title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
|---|---|---|---|---|
Hierarchical clustering and pathway analysis | Hierarchical clustering analysis was performed with MetaboAnalyst ( | PMC9825269 | ||
Validation | For proteomic analysis validation, fetuin-B measurements were performed using ELISA. Serum samples were diluted 1:10 000 with DPBS (Corning #20-031-CVR, Mediatech, Inc., Manassas, VA, USA) and kit-specific dilution buffer, and analyzed with a FETUB ELISA Kit (Cat No EKX-LDKNLJ-96; Nordic BioSite AB, Täby, Sweden), according to the manufacturer’s instructions. Graphpad Prism 9 (GraphPad Software, San Diego, CA, USA) was used for interpolation of the data. Corticosteroid-binding globulin (CBG) was measured as part of the other sub-study ( | PMC9825269 | ||
Statistics | The distributions of protein changes were examined with the Shapiro–Wilk test. Most changes were skewed; thus, non-parametric tests were used for the analyses. The changes within the study groups were analyzed with the Wilcoxon test using the Benjamini–Hochberg procedure to control false discovery rates.To investigate the differences between the study groups, we calculated the difference between the baseline and 9 weeks for all proteins. These differential variables were then analyzed with the Kruskal–Wallis test and the Benjamini–Hochberg procedure. Statistically significant results were further compared with the Mann–Whitney | PMC9825269 | ||
Results | PMC9825269 | |||
Study subjects | high-density lipoprotein | The baseline characteristics of the participants are shown in Baseline characteristics of the study groups taking a 9-week course of combined oral contraceptive.EE, ethinylestradiol; DNG, dienogest; EV, estradiol valerate; WHR, waist–hip ratio; BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; hs-CRP, high sensitivity C-reactive protein.Comparison between groups by one-way ANOVA. | PMC9825269 | |
Proteomic analysis | PMC9825269 | |||
Protein identification | A total of 446 proteins or protein families with two or more unique peptides were quantified. Some of the protein sequences are shared by many proteins (protein families), and some are unique in the human proteome. Depending on which peptides are identified, one can detect either a distinct protein or a protein family. Certain proteins were therefore identified and analyzed together as a family. Some proteins were detected both in high- and low-abundance analyses. The complete list of detected proteins is shown in | PMC9825269 | ||
Hierarchical clustering | Successful randomization was further confirmed by hierarchical clustering based on protein compositions (
| PMC9825269 | ||
Proteome alterations within groups | A total of 122 proteins/protein families changed significantly during the 9-week trial within at least one group: 121 in the EE + DNG and 5 in the EV + DNG group. No changes were observed in the DNG-only group. Some proteins were found in both low- and high-abundance fractions, indicating that proteins appeared both alone and in complexes with some high-abundance proteins, such as albumin. After consideration of these duplicate findings, the numbers of changing, unique proteins/families are shown in
| PMC9825269 | ||
Change in protein abundances between study groups | The change in protein abundance from baseline to 9 weeks was significantly different between the study groups for 63 proteins/protein families. In all, 58 proteins/protein families altered differently between the EE + DNG and EV + DNG groups, 61 between EE + DNG and DNG only and 17 between EV + DNG and DNG only. All significantly altered proteins between the groups are listed in Proteins with significantly differing alterations between study groups during the 9-week trial.Proteins with a statistically different change between the groups after the Kruskal–Wallis test and Benjamini–Hochberg method (in order of significance). The Mann–Whitney Statistically significant change within the group.A: ethinylestradiol (EE) + dienogest (DNG) versus estradiol valerate (EV) + DNG. B: EE + DNG versus DNG. C: EV + DNG versus DNG. S: Mann–Whitney | PMC9825269 | ||
Pathway analysis | Most changes in the serum proteins were detected in the EE + DNG group; therefore, the functionality analysis was based on the proteins with a significant change during this treatment. The 10 most significantly affected pathways are listed in
Full lists of normalized abundance data are included in | PMC9825269 | ||
Fetuin-B, CBG and SHBG | After proteomic analysis, fetuin-B (a novel finding with a significant difference between the study groups) was chosen for additional validation. We previously reported the changes in CBG (
| PMC9825269 | ||
Discussion | non-alcoholic fatty liver disease | ACUTE PHASE RESPONSE, INFLAMMATION, LYSIS, NON-ALCOHOLIC FATTY LIVER DISEASE, INSULIN RESISTANCE, DYSLIPIDEMIA | This study showed that 9 weeks of EE-based COC use had a multifold effect on the serum proteome compared with EV-based COC or DNG-only preparation; the number of affected proteins after exposure to EE + DNG was 24-fold the number for EV + DNG and 120-fold that for DNG only. Few proteins changed during the use of EV + DNG and no changes were detected during the use of DNG only. The most-affected pathways were the complement system, acute phase response signaling, metabolism-related LXR&FXR/RXR activation and the coagulation system. The findings of the proteomic analysis were validated with fetuin-B ELISA and our previously reported CBG ELISA and SHBG immunoassay, showing that treatment with EE + DNG increased serum levels of fetuin-B, CBG and SHBG more than EV + DNG or DNG only.To our knowledge, this is the first study to explore the effects of hormonal contraceptives on serum proteins with an untargeted, discovery-type proteomic analysis. Previously, only one study has utilized a proteomic analysis method during contraceptive use (EE-containing COCs have been shown to increase low-grade inflammation, reflected by increased levels of C-reactive protein (CRP) (EE is a highly potent estrogen known to have a major effect on hepatic protein synthesis: EE increases SHBG, CBG and angiotensinogen multifold compared with estradiol (In the pathway analysis, as many as 19 proteins related to the complement system were altered during EE + DNG treatment, which predicts inhibition of this pathway. The complement system is a complex immunological system involving ∼30 interacting proteins that compose a cascade of activation steps leading to activation of inflammation, opsonization of pathogens and cells for destruction, and direct killing of target cells or microbes by lysis (Untargeted proteomic analysis also enables the identification of interesting novel targets for future research. Fetuin-B is a relatively understudied hepatokine associated with insulin resistance, dyslipidemia, and non-alcoholic fatty liver disease (The main strength of the present study is that this randomized trial is the first comparison of EE- and EV-containing contraceptives combined with the same progestin. Randomization was successful regarding the clinical characteristics but also at the proteome level, as reflected in the mixed clustering of baseline samples. Therefore, the changes observed during the trial are likely related to the intervention and not to chance. However, we acknowledge that the 9-week study period is relatively short for concluding long-term effects. Therefore, these findings should be further examined in longer trials with specifically targeted measurements. Proteomic analysis was not considered in the original sample size calculation, given that the analysis was not the primary outcome. On the other hand, as no previous data exist, estimating power for a discovery-type setup is extremely challenging. However, in the field of discovery-type proteomics, the groups of 14 are quite extensive, especially considering the trial with repeated measurements. Despite these limitations, our results give valuable insight into the extent of the differences between the estrogen types in COCs.To conclude, EE + DNG had a greater impact on the serum proteome than that of EV + DNG or the DNG-only preparation. The differences between EE and EV go far beyond the well-known, traditional estrogen actions. Therefore, EV could provide a preferable option to EE in COCs in the future. Moreover, although our findings need to be validated in further studies utilizing targeted methods, this study provides a valuable basis for future research and guides the development of hormonal contraceptives. | PMC9825269 |
