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Participant characteristics at baseline. | ADVERSE EVENTS, DISEASE | Mean ± standard deviation or frequency (%) provided when applicable.All enrolled participants completed all study timepoints, however not all outcome measures could be performed due to disease severity, progression or adverse events (for example, falls with injury interfered with the 2MWT). On completion of the 26-week pilot study, a 12-month Open-Label Extension (OLE) was conducted at the request of 12 study participants, with reassessment at 6 and 12-month timepoints. Two participants did not enrol in the open-label study due to self-report of undesirable side effects relating to mood and/or libido observed whilst on testosterone. | PMC10089314 | |
Primary outcome | Differences between the groups are presented as mean differences along with 95% confidence intervals. There were no treatment-associated differences in quadriceps extension at 30 degrees in Newton meters (Nm) (mean difference [95% CI]: 4.69 Nm [-5.68,11.46]) and 60 degrees (2.31 Nm [-4.38, 6.84]) during the testosterone period versus the placebo period ( | PMC10089314 | ||
Changes in outcome measures across placebo and testosterone arms and the open label extension arm. | Results are presented as raw number, p value and 95% confidence intervals (lower, upper). Bolded results have significant 95% CI. Placebo = placebo phase, when the participants were provided with the placebo (either 0–12 weeks or 14–26 weeks depending on the participant). Testosterone = testosterone phase, when the participans were provided with testosterone (either 0–12 weeks or 14–26 weeks depending on the participant). OLE = open label extension. Difference Placebo / Testosterone refers to the difference between the placebo and testosterone phase of the trial. Difference end of study and OLE refers to the difference between the week 26 and the OLE 12 months result; and is presented in 95% CI and p values. Between the placebo and the testosterone phase was a wash out period. Nm = Newton meters, sec = seconds, kg = kilograms, cm = centimetre, m = meter. As not all participants were able to perform all outcome measures, n refers to the number of individuals analysed in each arm. | PMC10089314 | ||
Secondary outcomes | SECONDARY | There were no treatment-associated differences in lean body mass assessed by DXA (mean difference [95% CI]: 0.30 kg [-0.77,1.38]). The remainder of the secondary outcomes showed no treatment-associated differences ( | PMC10089314 | |
Safety blood results across baseline, placebo, testosterone arms and the OLE. | ADVERSE EVENTS | NA = not available and is also utilised when an individual withdrew from the trial. The highlighted numbers are listed as adverse events. The trial has been split into baseline, placebo and testosterone arms. Placebo = placebo phase, when the participants were provided with the placebo (either 0–12 weeks or 14–26 weeks depending on the participant). Testosterone = testosterone phase, when the participans were provided with testosterone (either 0–12 weeks or 14–26 weeks depending on the participant). The 6 months and 12 months columns refers to the OLE 6 month and 12 month time periods. | PMC10089314 | |
Patient reported outcome questionnaires | Within the RAND-SF-36, there was a difference between testosterone and placebo groups in the domain of emotional wellbeing (mean difference [95% CI]: 6 [1.71:10.29]), with participants scoring higher in this domain (indicating better health status) during the testosterone arm compared to the placebo arm ( | PMC10089314 | ||
Change in IBM-FRS total score across the study period. | The IBM-FRS consists of 10 questions, each of which can be scored 0–4. A score of 40 out of 40 indicates no impairment in function. This graph maps the change in total IBM-FRS score across the study arms. | PMC10089314 | ||
Comparison of the RAND-SF-36 and IBM-FRS testosterone and placebo results. | RAND-SF-36 | PMC10089314 | ||
Adverse events | cramping, pain | ADVERSE EVENTS | A high rate of participant adherence to the study protocol was verified through participant-reported medication and exercise diaries, combined with drug reconciliation processes. The most common adverse events (AEs) during the crossover period were falls and calf swelling, pain or cramping ( | PMC10089314 |
Adverse events dependent on trial arm. | ADVERSE EVENTS | The adverse events for this study are separated into placebo, testosterone and OLE arms. Placebo = placebo phase, when the participants were provided with the placebo (either 0–12 weeks or 14–26 weeks depending on the participant). Testosterone = testosterone phase, when the participans were provided with testosterone (either 0–12 weeks or 14–26 weeks depending on the participant). OLE = open lable extension. | PMC10089314 | |
Open label extension study | Two men declined to enter the OLE, leaving 12 participants. The results for the 2MWT, peak torque extension 60 degrees, right grip strength and left grip strength have been provided as graphs ( | PMC10089314 | ||
Results of the OLE study across 6 and 12 months. | SECONDARY | A summary of four of the secondary outcome measures separated into three timepoints—the end of the trial, 6 months and 12 months. The black line in the graphs refers to the average. Ids = participant IDs. | PMC10089314 | |
Post- trial survey | This optional survey was answered by 71% of participants (n = 10) and their partners (n = 10). Of these, 70% of participants and 60% of their partners correctly determined when the participant was on the testosterone arm of the study. From the participant perspective, this was because of perceived changes in libido (n = 1), energy (n = 3) or both (n = 2), although one participant did not notice either of these. Partners also noted changes in libido (n = 1), energy (n = 1) or both (n = 1). The remainder did not report any changes (n = 3). Many of the participants (n = 6) and partners (n = 7) discussed these changes together which may have led to some unintentional unblinding. | PMC10089314 | ||
Discussion | heterogenous, worsening disability, loss of muscle mass, pain, muscle disease | DISEASE PROGRESSION, ADVERSE EVENTS, EVENT, DISEASE, MUSCLE DISEASE | In this 26-week pilot study comparing the combination of testosterone supplementation and exercise training versus exercise alone, we were unable to detect a significant additional effect of testosterone on muscle strength or physical function in men with IBM over the 12-week intervention period. However, individuals on testosterone had improved emotional wellbeing on the RAND-SF-36. Twelve men requested the OLE due to perceived positive effects of testosterone.The emotional wellbeing aspect of the RAND-SF-36 refers to general mental health including questions related to psychological distress and well-being. In this study, there was an improvement in emotional wellbeing when on testosterone, which suggests it may have a positive influence on mood. Other aspects of the RAND-SF-36 scale did not change significantly between the two treatment periods, meaning that individuals did not feel that testosterone helped with physical functioning, social functioning, pain, energy or role limitations due to emotional / physical health.The natural history of IBM is one of relentless decline with progressive loss of muscle mass, strength and worsening disability. Prior studies have shown an annual decline in the IBMFRS between 2.7–3.8 points per year [The most commonly reported adverse events during the trial were falls. Unfortunately, due to the nature of IBM, falls can be a particularly common event independent of age and years since first symptoms [In the post study survey given to participants and their partners, 70% of participants and 60% of their partners correctly determined when the participant was on the testosterone arm due to perceived changes in libido and energy. This has the potential to unintentionally unblind the study and bias the results, but also highlights an important area for discussion with patients receiving testosterone therapy. Increases in libido and energy and mood changes are likely to impact