhelation, lower levels of pain scale and in critical condition when admitted were significantly associated with increased risk for PE (Fig. Univariate association of each clinical predictor with PE status. Odds ratio (OR) and 95% confidence interval (CI) were obtained from univariate logistic regression model. Hgb, hemoglobin; WBC, white blood cell count; NEUT, neutrophil count; MONO, monocyte count; PLT, platelet; CRP, c-reaction protein; abnormal BP, abnormal blood pressure; pro-BNP, N-terminal (NT)-pro hormone BNP; ALB, blood albumin; ALT, Alanine transaminase; GLO, globulin; Cr, creatinine; BUN, Blood Urea Nitrogen; UA, blood uric acid; cTNT, cardiac troponin test | PMC10408070 |
Incorporating D-Dimer with PECSS | Next, we incorporated D-Dimer with PECSS by seeking optimal D-Dimer cutoffs in each PECSS stratum. Distribution of D-Dimer across different PE severity grades and within each PECSS stratum can be found in Figure S Flowchart summary of the PECSS + D-Dimer screening approach | PMC10408070 |
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