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References | PMC10227122 |
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Subject terms | depressive disorder, depression, MDD, depressed | Major depressive disorder (MDD) is the most prevalent form of depression and is becoming a great challenge for public health and medical practice. Although first-line antidepressants offer therapeutic benefits, about 35% of depressed patients are not adequately treated, creating a substantial unmet medical need. A multicenter, double-blind, randomized, placebo-controlled phase 3 clinical trial was conducted in patients with MDD in China to assess the efficacy and safety of ansofaxine (LY03005), a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine. Eligible 588 MDD patients were included and randomly assigned (1:1:1) to 8-week treatment with ansofaxine 80 mg/day( | PMC10171157 |
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Introduction | overdose, toxicity, hyperactivity, depressive disorder, MDD, depression, depressive disorders | DYSFUNCTION, ADVERSE EFFECT, REMISSION, GENOTOXICITY, PATHOGENESIS | Major depressive disorder (MDD) is one of the most common depressive disorders, with an estimated 12-month prevalence rate of 6.6% and a lifetime prevalence rate of 16.2% [The pathogenesis of MDD is complex, including structure and function alterations of discrete brain regions, especially the hippocampus [Currently, most approved antidepressants for MDD primarily focus on the monoamine neurotransmitters 5-HT and NE. However, there are certain limitations to these antidepressants. For first-generation antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAIOs), most of them have a significant adverse effect profile as well as lethality in overdose and are not commonly used. The second generation of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are thought to carry less significant side effects and recommended as first-line treatment for most patients with MDD. The response rate to these drugs is moderate (40–60%), and the remission rate is relatively low [Anhedonia, loss of motivation, energy, and attention, which is one of the core symptoms of MDD, have been linked to the dysfunction of the DA system. DA is produced in small nuclei of tightly clustered neurons-predominantly the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). In animal models of depression, the DA system is downregulated due to hyperactivity of the infralimbic subregion (ilPFC), driving activity in the inhibitory basolateral amygdala (BLA)-ventral pallidum (VP) pathway while attenuating excitation via the Re-ventral subiculum of the hippocampus (vSub)-nucleus accumbens (NAc)-VP pathway [Ansofaxine hydrochlorideis [(±)-4-(2-(dimethylamino)-1-(1-hydroxycyclohexyl) ethyl) phenyl 4-methylbenzoate hydrochloride], a new triple reuptake inhibitor chemical entity, is formulated as an extended-release (ER) oral tablet for the treatment of adults with MDD. Ansofaxine inhibits the function of the transport proteins responsible for clearing dopamine, serotonin, and norepinephrine from the synaptic cleft. A Microdialysis study shows that ansofaxine can increase all three neurotransmitters in the striatum after oral drug administration. Furthermore, in the vitro binding affinities and reuptake inhibition effects trail, ansofaxine exhibits high affinities at SERT, NET, and DAT and differential inhibition potencies at the three transporters. The concentration required to inhibit uptake (IC50) values of ansofaxine on radioligand binding to SERT, NET, and DAT were 1,330 ± 82.5 nM, 2,200 ± 278 nM, and 227 ± 21.7 nM, respectively. The IC50 values for 5-HT, NE, and DA reuptake were 31.4 ± 0.4 nM, 586.7 ± 84 nM, and 733.2 ± 10 nM, respectively. The preclinical safety studies showed that ansofaxine was negative in the genotoxicity combination studies and had acceptable toxicity profiles in the general toxicity studies, fertility and early embryonic development studies, and good safety and tolerance [ | PMC10171157 |
Materials and methods | PMC10171157 |
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Study design | The study was a phase 3, multicenter, double-blind, randomized, fixed-dose, placebo-controlled clinical trial. The trial was conducted at 22 centers in China from December 2018 to December 2020. It was performed in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent prior to enrollment. Ethical approval was obtained from the local research ethics committees. See the full protocol in the supplementary information protocol. | PMC10171157 |
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Participants | allergic, seizures, gastrointestinal disease, febrile convulsions, depressive disorder, MDD, psychotic disorders, DSM-5 | SECONDARY, CHRONIC DISEASES, GASTROINTESTINAL DISEASE, FEBRILE CONVULSIONS | Participants were eligible if they were male and female outpatients aged 18 to 65 years with a diagnosis of MDD, meeting the DSM-5 (Exclusion criteria for all participants were: any other psychotic disorders (except for MDD); depressive disorder secondary to other mental illnesses or physical illnesses as well; be allergic to venlafaxine and desvenlafaxine; failed to respond to a full course of treatment with venlafaxine; a clear suicide attempt or behavior; pregnant or lactating women, or patient with a planned pregnancy in the near future; a history of seizures (except for seizures caused by febrile convulsions in children); received electroconvulsive therapy (ECT) or systematic psychotherapy (interpersonal relationship therapy, dynamic therapy, cognitive behavioral therapy) or transcranial magnetic stimulation (TMS) within 3 months prior to screening; receiving light therapy 2 weeks prior to screening; stopping psychotropic drugs for less than 7 half-lives prior to study randomization (monoamine oxidase inhibitor for at least 2 weeks, fluoxetine for at least 1 month); a history of gastrointestinal disease known to interfere with drug absorption or excretion; clinical abnormalities on total bilirubin (TBIL), alanine aminotransferase (ALT) or aspartate aminotransferase (AST), creatinine, thyroid stimulating hormone (TSH), or 12-lead electrocardiogram (ECG) at screening period; participating in other clinical trials within 3 months prior to screening; serious acute or chronic diseases, mental illnesses, of which investigators believe that the subjects are not suitable for this study. | PMC10171157 |
Procedures | depression | The study comprised a 1-week screening period and a 8-week double-blind treatment period (DBTP). During the screening period, the patients underwent physical examination, depression scale evaluations, 12-lead ECG, and laboratory examinations.Eligible patients were randomized at a 1:1:1 ratio to ansofaxine 80 mg/da y, 160 mg/day, or placebo group using a minimization random allocation system. The system used baseline MARDS total score, age, and gender as prognostic factors to ensure equilibrium among groups and monitored enrollment and allocated medication using a code matching the assigned medication.Study medication was dispensed ansofaxine 40 and 80 mg tablets and matching placebo tablets, identical in appearance and packaging. Participants would take one tablet of ansofaxine (40 mg) or one matched placebo pill daily in the first week and increase to one tablet of ansofaxine (80 mg) daily (or a matching placebo pill) daily in the second week. From week three to the end of DBTP, participants in the low-dose group administrated 80 mg tablet of ansofaxine and one 80 mg matched placebo pill, the high-dose group administrated two 80 mg tablets of ansofaxine, and the placebo group administrated two 80 mg matched placebo pills(see the electronic supplementary protocol.For every visit, the patients would go through vital signs monitoring, depression scale evaluations, AEs record, and combined medication record. The 12-lead ECG and laboratory examinations would be retaken at the end of week 4 and 8. | PMC10171157 |
