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Study procedures | ICH, diabetes | DIABETES | The ADREM study (Adjustment of insulin Degludec to Reduce post-Exercise (nocturnal) hypoglycaeMia in people with diabetes) was an open-label, randomised controlled, three-way crossover study, conducted in accordance with the principles of the Declaration of Helsinki, the Medical Research Involving Human Subjects Act and applicable International Conference on Harmonization (ICH) Good Clinical Practice guidelines. The study was approved by the local ethics committee and national competent authority. All participants gave their written informed consent before any study-related activity was performed. | PMC9988601 |
Study participants | hypoglycaemia | TYPE 1 DIABETES, EVENT, HYPOGLYCAEMIA | Adults aged 18–60 years were eligible for participation when they had been diagnosed with type 1 diabetes for at least 2 years, had been treated with a basal-bolus multi-dose insulin regimen for at least 1 year and were at increased risk of hypoglycaemia. The latter was defined as a history of at least one severe hypoglycaemia event in the past year and/or ≥2 points on the Dutch modified version of the Clarke questionnaire and/or ≥3 points on the Gold score [ | PMC9988601 |
Screening visit | A schematic overview of the study design is shown in Fig. Overview of the study. Ex, exercise day; Scr, screening visit | PMC9988601 | ||
Exercise days | Each participant engaged in 3 exercise days and was randomly assigned by the investigator to an order of the three post-exercise degludec treatment regimens, i.e. no adjustment of insulin degludec (CON), a 40% dose reduction of degludec (D40) and 8 h postponement with a 20% dose reduction of degludec (D20-P). For D40, the usual recommended long-acting insulin dose reduction of 20% was doubled, because degludec has a | PMC9988601 | ||
Study outcomes | EVENTS, EVENT | The primary outcome was the time below range (i.e. glucose <3.9 mmol/l) in the night (00:00–05:59 hours) following the exercise test. Secondary outcomes included times above range (i.e. glucose >10.0 mmol/l) and in range (i.e. glucose ≥3.9 mmol/l and ≤10.0 mmol/l), mean glucose concentration, number of hypoglycaemic and severe hypoglycaemic (requiring external assistance for recovery) events and total daily dose of short-acting insulin. All outcome variables were calculated during the first and second days (00:00–23:59 hours) after the exercise test as well as for the total 6 days following the exercise test. A hypoglycaemic event was defined as a glucose concentration <3.9 mmol/l for at least 15 consecutive minutes and a new event was calculated if the glucose concentration had been risen above this level for at least 15 min [ | PMC9988601 | |
Measurements | Plasma insulin was measured using an in-house radioimmunoassay, using an in-house-generated guinea pig anti-human insulin antibody and | PMC9988601 | ||
Statistical analyses | The sample size estimation was based on the two treatments for which the smallest difference was expected (D40 and CON). Given this was a crossover trial, it was expected that the other comparisons (with D20-P) would have sufficient power. No ɑ corrections were made to account for the multiple comparisons. Furthermore, it was assumed that the within-person correlation for the response measures on the different treatments was 0.65. We aimed at finding a significant decrease in time below range with at least 20% increase in time in range during the night after the exercise test and 50% increase in next-morning fasting glucose concentration [ | PMC9988601 | ||
Results | SD | HYPOGLYCAEMIA | A total of 19 participants were screened, 18 of whom were included. One participant was withdrawn after screening because of personal reasons unrelated to the study. All 18 included participants completed the study. Their baseline characteristics are shown in Table Baseline characteristicsData are presented as number (%), mean ± SD or median [IQR]IAH, impaired awareness of hypoglycaemia, i.e. ≥3 points on Clarke questionnaire and/or ≥4 points on Gold score | PMC9988601 |
Exercise tests | ST-segment depression | The three 45 min exercise tests were performed consistently across all treatment groups regarding heart rate (CON 144 ± 3, D40 145 ± 3, D20-P 144 ± 3 beats per minute). All participants cycled at 70% of their heart rate reserve, except for one participant, who cycled all three tests at 57% heart rate reserve because of mild ST-segment depression during CPET. The increase in blood lactate (Δ lactate CON 0.76 ± 0.15, D40 0.97 ± 0.35, D20-P 0.69 ± 0.14 mmol/l) and decrease in blood glucose levels (Δ glucose CON −3.88 ± 0.95, D40 −4.91 ± 0.50, D20-P −3.69 ± 0.58 mmol/l) during cycling did not differ for the three exercise tests (ESM Fig. | PMC9988601 | |