Supplementary Material | Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file. | PMC9825269 | ||
Acknowledgements | We thank M.Sc. Elisa Korhonen for statistical assistance and Mrs Maarit Haarala, Ms Elina Huikari and Mrs Pirjo Ikonen for expert technical assistance. | PMC9825269 | ||
Authors’ roles | T.T.P. | The study was designed by J.S.T. and O.H. in collaboration with T.T.P. and A.H. M.H.K., A.H., K.L., O.H., J.S.T. and T.T.P. contributed to the data collection. S.J., T.T., R.R., R.K.A. and M.H.K. performed the laboratory analyses and data interpretation. M.H.K. wrote the first draft of the manuscript; all authors contributed to revision and approved the final version of the manuscript. T.T.P., J.S.T. and O.H. supervised the project. | PMC9825269 | |
Funding | Funding was obtained from Helsinki University Hospital research funds (J.S.T. and A.H.), the Hospital District of Helsinki and Uusimaa (K.L., T.T. and O.H.), the Sigrid Juselius Foundation (J.S.T. and T.T.P.), the Academy of Finland (J.S.T. and T.T.P. 315921 and 321763), the Finnish Medical Association (M.H.K., A.H. and T.T.P.), the University of Oulu Graduate School (M.H.K.), the Emil Aaltonen Foundation (M.H.K.), the Swedish Cultural Foundation in Finland (A.H.), the Novo Nordisk Foundation (R.K.A.), Orion Research Foundation (A.H.) and the Northern Ostrobothnia Regional Fund (R.K.A.). The funders had no role in study design, data collection and analysis, publishing decisions or manuscript preparation. | PMC9825269 | ||
Conflict of interest | EVENTS | T.P. has received honoraria for lectures, consultations and research grants from Exeltis, Gedeon Richter, MSD, Merck, Pfizer, Roche, Stragen and Mithra Pharmaceuticals. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. | PMC9825269 | |
Data Availability | Normalized abundance data of high- and low-abundance fractions are included in | PMC9825269 | ||
References | PMC9825269 | |||
Introduction | Obesity, T2DM | OBESITY, TYPE 2 DIABETES | Obesity drives type 2 diabetes (T2DM) development. Laparoscopic adjustable gastric banding (LAGB) has lower weight reduction than other bariatric procedures. Liraglutide, a GLP-1 receptor agonist, improves weight and glycaemic control in patients with T2DM. This study aimed to determine the efficacy and safety of liraglutide 1.8 mg in participants undergoing LAGB. | PMC10599987 |
Methods | obesity, T2DM | OBESITY, SECONDARY | GLIDE, a pilot randomised, double-blind, placebo-controlled trial, evaluated LAGB with either liraglutide 1.8 mg or placebo in participants with T2DM and obesity. Participants were randomised (1:1) to 6-months therapy post-LAGB, with further 6 months off-treatment follow-up. The primary outcome was change in HbA1c from randomisation to the end of treatment, secondary outcomes included body weight change. A sample size of 58 (29 per group) had 80% power to detect a 0.6% difference in HbA1c between groups. | PMC10599987 |
Results | Twenty-seven participants were randomised to liraglutide ( | PMC10599987 | ||
Conclusions | SECONDARY | Our pilot data suggest no additional improvement in glycaemic control or BW with LAGB and liraglutide therapy. However, this trial was significantly underpowered to detect a significant change in the primary or secondary outcomes. Further trials are needed to investigate whether GLP-1 agonists, and particularly with more effective weekly agents (i.e. semaglutide or tirzepatide), are of benefit following metabolic surgery. | PMC10599987 | |
Clinical trial registration | -11 | EudraCT number 2015-005402-11.
| PMC10599987 | |
Subject terms | PMC10599987 | |||
Introduction | Obesity, adiposity | OBESITY, ADIPOSITY | Obesity is defined as excess adiposity causing a deterioration in health [Bariatric surgical procedures include laparoscopic adjustable gastric banding (LAGB), laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB) [There is evidence underpinning adjunctive GLP-1 therapy post-bariatric surgery [ | PMC10599987 |
Methods | PMC10599987 | |||
Trial design and oversight | -11 | We conducted a randomised, double-blind, placebo-controlled trial at three sites in the United Kingdom. The study was prospectively registered with EudraCT (Registration Number: 2015-005402-11) and overseen by the sponsor, King’s Health Partners. The study was conducted in adherence with the Good Clinical Practice Guidelines and the principles of the Declaration of Helsinki. The protocol was approved by London—Westminster Research Ethics Committee (REC Reference: 16/LO/1144). | PMC10599987 | |
Participants | We recruited adults (age 18–70) with a body mass index (BMI) of 30–50 kg/m | PMC10599987 | ||
Procedures | Participants underwent insertion of LAGB. Participants were randomised in a 1:1 ratio to either subcutaneous liraglutide 1.8 mg (Victoza) or placebo once daily within 6 weeks of surgery. Treatment allocation was fully concealed. Liraglutide was titrated as recommended to a maximum tolerated dose of 1.8 mg. The liraglutide/placebo intervention duration for each participant was 6 months (including the titration phase). Participants were followed up for 12 months and attended seven visits in total (Fig. Trial Flow Chart. | PMC10599987 | ||
Laparoscopic adjustable band procedures and follow up | CRF, ’ | CRF | This was a pragmatic trial. Although no specific surgical approach to LAGB placement was specified, as far as possible, standardisation in clinical approach was agreed upon amongst participating centres. The band’s type, size and specifications and operative procedure were documented in the clinical notes. When the gastric band was reviewed, this was recorded in the Case Report Form (CRF) along with any adjustments’ date(s). The participants’ follow-up was carried out according to clinical protocols, and need, including appropriate nutritional and hydration advice and band-fill adjustments by specialist dieticians or other appropriately trained staff blinded to the study arm, depending on local policy. | PMC10599987 |
Randomisation | diabetes | DIABETES | Randomisation was carried out by the King’s Clinical Trials Unit through a web-based randomisation software utilising a minimisation algorithm. Minimisation, including a random component (0.8), was carried out to protect the balance between groups. Factors used in minimisation were centre, BMI (≤42 and >42), use of insulin and diabetes duration (≤5 and >5 years). Participants were randomised to liraglutide or placebo. Once a participant was randomised, the system automatically generated emails to key staff within the study. Unblinded e-mails sent to site pharmacies alerted them to a participant’s treatment arm. The investigational medicinal product (IMP) was packaged with a unique dispensing unit number (DUN), and the pharmacy had a copy of the Total DUN List (TDL) which detailed the identity of each DUN. The pharmacy department used email and TDL to cross-check the trial prescription to ensure that the correct medication was being dispensed to the correct participant. The TDL was not available to any other research team members who remained blinded. Apart from pharmacy staff, all other site staff were blinded to the treatment arm of the participants. | PMC10599987 |