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Outcomes | Suicide ideation | ADVERSE EVENTS | The primary efficacy endpoint was the change of MADRS total score from baseline to the end of week 8. Secondary efficacy endpoints were the changes from baseline of the following scores at the end of week 8: Hamilton Rating Scale for Depression-17 item (HAM-DSafety assessments included adverse events (AEs), withdrawal due to AEs, vital signs, physical examination, laboratory tests (hematology, serum chemistry, serum prolactin, and urinalysis), and 12-lead ECGs. Suicide ideation and behavior and sexual function were assessed using Colombia-Suicide Severity Rating Scale (C-SSRS) [ | PMC10171157 |
Sample size | Sample size estimates were based on the primary efficacy endpoint, MADRS total score changes from baseline, referred to phase II clinical trial result and calculated by PASS 15 software (NCSS, LLC, USA). 140 patients were calculated in each group. Considering a 25% drop-out rate, 186 subjects were planned in each group, and a total of 558 subjects were in three groups. | PMC10171157 |
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Blinding | Patients, clinicians, and independent outcome raters were masked to treatment allocation, and tablets in each group were identical in package and appearance. The database was locked when the final visit of the last randomized patient was completed, data entry for all patients was completed, and the database for all patients was deemed clean without any outstanding queries. After all of the above work was completed, an independent statistician operated the unblinding method, and a two-level unblinding method was used in the study. | PMC10171157 |
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Statistical analysis | ADVERSE EVENTS | Statistical analysis was performed using SAS®9.4 (SAS Institute, Cary, NC, USA). Continuous data were summarized in terms of the mean and standard deviation (SD). Categorical variables were summarized in terms of frequency and percentages. The efficacy analysis was based on the full analysis set (FAS), and the safety analysis was based on the safety analysis set (SS), see in the supplementary information protocol.The primary efficacy analysis compared MADRS at Week 8 in the FAS using a mixed model for repeated measurements (MMRM) with the change from baseline in the MADRS total score at each time point after treatment as a dependent variable, baseline MADRS scale total scores as a covariate, baseline MADRS total score strata (26–34, ≥35), age strata (18–30, 31–40, 41–50, and 51–65 years), gender, and the group as fixed effects, and each fixed effect factor and the covariate were nested within each visit. The adjusted mean and its 95% confidence interval (CI) of the changes from baseline in MADRS scale total scores to week 8 in each group were calculated according to this model, as well as the difference and its 95% CI of the adjusted mean for the investigational drug 80 mg group, 160 mg group versus the placebo group.For safety analysis, the type, severity, frequency, and relationship with the study drug for all treat-emergent adverse events (TEAEs) were summarized, and subjects who dropped out from the study due to adverse events and those with serious adverse events were listed. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA). Shift tables were used to summarize the changes of clinical significance evaluation (based on the clinician’s evaluation) of laboratory parameters, and all abnormal parameters with clinical significance were listed. | PMC10171157 |
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Results | PMC10171157 |
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Study design and flow diagram. | ADVERSE EVENT | AE, adverse event. | PMC10171157 |
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The Changes from baseline in MADRS total score (FAS). | ** indicates | PMC10171157 |
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Secondary efficacy endpoints | The adjusted mean changes from baseline in the HAM-DA statistical significance was observed in the mean changes of CGI-S score, HAMA total score, and SDS total score from baseline for both dosages of ansofaxine CGI-I and CGI-S scores differed significantly for ansofaxine in both dose groups | PMC10171157 |
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Distribution of CGI-I score and CGI-S score at the last observation (FAS). | FAS, full analysis set; CGI-I, Clinical Global Impressions-Improvement. CGI-S, Clinical Global Impressions-Severity.MADRS response rate at the end of week 8 was achieved in 79.89%, 73.91%, and 42.39% in the ansofaxine 80 mg, 160 mg, and placebo groups, respectively. The difference reached a statistical significance for ansofaxine 80 mg/day group Patients in the ansofaxine 80 and 160 mg groups had a significantly higher HAM-DAt the end of the final evaluation, the changes of SDS total score from baseline were −8.3 ± 6.59, −8.2 ± 6.11, and −6.9 ± 6.05 in 80 mg, 160 mg and placebo groups, respectively (Table To understand how the MADRS anhedonia factor was influenced in this study, we did an additional analysis. Mean changes in MADRS anhedonia factor score from baseline to the end of week 8 were −6.66,−8, and −5.08 in the ansofaxine 80 mg, 160 mg, and placebo groups, respectively. A statistically significant decrease in LSM compared to placebo was observed in the ansofaxine 80 mg/day with a value of −1.58 [95% CI: (−2.24, −0.92), | PMC10171157 |
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Safety | diarrhoea, Headache, nausea, abdominal pain, palpitations, dysphoria, paresthesia, TEAEs, constipation, dizziness, sexual dysfunction, insomnia, headache, abortion, depression, deaths, nausea, vomiting | ADVERSE EVENTS, PARESTHESIA, WOUND INFECTION, SPINAL OSTEOARTHRITIS, ECTOPIC PREGNANCY, EVENTS | TEAEs were reported by 137 (74.46%) patients in the ansofaxine 80 mg group, 144 (78.26%) patients in the ansofaxine 160 mg, and 125 (67.93%) patients in the placebo group. Most TEAEs were mild or moderate in severity. Fourteen subjects had severe TEAEs, reported by 4 (2.17%, 5 events), 4 (2.17%, 6 events), and 6 (3.26%, 8 events) in the ansofaxine 80 mg, ansofaxine 160 mg, and placebo groups, respectively. The severe TEAEs in 80 mg group were abdominal pain, diarrhoea, headache, insomnia, and suicidal ideation. The severe TEAEs in 160 mg group were nausea, vomiting, constipation, white blood cells, urine positive, and urine ketone body present. The severe TEAEs in the placebo group were abdominal pain, white blood cells urine positive, blood creatine phosphokinase increased, dizziness, paresthesia, palpitations, dysphoria, and spinal osteoarthritis.A total of 31 subjects withdrew from the trial due to TEAEs; 25 out of the 31 subjects withdrew from the trial due to the study drug as judged by the investigator, including seven patients (3.80%) in the 80 mg ansofaxine group, thirteen patients (7.07%) in the 160 mg ansofaxine group, five patients (2.72%) in the placebo group. Headache (4 cases) and insomnia (3 cases) were the top two TRAEs that resulted in withdrawal in the 80 mg group, whereas nausea (6 cases) and abdominal discomfort (4 cases) were the top two causes of withdrawal in the 160 mg group. Unlike the ansofaxine dose groups, the top two reasons causing withdrawal in the placebo group were dizziness (2 cases) and palpitations (2 cases).The incidence of treatment-related adverse events (TRAEs) was reported to be 59.24% (109 cases, 233 events), 65.22% (120 cases, 296 events), and 45.11% (83 cases, 170 events) in ansofaxine 80 mg, 160 mg, and placebo groups, respectively.TRAEs with an incidence ≥5% in any group, sorted by descending incidence in each System Organ Class (SOC), were shown in Table Treatment-related adverse events with an incidence ≥ 5% in any treatment group during double-blind period (SS).Note: There were 184 patients in each group. A total of 6 cases of serious adverse events (SAE) occurred in 5 subjects throughout the study, including 2 cases in 2 subjects in the 80 mg group (wound infection, arteriosclerosis coronary artery), 3 cases in 2 subjects in the 160 mg group (ectopic pregnancy and abortion induced in 1 subject, depression in the other subject) and 1 case in 1 subject in the placebo group (spinal osteoarthritis), and all of the cases were judged by investigators as unrelated with the study drug. No deaths occurred in this study. The detailed information regarding vital signs, physical examination, laboratory tests, 12-lead ECG, and C-SSRS was described in the supplementary information. After the 8-week treatment, changes from baseline in ASEX total score were (−1.6 ± 4.83), (−1.1 ± 4.70) in ansofaxine 80 mg and 160 mg groups, respectively, and no significant difference was shown vs. placebo (−0.5 ± 4.27). No cases were reporting newly developed sexual dysfunction in this study. | PMC10171157 |