Study outcomes | PMC9988601 | |||
Time below range and hypoglycaemic events | Time below range in the night after the exercise test was generally low and occurrence did not differ significantly between the treatment regimens (three participants in CON, one in D40, three in D20-P). The day after the exercise test, time below range was greater for CON compared with D40 (18 [0–55] vs 0 [0–23] min, | PMC9988601 | ||
Mean glucose concentration | No differences in mean glucose concentration were found between the treatment regimens the night after the exercise test (Fig. Time course of the mean glucose concentration over the first ( | PMC9988601 | ||
Time above range | No differences in time above range were found between the treatment regimens the night after the exercise test. The day after the exercise test, D20-P led to significantly more time above range (584 ± 81 min) compared with CON (364 ± 66 min, Percentage of time spent above range, in range and below range the first night ( | PMC9988601 | ||
Time in range | The night following the exercise test, D20-P was associated with less time in range compared with D40 (229 ± 30 vs 287 ± 26 min, | PMC9988601 | ||
Sensitivity analyses | Repeating the analyses according to the actual sleep times of the participants did not materially change the results, except that the night after the exercise test, the mean glucose concentration was higher for D20-P compared with CON (9.8 ± 0.8 vs 8.5 ± 0.5 mmol/l, | PMC9988601 | ||
Fasting ketones | Fasting ketones in the morning after the exercise tests were generally low (all ≤0.8 mmol/l), but were significantly higher for D20-P than D40 (0.27 ± 0.04 vs 0.16 ± 0.03 mmol/l, | PMC9988601 | ||
Short-acting insulin and carbohydrate intake | HYPERGLYCAEMIA, EVENT, HYPOGLYCAEMIA | The evening after the exercise test, three people (17%) in CON, one (6%) in D40 and one (6%) in D20-P injected additional short-acting insulin because of profound hyperglycaemia. During this evening, nine people (50%) in CON, five (28%) in D40 and two (11%) in D20-P ingested additional carbohydrates to prevent hypoglycaemia. However, of these participants, only one within each treatment arm ingested carbohydrates after 23:00 hours without experiencing a nocturnal hypoglycaemic event. No differences were found in the total daily dose of short-acting insulin used between the treatment regimens on the first and second days after the exercise test (ESM Fig. | PMC9988601 | |
Discussion | generalised, hypoglycaemia | EVENTS, TYPE 1 DIABETES, NOCTURNAL HYPOGLYCAEMIA, HYPOGLYCAEMIA | The main finding of this study is that adjustment of insulin degludec dosing after aerobic exercise performed in the afternoon had no effect on the incidence of subsequent nocturnal hypoglycaemia in people with type 1 diabetes. While next-day time below range was slightly reduced in the 40% dose reduction group, this did not translate to fewer hypoglycaemic events. Postponement of degludec to the next morning at a 20% lower dose led to more time above range and less time in range during that day, as well as slightly more time below range on the subsequent second day. Altogether, these results do not support dose adjustments of degludec in people with type 1 diabetes after afternoon aerobic exercise.Two recent studies have reported a relatively low incidence of nocturnal hypoglycaemia after aerobic exercise in people with type 1 diabetes using insulin degludec [Heise et al reported insulin glargine and insulin degludec to have a similar (nocturnal) hypoglycaemic risk profile after performing aerobic exercise of moderate intensity in people with type 1 diabetes, without insulin dose reductions [For people with type 1 diabetes, the risk of hypoglycaemia is increased for at least 24 h after aerobic exercise, in particular, when performed in the afternoon [We chose postponement of insulin degludec as one of the dosing adjustment regimens because of previous data showing that alternating degludec dosing at flexible intervals of 8 to 40 h provided about similar glycaemic control to dosing every 24 h [Strengths of our study are the randomised crossover study design, the robust and highly reproducible exercise protocol, the use of CGM and the daily life setting, all of which are relevant in the context of the potential need for dose adjustments.Our study also has limitations. First, it may be