Statistics | Diabetes, diabetes | REGRESSION, DIABETES, DIABETES | A statistical plan was drafted a priori and approved by the ethics committee. A sample size of 58 (29 per group) had 80% power to detect a 0.6% difference in HbA1c (above the minimum clinically important difference of 0.5%) between groups. This accounted for 20% drop-out or loss to follow-up. All analyses followed the intention-to-treat principle and significance was taken at the 5% level. The statistician was blinded to treatment allocation until the last participant had completed follow-up. Patient characteristics were summarised as mean and standard deviation and/or median and interquartile range for each treatment arm and compared between arms using Wilcoxon rank-sum or Kruskal-Wallis tests.Multivariable linear regression models were used to test for a difference in key outcomes between treatment arms while controlling for minimisation variables (centre, BMI (≤42 and >42 kg/mA multivariable logistic regression model following the same principle as the linear models was used to test for a difference in diabetes resolution between treatment arms. Diabetes resolution is defined as the patient achieving an HbA1c of <48 mmol/mol and off all diabetes medications. | PMC10599987 |
Results | Between 27/03/2018 and 25/03/2020, 66 participants were screened for eligibility. Of these participants 39 were screen failures and 27 participants were randomly assigned to subcutaneous liraglutide 1.8 mg once daily or placebo for 6 months. Twenty-seven of the target 58 participants were therefore randomised to this trial. Of the participants randomised two were lost to follow-up ( | PMC10599987 | ||
Primary outcome: HbA1c | PMC10599987 | |||
HbA1c | At screening, median HbA1c was 51 mmol/mol in the liraglutide (L) arm and 58 mmol/mol in the placebo (P) arm (Difference in HbA1c and Body Weight at 6 months as well as at all other follow-up timepoints.Variables with missing data are indicated. All variables are reported as Median (Interquartile Range) due to a number of non-normally distributed variables. Differences between treatment groups were examined using Wilcoxon rank-sum test. | PMC10599987 | ||
Body weight | At screening, the groups had an equivalent body weight of 107.4 kg (Table Supplementary Results Description | PMC10599987 | ||
Diabetes remission and glycaemic control | T2DM | On visual inspection of graphs depicting the distribution of T2DM duration between groups, (Supplementary Fig. | PMC10599987 | |
Concomitant medications | ® | At randomisation, on average, individuals in both arms were treated with one glucose-lowering agent. There were 14 recorded medications for the liraglutide arm; all patients were treated with metformin (13/13), and one was additionally treated with insulin (Tresiba®/degludec insulin). For the placebo arm, there were 20 recorded medications, 100% (14/14) of patients were treated with metformin, 14.3% (2/14) were on dapagliflozin, 7.1% (1/14) were treated with either gliclazide, Humulin I®, Insulutard® or Victoza®. During follow-up, 6 new glucose-lowering medications were used in the liraglutide group and 3 new glucose-lowering medications in the placebo group. For the liraglutide group participants were started on: 2 metformin, 2 empagliflozin, 1 canagliflozin, 1 semaglutide. For the placebo arm participants were started on: 1 metformin, 2 dapagliflozin (Supplementary Table | PMC10599987 | |
Adverse events | cholecystitis, gastro-intestinal symptom-related, vomiting | ADVERSE EVENTS, ADVERSE EVENT, CHOLECYSTITIS | Forty-two adverse events (AE) occurred during the trial: 32 were in the liraglutide arm, and 10 were in the placebo arm. There were three serious adverse events (SAEs) during the trial: 2 in the liraglutide arm and 1 in the placebo arm. The most serious occurred in the placebo arm: cholecystitis requiring cholecystectomy. Investigational medicinal product was stopped for 5 participants in the liraglutide arm due to adverse events (5/13). Twenty-seven gastro-intestinal symptom-related AEs occurred: 20 in the liraglutide arm and 7 in the placebo arm. Gastric Band-related side effects also occurred more commonly in the liraglutide arm (L: 15 band-related AEs, P: 5 band-related AEs). 7 adverse events were ongoing at the end of the study, all in the liraglutide arm. Gastrointestinal side-effects occurred more frequently in the liraglutide arm, the most frequent being vomiting (Adverse events.Average number of adverse events (AEs) per patient as well as average time to AE and duration of AE across patients is reported as median (interquartile range). The number of patients with surgery-related and gastric band-related AEs is reported as | PMC10599987 |
Band adjustments | Four participants (two in each treatment arm) had no reported band adjustments. On average participants had 3 band adjustments during the trial, this number did not significantly differ between groups (L:3.0, P:3.0, | PMC10599987 | ||
Discussion | cholecystitis, abdominal pain, gastrointestinal AEs, Weight loss, pain, weight gain, Diabetes, weight loss, T2DM, diabetes | CHOLECYSTITIS, ADVERSE EVENTS, SECONDARY, REMISSION, DIABETES, DIABETES | The GLIDE trial aimed to assess the metabolic impact of the addition of a GLP-1 receptor agonist in the form of liraglutide 1.8 mg once daily following a LAGB in patients with T2DM. We hypothesised that the addition of a GLP-1 receptor agonist would increase the efficacy of LAGB compared to LAGB alone. To our knowledge, this is the first randomised, double-blind, placebo-controlled trial investigating the impact of GLP-1 receptor agonist treatment following LAGB insertion.Our findings did not reveal significant differences in either HbA1c or weight at 6 months between the LAGB and liraglutide arm compared to LAGB and placebo. However, after cessation of IMP at 6 months, those in the liraglutide arm experienced both a statistically significant rise in HbA1c and weight that was not seen in the placebo arm. These results may be reflective of a suppressant effect of liraglutide on weight and HbA1c in the treatment arm. However, the trial’s target sample size was 58 in total and was therefore underpowered to detect a significant difference in the primary and secondary endpoints at all time points.Remission of T2DM in both the liraglutide and placebo arms was similar, with three patients in both groups achieving full remission of T2DM at 12 months as defined by HbA1c < 48 mmol/mol and stopping all diabetes medication. Weight loss of around 10–15% leads to remission of T2DM in patients with early T2DM [Importantly, whilst there was no significant difference between groups in diabetes duration at screening, graphs showed that seven participants in liraglutide arm had duration ≥5 years, but only four participants in placebo had duration ≥5 years. In addition, two participants in the liraglutide and seven in the placebo arm had diabetes duration ≤2 years duration. Diabetes duration affects chance of diabetes remission following weight loss [There were no other significant metabolic differences between the two arms at 6 and 12 months, except for an improvement in diastolic blood pressure in the placebo arm. This is likely to have been driven by the additional weight loss in the placebo arm compared to the relative weight gain after cessation of GLP-1 therapy in the liraglutide arm. No significant differences were observed between the two groups in terms of quality-of-life scores, indicating that additional liraglutide therapy is safe and not detrimental to quality of life.This randomised controlled trial had a target sample size of 58 (29 per group), however only 27 participants were randomised to the trial. This trial was therefore significantly underpowered to detect a difference between groups in the primary and secondary endpoints. This principally relates to the change in practice over time whereby the LAGB is now less popular, with RYGB and LSG being the preferred procedures. However, this data