patients’ relationships and this may in turn affect the acceptability of testosterone as a therapy. Future studies need to consider and potentially allow for the impact of testosterone on these domains within the study design.Strengths of this study include the randomised study allocation and its double-blind crossover design. Many parameters were assessed to enable a more comprehensive analysis of the potential relationship between IBM and testosterone replacement therapy. Participant adherence was excellent throughout the crossover study with no participant drop out. Limitations include the small, heterogenous population of individuals with IBM. However this is a relatively large sample size for a single centre randomised trial given the prevalence of the disease within Australia and globally. Given that this is a relatively rare condition, individuals enrolled were at vastly different stages of disease progression. This posed a challenge in creation of homogenous exercise programmes and determining suitable outcome measures, as some individuals were wheelchair-bound or unable to participate in some physical assessments. The crossover trial design attempted to mitigate this issue, however a large multi-centre study would be better as it will allow for selection of a larger, more homogenous group of individuals with IBM with outcome measures better suited to their functional level. There is also the possibility that no significance was noted in this study because the 12-week duration of intervention was too short. Although 12 weeks should be sufficient in healthy populations to detect changes in the predetermined outcome measures adopted here, perhaps in an older population with muscle disease a longer duration study is required to be able to measure a significant difference. For trials in the future, it may be beneficial to perform a double blinded, randomised controlled trial over a longer duration (e.g. 6 to 12 months).In conclusion, this pilot study did not suggest a significant additive effect of testosterone combined with exercise over 12 weeks to improve muscle strength or physical function in men with IBM. However, testosterone improved patient perceived emotional wellbeing; and may confer a stabilisation effect on specific measures muscle strength and physical function. The complete retention rate of the main study and the willingness of most participating men to enter an OLE suggests that larger and longer duration studies using testosterone are warranted and feasible in this population. | PMC10089314 |
Supporting information | PMC10089314 | |||
CONSORT 2010 checklist: Testosterone treatment combined with exercise to improve muscle strength, physical function and quality of life in men affected by inclusion body myositis: A randomised, double-blind, placebo-controlled, crossover trial. | (PDF)Click here for additional data file.We would like to acknowledge Benjamin Adams & Behnaz Shatahmassebi; as well as the IBM patients who participated in this study, their partners and support networks. | PMC10089314 | ||
References | PMC10089314 | |||
Background | TYPE 2 DIABETES | We assessed the impact of 24 months of treatment with ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on endothelial function in patients with type 2 diabetes as a sub-analysis of the PROTECT study. | PMC10199575 | |
Methods | VASODILATION | In the PROTECT study, patients were randomized to receive either standard antihyperglycemic treatment (control group, n = 241 ) or add-on ipragliflozin treatment (ipragliflozin group, n = 241) in a 1:1 ratio. Among the 482 patients in the PROTECT study, flow-mediated vasodilation (FMD) was assessed in 32 patients in the control group and 26 patients in the ipragliflozin group before and after 24 months of treatment. | PMC10199575 | |
Results | HbA1c levels significantly decreased after 24 months of treatment compared to the baseline value in the ipragliflozin group, but not in the control group. However, there was no significant difference between the changes in HbA1c levels in the two groups (7.4 ± 0.8% vs. 7.0 ± 0.9% in the ipragliflozin group and 7.4 ± 0.7% vs. 7.3 ± 0.7% in the control group; P = 0.08). There was no significant difference between FMD values at baseline and after 24 months in both groups (5.2 ± 2.6% vs. 5.2 ± 2.6%, P = 0.98 in the ipragliflozin group; 5.4 ± 2.9% vs. 5.0 ± 3.2%, P = 0.34 in the control group). There was no significant difference in the estimated percentage change in FMD between the two groups (P = 0.77). | PMC10199575 | ||
Conclusions | TYPE 2 DIABETES | Over a 24-month period, the addition of ipragliflozin to standard therapy in patients with type 2 diabetes did not change endothelial function assessed by FMD in the brachial artery. | PMC10199575 | |
Keywords | Registration Number for Clinical Trial: jRCT1071220089 ( | PMC10199575 | ||
Introduction | heart failure, atherosclerosis | ENDOTHELIAL DYSFUNCTION, ATHEROSCLEROSIS, EVENTS, HEART FAILURE, TYPE 2 DIABETES | Sodium glucose cotransporter 2 (SGLT2) inhibitors are oral glucose medicines that lower glucose levels by reducing the renal reabsorption of glucose. Some meta-analyses and large clinical trials have shown that SGLT2 inhibitors reduce cardiovascular events in patients with type 2 diabetes and reduced the rate of hospitalization for heart failure in patients with heart failure [Endothelial dysfunction is regarded as the first stage in the etiology of atherosclerosis and plays a significant role in the progression of atherosclerosis, leading to cardiovascular issues [The PROTECT study was a multicenter prospective study designed to test the inhibitory impact of an SGLT2 inhibitor on the development of atherosclerosis based on intima-media thickness over a 24-month follow-up period [ | PMC10199575 |
Methods | PMC10199575 | |||
Study design and patients | TYPE 2 DIABETES | The rationale and design of the PROTECT study (University Hospital Medical Information Network Center: ID000018440) have already been explained [Between September 2015 and June 2018, 488 patients with type 2 diabetes were enrolled, and 482 patients were randomized to receive either standard antihyperglycemic treatment (control group, n = 241) or add-on ipragliflozin treatment (ipragliflozin group, n = 241) at a 1:1 ratio (Fig.
Flow diagram of participants in the PROTECT studyIn the PROTECT study, the primary endpoint in the main analysis was the change in the mean common carotid artery IMT from baseline to 24 months after the start of treatment; the results have already been reported [Of the 488 patients, serial FMD measurements were performed in 32 patients in the control group and 26 patients in the ipragliflozin group before and after 24 months of treatment (Fig. | PMC10199575 | |
FMD measurement protocol | artery transducer | REACTIVE HYPEREMIA | After overnight fasting, all experiments were conducted in the morning. All of the patients were kept in the supine position in a calm, dark, air-conditioned room with a constant temperature of 22 ℃–25 ℃ throughout the study. A 23-gauge polyethylene catheter was placed in the left deep antecubital vein to collect blood samples. Endothelium-dependent FMD was assessed based on the vascular response to reactive hyperemia in the brachial artery. Observers were blinded to the examinations.FMD was measured using the same ultrasound device designed for FMD measurements and the same protocol in all institutions. A high-resolution linear artery transducer was coupled to computer-assisted analysis software (UNEXEF18G, UNEX Co, Nagoya, Japan), which uses an automated edge detection system for the measurement of brachial artery diameter [ | PMC10199575 |
Statistical analysis | REGRESSION | Results are presented as means ± SD. Statistical significance was defined as a probability value < 0.05, and all stated probability values were two-sided. The chi-square test was used to compare categorical variables and an unpaired Student’s t-test was used to compare the mean values of continuous variables between the groups. A paired Student’s t-test was used to assess the differences in the mean values of continuous variables between baseline and 24 months. A linear regression model was used to estimate the changes in FMD over time by treatment (control vs. ipragliflozin group). To estimate the group differences in the percentage changes in FMD, the models included treatment, age, sex, and baseline FMD. Data were processed using R 4.0.1 (R Foundation for Statistical Computing, Vienna, Austria). | PMC10199575 | |