Discussion | Sexual dysfunction, anhedonia, anxiety, TEAEs, hypomanic/manic, Psychiatric disorders, psychosis, psychiatric, MDD | SIDE EFFECT, DISORDERS, ADVERSE EFFECTS, SECONDARY, REMISSION | On the primary outcome measure of changes from baseline in MADRS total score, the superiority of both dosages of ansofaxine to placebo was statistical significance, with a prominent mean treatment difference of −5.46 points for 80 mg/day and −5.06 points for 160 mg/day. However, the change in the total MADRS score from baseline in the placebo group was 14.6 points, which was slightly higher than usual. The reduction compared with placebo is much greater than the two-point average for approved antidepressants [Response rate is also frequently used as a measure of clinical relevance, and a average of approximately 15% difference between drug and placebo is regarded as sufficient to establish antidepressant treatment advantage [Similarly, treatment with ansofaxine was associated with a statistically significant greater MADRS remission rate (MADRS total score ≤10) of 51.63% and 52.17% in the 80 mg and 160 mg groups, respectively (The results are much higher than the moderate response rate of 40%–60% and low remission rate demonstrated by many first-line or widely prescribed antidepressants [Significant differences versus placebo were consistently observed across secondary and additional efficacy measures in treatment groups. Improvement in HAM-DAnsofaxine showed a beneficial effect on symptoms of anxiety in patients with MDD over placebo, as demonstrated by a decrease of HAMA total score of 11.5 (80 mg/day) and 11.1 (160 mg/day) throughout the 8-week treatment period (A predicament for treatment in patients with MDD is the common symptom and critical diagnostic criterion of anhedonia, a predictor of non-response to plenty of antidepressants [It was observed that changes from baseline to the end of week 8 in SDS score were significantly greater for ansofaxine, with the inter-group difference Treatment with ansofaxine was generally safe and well tolerated in this trial, and TEAEs were mild to moderate in severity in most cases. No new safety findings were observed, and no new, unexpected, drug-related, serious AEs occurred with ansofaxine therapy. The incidence of TEAEs was similar to the data in a meta-analysis [Ansofaxine 80 and 160 mg did not increase suicide risks compared to the placebo group. There was no significant difference in laboratory tests and weight in the ansofaxine 80 mg/day and 160 mg/day group compared with the placebo. No clinically relevant changes were observed in 12-lead ECG and vital signs parameters.Sexual dysfunction, a frequent side effect of drugs with serotonin reuptake inhibitor properties, is a common reason for therapeutic discontinuation. It had been reported that the prevalence of sexual dysfunctions in patients on antidepressants was two times higher than that in patients on control (50% Psychiatric disorders, such as hypomanic/manic, psychosis, is an adverse effects of the drug in people receiving antidepressant therapy. However, AEs related to psychiatric disorders were mild or moderate,while hypomanic/manic or psychosis cases were not collect in our clinical trial. The incidence of hypomanic/manic or psychosis depends on the study sample characteristics (inpatient vs. outpatient populations), antidepressant class (studies with TCAs or MAOIs monotherapy reported higher rates), diagnostic criteria (DSM vs. Research Diagnostic Criteria), and study duration (studies with longer follow-up reported higher rates) [In conclusion, the results of this trial demonstrate that both dosages of ansofaxine 80 mg and 160 mg are safe, generally well tolerated, and remarkably effective at a clinically relevant level for the treatment of MDD. | PMC10171157 |
Limitations | MDD | Limitations of our study include the need for more active controls, the size of the sample, the short duration of treatment, and strict inclusion and exclusion criteria that may limit the generalizability of the results. Additional demographic factors (e.g., the age of participants and the proportion of the first episode) may have further affected the results of our study. Therefore, more evidence could be required to prove the efficacy of ansofaxine in older MDD patients. | PMC10171157 |
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Supplementary information | The online version contains supplementary material available at 10.1038/s41398-023-02435-0. | PMC10171157 |
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Author contributions | Jicai, CJD | RECRUITMENT, DISORDERS, CJD, BRAIN | ZHY, TJW had full access to all of the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. The protocol design was attributed to all of the authors. DXL, XXF, WHN, WGQ, ZKR, TF, LJ, YCJ, ZYF, XSP, ZH, WB, YD, CZH, LY, CJD, LSY, and YQZ contributed to participant recruitment. The data acquisition, analysis, and interpretation were performed by ZHY, TJW, MWF, and JZW. Drafting of the manuscript was performed by ZHY, MWF, TJW. Critical revision of the manuscript for important intellectual content was performed by ZHY, LHF, LLH, WYM and TJW. The statistical analysis was performed by JZW. Funding was obtained by TJW. Administrative, technical, and material support were provided by ZHY, TJW. All authors reviewed the manuscript and are in agreement with regard to the contents. We still thank the following 22 hospitals and their teams for conducting the trial:1. Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital). Yi Fu, Xiaonan Hao. 2. Beijing Huilongguan Hospital. Zhimin Lan, Yu Zhu. 3. The Affiliated Hospital of Guizhou Medical University. Lixia Yang, Fangxian Chai. 4. Shanghai Mental Health Center, Shanghai. Wenjuan Yu, Zhiqing Xiang. 5. First Affiliated Hospital of Kunming Medical University. Jicai Wang. 6. Second Xiangya Hospital of Central South University. Yan Qiu, Wenli Zhao. 7. First Affiliated Hospital of the Fourth Military Medical University of Chinese People’s Liberation Army. Ping Zhou, Zhongheng Wang. 8. Wuxi Mental Health Center. Zhiqiang Wang, Xinyu Chen. 9. First Hospital of Shanxi Medical University. Zhifen Liu, Jianhong Li. 10. Second Hospital of Shanxi Medical University. Hong Gao. 11. Beijing Anding Hospital of Capital Medical University. Dan Wang, Huanhuan Huang. 12. The Affiliated Brain Hospital of Guangzhou Medical University. Qing Chang, Xuanzi Li. 13. Shenzhen Kangning Hospital. Jie Liang, Yunfei Zhou. 14. Nanjing Brain Hospital. Shuiping Lu, Yu Chen. 15. Huzhou Third Municipal Hospital. Shikai Wang, Ping Guo. 16. Xi ‘an Mental Health Center. Luying Zhang, Jin Wang. 17. Hunan Brain Hospital. Li Xie. 18. Renmin Hospital of Wuhan University. Qirong Wan. 19. Wuhan Mental Health Center. Xiaojin Xu. 20. Xiamen Xianyue Hospital. Zhiyuan Huang, Fang Huang. 21. The Fourth People Hospital of Urumqi. Xin Wang, Min Zhang. 22. The First Affiliated Hospital of Xinjiang Medical University. Qizhong Yi. | PMC10171157 |
Funding | This study was supported by grants from the National Science and Technology (no. 2009ZX09103-100, 2013ZX09402201-002, 2017GSF218106, 2018ZX09303015, and 2021ZD0204004). Shandong Luye Pharmaceutical Co., Ltd, is the sponsor, it provided the clinical trial funds and ansofaxine ER tablets and its placebo for the clinical trial. The sponsor fulfilled the responsibilities according to the Good Clinical Practice without interfering with implementing clinical trials. | PMC10171157 |