does provide important pilot data regarding adjuvant GLP-1 receptor agonist therapy following bariatric surgery.Our study showed no differences in HbA1c or weight at 6 months between the two arms. However given the treatment duration of only 6 months, small sample size and the use of relatively less powerful adjunctive therapy further evaluation may be warranted post-metabolic surgery. A Study in rodents, although without diabetes, revealed that the administration of a GLP-1 agonist enhanced the effect of gastric banding [Additional observational and clinical studies have evaluated liraglutide post-bariatric surgery [The number of glucose-lowering therapies varied between trial groups during follow-up. In the liraglutide arm six patients commenced new medications, whereas only three patients in the placebo arm did. This may be due to liraglutide being stopped at 6 months following randomisation, and consequently glycaemic control worsened. In addition, as per the trial protocol, we stopped metformin if HbA1c < 48 mmol/mol. In the intervention arm the HbA1c at 6 months was on average 42.5 mmol/mol, whereas in placebo was 52.0 mmol/mol. Finally, liraglutide was stopped in five instances due to AE, this could have contributed towards sub-optimal glycaemic response.The study intervention was safe, with no statistical differences reported in total adverse events between the placebo and liraglutide arms. There was a numerically higher number of gastrointestinal AEs with liraglutide, in line with previous experience with GLP-1 therapy.. There was a numerically higher number of gastric-band-related AEs in the liraglutide arm vs placebo, although unlikely to be related to GLP-1 therapy. The number of band adjustments was similar in both groups, with an average of 3 band adjustments over 12 months. This number is generally lower than seen in routine clinical practice over 12 months and is likely to be related to a reduction in face-face appointments and limited band adjustments during the Covid-19 pandemic. This may also explain the suboptimal response to gastric band intervention in both groups in terms of body weight and glycaemic response. Importantly, in terms of serious adverse events there was one in the placebo arm (cholecystitis) and two in liraglutide arm (left upper quadrant pain and abdominal pain). The cholecystitis required cholecystectomy and hospital admission. The left upper quadrant abdominal pain required analgesia and anti-emetics, and the abdominal pain required cessation of IMP. Overall, this shows the safety of liraglutide in combination with LAGB. | PMC10599987 |
Strengths and limitations | weight loss, T2DM | SECONDARY | The GLIDE clinical trial has several strengths. It used a randomised, double-blind, placebo-controlled design which increased the validity of the results. The study mirrors routine clinical care to reduce the patient burden taking part in the research. Finally the study provides data to power further randomised controlled trials.However, the trial has several limitations. Importantly, the study did not achieve its estimated sample size, with several reasons accounting for this. Firstly, we noted a change in clinical practice over the time of the trial, with a general preference for a LSG or RYGB procedure compared to LAGB, especially in participants with T2DM. Secondly, inclusion criteria limited the duration of T2DM for participants to <10 years, excluding many of our patients from the trial who often present with a long duration of T2DM. Thirdly, the COVID-19 pandemic significantly impacted the study, with the majority of participants either randomised just before the pandemic or reaching the critical 6 month and 12-month trial milestones during the pandemic. This resulted in missing critical primary and secondary outcome data for some participants, including weight and HbA1c data, and restricted face-to-face appointments for band adjustment. This may partly underpin the sub-optimal metabolic and weight outcomes in both groups. A further limitation was the study’s relatively short duration (26 weeks) with liraglutide 1.8 mg. The GLIDE trial showed the worsening effect of HbA1c and weight after cessation of therapy, and it would have been of interest to determine the longer-term impact of GLP-1 therapy beyond 6 months. As per its license for the treatment of T2DM, participants were given liraglutide at a maximum dose of 1.8 mg once daily. Evidence has shown more significant weight loss with liraglutide 3 mg; at 6 months, some patients may have not yet achieved their nadir weight [ | PMC10599987 |
Conclusions | T2DM | SECONDARY | In conclusion, our pilot randomised controlled trial showed that the addition of the GLP-1 agonist receptor liraglutide after LABG did not significantly improve HbA1c or weight compared to placebo at 6 months. Importantly this trial was underpowered to detect a significant difference between groups in the primary and secondary endpoints. Results are limited by the relatively small sample size and the sub-optimal number of band-adjustments which is, in part, related to the COVID pandemic and may underpin the sub-optimal weight and glycaemic responses in both groups. Future larger randomised controlled trials of longer duration, more intensive LAGB follow-up and with more effective agents (i.e. semaglutide, tirzepatide) are required to confirm whether adjunctive GLP-1 agonist therapy and other gut hormone therapies are beneficial post-metabolic surgery in patients with T2DM. | PMC10599987 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41366-023-01368-4. | PMC10599987 | ||
Acknowledgements | We thank the participants for taking part in the GLIDE trial. We would also like to thank the clinical research teams at each study site who worked on the GLIDE trial. This study was funded by Novo Nordisk Investigator Led Grant. Novo-Nordisk had no input in the design, conduct, or interpretation of the results. | PMC10599987 | ||
Author contributions | All authors made substantial contributions to all of the following: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted. BM takes responsibility for the integrity of the work as a whole, from inception to finished article. | PMC10599987 | ||
Data availability | Data for the trial are available upon reasonable request to the corresponding author. | PMC10599987 | ||
Competing interests | Johnson & Johnson, Boehringer | AEL does not declare any conflicts of interest. CLR declares grants to his institution from the Irish Research Council, Health Research Board, Science Foundation Ireland and Anabio; consulting fees from NovoNordisk, Eli Lily, Johnson & Johnson, Boehringer Ingelheim, GI dynamics and Herbalife; Honoraria for presentations and support for attending meetings from NovoNordisk, Herbalife and Johnson & Johnson; unpaid leadership roles for the Irish Society for Nutrition and Metabolism and stocks in Keyron. BM is a shareholder in Reset Health and also performs Advisory and educational work for Novonordisk and Advisory work for Lilly. DP declares honoraria and consulting fees from Johnson & Johnson, honoraria from Medtronic and NovoNordisk and unpaid leadership roles at the Royal College of Surgeons, England. All other authors do not declare any conflicts of interest. | PMC10599987 | |
Ethics approval | Approved by London – Westminster Research Ethics Committee (REC Reference: 16/LO/1144). | PMC10599987 | ||
References | PMC10599987 | |||
Objectives | Augmented reality (AR), which entails overlay of in situ images onto the anatomy, may be a promising technique for assisting image-guided interventions. The purpose of this study was to investigate and compare the learning experience and performance of untrained operators in puncture of soft tissue lesions, when using AR ultrasound (AR US) compared with standard US (sUS). | PMC10017581 | ||