Results | PMC10199575 | |||
Changes in clinical characteristics after 24 months | In the ipragliflozin group, body mass index was significantly decreased after 24 months (28.4 ± 3.8 vs. 26.7 ± 3.8 kg/m | PMC10199575 | ||
Glycemic control | The baseline HbA1c and fasting plasma glucose levels were comparable between the two groups. The HbA1c level significantly decreased after 24 months of treatment compared to the baseline value in the ipragliflozin group (7.4 ± 0.8% vs. 7.0 ± 0.9%; P < 0.01), but not in the control group (7.4 ± 0.7% vs. 7.3 ± 0.7%; P = 0.27). However, there was no significant difference between changes in HbA1c levels in the two groups (7.4 ± 0.8% vs. 7.0% ± 0.9% in the ipragliflozin group and 7.4 ± 0.7% vs. 7.3 ± 0.7% in the control group; P = 0.08 Table | PMC10199575 | ||
Endothelial function | VASODILATION | Figure
Changes in estimated percentage change in flow-mediated vasodilation (FMD) in the ipragliflozin group and the control group. The mixed-effects model included treatment, age, sex, and FMD at baseline | PMC10199575 | |
Discussion | TYPE 2 DIABETES | The present study demonstrated that adding ipragliflozin to standard therapy for 24 months in patients with type 2 diabetes did not change endothelial function as measured by FMD in the conduit brachial artery. | PMC10199575 | |
Impact of SGLT2 inhibitors on FMD | TYPE 2 DIABETES | The short-term impacts of SGLT2 inhibitors on the vascular function in patients with type 2 diabetes are controversially reported [ | PMC10199575 | |
Impact of SGLT2 inhibitors on endothelial function | heart failure | EVENTS, HEART FAILURE, TYPE 2 DIABETES | Several clinical trials have shown that SGLT2 inhibitors can prevent cardiovascular events in patients with type 2 diabetes and heart failure [ | PMC10199575 |
Study limitations | TYPE 2 DIABETES | This study has some limitations. First, the number of subjects in the present study, as a sub-analysis of the PROTECT trial, was relatively small. Because FMD was an optional measurement in the PROTECT trial, there was an insufficient sample size for power calculation, and the analysis may have been underpowered. However, the results of analysis of the PROTECT trial, a multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, provide valuable information that may help us to understand the impact of ipragliflozin on endothelial function in patients with type 2 diabetes. Further studies with a larger number of participants are required to validate the long-term impacts of SGLT2 inhibitors on endothelial function in patients with type 2 diabetes. Second, LDL cholesterol levels in the control group after 24 months were significantly lower than those in the ipragliflozin group after 24 months, although there was no change in the use of dyslipidemia-improving drugs, including statins, ezetimibe, fibrates, and eicosapentaenoic acid, in either group. Lowering LDL cholesterol levels improves vascular endothelial function. The lower LDL cholesterol level in the control group at 24 months may have been one reason for the lack of a significant difference in FMD between the two groups. However, there was no significant difference in FMD between the two groups after adjusting for LDL cholesterol. | PMC10199575 | |
Conclusion | TYPE 2 DIABETES | Over a 24-month period, the addition of ipragliflozin to standard therapy in patients with type 2 diabetes did not change the endothelial function assessed by FMD in the brachial artery. | PMC10199575 | |
Acknowledgements | Shinichi, Kondo, Tadaaki, Hirotsugu | TAKAHARA, HEART, CROSS, SHIGA | The authors thank all the participants, investigators, board members, and medical staff involved in the RPOTECT study. The authors are also grateful to the members of the Data and Safety Monitoring Board: Munehide Matsuhisa, MD, PhD (Tokushima University Graduate School, Tokushima, Japan), Junya Ako, MD, PhD, (Kitasato University, Sagamihara, Japan), Yoshimasa Aso, MD, PhD (Dokkyo Medical University, Mibu, Japan), Masaharu Ishihara, MD, PhD (Hyogo College of Medicine, Nishinomiya, Japan), Kazuo Kitagawa, MD, PhD (Tokyo Women’s Medical University, Tokyo, Japan), and Akira Yamashina, MD, PhD (Kiryu University, Midori, Japan). Protect study investigators and organization:Principal Investigators: Koichi Node, MD, PhD (Saga University, Saga, Japan) and Toyoaki Murohara, MD, PhD (Nagoya University, Naogya, Japan). Masafumi Kitakaze, MD, PhD (Hanwa Daini Senboku Hospital, Sakai, Japan). Steering Committee: Yoshihiko Nishio, MD, PhD (Kagoshima University, Kagoshima, Japan), Teruo Inoue, MD, PhD (Dokkyo Medical University, Mibu, Japan), Mitsuru Ohishi, MD, PhD (Kagoshima University, Kagoshima, Japan), Kazuomi Kario, MD, PhD (Jichi Medical University School of Medicine, Shimotsuke, Japan), Masataka Sata, MD, PhD (Tokushima University Graduate School, Tokushima, Japan), Michio Shimabukuro, MD, PhD (Fukushima Medical University, Fukushima, Japan), Wataru Shimizu, MD, PhD (Nippon Medical School, Tokyo, Japan), Hideaki Jinnouchi, MD, PhD, (Jinnouchi Hospital, Kumamoto, Japan), Isao Taguchi, MD, PhD, (Dokkyo Medical University, Saitama Medical Center, Saitama, Japan), Hirofumi Tomiyama, MD, PhD (Tokyo Medical University, Tokyo, Japan), and Koji Maemura, MD, PhD (Nagasaki University, Nagasaki, Japan). Executive Committee: Makoto Suzuki, MD, PhD (Yokohama Minami Kyosai Hospital, Yokohama, Japan), Shinichi Ando, MD, PhD (Saiseikai Futsukaichi Hospital, Chikushino, Japan), Kazuo Eguchi, MD, PhD (Saitama Red Cross Hospital, Saitama, Japan), Haruo Kamiya, MD, PhD (Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan), Tomohiro Sakamoto, MD, PhD (Saiseikai Kumamoto Hospital, Kumamoto, Japana), Hiroki Teragawa, MD, PhD (JR Hiroshima Hospital, Hiroshima, Japan), and Mamoru Nanasato, MD, PhD (Sakakibara Heart Institute, Fuchu, Japan). Data and Safety Monitoring Board: Munehide Matsuhisa, MD, PhD (Tokushima University Graduate School, Tokushima, Japan), Junya Ako, MD, PhD, (Kitasato University, Sagamihara, Japan), Yoshimasa Aso, MD, PhD (Dokkyo Medical University, Mibu, Japan), Masaharu Ishihara, MD, PhD (Hyogo College of Medicine, Nishinomiya, Japan), Kazuo Kitagawa, MD, PhD (Tokyo Women’s Medical University, Tokyo, Japan), and Akira Yamashina, MD, PhD (Kiryu University, Midori, Japan). Imaging Core Laboratory: Tsukuba Echo Core Laboratory. LLC, Tomoko Ishizu, MD, PhD (Tsukuba University, Tsukuba, Japan). Monitoring: Yumi Ikehara, MSc and Shinichiro Ueda, MD, PhD (Clinical Trial and Management Center, University of Ryukyus Hospital, Nishihara, Japan). Audit Team: Clinical Research Support Center, University of the Ryukyus, Nishihara, Japan. Data Center and Data Management: Ayako Takamori, Ph.D. (Clinical Research Center, Saga University Hospital, Saga, Japan). Statistical Analysis: Hisako Yoshida, PhD (Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan) and Takumi Imai, PhD (Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan). Study Secretariat: Atsushi Tanaka, MD, PhD (Saga University, Saga, Japan), Miki Mori (Saga University, Saga, Japan), Kaori Yamaguchi (Saga University, Saga, Japan), Soiken Inc., Tokyo, Japan, and the Organization for Clinical Medicine Promotion, Tokyo, Japan. Site Investigators (duplicates excluded): Drs. Machiko Asaka and Tetsuya Kaneko (Saga University, Saga, Japan), Drs. Masashi Sakuma, Shigeru Toyoda, Takahisa Nasuno, Michiya Kageyama, Jojima Teruo, Iijima Toshie, and Haruka Kishi (Dokkyo Medical University, Mibu, Japan), Dr. Hirotsugu Yamada, Kenya Kusunose, Daiju Fukuda, Shusuke Yagi, Koji Yamaguchi, Takayuki Ise, Yutaka Kawabata, and Akio Kuroda (Tokushima University Graduate School, Tokushima, Japan), Drs. Yuichi Akasaki and Mihoko Kurano (Kagoshima University, Kagoshima, Japan), Drs. Satoshi Hoshide, Takahiro Komori, Tomoyuki Kabutoya, and Yukiyo Ogata (Jichi Medical University School