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Competing interests | The authors declare no competing interest. | PMC10171157 |
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References | PMC10171157 |
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Background | Physical activity in female employees is a healthy behavior and increases strength, endurance, improves flexibility, improves the feeling of vitality and freshness, improves health, and ultimately increases life expectancy. Health messages are one of the most effective ways to engage people and motivate them to perform healthy behaviors. The purpose of this study was to the study of the effectiveness of education based on message framing through mobile phone (whatsapp) on the physical activity of women employees of universities and higher education institutions in Ahvaz city. | PMC10666411 |
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Method | In this interventional study, 90 of female employees of three universities and higher education institutions of Ahvaz city were selected by random sampling and randomly divided into three groups (30 participants) receiving gain framed messages, receiving loss framed messages and the control group. The tools of data collection were demographic information questionnaire and international physical activity questionnaire (IPAQ). The participants of the intervention groups received educational messages about physical activity behavior in two different gain and loss framed messages through whatsapp for one month. Data were collected from three groups at the beginning of the study, immediately and two months after the intervention, and were analyzed using SPSS version 26. | PMC10666411 |
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Results | The results showed that there was a significant increase in the average physical activity score after the intervention in two interventional groups. by comparing the increase of this score, 53% improvement in physical activity is observed in the gain message group and 15% in loss massage group but there was no significant increase in the control group. | PMC10666411 |
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Conclusion | The results of this study showed that the design and implementation of education programs based on message framing, especially gain framed messages through online education (Whatsapp) can improve and promote physical activity behavior in women employees. | PMC10666411 |
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Keywords | PMC10666411 |
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Introduction | Women’s health is one of the priorities of every society. Therefore, promoting and ensuring women’s health is one of the important pillars of the progress of societies and should always be paid attention to [ | PMC10666411 |
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Methods | PMC10666411 |
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Study design and setting | This study was taken from the research plan approved with the code of ethics IR.ACECR.AVICENNA.REC.1399.028. This research a three-group intervention study, including a control group and two case groups. The number of samples was used to calculate the sample size in the Pocock analytical studies. The sample size calculation was based on similar study [ | PMC10666411 |
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Data collection tools | The data collection tool was 2 questionnaires, including a researcher-made questionnaire based on the message framing model and the International Physical Activity Questionnaire (IPAQ), which estimated women’s physical activity in the last week in terms of MET-minutes/week. This questionnaire contains 27 items and its interpretation and scoring were done based on the IPAQ scoring protocol [ | PMC10666411 |
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Data analysis | Data were analyzed using SPSS software version 26. Descriptive statistics such as mean ± Standard Deviation (SD), frequency and percentage for (qualitative variables) were used to describe the quantitative and qualitative variables. one-way analysis of variance, Pearson’s correlation coefficient, Repeated Measure, Paired t-Test was used to compare quantitative variables in each group. An Independent t-test was applied to compare the mean between the two groups, and a Chi-square test was used to compare the frequency of variables between the two groups. All tests were performed at a level of confidence of 95% and the data were analyzed by SPSS version 26 software at a significance level of 0.05 with s. | PMC10666411 |
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Discussion | According to the results of this study, the studied groups, including the groups that received gain messages, loss messages, and control groups, did not have any difference in physical activity behavior before intervention. Also, immediately after educational intervention, there was no difference in the physical activity behavior of the groups, but two months after the educational intervention, a significant difference was observed between the three groups. Physical activity behavior in the intervention groups increased significantly after receiving the messages compared to before it, and it shows that education based on message framing using mobile phones (What Sapp) improved physical activity behavior. Alshahrani et al. [ | PMC10666411 |
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Conclusion | The present study was designed and conducted in order to survey the effect of education based on the framing of educational messages through mobile phone (WhatsApp) on the physical activity improve of female employees of universities and higher education institutions in Ahvaz. The results obtained from this study showed that education based on the framing of educational messages through social networks (WhatsApp) in order to improve physical activity behavior in women can be effective. Also, regarding physical activity behavior, it seems that educational messages with a positive frame or gain messages can be more effective than loss messages. | PMC10666411 |
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Acknowledgements | This article is taken from the research plan approved with the code of ethics IR.ACECR.AVICENNA.REC.1399.028. The researchers sincerely thank all those who cooperated with the research team in conducting this study. | PMC10666411 |
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Authors’ contributions | Ghodratollah Shakerinejad contributed to the study design, performing statistical analysis, Zahra Baji performing statistical analysis and revising the manuscript. Masoumeh Tehrani contributed to data collection, study design, Farzaneh Jarvandi contributed to performing statistical analyses. Maria Cheraghi manuscript drafting and revising. Nasser Hatamzadeh contributed to the study design and revising the manuscript. All authors read and approved the final manuscript. | PMC10666411 |
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Funding | Academic Center for Education, Culture and Research (ACECR)- Khuzestan, Ahvaz, Iran funded the study code 20-3088. The fund was spent on preparing materials such as questionnaires and data collection. | PMC10666411 |
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Data Availability | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10666411 |
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Declarations | PMC10666411 |
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Ethics approval and consent to participate | The study was approved by the Ethics Committee of ACECR- Khuzestan, Ahvaz, Iran (Registration IR.ACECR.AVICENNA.REC.1399.028). All methods were carried out in accordance with declaration of Helsinki. Written informed consent obtained from participants. In this study, female employees were adults and none were under 16 years of ages. | PMC10666411 |