Methods | Forty-four medical students (28 women, 16 men) who had completed a basic US course, but had no experience with AR US, were asked to perform US-guided biopsies with both sUS and AR US, with a randomized selection of the initial modality. The experimental setup aimed to simulate biopsies of superficial soft tissue lesions, such as for example breast masses in clinical practice, by use of a turkey breast containing olives. Time to puncture(s) and success (yes/no) of the biopsies was documented. All participants completed questionnaires about their coordinative skills and their experience during the training. | PMC10017581 | ||
Results | Despite having no experience with the AR technique, time to puncture did not differ significantly between AR US and sUS (median [range]: 17.0 s [6–60] and 14.5 s [5–41], | PMC10017581 | ||
Conclusions | Students considered AR US to be the preferable and more enjoyable modality for learning how to obtain soft tissue biopsies; however, they did not perform the biopsies faster than when using sUS. | PMC10017581 | ||
Key Points | • • • | PMC10017581 | ||
Keywords | Open access funding provided by University of Zurich | PMC10017581 | ||
Introduction | HMD | Within the last few years, virtual reality and augmented reality (AR) have been increasingly used in the fields of entertainment and gaming. More recently, they have also been implemented in the field of medicine, particularly for training [For example, superimposing a computed tomography (CT) image over anatomical structures enables the operator to visualize deeper structures that would otherwise not be visible on just the surface. This, in combination with planned navigation, has been used to guide injections or biopsies [In this study, we assessed AR US, which has the following capabilities: Images seen through a HMD can by using a voice command either be set steady, to follow the eyes, or be positioned at a certain location, for example below an ultrasound (US) probe. Furthermore, use of tracking objectives by implementing a quick response (QR) code at the US probe can enable the image to follow the tracked US probe. The US image can thus be displayed directly below the US probe in the exact real time anatomical position (in situ image). In a previous phantom study, the performance of inexperienced operators was found to be superior when they used an AR in situ technique [ | PMC10017581 | |
Materials and methods | PMC10017581 | |||
Operators | The institutional review board approved this prospective, randomized study, and the participants gave their consent to participation.The study cohort comprised 44 medical students (28 women, 16 men) who had no experience in performing biopsies but had completed a standard US course (16 lessons). | PMC10017581 | ||
Soft tissue/breast phantom (as used by the Minimally Invasive Breast Biopsies Working Group of the Swiss Society of Radiology) | The breast phantoms comprised four turkey breasts (each 2–3 kg) filled with olives (Ultrasound guided biopsy using standard US (sUS). Note the turkey breast containing olives simulating a breast with soft tissue lesions | PMC10017581 | ||
US techniques | The sUS system used was a GE Logiq S7 expert (General Electric) with a matrix linear probe (ML 6-15) (Fig. The AR in situ US was composed of a conventional US system (SuperSonic Aixplorer Ultimate) with a linear probe (SL 18-5) and custom-developed software that transmitted the US image to an industry-grade head-mounted AR display (Microsoft Hololens). Furthermore, a QR code that tracked the probe to any position within the room was attached to the US probe (Fig. Ultrasound guided biopsy using augmented reality (AR US). The location of the image to be displayed below the US probe at the exact anatomical position was calculated using the world coordinate system of the head-mounted device and adjusted for a relative offset generated by the US probe head, marked with the QR code. The geometrical properties of the US probe head are exactly known and, together with the applied QR tracking code, an initial calibration to anchor the in situ image correctly in space, as already reported in our previously performed phantom study [This in situ image was relatively small, showing the actual dimensions without magnification (1:1); however, it supports the direct eye-hand coordination for the interventional steps by avoiding size and spatial abstraction (Fig. | PMC10017581 | ||
Briefing of the operators before the procedure performance | Before the experiments, students were instructed during 15 min in a standardized fashion regarding the usage of the probe, locating and targeting the lesion, as well as performing the biopsy. | PMC10017581 | ||
Study workflow | FEMALE BREAST, SECONDARY | Each participant was required to puncture the turkey breast containing the olive-simulated lesions with a 14G disposable core biopsy needle (Bard Magnum) used in concert with a Bard Magnum Biopsy instrument. The students were asked to perform the procedure three times using AR in situ US and three times using sUS. The initial modality was selected randomly, but balanced, 22 participants starting with AR in situ US and 22 with sUS.AR in situ US and sUS were performed in two different rooms with two different supervisors. For sUS, the supervisor was a radiologist who was specialized in imaging of women, whereas for AR US the supervisor was a gynecologist who was specialized in female breast biopsies. Both supervisors had more than 20 years of experience with US-guided biopsies. US settings (including focal zone) were prepared by supervisors, before start of the operator’s task.Primary endpoints were the speed and the accuracy with which the target was punctured. The times taken to identify a target(s) and to puncture that target(s) were measured. In addition, whether the biopsy was successful (more than > 25% of the core biopsy needle filled with olive pulp) or unsuccessful (no or < 25% olive pulp in the core biopsy) was documented.Secondary endpoints were educational experience, relationship to manual coordination in other activities, and ergonomics efficiency. To enable assessment of the secondary endpoints, all participants filled out a questionnaire concerning their coordinative skills, before the interventions. This questionnaire included items such as history of sport activities with hand-eye coordination (such as tennis), playing an instrument, video gaming, and making a self-assessment of their coordinative skills (ranging from 0 to 5). Having a gaming history was defined as regularly playing video games at least once a month.The students also filled out a second questionnaire after the interventions to report which modality they preferred (AR US vs. sUS), which provided a more enjoyable learning experience, and which image they preferred when using the AR US, and which modality was more ergonomically efficient.Study data were collected and managed using REDCap electronic data capture tools hosted at Balgrist University Hospital [ | PMC10017581 | |
Statistical analysis | Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 27. Descriptive statistics were used to express career aspiration by gender, self-assessment of manual skills, history of playing video games, significant coordinative skills, and number of missed hits using sUS and AR US. Further descriptive statistics were used to assess which of the two techniques was preferred, easier to learn with, and fun to learn with.Medians and ranges were used to report non-parametric data, such as time taken to puncture the targets. Wilcoxon matched-pairs signed rank tests were applied to test for any significant difference between the two US techniques. A | PMC10017581 | ||