of Medicine, Shimotsuke, Japan), Drs. Yuji Koide, Hiroaki Kawano, Satoshi Ikeda, Satoki Fukae and Seiji Koga (Nagasaki University, Nagasaki, Japan), Dr. Yukihito Higashi, Shinji Kishimoto, Masato Kajikawa, and Tatsuya Maruhashi (Hiroshima Universsity, Hiroshima, Japan), Dr. Yoshiaki Kubota (Nippon Medical School, Tokyo, Japan), Drs. Yoshisato Shibata and Nehiro Kuriyama (Miyazaki Medical Association Hospital, Miyazaki, Japan), Dr. Ikuko Nakamura (Saga-Ken Medical Centre Koseikan, Saga, Japan), Dr. Kanemitsu Hironori (International University of Health and Welfare, Nasushiobara, Japan), Dr. Bonpei Takase (National Defense Medical College, Tokorozawa, Japan), Drs. Yuichi Orita, Chikage Oshita, and Yuko Uchimura (JR Hiroshima Hospital, Hiroshima, Japan), Drs. Ruka Yoshida, Yukihiko Yoshida, Hirohiko Suzuki, Yasuhiro Ogura, Mayuho Maeda, Masaki Takenaka, Takumi Hayashi, and Mirai Hirose (Nagoya Daini Red Cross Hospital, Nagoya, Japan), Dr. Itaru Hisauchi (Dokkyo Medical University, Saitama Medical Center, Saitama, Japan), Drs. Toshiaki Kadokami and Ryo Nakamura (Saiseikai Futsukaichi Hospital, Chikushino, Japan), Dr. Junji Kanda (Asahi General Hospital, Asahi, Japan), Dr. Kazuo Matsunaga (Imari Arita Kyoritsu Hospital, Matsuura, Japan), Drs. Masaaki Hoshiga, Koichi Sohmiya, and Yumiko Kanzaki (Osaka Medical and Pharmaceutical University), Dr. Arihiro Koyosue (Tokyo-Eki Center-Building Clinic, Tokyo, Japan), Drs. Hiroki Uehara, Naoto Miyagi, Toshiya Chinen, Kentaro Nakamura, Chikashi Nago, Suguru Chiba, Sho Hatano, Yoshikatsu Gima, and Masami Abe (Urasoe General Hospital, Urasoe, Japan), Drs. Masayoshi Ajioka, Hiroshi Asano, Yoshihiro Nakashima, Hiroyuki Osanai, Takahiro Kanbara, and Yusuke Sakamoto (Tosei General Hospital, Seto, Japan), Drs. Mitsutoshi Oguri, Shiou Ohguchi, Kunihiko Takahara, Kazuhiro Izumi, and Kenichiro Yasuda (Kasugai Municipal Hospital, Kasugai, Japan), Drs. Akihiro Kudo and Noritaka Machii (Fukushima Medical University, Fukushima, Japan), Drs. Ryota Morimoto, Yasuko Bando, Takahiro Okumura, and Toru Kondo (Nagoya University, Naogya, Japan), Drs. Shin-ichiro Miura, Yuhei Shiga, Joji Mirii, Makoto Sugihara, and Tadaaki Arimura (Fukuoka University School of Medicine, Fukuoka, Japan), Dr. Junko Nakano (Saiseikai Fukushima General Hospital, Fukushima, Japan), Drs. Tomohiro Sakamoto and Kazuhisa Kodama (Saiseikai Kumamoto Hospital, Kumamoto, Japan), Drs. Nobuyuki Ohte, Tomonori Sugiura, and Kazuaki Wakami (Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan), Drs. Yasuhiko Takemoto, Minoru Yoshiyama, Taichi Shuto, and Kazuo Fukumoto (Osaka City University, Osaka, Japan), Drs. Yosuke Okada, Kenichi Tanaka, Satomi Sonoda, Akemi Tokutsu, Takashi Otsuka, Fumi Uemura, Kenji Koikawa, Megumi Miyazaki, Maiko Umikawa, and Manabu Narisawa (University of Occupational and Environmental Health, Japan, Kitakyusyu, Japan), Dr. Machi Furuta (Wakayama Medical University, Wakayama, Japan), Dr. Hiroshi Minami (Aidu Chuo Hospital, Aiduwakamatsu, Japan), Dr. Masaru Doi (Doi Naika Clinicm Kumamoto, Japan), Drs. Kazuhiro Sugimoto and Susumu Suzuki (Ohta Nishinouchi Hospital, Koriyama, Japan), and Drs. Akira Kurozumi and Kosuke Nishio (Wakamatsu Hospital of the University of Occupational and Environmental Health, Japan, Kitakyusyu, Japan). | PMC10199575 |
Authors contributions | HT | YH and SK drafted the manuscript and conceived the study. TI performed statistical analyses. SK, YH, KE, KF, HT, and KM measured the FMD. AT and KN critically revised the manuscript for important intellectual content. All the authors contributed to the manuscript and approved the submitted version. All authors read and approved the final manuscript. | PMC10199575 | |
Funding | This study was funded by Astellas Pharma Inc. Japan, and Prof. Koichi Node received the funding. The funding agency of the trial had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. | PMC10199575 | ||
Availability of data and materials | The data are available upon reasonable request from researchers who submit a detailed proposal outlining their intended use of the data and after approval by the principal investigators and steering committee of the PROTECT study. Inquiries must be addressed to the corresponding author (or the study secretariat: substudy_protect@clin-med.org). | PMC10199575 | ||
Declarations | PMC10199575 | |||
Ethics approval and consent to participate | The study protocol for this sub-analysis was approved by the Ethics Committee of Saga University Hospital (2022-09-02) and registered (jRCT1071220089). All the individuals provided written informed consent to participate in the study. All methods were performed in accordance with the Declaration of Helsinki and relevant guidelines and regulations in Japan. | PMC10199575 | ||
Consent for publication | All authors have read and approved the submission of the manuscript. | PMC10199575 | ||
Competing interests | Competing interestsYH received honoraria
from Astellas, AstraZeneca, MSD, Boehringer Ingelheim, Takeda, Bayer, Novo
Nordisk, Fuji, Mochida, Eli Lilly, Teijin Pharma, Daiichi Sankyo, Otsuka, Kowa,
Novartis, and Mitsubishi Tanabe and a research grant from Kao. TI received
lecture fees from JCR Pharmaceuticals and Kyowa Kirin and outsourcing fees from
the Organization for Clinical Medicine Promotion. KM received honoraria from
Daiichi Sankyo, Novartis, Takeda, and Pfizer and a research grant from Daiichi
Sankyo and Biotronik. AT received honoraria from Boehringer Ingelheim and
research funding from GlaxoSmithKline, Takeda, Bristol, Myers Squibb, and Novo
Nordisk. NK has received honoraria from AstraZeneca, Bayer Yakuhin, Boehringer
Ingelheim Japan, Daiichi Sankyo, Eli Lilly Japan, Mitsubishi Tanabe Pharma,
MSD, Novartis Pharma, Ono Pharmaceutical, Otsuka; Research grants from Asahi Kasei, Astellas,
Boehringer Ingelheim Japan, Fujiyakuhin, Mitsubishi Tanabe Pharma, Mochida
Pharmaceutical, Novartis Pharma, and Teijin Pharma; and scholarships from Bayer
Yakuhin, Japan Lifeline, and Teijin Pharma. The authors declare that they have no competing
interests. | PMC10199575 | ||
References | PMC10199575 | |||
Background | menopausal syndrome, senile dementia, osteoporosis, senile diseases | MENOPAUSAL SYNDROME, SENILE DEMENTIA, OSTEOPOROSIS | Edited by: Andrew Scott LaJoie, University of Louisville, United StatesReviewed by: Seyedmohammad Mirhosseini, Shahroud University of Medical Sciences, Iran; Kristi King, University of Louisville, United StatesThis article was submitted to Public Health Education and Promotion, a section of the journal Frontiers in Public Health†These authors share first authorshipMenopausal women may experience menopausal syndrome and long-term effects caused by low estrogen levels, such as senile dementia and osteoporosis in the elderly. Most menopausal women may have misconceptions about menopause and low use of pharmacological interventions. These misconceptions may damage the quality of life and miss the critical period for preventing senile diseases. Thus, enhancing the awareness of menopausal women regarding psychosocial and physical changes through health education programs was a way to improve positive attitudes toward menopause and make further treatment options. | PMC10060660 |
Objectives | menopausal syndrome | MENOPAUSAL SYNDROME | This study aimed to evaluate the effect of multidisciplinary health education based on lifestyle medicine on menopausal syndrome and lifestyle behaviors of menopausal women. | PMC10060660 |
Methods | The study was conducted in several hospitals in Chongqing, China. The two groups were from different hospitals with similar medical levels in order to reduce information contamination. It was designed as a clinical controlled trial in which the intervention group ( | PMC10060660 | ||
Results | menopausal syndrome | MENOPAUSAL SYNDROME | Post intervention testing indicated that menopausal syndrome of participants was significantly improved in the intervention group compared to the control group ( | PMC10060660 |