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Conflict of interest | The authors declare no conflict of interest. | PMC10666411 |
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Consent for publication | Not applicable. | PMC10666411 |
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References | PMC10666411 |
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1. Introduction | Following the recent deployment of fifth-generation (5G) radio frequencies, several questions about their health impacts have been raised. Due to the lack of experimental research on this subject, the current study aimed to investigate the bio-physiological effects of a generated 3.5 GHz frequency. For this purpose, the wake electroencephalograms (EEG) of 34 healthy volunteers were explored during two “real” and “sham” exposure sessions. The electromagnetic fields were antenna-emitted in an electrically shielded room and had an electrical field root-mean-square intensity of 2 V/m, corresponding to the current outdoor exposure levels. The sessions were a maximum of one week apart, and both contained an exposure period of approximately 26 min and were followed by a post-exposure period of 17 min. The power spectral densities (PSDs) of the beta, alpha, theta, and delta bands were then computed and corrected based on an EEG baseline period. This was acquired for 17 min before the subsequent phases were recorded under two separate conditions: eyes open (EO) and eyes closed (EC). A statistical analysis showed an overall non-significant change in the studied brain waves, except for a few electrodes in the alpha, theta, and delta spectra. This change was translated into an increase or decrease in the PSDs, in response to the EO and EC conditions. In conclusion, this studhy showed that 3.5 GHz exposure, within the regulatory levels and exposure parameters used in this protocol, did not affect brain activity in healthy young adults. Moreover, to our knowledge, this was the first laboratory-controlled human EEG study on 5G effects. It attempted to address society’s current concern about the impact of 5G exposure on human health at environmental levels.Radio frequencies (RF) are electromagnetic signals, ranging from 10 MHz to 300 GHz, and are used in wireless communication, among other technologies. These radiations have been classified as possibly carcinogenic to humans [Electrical brain activity generates five main wavebands associated with different physiological functions [Nonetheless, with the evolution of wireless communication, fifth-generation RF (5G) has emerged, promising a faster connection and faster data transfers, among other advantages. One of the first deployed bands was 3.4–3.8 GHz. Higher frequencies around 26 GHz will be introduced later for infrastructure and industrial use. Nevertheless, concerns regarding the health impact of 5G networks are still expressed. Thus far, the published studies addressing this issue are limited and probably do not represent the current regulations and safety limits imposed by health authorities [Consequently, this project aimed to explore the electrical activity of the brain (beta, alpha, theta, and delta), along with other parameters of the autonomic nervous system, in healthy human participants when exposed to 5G in a restful waking environment. The frequency generated was 3.5 GHz, with exposure levels below the regulatory limits of public use [ | PMC10530694 |
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2. Materials and Methods | PMC10530694 |
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2.1. Volunteers | RECRUITMENT | Thirty-four healthy volunteers (seventeen males and seventeen females with a mean ± standard deviation [SD] age of 26.6 ± 4.7 years and a mean ± SD body mass index of 23.3 ± 4.1 kg/mThe experimental protocol (ID-RCB n°:2020-A03127-32) was approved by the French national ethical committee “CPP Sud-Ouest et Outre-Mer 1”, and the selected volunteers were only allowed to participate after signing an informed consent form. Furthermore, the participants were asked to refrain from consuming any stimulating beverages or substances (caffeine, alcohol, chocolate, etc.) 24 h before each experimental session.It is noteworthy that the recruitment process included participants from diverse cultural and multinational backgrounds. Moreover, sex was determined through a self-report measure based on the type of reproductive system. The volunteer characteristics are detailed in | PMC10530694 |
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2.2. Study Design and Experimental Protocol | The study was triple-blinded for the volunteers, the experimenter (L.J.), and the data analysts (L.J. and L.Y.C.). All participants underwent two counterbalanced cross-over and randomised “real” and “sham” exposure sessions. B.S. determined the random allocation, whereas L.H. ensured the blinding process.The time interval between the sessions was no longer than one week. In addition, for each participant, both sessions took place at the same time of the day, either in the morning (9–11 a.m. ± 30 min) or in the afternoon (2–4 p.m. ± 30 min), to prevent any potential modification related to the circadian rhythm. Each session lasted around 2 h (120 ± 30 min) and contained a “baseline” and a “post-exposure” period of 17 min each with no RF exposure. These were separated by either a “real” or “sham” exposure period of 25 min and 30 s. These periods included 2–3 runs of 8 min and 30 s, as shown in In addition, temperature measurements along with some salivary biomarkers of stress, namely cortisol, α-amylase, and chromogranin-A, were analysed to explore potential alterations in the autonomic nervous system. However, we only discuss the EEG outcomes here; the other parameters will be presented in the future. | PMC10530694 |
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2.4. Signal Acquisition and Data Processing | blinks | BRAIN | The EEGs were recorded in a dimly lit and electrically shielded room with a wakeful resting state, using a 64-channel cap (actiCAP-Snap, EASYCAP GmbH, Brain Products GmbH, Wörthsee, Germany) with active electrodes (actiCAP-slim electrodes, EASYCAP GmbH, Brain Products GmbH, Wörthsee, Germany). The 64 electrodes (Fp1, Fp2, AF7, AF3, AFz, AF4, AF8, F7, F5, F3, F1, Fz, F2, F4, F6, F8, FT9, FT7, FC5, FC3, FC1, FC2, FC4, FC6, FT8, FT10, T7, C5, C3, C1, Cz, C2, C4, C6, T8, TP9, TP7, CP5, CP3, CP1, CPz, CP2, CP4, CP6, TP8, TP10, P7, P5, P3, P1, Pz, P2, P4, P6, P8, PO7, PO3, Poz, PO4, PO8, O1, Oz, O2, and Iz) were arranged according to the extended 10–20 (10%) system [Six disposable electrodes (Ambu® Neuroline 720, Neurology auto-adhesive surface electrodes, Ambu Sarl, Bordeaux, France) were used to detect blinks and cardiac artefacts. Two electrodes were placed near the outer canthus of each eye for the horizontal electrooculogram (EOG), while two more were positioned above and below the right eye for the vertical EOG. In contrast, one electrode was placed on the right clavicle and another on the left lower hip for ECG monitoring.A sampling frequency of 1000 Hz and a bandwidth of 0.016–250 Hz were used for data acquisition by the Brain Vision recorder software (version 1.23.0003). With the help of a conductivity gel (Electro Gel, Electro Cap Center B.V., Nieuwkoop, the Netherlands), the electrical impedance was maintained below 30 kΩ.Regarding signal pre-processing, with the aid of MNE-python (version 0.19.2) [Furthermore, log-transformed PSD values were used for the final data analysis to ensure that the data followed a normal distribution. Subsequently, these transformed values were averaged based on their respective time periods, which included baseline measurements (run 01 and run 02), exposure periods (run 03, run 04, and run 05), and post-exposure periods (run 06 and run 07). This was achieved by using an adapted MNE-python (version 0.19.2) script code. Following this averaging, the statistical analysis was carried out. Additionally, baseline-corrected exposure and post-exposure data were computed to conduct a different type of statistical analysis, as elaborated in the subsequent section. | PMC10530694 |