Discussion | HMD | MINOR, INFILTRATION | Use of AR technology is increasing in several fields, including medicine. Early adaptations include image-guided infiltrations [We failed to confirm that our initial hypothesis, which was that inexperienced operators would perform biopsies of soft tissue lesions faster when using AR US than when using sUS, as demonstrated in a previously reported study [Second, in this study, the HMD application displayed two US images, one below the US probe at the exact anatomical location (in situ image), and a second image being the same but magnified and visible only when the head was lifted. The in situ image appeared rather small, as its actual dimensions were being viewed. The magnified US image, which was displayed when the head was lifted, was approximately the same size as on a sUS monitor and this magnified image followed the operator’s eyes. Many of the participants were probably initially overwhelmed by the two images, as indicated by the fact that they tended to look up and down repeatedly, presumably deciding which image they preferred for performing the biopsy. With the benefit of hindsight, we should have trained the participants in the AR US technique for better comparability. We tried to compensate for this issue by performing stratified analysis.Third, in the study cited above [Other limitations of the present study were that the supervisors did not change the modality and may have influenced the operators. Additionally, the turkey breast phantoms were not identical in that the olives were inserted randomly. Thus, the ease of obtaining a biopsy may have varied between the prepared phantoms. Further, some air artifacts might have influenced the operators as for 44 operators only four turkey breast were prepared. However, as more than 15 olives were inserted in each turkey breast we think, that the artifacts were of minor relevance. However, given that we used four different breast phantoms, the differences were hopefully distributed approximately equally. Of note, not all four breast phantoms were punctured with both modalities: they were punctured by all operators, but each with only one modality. Retrospectively, it would have been preferable to exchange both the supervisors and breast phantoms between the two modalities. Also, the fact that we had two different US apparatus could have influenced our results. However, we believe that this is negligible, considering that the lesions were easily visible with both US apparatus, and similar US probes were used.Even with all these limitations having deleterious effects on the AR US data, the participants did not generally perform the US-guided biopsies significantly more slowly and the learning curve was better for AR US than for sUS.Detailed analysis of gender distribution showed a tendency for women to perform the biopsies more slowly than their male colleagues when using the AR US technique; however, this difference was not statistically significant. This trend may have been related to the fact that male operators were more comfortable with the AR US technique and some of them had previously worn HMDs, probably associated with gaming histories. Although former studies have found a possible association between experience with gaming and superior performance of laparoscopic surgery [Interestingly, although puncturing with AR US was performed more slowly, most participants preferred the AR US technique and reported that it provided a better learning experience. The latter observation is concordant with several reports describing the advantages of 3D teaching and learning by AR use and is of utmost importance [The present data indicate that operators who have completed a basic sUS course perform US-guided biopsies similarly whether using AR US or sUS. However, most students preferred the AR US technique and the learning curve was steeper when using AR US. Further development of AR-based techniques may shift the equilibrium towards broader use of AR US. This evolution should be accompanied by innovation and research. | PMC10017581 |
Acknowledgements | We would like to thank Connie Maag, medical practice assistant, and Silke Callies, study nurse, both at the Institute of Radiology, Kantonsspital Baden, Mirdita Useini, and Yaël Weissmann from the medical education team at ETH Zurich, as well as Regula Schüppbach, study nurse, at the Balgrist University Hospital, for their organizational support in conducting this study. Additionally, we thank Dr. Trish Reynolds, MBBS, FRACP, from Edanz Group ( | PMC10017581 | ||
Funding | Open access funding provided by University of Zurich. The study has been supported by an unrestricted grant of Bayer (Schweiz) AG. | PMC10017581 | ||
Declarations | PMC10017581 | |||
Guarantor | The scientific guarantor of this publication is Nadja A. Farshad-Amacker. | PMC10017581 | ||
Conflict of interest | The authors of this manuscript declare relationships with the following companies: Incremed, Zurich, Switzerland. The husband of NF is cofounder and shareholder of the company Incremed (start-up company of the University of Zurich), who invented the augmented reality system (including patent) | PMC10017581 | ||
Statistics and biometry | Two of the authors have significant statistical expertise (ChK and JG). | PMC10017581 | ||
Informed consent | No informed consent was needed in this phantom study. | PMC10017581 | ||
Ethical approval | Institutional Review Board approval was obtained. | PMC10017581 | ||
Methodology | • prospective• experimental study• multicenter study | PMC10017581 | ||
References | PMC10017581 | |||
Background | PCOS, endocrine disorder | POLYCYSTIC OVARY SYNDROME 1, ENDOCRINE DISORDER | Polycystic Ovary Syndrome (PCOS) is a very common endocrine disorder with a variety of symptoms. Current treatment options include the contraceptive pill as well as metformin, however both treatments are limited to specific symptoms and have common side effects. | PMC10106320 |
Methods | PCOS | SECONDARY | This phase IV study is a monocentric, double blinded randomized clinical trial comparing the effects of six months of probiotic intervention to a placebo, with an additional open-label metformin arm as a positive control in a total of 180 participants with PCOS. The first of three visits is the screening visit, where inclusion/exclusion criteria are assessed. At the first visit, they are randomised into one of the three treatment arms equally and receive their study medication. After six months, all assessments from the first two visits are repeated. The primary endpoint is the change in free testosterone levels after the intervention, while secondary endpoints include changes in hormonal and metabolic parameters associated with PCOS as well as the gut microbial composition and diversity after intervention. | PMC10106320 |
Discussion | PCOS | Based on new insights into the role of the gut microbiome in PCOS development, this study is exploring the potential of using probiotics to treat women with PCOS symptoms. If successful, this new therapy approach could open a new realm of possibilities for treating PCOS. To our knowledge, this is the first study comparing probiotic intervention with not only placebo treatment, but also metformin. This study has been approved by the ethics committee of the Medical University of Graz (EC number 32–230 ex 19/20). | PMC10106320 | |
Registration | -20 | EudraCT number: 2020-000228-20. Clinicaltrials.gov identifier: NCT04593459. | PMC10106320 | |
Protocol version | Version 1.5 dated 29th November 2021. | PMC10106320 | ||
Keywords | PMC10106320 | |||
Background | PMC10106320 | |||
PCOS and current therapeutic options | obesity, metabolic disorder, PCOS, hirsutism, weight loss | OBESITY, METABOLIC DISORDER, INSULIN RESISTANCE, HIRSUTISM, POLYCYSTIC OVARY SYNDROME 1 | Polycystic Ovary Syndrome (PCOS) is a hormonal and metabolic disorder affecting up to 20% of women worldwide, depending on the diagnostic criteria used [As the exact pathomechanisms of PCOS have not yet been established, therapeutic options mainly focus on specific symptoms. For obesity, insulin resistance and other metabolic symptoms, lifestyle changes, weight loss and off-label use of metformin are most commonly recommended and prescribed. Combined oral contraceptives (COCs) are most frequently used to alleviate hormonal symptoms (oligo-/amenorrhea, hirsutism) [ | PMC10106320 |