Conclusions | menopausal syndrome | MENOPAUSAL SYNDROME | The multidisciplinary health education based on lifestyle medicine was effective in improving the menopausal syndrome and healthy lifestyle behaviors of menopausal women. Studies with extended observation period and larger sample size are in need to evaluate the long-term scale-up effects of the multidisciplinary health education. | PMC10060660 |
1. Introduction | insomnia, chronic disease, depression, menopausal syndrome, osteoporosis, arthralgia | DISEASE, SENILE DEMENTIA, MENOPAUSAL SYNDROME, OSTEOPOROSIS, CHRONIC DISEASE | Women typically enter menopause gradually at the age of 40 and continue until the age of 60. Due to declining ovarian function and falling estrogen levels, women in this period may experience menopausal syndrome which may manifest as hot flashes, arthralgia, insomnia, depression and so on (Despite many complaints that menopausal women may experience, there are some medical measures that can be improved and prevented. Menopausal hormone therapy (MHT) may be one the most effective measure to alleviate women's menopausal syndrome and prevent senile dementia and osteoporosis in the elderly (Despite the acknowledged benefits of MHT, many menopausal women have misconceptions about menopause and low use of pharmacological interventions, which may depend on cultural, social and lifestyle factors (Lifestyle Medicine (LM) is a growing field of medicine, which is most comprehensively defined as “the integration of lifestyle practices into the modern practice of medicine both to lower the risk factors for chronic disease and/or, if disease already present, serve as an adjunct in its therapy” (Physical exercise and healthy diet have many benefits for menopausal women. Exercise has been assessed as an alternative treatment option for alleviating menopausal symptoms, including, psychological, vasomotor, somatic and sexual symptoms in Stojanovska et al.'s study (Even though previous studies ( | PMC10060660 |
2. Methods | PMC10060660 | |||
2.1. Study setting and participants | menopausal syndrome | MENOPAUSAL SYNDROME, DISEASES, OSTEOPOROSIS | The study was conducted in six hospitals in Chongqing, China from August 2021 to August 2022. Participants were from different hospitals with Grade-A Tertiary Hospital in order to reduce information contamination. Located in southwestern China, Chongqing is known as a “miniature of China” because its urban-rural distribution, social-economic profile, and geographic characteristics were close to the national average. Currently, Chongqing consists of 38 districts and counties with 34.13 million residents, among which middle-aged woman account for 38.7% (Participants were recruited in the study if they met the following inclusion criteria: women aged 40–60 years and suffered from menopausal syndrome assessed by the modified Kupperman Menopause Index (mKMI). The following exclusion criteria were applied: (1) without these diseases such as malignant tumors/severe organic dysfunction/acute infectious diseases/severe osteoporosis; (2) receiving psychological treatment; (3) cannot exercise. | PMC10060660 |
2.2. Sample size calculation | Sample size for the study was decided by comparing the KMI before and after the MHELM among participants in polit, using the formula | PMC10060660 | ||
2.3. Intervention | This study was designed as a clinical controlled trial in which intervention group and control group were matched for age, age at menarche, menopausal symptoms and drug use status at enrollment. The criterion of matching referred that no statistical significance was detected in the difference analyses of baseline indicators according to clinical consideration (Comparison of the baseline characteristics between groups.Two group were matched for age, age at menarche, menopausal symptoms and drug use status.CONSORT flow chart. | PMC10060660 | ||
2.3.1. Multidisciplinary health education based on lifestyle medicine | MHELM comprised of three parts: 1-day Multidisciplinary Health Education Sessions offline, 7-week Group Healthy Lifestyle Management online, and half-day Patient Symposium offline. | PMC10060660 | ||
2.3.1.1. One-day multidisciplinary health education sessions | hypoestrogenism, pelvic muscle, osteoporosis | OSTEOPOROSIS | The sessions were provided by a multidisciplinary team (MDT) consisting of six experts under the professional background of gynecologic endocrinology, sports medicine, nutrition, music therapy, psychology, pharmacy, and osteoporosis. The sessions focused on menopausal symptom management, encouragement of physical activity, healthy diet, and spiritual support, osteoporosis prevention, pelvic muscle rehabilitation and medication guidance. The key topics of the sessions included the importance of menopause, the health implications of hypoestrogenism, the risks and benefits of hormonal and complementary therapy for menopausal symptoms and the importance of lifestyle medicine in the menopause stage, particularly on important topics of nutritionally-balanced diets and exercise (The 1 day of multidisciplinary health education sessions flow. | PMC10060660 |
2.3.1.2. Seven-week group healthy lifestyle management | Seven-week Group Healthy Lifestyle Management following the 1-day multidisciplinary health education sessions were provided by professionals through WeChat. The content of the online group intervention included: reading, audio and video products of science popularization on the knowledge of menopausal health, reasonable diet and exercise. Psychological counseling was also provided based on music therapy, including music meditation, music rhythm, painting with music, music singing and listening to pure music. WeChat log of the daily physical activities and diet of participants were shared to professionals for assessment and guidance. Additionally, reminders were given by phone calls to the women who failed to adhere. | PMC10060660 | ||
2.3.1.3. Half-day patient symposium | After completing the 7-week Group Healthy Lifestyle Management, patients revisited the hospital for the Half-day Patient Symposium. In the symposium, experts reemphasized the importance of MHELM, and participants were encouraged to share their feelings and experience on MHELM. Participants who completed the whole process of MHELM would obtain a small gift. | PMC10060660 | ||
2.3.2. Control group | Participants in the control group filled out the pre- and post- questionnaires with a 2-month interval of follow-up, and in between they only received routine outpatient health guidance from perimenopausal physicians on the knowledge of perimenopausal symptoms and healthy lifestyle at enrollment. | PMC10060660 | ||
2.3.3. Ethical considerations | All the participants voluntarily signed the informed consent before the study. This study was approved by Institutional Review Board of the Third Affiliated Hospital of Chongqing Medical University (Number: 202112) and has been registered in Chinese Clinical Trial Registry (Registration number: ChiCTR2100049969). | PMC10060660 | ||
2.4. Outcomes measurement | menopausal syndrome | MENOPAUSAL SYNDROME | All participants filled out a pre-testing questionnaire at baseline and a post-testing questionnaire after 2 months. The primary outcomes included changes of women's menopausal syndrome and lifestyle behaviors such as physical activity and dietary status. Participants' feedback of MHELM group were interviewed as the second outcome for qualitative summary. The Questionnaires consisted of modified Kupperman Menopausal Index (mKMI) for menopausal syndrome, International Physical Activity Questionnaire (IPAQ) for physical activities and Dietary Habits Questionnaire. Socio-demographics regarding age, age at menarche, level of education, income, reproductive number and drug use status were collected as well. | PMC10060660 |
2.4.1. mKMI for menopausal syndrome | menopausal syndrome, Menopausal syndrome | MENOPAUSAL SYNDROME, MENOPAUSAL SYNDROME | Menopausal syndrome was evaluated by the mKMI, which was a widely used scale to measure the presence and severity of menopausal syndrome. mKMI consisted of 13 items assessing the situation of women over the past week. The items included somatic, psychological and urogenital symptoms. The severity of each symptom was rated on a scale ranging from 0 to 3 (0, none; 1, mild; 2, moderate; 3, severe). The total scores ranged from 0 to 63; the higher the scores were, the more severe the symptoms would be. Severity of menopausal syndrome was categorized as: none (0–5 points); mild (6–14 points); moderate (15–30 points); severe (>30 points) ( | PMC10060660 |