questioned to what extent our results can be generalised to people performing morning exercise or injecting degludec in the morning. However, morning exercise leads to a lower risk of late-onset hypoglycaemia compared with afternoon exercise in people with type 1 diabetes on insulin pump therapy [In conclusion, adjustment of insulin degludec dosing after aerobic exercise in the late afternoon has no effect on subsequent nocturnal hypoglycaemia in people with type 1 diabetes. In fact, postponing the administration of degludec leads to more time above range, which underscores the importance of adhering to insulin degludec dosing around exercise, especially when insulin doses are low. Adjustments in meal-related short-acting insulin both before and after exercise may be advisable for people using degludec, but our data do not provide support for standard insulin degludec dose adjustment after exercise in people with type 1 diabetes. These data add evidence for the ease of use of insulin degludec for most people with type 1 diabetes who want to engage in aerobic exercise. | PMC9988601 |
Supplementary information |
(PDF 450 kb) | PMC9988601 | ||
Acknowledgements | Diabetes | DIABETES | The authors thank all volunteers for their participation. The authors also express their gratitude to B. Kersten and E. Bakker from the Department of Physiology, Radboud University Medical Center, Nijmegen, the Netherlands, for assistance during the exercise tests and with analysing activity tracker data, respectively. The authors also thank T. van Herwaarden from the Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands, for assistance with determining the analyses methods for the laboratory measurements. They received no financial support for their participation. Some of these data were presented in abstract form at the Annual Dutch Diabetes Research Meeting (ADDRM) in 2022 and at the 58th EASD Annual Meeting in 2022. | PMC9988601 |
Authors’ relationships and activities | BEdG is associate editor for | PMC9988601 | ||
Contribution statement | EJA, CJT and BEdG designed the study. LCAD recruited the participants, performed the experiments, collected the data, analysed the data and wrote the first version of the manuscript. LCAD, MA and LR performed the statistical analyses. All authors discussed the results and implications, commented on the manuscript at all stages and approved the final version of the manuscript. The guarantor (BEdG) accepts full responsibility for the work and conduct of the study, has access to the data and controlled the decision to publish. | PMC9988601 | ||
Funding | Nordisk | This study was conducted with an unrestricted grant from Novo Nordisk, Denmark. Novo Nordisk was not involved in the collection, analyses and interpretation of data, nor in writing the report and the decision to submit for publication. | PMC9988601 | |
Data availability | The datasets generated during and/or analysed in the current study are available from the corresponding author upon reasonable request. | PMC9988601 | ||
References | PMC9988601 | |||
Subject terms | Mediolateral weight-shifting is an important aspect of postural control. As it is currently unknown whether a short training session of mediolateral weight-shifting in a virtual reality (VR) environment can improve weight-shifting, we investigated this question and also probed the impact of practice on brain activity. Forty healthy older adults were randomly allocated to a training (EXP, n = 20, age = 70.80 (65–77), 9 females) or a control group (CTR, n = 20, age = 71.65 (65–82), 10 females). The EXP performed a 25-min weight-shift training in a VR-game, whereas the CTR rested for the same period. Weight-shifting speed in both single- (ST) and dual-task (DT) conditions was determined before, directly after, and 24 h after intervention. Functional Near-Infrared Spectroscopy (fNIRS) assessed the oxygenated hemoglobin (HbO | PMC10638445 | ||
Introduction | Weight-shifting constitutes an important component of dynamic postural control, which refers to the ability to keep one’s bodyweight within the base of supportMost studies on learning-induced neural activation changes have focused on upper extremity tasksFunctional Near-Infrared Spectroscopy (fNIRS) is a mobile neuroimaging method able to capture brain hemodynamics when in the upright position, albeit at a much lower spatial resolution than fMRIGiven the above gaps in the literature, we set out to investigate older adults’ ability to improve weight-shifting using a VR-game and whether these effects would be retained after a period without training. Additionally, we wanted to examine whether the effects of weight-shift training were maintained when cognitively distracted | PMC10638445 | ||