PCOS and microbiome interactions | PCOS | Our group was among the first to discover lower bacterial abundances and significant differences in stool microbiome composition between women with PCOS and healthy controls in 2017 [Gut microbiota also play a critical role in phytoestrogen metabolism in our body. For women with PCOS, the isoflavone metabolite equol may be of particular interest. Daidzein, one of the most abundant isoflavones found in plant products, can only be metabolized to equol via certain bacterial species in the human gut [Several studies have already tested probiotic products for therapeutic use for women with PCOS [ | PMC10106320 | |
Hypothesis and objectives | PCOS, PCOS symptoms | SECONDARY | The working hypothesis of this randomized controlled trial (RCT) is an improvement of PCOS symptoms and androgen levels after six months of probiotic intervention. To that end, the trial is designed to primarily compare the probiotic intervention to a placebo treatment and secondarily to a standard non-hormonal treatment option such as metformin. To our knowledge, this RCT is the first trial to compare the effects of probiotics to placebo and to include metformin as a benchmark treatment arm.Two other secondary objectives are to determine the prevalence and impact of equol production in women with PCOS compared to previous reports in literature based on the general population [ | PMC10106320 |
Methods and analysis | PMC10106320 | |||
Study design | This phase IV trial is monocentric, randomized and double-blinded with one additional open-label treatment arm serving as the positive control. Two randomizations are performed. In the first randomization, participants are randomized in a 2:1 ratio to either the double-blind part or open-label metformin part. This open randomization is performed via the web-based randomization service “Randomizer” (Randomizer; Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria; available at: The patients who are randomized to the double-blind part are further randomized in a 1:1 ratio to either the probiotic group or the placebo group. The second randomization as well as the allocation concealment is performed by Winclove Probiotics B.V, Netherlands. To ensure that the 30 participants undergoing endoscopic procedures are balanced over the three groups, both randomizations are stratified for endoscopy (yes/no). Both randomizations are performed at visit 1.The study takes place at Graz University Hospital, Department of Internal Medicine, Division of Endocrinology and Diabetology, Endocrinology Outpatient Clinic.The treatment arms are the following:
Probiotic (number n = 60).Probiotic placebo (n = 60).Open-label metformin (500 mg twice daily, n = 60).The framework of the study is to show that the effects of the probiotic intervention are superior to the placebo arm. The metformin arm serves as a standard benchmark treatment arm and positive control. The study design is outlined in Fig.
Study design of the ProPCO-RCT study; First, the participants´ inclusion/exclusion criteria are determined with detailed patient histories, questionnaires and blood analysis at the screening visit. Then, 30 out of the total 180 participants voluntarily submit to an endoscopy in order to obtain gut biopsy samples for detailed microbiome analysis. Next, all participants perform a soy challenge test and a gut permeability test at home and collect stool and urine samples, which they return at visit (1) There they will be randomized into either the open-label metformin arm or the double-blinded probiotic-placebo arms, with the 30 endoscopy participants being allocated equally across the three groups. If they are randomized into the probiotic or placebo groups, they receive a randomized package containing the blinded trial substances. They then take the study medication for 6 months, before repeating both the endoscopies and the tests at home and returning for visit (2) There all assessments from the screening visit are repeated. Participants of the probiotic and placebo arms may prolong their participation by taking the probiotic product in a 6-months follow-up period, before returning for the final follow-up visit, which is identical to the visit 2; w endo: with a scheduled endoscopy visit; wo endo: without a scheduled endoscopy visit; | PMC10106320 | ||
Timeline | depression, PCOS | For this purpose, potential participants have a screening visit, where participants give written informed consent, blood and urine samples are collected and extensive patient history as well as questionnaires on PCOS symptoms, probiotic intake, depression symptoms and diet are collected. A soy challenge test as well as a functional gut permeability test are scheduled at home, requiring the participants to take urine and stool samples. For the soy challenge test, participants consume 2 × 250 ml soy drinks for two consecutive days, followed by urine sample collection at home each morning the day after soy consumption, similar to Setchell et al. [At the first visit (taking place four weeks at the latest after the screening visit), participants deliver the collected stool and urine samples and receive a randomized package of intervention product, which they will take for the next six months. The probiotic and placebo arms get 200 sachets each respectively, to be taken once daily. The metformin group receives 400 tablets of 500 mg metformin, to be taken once daily for the first 7 days of intervention before increasing the dosage to twice daily.Participants are asked to document any significant health changes or dietary intakes as well as the first day of each menstrual cycle. The intervention is scheduled to last 161 to 180 consecutive days, depending on the date of the second visit.At the end of their intervention, they will repeat the isoflavone challenge and the functional gut permeability tests at home and deliver the respective samples to the outpatient clinic at their second visit (taking place 24–26 weeks after the first visit). There, the blood and urine tests from the screening visit will be repeated.Participants in the blinded arms of the trial have the option to further take part in a follow-up period of an additional six months, during which they would take the probiotic formula (without placebo), followed by a follow-up visit scheduled one year after trial enrollment.In addition, two gastro-/sigmoidoscopies each will be performed at the beginning and the end of the intervention period in 30 voluntary participants (10 from each treatment arm planned) in order to obtain biopsy samples from the stomach, duodenum and sigmoid colon. These samples are used for the assessment of the mucosal gut microbiome as opposed to the luminal gut microbiome composition in stool samples. An overview of the timeline and visit schedule is provided in Table
Overview of number of visits and outcome assessmentsWeeks+/- 3 or more days(-4)-(-1)(+/-3 days)-1(+/-3 days)0(+/-3 days)24–26(+/-3 days)26(+/-3 days)52(+/-3 days) | PMC10106320 | |