2.4.2. IPAQ for physical activities | IPAQ long form was applied to assess physical activity (PA) of the participants. It consisted of 27 items which reflected on the consumed time on walking and engaging in moderate-intensity plus vigorous-intensity activities in terms of different domains in the past week: (1) occupational PA; (2) traffic PA; (3) housework PA; (4) exercise PA; and (5) time spent sitting. Occupational, traffic and housework PA can be integrated as non-exercise daily PA. Weekly energy expenditure of total PA, non-exercise daily PA and exercise PA (MET-min week | PMC10060660 | ||
2.4.3. Dietary habits questionnaire | Dietary status of the participants was assessed by the Dietary Habits Questionnaire, which was adapted from a questionnaire developed by the National High-tech Health Industry Working Committee of China and took account of dietary characteristics of menopausal women ( | PMC10060660 | ||
2.4.4. Participants' feedback in the intervention group | Feedback from the participants in MHELM, including feelings, experience and suggestions, were collected through focus group discussions (FGDs) during the Half-day Patient Symposium. The process of discussions were assessed by perimenopausal physicians and recorded by two other professionals. Thematic analysis method was used to summarize the highlighting viewpoints. | PMC10060660 | ||
2.5. Statistical analysis | Continuous variables that were normally distributed were presented with mean ± standard deviation, and compared using Paired | PMC10060660 | ||
3. Results | PMC10060660 | |||
3.2. Comparison of women's menopausal syndrome, lifestyle behavior | Comparisons of mKMI, IPAQ and dietary status within and between groups were listed in Comparison of mKMI, IPAQ and dietary status within and between groups.PA, physical activity. | PMC10060660 | ||
3.3. Changes in women's menopausal syndrome, lifestyle behavior according different drug use status | Comparisons of the changes on mKMI, IPAQ and dietary status were listed in Changes of KMI, IPAQ and dietary status within and between groups according different drug use status.The value of comparison within and between groups is the change value of the test (the post-test value minus the pre-test value); PA, physical activity. | PMC10060660 | ||
3.4. The participants' feedback in the intervention group | The women's feedback after participating MHPEI were summarized into the following four themes including relief of menopausal symptoms, awareness and behavior of menopausal health management, relief of negative emotions and improvement of menopausal cognition. Highlighting statements were shown in Participants' feedback in the intervention group (60/100 = 60%). | PMC10060660 | ||
4. Discussion | menopausal syndrome | CHRONIC DISEASES, ESTROGEN DEFICIENCY, MENOPAUSAL SYNDROME, DISEASES, OSTEOPOROSIS | The present study took the lead in exploring the effects of multidisciplinary health education intervention based on lifestyle medicine on menopausal women in China. The current study revealed that MHELM helped the women to feel relief from troublesome menopausal syndrome, improve healthy lifestyle behaviors and enhance awareness of menopausal health management.In our findings, the menopausal syndrome of participants was significantly improved in the intervention group compared to the control group when drug usage was matched between groups. This confirmed that the MHELM intervention was effective in improving the menopausal syndrome. Our observations were consistent with some studies which reported the effectiveness of health education interventions (We observed that the control group had a significant improvement on the symptoms of menopausal syndrome without MHELM intervention. Moreover, the results indicated that the menopausal syndrome of participants had a significant improvement in the hormone drug group compared to the non-hormone drug group. The evidence further confirmed that appropriate medical treatment, especially for MHT, should be taken to relieve the painful symptoms of menopausal women. Furthermore, the symptoms were essentially caused by estrogen deficiency in which case MHT could be the recommended measure to relieve them. Worldwide guidelines have allowed healthcare professionals to gain more clarity into the role of MHT, not only in the relief of troublesome menopausal symptoms, but also in the prevention of chronic diseases associated with aging (In our study, the MHELM intervention has significantly increased the energy expenditure of physical activities, especially in exercise physical activities, and improved the dietary status of women compared to those in control group. Meanwhile, similarly significant improvements were observed in the hormone drug group. Although our findings were consistent with previous studies which reported the effectiveness of lifestyle interventions, previous studies on lifestyle interventions were implemented mostly from the perspective of individuals (Access to the correct information about menopause can help women have more realistic expectations about this period and make better choices among treatment options for coping with menopausal symptoms (The effectiveness of the MHELM intervention depended on the MDT health management, useful lifestyle medicine theoretical framework and close progress monitoring. Thus, the success of our health education intervention would be attributed to a few reasons. Firstly, MHELM intervention was delivered by MDT from expertise of gynecologic endocrinology, sports medicine, music therapy, psychology, nutrition, pharmacy, osteoporosis. The core concept of MDT was patient-centered, individualized and continuously comprehensive treatment schemes for specific diseases based on the multidisciplinary team, which has been widely used over the world in recent years (There were also several limitations of this study. Firstly, we only evaluated the short-term effects of MHELM and long-term effects need to be assessed by extended study period with a scale-up sample. Secondly, in our study only subjective indicators were involved in the assessment from self-reports by questionnaire, suggesting that clinical indicators such as body composition, blood lipid and glucose could be taken in account in future studies. | PMC10060660 |
5. Conclusion | menopausal syndrome | MENOPAUSAL SYNDROME | This study showed that multidisciplinary health education based on lifestyle medicine was effective in improving the menopausal syndrome and healthy lifestyle behaviors of menopausal women. The MHELM may lighten the design and implementation of similar interventions in future studies. Studies with extended Observation period and larger sample size are in need to evaluate the long-term scale-up effects of the multidisciplinary health education. | PMC10060660 |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10060660 | ||
Ethics statement | The studies involving human participants were reviewed and approved by the Institutional Review Board of the Third Affiliated Hospital of Chongqing Medical University (202112). The patients/participants provided their written informed consent to participate in this study. | PMC10060660 | ||
Author contributions | YML participated in field investigation, data collection, and drafting of the manuscript. HYH participated in the design of the study and field investigation and data collection. JXW, YFC, CYW, XYL, and AQD participated in field investigation and data collection. YL participated data analysis. YF, XX, JH, MZ, MFZ, and PY participated in the design of the study. XL and LLY participated in the design of the study, field investigation, data collection, and review of the manuscript. All authors saw and approved the final version.We thanked all women who took the time to participate in this study. | PMC10060660 | ||