2.5. Statistical Analysis | The sample size was calculated with the G*power software (version 3.1.9.2), considering a statistical inference of 80% power with a medium effect size (0.5) and 95% confidence interval for analysis of variance (ANOVA) F-tests.Following data processing and curation, statistical tests were conducted using a customised MATLAB toolbox (version 2019b) [ | PMC10530694 |
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3. Results | As mentioned in the statistical plan, we conducted a three-way repeated-measures ANOVA—5G exposure (Factor 1: “real” vs. “sham” conditions), time period (Factor 2: baseline vs. exposure or post-exposure phases), and eye condition (Factor 3: EO vs. closed EC)—on each brain wave frequency band. We present the findings of each assessed factor, including those of 5G. However, for simplicity, only the electrodes showing significant outcomes related to 5G (Factor 1) are indicated with an arrow in the figures. | PMC10530694 |
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3.1. Beta Spectral Power | PMC10530694 |
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3.1.1. 5G Exposure (Factor 1) | The three-way ANOVA showed no significant difference between “real” and “sham” sessions (Factor 1) in the overall studied electrodes, except for Fp1 ( | PMC10530694 |
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3.1.2. Time Period (Factor 2) | Moreover, regarding the effect of the time period, there was no significant difference between the baseline and the exposure periods following three-way ANOVA. Likewise, when we compared the baseline and post-exposure periods, only the AFz ( | PMC10530694 |
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3.1.3. Eye Condition (Factor 3) | Regarding the eye condition, the difference was notably significant in 40 out of 64 electrodes when comparing the baseline and exposure periods (Fp1, Fp2, AF7, AF3, AFz, AF4, AF8, F7, F5, F3, F1, F2, F4, F6, F8, FT9, FT7, FC5, FC3, FC2, FC4, FC6, FT8, FT10, T7, C5, T8, Pz, P2, P4, P6, PO7, PO3, Poz, PO4, PO8, O1, Oz, O2, and Iz). Moreover, 39 out of 64 electrodes were significant when comparing the baseline and post-exposure periods (Fp1, Fp2, AF7, AF3, AFz, AF4, AF8, F7, F5, F3, F2, F4, F6, F8, FT9, FT7, FC5, FC3, FC4, FC6, FT8, T7, C5, C6, T8, Pz, P2, P4, P6, P8, PO7, PO3, Poz, PO4, PO8, O1, Oz, O2, and Iz), as shown in | PMC10530694 |
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3.1.4. Interaction among Factors | Regarding the interaction of 5G exposure with other factors, only T7 ( | PMC10530694 |
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3.2. Alpha Spectral Power | PMC10530694 |
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3.2.1. 5G Exposure (Factor 1) | There was no significant change in the studied electrodes due to the 5G factor following the three-way ANOVA, except for the AF7 electrode (Following the one-way ANOVA of the baseline-corrected data, the PSD values of the overall electrodes were not significantly different between “real” and “sham” exposures, except for P7 ( | PMC10530694 |
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3.2.2. Time Period (Factor 2) | Concerning the time period, the comparison of the baseline and exposure periods showed 51 significant electrodes following the three-way ANOVA (F3, F1, F2, F4, F6, F8, FT9, FT7, FC3, FC1, FC4, FC6, FT8, FT10, T7, C5, C3, C1, C2, C4, C6, T8, TP9, TP7, CP5, CP3, CP1, CPz, CP2, CP4, CP6, TP8, TP10, P7, P5, P1, Pz, P2, P4, P6, P8, PO7, PO3, Poz, PO4, PO8, O1, Oz, O2, and Iz). On the other hand, 52 electrodes exhibited a significant difference when we compared the baseline and post-exposure periods (F3, F1, F6, F8, F7, FT9, FT7, FC5, FC3, FC1, FC4, FC6, FT8, FT10, T7, C5, C3, C1, Cz, C2, C4, C6, T8, TP9, TP7, CP5, CP3, CP1, CPz, CP2, CP4, CP6, TP8, TP10, P7, P5, P3, P1, Pz, P2, P4, P6, P8, PO7, PO3, Poz, PO4, PO8, O1, Oz, O2, and Iz), as illustrated in | PMC10530694 |
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3.2.3. Eye Condition (Factor 3) | The eye condition factor displayed a significant effect in all the studied electrodes in the exposure and post-exposure periods when compared with the baseline period ( | PMC10530694 |
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3.2.4. Interaction among Factors | There were no significant interactions among the studied factors aside from a few electrodes in specific factor combinations ( | PMC10530694 |
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3.3. Theta Spectral Power | PMC10530694 |
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3.3.1. 5G Exposure (Factor 1) | Based on the three-way ANOVA results, the 5G factor did not modify the PSD values of theta waves (Regarding the baseline-corrected data and the 5G factor, the one-way ANOVA revealed no significant difference in the overall analysed electrodes except for the EC condition in P2 ( | PMC10530694 |
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3.3.2. Time Period (Factor 2) | Following three-way ANOVA, the only significant differences were for P8 ( | PMC10530694 |
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3.3.3. Eye Condition (Factor 3) | The results of the eye condition variable of the three-way ANOVA showed that 57 out of 64 electrodes were significantly different in the exposure and post-exposure periods compared with the baseline (F7, F5, F3, F1, Fz, F2, F4, F6, F8, FT9, FT7, FC5, FC3, FC1, FC2, FC4, FC6, FT8, FT10, T7, C5, C3, C1, Cz, C2, C4, C6, T8, TP9, TP7, CP5, CP3, CP1, CPz, CP2, CP4, CP6, TP8, TP10, P7, P5, P3, P1, Pz, P2, P4, P6, P8, PO7, PO3, Poz, PO4, PO8, O1, Oz, O2, Iz), as shown in | PMC10530694 |
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3.3.4. Interaction among Factors | Only some random electrodes showed significant interactions among the studied factors ( | PMC10530694 |
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3.4. Delta Spectral Power | PMC10530694 |
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3.4.1. 5G Exposure (Factor 1) | Based on the three-way ANOVA, all electrodes showed a non-significant difference in delta PSDs under “real” and “sham” exposure conditions in the exposure and post-exposure periods ( | PMC10530694 |
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3.4.2. Time Period (Factor 2) | We found that 58 of 64 electrodes showed significant differences due to the time period in the three-way ANOVA when we compared the baseline and post-exposure periods (Fp1, Fp2, AF7, AF3, AFz, AF4, AF8, F7, F5, F3, F1, Fz, F2, F4, F6, F8, FT9, FT7, FC5, FC3, FC1, FC2, FC4, FC6, FT8, T7, C5, C3, C1, Cz, C2, C4, C6, T8, TP7, CP5, CP3, CP1, CPz, CP2, CP4, CP6, TP8, P7, P5, P1, Pz, P2, P4, P6, PO7, PO3, Poz, PO4, PO8, Oz, O2, and Iz). However, there were no significant differences when we compared the baseline and exposure periods ( | PMC10530694 |
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3.4.3. Eye Condition (Factor 3) | This factor significantly altered the delta brain waves in both exposure (Fp2, FT7, FC5, FC3, FC1, FC2, FC4, FC6, FT8, C5, C3, C1, C2, C4, C6, T8, TP9, TP7, CP5, CP3, CP1, CP4, CP6, TP8, TP10, P7, P5, P3, P1, Pz, P2, P4, P6, P8, PO7, PO3, PO4, PO8, O1, O2, and Iz) and post-exposure (Fp1, FC4, FC6, FT8, FT7, FC3, C5, C3, C1, C4, C6, TP7, CP5, CP3, CP1, CPz, CP4, CP6, TP8, TP10, P7, P5, P3, P1, Pz, P2, P4, P6, P8, PO7, PO3, Poz, PO4, PO8, O1, and O2) periods when compared with baseline, as illustrated in | PMC10530694 |
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3.4.4. Interaction with 5G | As shown in | PMC10530694 |