Eligibility criteria | cancer, PCOS, gastrointestinal tract, allergies, stoma, acute gastrointestinal infection, hyperandrogenism, chronic disease | INFLAMMATORY BOWEL DISEASE, CANCER, TYPE 1 DIABETES, MALIGNANCIES, ALLERGIES, HYPERANDROGENISM, TYPE 2 DIABETES, CHRONIC DISEASE | In order to be eligible for the trial, women should be between 18 and 45 years of age, they should have at least two out of three Rotterdam criteria and they have to sign the informed consent form before starting the trial.Women can only participate if they do not have: hyperandrogenism of any cause other than PCOS; pregnancy or nursing period; soy or other allergies related to the study procedures; type 1 diabetes; chronic inflammatory bowel disease, history of cancer in the gastrointestinal tract or acute gastrointestinal infection; any malignancies requiring treatment in the 3 years preceding trial participation; any other chronic disease requiring medical check-ups or hospital treatments at least once every three months (exception: type 2 diabetes); major surgery in the gastrointestinal tract (e.g. colectomy, gut segment excision with stoma surgery, Whipple´s surgery; removal of the appendix or the gall bladder is not considered major surgery); chronic therapy with antidiabetic drugs, proton pump inhibitors, systemic intake of steroids or hormonal contraceptives in the six months preceding trial participation; antibiotic treatment within three months prior to trial procedures; alcohol or drug abuse. | PMC10106320 |
Intervention | PMC10106320 | |||
Probiotic and placebo | ® | The main intervention in this trial is a dietary food supplement powder containing seven probiotic bacterial strains: lactobacillus salivarius W57, lactobacillus casei W56, lactobacillus rhamnosus W71, lactococcus lactis W58, enterococcus faecium W54, lactobacillus plantarum W62 and lactobacillus acidophilus W22 (manufactured by Winclove Probiotics B.V., Netherlands; marketed as OMNi-BiOTiC® metabolic by Institut AllergoSan GmbH, Graz, Austria) In addition, the probiotic contains 2000 IU cholecalciferol. Other ingredients are corn starch, maltodextrin, fructo-oligosaccharides, galacto-oligosaccharides, polydextrose, plant proteins, potassium chloride, magnesium sulfate, manganese sulfate and lactose. By comparison, the placebo is very similar to the probiotic visually and in taste and smell. Its ingredients are corn starch, maltodextrin, potassium chloride, magnesium sulfate and manganese sulfate. Both Verum and Placebo are packaged in blank sachets, so that patients, caregivers, investigators and outcome assessors are blinded to their content.On each sachet, the expiration date and the study acronym (ProPCO-RCT) is clearly shown. 50 sachets are packed in one box, where the instruction for ingestion, the expiration date, the randomization code and the ingredients are noted. The bacterial strains are mentioned on every box with the symbol +/- (regardless if the strains are included or not). Every participant receives 4 boxes, in total 200 sachets. An excess number of sachets (the intervention period is only 180 days) is included in case the participant loses a few. | PMC10106320 | |
Metformin | The metformin drug used in this trial is Glucophage, a commercially available extended release metformin-hydrochloride pill, owned by Merck GmbH, Vienna, Austria. It is packaged in boxes containing 200 pills with no special markings regarding the trial. | PMC10106320 | ||
Blinding | COMPLICATIONS | The blinding is applied to the trial participants and the investigators, who serve as both care providers and outcome assessors.A treatment code table was generated via Winclove Probiotics B.V., Netherlands. Each Verum/Placebo box containing 50 sachets receives a unique code, corresponding to the treatment code table. The blinding of the sachet boxes is also done at Winclove Probiotics B.V., Amsterdam, Netherlands.To ensure proper stratification of the 20 individuals taking probiotics/placebos who also have two endoscopies during the trial, the randomisation is separated into two lists: The first list contains the 100 individuals without endoscopies, and the second list consists of the 20 participants that are assigned to the endoscopic procedures. The investigators have both lists available and assign participants the corresponding code in ascending order.Since we are only randomizing dietary supplements and placebos in a blinded manner in healthy participants, we do not expect any complications from the trial participation that would require emergency unblinding. However, in case of a medical emergency involving a participant of the trial, study investigators may be reached through the Endocrinology Ward, Division of Endocrinology and Diabetology, Medical University of Graz on a 24/7 basis.The randomization can be unblinded at the Endocrinology ward, where 120 sealed envelopes contain the allocation of each number. Only the envelope containing the treatment number for the patient in question may be opened. Both the principal investigator and the sponsor have to be notified as soon as possible of the emergency unblinding. | PMC10106320 | |
Concomitant therapies | infection, PCOS, CRF | INFECTION, THYROID, CRF | Apart from the metformin and the probiotic formula as well as the placebo, no additional medicinal products will be administered by the investigators as part of this study. However, a subgroup of PCOS patients has additional diagnoses and therefore we need to account for any medications the participants might have to take. If a participant takes any non-permissible concomitant therapy (for example antibiotic treatment), this has to be documented in the CRF at the next visit. Thyroid hormone derivatives, renin-angiotensin-aldosterone system inhibitors (such as angiotensin-converting enzyme inhibitors, angiotensin I and II inhibitors), as well as topical or locally applied ointments, drops, creams, salves, gels and powders (provided their ingredients do not have a systemic effect) may be taken during the trial without further need for documentation.In contrast, antibiotic treatments, metformin and other antidiabetic drugs, antacid medication (proton pump inhibitors), steroid hormone treatments as well as probiotic products (not including probiotics contained in food products such as yoghurt) should not be taken during the trial as well as prior to the trial based on the exclusion criteria. Should a situation require a trial participant to take any of these substances (such as an antibiotic due to infection), the circumstances and duration of the drug intake should be documented in the CRF at the next visit. | PMC10106320 |
Outcome parameters | PMC10106320 | |||
Primary outcome | PCOS | The primary endpoint of the study is a change in serum free testosterone concentration in women with PCOS after a 6-month intervention with probiotics compared to placebo treatment.PCOS combines several different phenotypes and symptoms which may vary greatly, however free testosterone is one of the most consistent biomarkers of PCOS and its symptoms and therefore the most suited for designation as the primary outcome measure and may provide the most benefit if successfully lowered due to the intervention [ | PMC10106320 | |
Secondary outcomes | inflammation, depression, PCOS | INFLAMMATION |
Glucose metabolism via HOMA and Matsuda indices as determined through an oral glucose tolerance test.Other hormonal parameters of PCOS (Anti-Müllerian hormone; androstenedione; follicle-stimulating hormone FSH; luteinizing hormone LH; dehydroepiandrosterone-sulphate DHEA-S; 17α-hydroxy-progesterone; 17β-hydroxy-estradiole; total testosterone, 25-hydroxy-cholecalciferol).Hirsutism (modified Ferriman-Gallwey score).Body weight (body-mass-index BMI; waist-to-hip-ratio).Gut permeability and inflammation (functional sucrose-lactulose-mannitol test; surrogate parameters: serum diaminooxydase; stool zonulin; calprotectin; lipopolysaccharide; soluble cluster of differentiation sCD14; bacterial DNA).Gut lumen and mucosa microbiome composition (16 S-RNA gene sequencing).Phytoestrogen production -log10 (equol to daidzein concentration ratio in urine) obtained via the soy challenge test)Quality of life (PCOS questionnaire; depression questionnaires; diet questionnaires). | PMC10106320 |
Exploratory outcome measures |
Lipid metabolism (low-density lipoprotein LDL; high-density lipoprotein HDL; lipoprotein a LP(a); triacylglycerol;)FACS analysis (B cell subtypes).Metabolomics of stool and blood.Gene expression analysis in blood and biopsy samples.Changes in incretin levels. | PMC10106320 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.