Abbreviations | MHT, Menopausal hormone therapy; MHELM, multidisciplinary health education based on lifestyle medicine; mKMI, modified Kupperman Menopause Index; MDT, multidisciplinary team; IPAQ, International Physical Activity Questionnaire; PA, physical activity. | PMC10060660 | ||
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. | PMC10060660 | ||
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. | PMC10060660 | ||
References | PMC10060660 | |||
Subject terms | Adenotonsillectomy, pain | Adenotonsillectomy is the most common daytime surgery performed on children. Anesthesiologists must select the optimal combination of drugs to ensure effective anesthesia effect and prompt recovery in children. The optimal induction dose of ciprofol in children is unclear. In this study, we aim to investigate the effect of different doses of ciprofol on anesthesia induction in children undergoing daytime adenotonsillectomy and provide a reference for clinical use. 144 children aged 3–12 years, ASA I-II, undergoing daytime adenotonsillectomy, were included in this clinical trial. The children were randomly divided into three groups and given 0.4 mg/kg (C4), 0.6 mg/kg (C6), or 0.8 mg/kg (C8) of ciprofol for anesthesia induction. The primary outcome was intubation conditions. Vital signs and injection pain were also recorded. The rates of unacceptable intubation conditions were 30.6%, 8.7%, and 8.2% in the C4, C6, and C8 groups ( | PMC10721598 | |
Introduction | Adenotonsillectomy, respiratory depression, pain | RESPIRATORY DEPRESSION | Anesthesiologists face greater challenges when administering anesthesia to children during daytime surgeries. It requires careful selection of medications and their optimal combination to ensure effective anesthesia and prompt recovery of the child.Adenotonsillectomy is the most common daytime surgery for children. Anesthesiologists typically use tracheal intubation to ensure the safety of the airway during the procedure. Neuromuscular blockers (NMBs) are commonly used to facilitate smooth intubation. In certain elective surgeries, anesthesiologists may try to perform intubation using propofol and opioids without NMBs. However, this approach can pose challenges in achieving optimal intubation conditionsCiprofol is a novel general anesthetic that exhibits rapid onset and recovery times comparable to propofol. It also has low incidences of injection pain and respiratory depression | PMC10721598 |
Materials and methods | comorbid inherited metabolic diseases, allergies, traumatic, trauma | ALLERGIES | This study was approved by the Medical Ethics Committee of Hunan Children’s Hospital (HCHLL-2022–079) and registered with the Chinese Clinical Trial Registry (Registration number: ChiCTR2200063144, Date of Registration: 31/08/2022). All experiments were conducted in compliance with the Declaration of Helsinki and relevant guidelines.Children aged 3–12 years, who had a normal preoperative examination, no history of surgery or trauma, BMI ≤ 20, and an ASA class I–II, were selected to sign an informed consent form prior to undergoing daytime adenotonsillectomy at our hospital. The exclusion criteria included a history of traumatic surgery or allergies, abnormal preoperative findings, comorbid inherited metabolic diseases, and altered surgical procedures.Children were randomly divided into the C4, C6, and C8 groups, and were respectively injected with ciprofol at doses of 0.4 mg/kg, 0.6 mg/kg, and 0.8 mg/kg during the induction. Our study employed double-blinding. After the parents of the children have signed the informed consent form, the investigator will open their randomization envelope and assign the child to the corresponding group. At the same time, the investigator handed the pre-prepared induction medication to the anesthesiologist in charge of the surgery. The medication, ciprofol, is contained in a syringe with an obscured barrel, making the volume of the medication not visible to the anesthesiologist. Assessment of endotracheal intubation and intubation conditions was conducted by an experienced anesthetist with over 5 years of expertise in pediatric anesthesia. This individual was also responsible for documenting vital signs. Children, their parents, and anesthesiologists were blinded to group allocation. | PMC10721598 |
Anesthesia process | pain | SECONDARY | Children were admitted to the operating room with a peripheral intravenous catheter. Their heart rate (HR), mean arterial pressure (MAP), oxygen saturation, and bispectral index (BIS) were monitored. The selected dose of ciprofol was injected during anesthesia induction, and the injection took 30 s. Children were asked if they experienced any injection pain or other discomfort. Afterward, they were administered sufentanil 0.4 mcg/kg and rocuronium 0.3 mg/kg.Endotracheal intubation was performed 90 s after the injection of rocuronium. Intubation conditions were also evaluated. Ciprofol 0.2 mg/kg was administered when BIS was above 75 prior to tracheal intubation (T3). When the intubation conditions were unacceptable, 0.3 mg/kg of rocuronium was administered to ensure successful intubation.Anesthesia was maintained with sevoflurane 2.5–3% (inspired concentration), which was adjusted based on the patient’s vital signs. Sevoflurane inhalation was discontinued at the end of the procedure, and the child was transferred to the postanesthesia care unit (PACU). Extubation and awakening were completed in the PACU, and sugammadex 2 mg/kg was administered to reverse the effect of rocuronium. The child was extubated when spontaneous breathing returned and end-tidal COThe primary outcome was intubation conditions, and the secondary outcomes included vital signs and injection pain. The HR, MAP, and BIS values of the children were recorded at different time points: before induction (T1), 30 s after ciprofol injection (T2), before intubation (T3), 1 min after intubation (T4), and 5 min after intubation (T5). Intubation conditions were assessed as described in previous literature (Table Assessment of intubation conditions.The overall intubation condition was assessed according to the circumstances of each variable: if all variables were rated as excellent or good, the intubation condition was clinically acceptable, and if either variable was assessed as poor, the intubation condition was clinically not acceptable. | PMC10721598 |
Statistical analysis | The sample size was calculated by 90% power of the study. Fifty children per group were required to determine a minimal allowable difference of 15% in clinically unacceptable intubation conditions between groups by an alpha error of 0.05. Comparisons between groups for intubation conditions in children were performed using the χ | PMC10721598 | ||
Discussion | Adenotonsillectomy, fasciculation, pain, agitation, hyperexcitability, fasciculations | ADVERSE EFFECTS, CORTEX | Anesthesia for day surgery in pediatric patients is more challenging than in adults due to physiological peculiarities. Adenotonsillectomy is a frequently performed pediatric day surgery procedure that often necessitates endotracheal intubation to ensure the child’s airway secured. Neuromuscular blockers (NMBs) are typically administered to facilitate intubation. To achieve this, high doses of NMBs are used for a rapid onset timePropofol is currently the most commonly used anesthetic in clinical settings. It is known for its effectiveness in including rapid awakening and is often the preferred choice for pediatric day surgery. However, one of the most common adverse effects of propofol is injection pain, which affects approximately 25–85% of childrenThe overall incidence of injection pain for ciprofol in our study was 3.5%, which was much lower than the incidence of propofol injection pain reportedPropofol causes a dose-dependent decrease in blood pressure and HR during inductionBIS is correlated with clinical indicators of anesthesia. As the depth of anesthesia increases, BIS diminishesSufentanil at a dose of 0.4 mcg/kg was administered for induction, taking into account the estimated duration of the operation (approximately 30 min). It was not planned to administer any additional doses of sufentanil during the operation. Studies have shown that it would counteract the cardiovascular