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4. Discussion | In this study, we explored the effects of 3.5 GHz, representing one of the earliest exploited 5G bands, via the EEG of healthy human volunteers. Thirty-four participants took part in two triple-blinded, “real” and “sham” exposure sessions. The latter were randomised and counterbalanced in a wake-rested state, where the brain activity was recorded in the EO and EC conditions. Each session contained a baseline recording period to correct the subsequent exposure and post-exposure acquisition phases. The frequency used was pulse-modulated to simulate far-field antenna exposures within public regulation limits [Statistical analysis with repeated-measures ANOVA showed no significant changes in the EEG waves in the subjects exposed to the 5G signal, except for a few electrodes in the alpha and beta oscillations, as mentioned in As far as we know, this project is the first pilot study tackling the effects of low-band 5G frequencies on human brain activity. Hence, comparing our outcomes to other 5G studies is not currently possible. On the other hand, because the overall electrodes demonstrated non-significant modulation in the analysed brain waves, we cannot conclude that 3.5 GHz can change EEG profiles. However, our previous investigation of 2G GSM (The Global System for Mobile Communications) signals (900 MHz) revealed a significant decrease in alpha activity during and after exposure in the EC condition [Similarly to our 5G findings, the authors of other studies investigating higher RF (3G, 4G, and Wi-Fi) effects on healthy waking human EEG have found no significant change in the explored cerebral waves due to exposure [We only included healthy young volunteers. Introducing all age ranges would provide a better representation of the exposed population to explore the age factor as studied elsewhere [In addition to the 5G effect, the EEG signals showed a significant outstanding difference between the EO and EC status in all the studied spectra, confirming the literature findings regarding the eye condition influence on EEG activity even in restful environments [ | PMC10530694 |
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5. Conclusions | Our statistical analysis revealed an overall non-significant difference in beta, alpha, theta, and delta brain oscillations relative to 5G exposure. However, a few electrodes in the baseline-corrected exposure and post-exposure periods exhibited significant modulation corresponding to the eye condition only in the alpha, theta, and delta rhythms, which did not survive the posterior statistical correction. Thus, 3.5 GHz within regulated exposure levels and under the current experimental conditions does not affect EEG activity in humans. However, the potential impacts of chronic 5G exposure remain unknown, necessitating large longitudinal cohort studies to understand the biological responses to this modern technology. | PMC10530694 |
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Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10530694 |
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Author Contributions | Conceptualisation, B.S.; methodology, L.J., L.Y.-C., L.H., P.M. and P.L.; investigation, L.J.; software, L.Y.-C., L.H. and P.L.; validation, B.S., L.Y.-C. and P.L.; formal analysis, L.J., L.Y.-C. and P.L.; resources, L.Y.-C., L.H., P.M. and P.L.; data curation, L.J. and L.Y.-C.; writing—draft preparation, L.J.; writing—review and editing, B.S., L.Y.-C. and P.L.; visualisation, L.J. and L.Y.-C.; supervision, B.S. and L.H.; project administration, B.S.; funding acquisition, B.S. All authors have read and agreed to the published version of the manuscript. | PMC10530694 |
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Institutional Review Board Statement | -20 | The study was conducted in accordance with the Declaration of Helsinki and approved by the French national ethical committee of “CPP Sud-Ouest et Outre-Mer 1” (protocol code n° 2020-A03127-32 [ID RCB] and 1-20-097 ID 10481 [ID CPP], approved on 15 March 2021). | PMC10530694 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the participants to publish this paper. | PMC10530694 |
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Data Availability Statement | The data presented in this study are available on request from the corresponding author. The data are not publicly available due to confidentiality and privacy considerations. | PMC10530694 |
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Conflicts of Interest | Neither the authors nor their collaborators declare any conflict of interest. Nevertheless, the opinions expressed are those of the authors and not necessarily those of the granting authorities, which cannot be held responsible for them. | PMC10530694 |
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Appendix A | The beta band outcomes after three-way repeated-measures analysis of variance (ANOVA). Baseline values were compared with the exposure (The alpha band outcomes after three-way repeated-measures analysis of variance (ANOVA). Baseline values were compared with the exposure (The theta band outcomes after three-way repeated-measures analysis of variance (ANOVA). Baseline values were compared with the exposure (The delta band outcomes after three-way repeated-measures analysis of variance (ANOVA). Baseline values were compared with the exposure ( | PMC10530694 |
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References | The experimental protocol was preceded by a volunteer preparation phase of approximately 60 min. The protocol included three exposure conditions: the pre-exposure (Baseline), “real” or “sham” exposure, and post-exposure periods. Each exposure and post-exposure period contained 2–3 runs of recording phases that started with the acquisition of electrodermal activity (EDA). Subsequently, 3 min of the eyes-open (EO) condition followed by 3 min of the eyes-closed (EC) condition were recorded in a wakeful resting environment, where an electroencephalogram (EEG) and an electrocardiogram (ECG) were continuously acquired in an electrically shielded room. Four saliva samples were also collected in both sessions to assess some salivary biomarkers of stress.The exposure system setup comprised a horn antenna, a dosimeter to control the exposure parameters, and a 3.5 GHz generator connected to a signal amplifier. The experimental protocol was performed in an electrically shielded room. Abbreviations: EEG, electroencephalography; RF, radiofrequency.Topographical maps of the beta electroencephalographic (EEG) band of the baseline-corrected exposure (Topographical maps of the alpha electroencephalographic (EEG) band of the baseline-corrected exposure (Topographical maps of the theta electroencephalographic (EEG) band of the baseline-corrected exposure (Topographical maps of the delta electroencephalographic (EEG) band of the baseline-corrected exposure ( | PMC10530694 |
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Background | The cardiovascular (CV) benefits of sodium-glucose transport protein 2 inhibitors have been attributed, in part, to cardiac reverse remodelling. The EMPA-HEART CardioLink-6 study reported that sodium-glucose cotransporter-2 inhibition for 6 months with empagliflozin was associated with a significant reduction in left ventricular mass indexed to body surface area (LVMi). In this sub-analysis, we evaluated whether baseline LVMi may influence how empagliflozin affects cardiac reverse remodelling. | PMC10303338 |
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Methods | coronary artery disease | TYPE 2 DIABETES, CORONARY ARTERY DISEASE | A total of 97 patients with type 2 diabetes and coronary artery disease were randomized to empagliflozin (10 mg/d) or matching placebo for 6 months. The study cohort was divided into those whose baseline LVMi was ≤ 60 g/m | PMC10303338 |
Results | Baseline LVMi was 53.3 g/m | PMC10303338 |
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Conclusions | REGRESSION | Patients with higher LVMi at baseline experienced greater LVM regression with empagliflozin. | PMC10303338 |
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Keywords | PMC10303338 |