responses conferred by intubation only when sufentanil amounts are ≥ 0.3 mcg/kgAlthough rocuronium 0.6 mg/kg (2 × ED95) has a rapid onset of action and provides satisfactory intubation conditionsOur results suggest that the rate of unacceptable intubation conditions in the C4 group was much higher than that of the other two groups, indicating that the induction dose of 0.4 mg/kg ciprofol was too low for pediatric patients. Notably, the recommended starting dose for adult induction is 0.4 mg/kg. This difference may be attributed to a larger extracellular fluid volume in children. When we increased the induction dose to 0.6 mg/kg, the rate of intubation conditions that were clinically acceptable significantly increased. Increasing the ciprofol dose to 0.8 mg/kg did not further improve intubation conditions, suggesting that the anesthetic effect of ciprofol may have reached a plateau. As observed in the specific parameters for assessing intubation conditions, the primary difference among the three groups was predominantly in limb movement. This difference was most pronounced at the low dose, possibly due to fasciculation. There is a possibility that fasciculations, which are caused by the inhibition of gamma-aminobutyric acid and result in increased sensitizes of the cortex, can lead to hyperexcitability in response to even small amounts of stimulation. This condition is mostly associated with low doses of anesthetic drugs, as most fasciculations occur at low drug concentrations during the induction and awakening periodsBased on these findings, we conclude that a combination of 0.6 mg/kg ciprofol and low-dose rocuronium can provide satisfactory intubation conditions in children undergoing daytime adenotonsillectomy. This combination also helps maintain circulatory stability and ensures prompt awakening.Our study had some weaknesses. Aspects of vital signs were only observed during the induction phase. It was not whether ciprofol can affect circulatory function during surgery. In addition, we only observed the overall incidence of injection pain and did not investigate whether it was correlated with the dosage of ciprofol. Last, we did not record whether the children experienced agitation upon awakening after extubation, which is an important factor in evaluating the effectiveness of the medication. | PMC10721598 |
Acknowledgements | We would like to thank all staff from the Anesthesia Department of Hunan Children's Hospital for their help in collecting the data. | PMC10721598 | ||
Author contributions | D.P.: Conceptualization, Methodology, Formal analysis, Writing-Original Draft. L.Z.: Resources, Data Curation. T.X., L.W.: Investigation. L.W., S.W.: Formal analysis, Validation. Z.D., S.Q.: Supervision, Project administration. All authors read and approved the final submitted version. | PMC10721598 | ||
Funding | The research was supported by the Scientific Research Fund of Hunan Medical Association (HNA202101020) and the Scientific Research Project of Hunan Provincial Health Commission (D202304118023). | PMC10721598 | ||
Data availability | The data that support the findings of this study are available from the corresponding author Shuangquan Qu upon reasonable request. | PMC10721598 | ||
Competing interests | The authors declare no competing interests. | PMC10721598 | ||
References | PMC10721598 | |||
Abstract | P. | P. J. and W. H. K. S. contributed equally to this work.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. | PMC10640773 | |
Background | coronavirus disease 2019 | CORONAVIRUS DISEASE 2019 | Uncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted in varying treatment guidelines. | PMC10640773 |
Methods | ASYMPTOMATIC COVID-19, SEVERE ACUTE RESPIRATORY SYNDROME, CORONAVIRUS | In a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 of 8 treatment arms including intravenous remdesivir (200 mg followed by 100 mg daily for 5 days) or no study drug. The primary outcome was the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log | PMC10640773 | |
Results | The 2 study arms enrolled 131 patients (remdesivir n = 67, no study drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated viral clearance by 42% (95% credible interval, 18%–73%). | PMC10640773 | ||
Conclusions | coronavirus disease 2019 | ASYMPTOMATIC COVID-19, CORONAVIRUS DISEASE 2019 | Parenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the method described can determine in vivo clinical antiviral efficacy rapidly and efficiently.In early symptomatic COVID-19, intravenous remdesivir accelerated viral clearance compared with no treatment.Remdesivir has been used extensively as a parenteral treatment for coronavirus disease 2019 (COVID-19) in some regions, although therapeutic recommendations have varied widely [Large randomized controlled trials have since demonstrated the clinical efficacy of multiple small molecule drugs in the treatment of early COVID-19, notably molnupiravir and ritonavir-boosted nirmatrelvir [ | PMC10640773 |
METHODS | ASYMPTOMATIC COVID-19 | PLATCOV is an ongoing phase 2 open-label, randomized, controlled, adaptive, pharmacometric platform trial (ClinicalTrials.gov identifier NCT05041907). It provides a standardized quantitative comparative method for in vivo assessment of potential antiviral treatments in low-risk adults with early symptomatic COVID-19. The primary outcome measure is the viral clearance rate derived from the slope of the log | PMC10640773 | |
Randomization and Interventions | Randomization was performed via a centralized web application designed by MORU software engineers using RShiny, hosted on a MORU webserver. The control arm comprised a minimum proportion of 20% of patients with uniform randomization ratios applied across the treatment arms. All patients received standard symptomatic treatment. Remdesivir (Covifor: Hetero Drugs Ltd, Hyderabad, India [in Thailand, n = 58], and Veklury: Gilead Sciences, Foster City, California [in Brazil, n = 9]) was given by rate-controlled intravenous infusion over 60 minutes (reconstituted and added to 250 mL 0.9% saline) in an initial adult dose of 200 mg, followed by 100 mg once daily for 4 days to complete a 5-day course ( | PMC10640773 | ||
Participants and Procedures | chronic illness, hypersensitivity, comorbidity | ASYMPTOMATIC COVID-19, CHRONIC ILLNESS, HYPERSENSITIVITY | Previously healthy adults aged between 18 and 50 years were eligible for enrollment if they had early symptomatic COVID-19 (i.e., reported symptoms for ≤4 days), oxygen saturation ≥96%, were unimpeded in activities of daily living, and gave fully informed consent. SARS-CoV-2 positivity was defined either as a nasal lateral flow antigen test that became positive within 2 minutes (STANDARD Q COVID-19 Ag Test, SD Biosensor, Suwon-si, Korea) or a positive polymerase chain reaction (PCR) test within the previous 24 hours with a cycle threshold value <25 (all viral gene targets), both suggesting high viral loads. Exclusion criteria included taking any potential antivirals or preexisting concomitant medications, chronic illness or significant comorbidity, hematological or biochemical abnormalities, pregnancy (a urinary pregnancy test was performed in females), breastfeeding, or contraindication or known hypersensitivity to any of the study drugs.Enrolled patients were either admitted to the study ward (in Thailand) or followed as outpatients at home (in Brazil). After randomization and baseline procedures (The TaqCheck SARS-CoV-2 Fast PCR Assay (Applied Biosystems, Thermo Fisher Scientific, Waltham, Massachusetts) quantitated viral loads (RNA copies/mL). This multiplexed real-time PCR method detects the SARS-CoV-2 N and S genes, and human RNase P in a single reaction. RNase P helped correct for variation in sample human cell content. Viral loads were quantified against ATCC heat-inactivated SARS-CoV-2 (VR-1986HK strain 2019-nCoV/USA-WA1/2020) standards. The lower limit of detection (LLOD) of the assay is approximately 50 copies/mL, and the lower limit of quantification (LLOQ) is approximately 200 copies/mL. Viral variants were identified using Whole Genome Sequencing ( | PMC10640773 |
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