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Background | cardiovascular and renal benefits, T2D, type 2 diabetes, LVH | LVH, TYPE 2 DIABETES, SUDDEN DEATH, LEFT VENTRICULAR HYPERTROPHY | Sodium-glucose transport protein 2 inhibitors (SGLT2i) have shown marked cardiovascular and renal benefits in patients with type 2 diabetes (T2D) [There have been many suggested mechanisms to explain the cardiovascular benefits associated with SGLT2i [Left ventricular hypertrophy (LVH) is an established predictor of poor cardiovascular outcomes, while increases in LVMi have been independently associated with all-cause mortality and sudden death [ | PMC10303338 |
Methods | SECONDARY | A detailed description of the design and primary results of the EMPA-HEART CardioLink-6 trial has been published previously [Given that the median baseline LVMi for the empagliflozin-assigned group was 58 kg/mOur secondary analyses included assessment of the relationship between baseline LVMi and changes in left ventricular end-systolic volume indexed to body surface area (LVESVi), left ventricular end-diastolic volume indexed to body surface area (LVEDVi), and left ventricular ejection fraction (LVEF) from baseline to 6-months. We also tested the associations between baseline LVMi and baseline left ventricular end-systolic volume (LVESV), LVESVi, left ventricular end-diastolic volume (LVEDV), LVEDVi, and LVEF. | PMC10303338 |
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Statistical analyses | Normality of continuous variables was tested with the Skewness and Kurtosis test and examined with visual inspection of a histogram. Continuous variables are reported as medians with interquartile ranges (IQR) or mean ± standard deviation (SD); frequencies and percentages are used to describe categorical data. Continuous variables were assessed with the Mann-Whitney U-test. Categorical variables were evaluated with the Pearson’s chi-square test (or Fisher’s exact test if appropriate). To assess the treatment effect on 6-month change in LVMi in each of the LVMi stratified sub-groups we used a linear model adjusting for baseline differences in LVMi (ANCOVA), that included an interaction term between the baseline LVMi subgroup and treatment. We also estimated treatment effect over baseline LVMi values from 40 to 90 g/m | PMC10303338 |
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Results | PMC10303338 |
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Baseline characteristics | TIA, high-density lipoprotein | TIA, TRANSIENT ISCHEMIC ATTACK | Upon stratification of the EMPA-HEART cohort, most baseline characteristics were found to be similar between patients with an LVMi ≤ 60 g/m
Baseline characteristics of the EMPA-HEART CardioLink-6 participants as stratified by baseline LVMi of ≤ or > 60 g/mData are presented as either frequency (%) or median (IQR).ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; ASA, acetylsalicylic acid; CABG, coronary artery bypass graft; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; IGFBP7, Insulin-like growth factor binding protein 7; LDL, low-density lipoprotein; LVMi, left ventricular mass index; NT-proBNP, N-terminal pro-b-type natriuretic peptide; PCI, percutaneous coronary intervention; TIA; transient ischemic attack.
Baseline cMRI parameters of the EMPA-HEART CardioLink-6 participants stratified by baseline LVMi of ≤ or > 60 g/m*All data are presented as median (IQR). LVMi, left ventricular mass index; LVM, left ventricular mass; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume; LVEDVi; left ventricular end diastolic volume indexed; LVESVi, left ventricular end systolic volume indexed; LVEF, left ventricular ejection fraction. | PMC10303338 |
Primary outcomes | LVMi ≤ | REGRESSION, TYPE 2 DIABETES MELLITUS | The effect of empagliflozin on LVMi regression over 6 months was significantly different between patients with a baseline LVMi ≤ 60 g/m
Treatment with empagliflozin (10 mg/d) and 6-month change in LVMi stratified by baseline LVMi of ≤ 60 g/m*ANCOVA model adjusted for duration of type 2 diabetes mellitus, glucose (random), previous history of PCI in addition to baseline LVMi. LVMi, left ventricular mass indexed to body surface area.The 6-month change in LVMi from estimation of a fractional polynomial of baseline LVMi stratified by the treatment arm is shown in Fig.
Treatment with empagliflozin (10 mg/d) and 6-month change in LVMi estimated over baseline LVMi values fitted to fractional-polynomial prediction with associated 95% confidence intervals. LVMi, left ventricular mass indexed to body surface area | PMC10303338 |
Secondary outcomes | In analyses evaluating the relationship of baseline LVMi and change in LVESVi from baseline to 6 months, we observed no significant association (
Association between treatment with empagliflozin (10 mg/d) and 6-month changes in LVESVi, LVEDVi, and LVEF stratified by baseline LVMi of ≤ 60 g/mLVEDVi; left ventricular end diastolic volume indexed; LVESVi, left ventricular end systolic volume indexed; LVEF, left ventricular ejection fraction. | PMC10303338 |
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Discussion | diabetes, T2D, LVH, g/mReductions | ACUTE MI, HEART FAILURE, LVH, DIABETES | In this exploratory sub-analysis of the EMPA-HEART CardioLink-6 trial, we evaluated the influence of baseline LVMi on cardiac reverse remodelling with empagliflozin. Our analysis yielded the key finding that patients with a baseline LVMi > 60 g/mReductions in LVM are associated with cardiovascular risk reduction and improved clinical outcomes [A post hoc subgroup analysis of the EMPA-REG OUTCOME trial demonstrated that risk reduction of 3-point MACE with empagliflozin was greater in patients who had LVH at baseline when compared those without [In a recent meta-analysis of RCTs using cMRI to examine SGLT2i-mediated cardiac reverse remodelling in patients with T2D and/or heart failure, treatment with an SGLT2i was associated with a significant reduction in LVM [This study provides important and valuable information regarding the role of empagliflozin in cardiac reverse remodelling in patients with diabetes, however it must be noted that the current study also has limitations. First, the sample size was small. Second, the participants in this study were only followed for 6 months and it has been shown that, at least after an acute MI, LV remodelling can continue for as long as 2 years. Third, given the nature of this analysis, the findings should be considered hypothesis-generating. | PMC10303338 |
Conclusions | In conclusion, patients with larger LVMi at baseline experienced significantly greater cardiac reverse remodelling with empagliflozin than patients with a lower LVMi at baseline. Studies with larger cohorts and longer follow-ups are warranted to investigate the influence of baseline LVM on SGLT2i-mediated cardiac reverse remodelling and the treatment benefits received from treatment with empagliflozin. | PMC10303338 |
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Acknowledgements | Not Applicable. | PMC10303338 |
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Authors’ contributions | MH | Project conception (PP, CDM, ATY, KAC, SV), Data analysis (MH), Data Interpretation (PP, MH, CDM, SV), Original Draft (PP, SV). All authors provided critical review and approved the final manuscript for submission. | PMC10303338 |
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Funding | Pain | This work was supported by an unrestricted investigator-initiated study grant from Boehringer Ingelheim. CDM is supported by a Merit Award from the University of Toronto Department of Anesthesiology and Pain Medicine and holds the Cara Phelan Chair in Critical Care at St. Michael’s Hospital-Unity Health Toronto. KAC holds the Keenan Chair in Research Leadership at St. Michael’s Hospital-Unity Health Toronto, University of Toronto. SV holds a Tier 1 Canada Research Chair in Cardiovascular Surgery. | PMC10303338 |
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Data Availability | The datasets analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request. | PMC10303338 |