Results | Some missing data were apparent due to recording problems (once due to the fNIRS-cap and once due to the wasp game). One participant in EXP was not willing to perform the DT condition, and one participant in CTR found the fNIRS system uncomfortable at retention. | PMC10638445 | ||
Participant characteristics | SD | Participants were recruited, trained and tested between January 4th and June 16th, 2021. Forty-three healthy older adults were initially recruited for participation, as three participants had to be excluded after signing the informed consent. Two did not meet the in/exclusion criteria (one had a MoCA score below 26 and one was younger than 65 years). The third had a large difference in leg length (2.5 cm), influencing weight-shifting performance. Table Participant characteristics for the training and control group.Normally distributed data are displayed as mean ± SD, and not normally distributed data as median (first quartile, third quartile). | PMC10638445 | |
Behavioral results | PMC10638445 | |||
Training effects on weight-shifting performance in ST | Significant time by group interactions were revealed for all three outcomes (speed: F( | PMC10638445 | ||
Training effects on weight-shifting performance in DT | When adding the cognitive DT to the weight-shifting assessments, a comparable pattern of interaction effects was found (speed: F | PMC10638445 | ||
Training effects on functional limits of stability and overall balance | Figure Functional limits of stability (fLOS) for the ( | PMC10638445 | ||
fNIRS results | PMC10638445 | |||
Training effects on cortical hemodynamics | Cortical hemodynamics during ST showed a significant interaction effect for the SMA left (F(fNIRS HbOValues are displayed as mean ± SD (μmol/L). Bold values indicate statistical significance and effect sizes of significant post-hoc tests. Note that only within-group time effects were explored post-hoc. | PMC10638445 | ||
Exploratory analyses | To determine which people responded best to training, correlation analyses were conducted and revealed that participants in EXP who had a better overall balance at baseline (higher MiniBEST score) also tended to have a larger ST speed improvement from pre-assessment to 24 h-retention (r = 0.456, p = 0.043, see Supplementary Fig. To explore the association of the HbO( | PMC10638445 | ||
Discussion | BLIND | This is the first study that investigated whether a single-session VR-based balance training led to changes in weight-shifting behavior and brain activity in older adults. Older adults were able to improve their weight-shifting capacity after the session during ST and DT test-conditions, the latter reflecting that the gains were resistant to DT-interference. In addition, and as hypothesized, training effects were retained after 24 h and transferred to improved limits of stability outside the game-setting, though this transfer was only present in two directions and disappeared the next day. We also hypothesized that training-induced changes in HbOThe finding that EXP displayed better weight-shifting compared to CTR was not only confirmed by better game outcomes (increases in wasp-hits), but more importantly by a better control of the CoM (higher speed and accuracy). Learning led to larger effect sizes in EXP (speed: d ≥ 0.94) versus CTR (speed: d ≤ 0.09), which were retained over a 24 h-retention period. These findings are in line with a systematic review on balance training in older adultsNext, we could also demonstrate that weight-shift training effects were resilient to DT interference. Similar results were found in other studies investigating DT balance trainingImportantly, after mediolateral weight-shift training the EXP showed improvements of the stability limits in two directions. These fLOS gains could be considered as indications of near-transfer, referring to the greater likelihood to generalize learning outcomes when a high degree of similarity between the learned and the transfer task is apparentAs for neural activity, previous work demonstrated that changes in the brain are different for acquisition than retentionA similar pattern of results was found in the left SSC during DT-assessment, revealing an increase in HbOEven though we expected that early learning from pre- to post-training would require an increasing need for attentionEarlier work also showed that learning is often accompanied by a shift of activity to subcortical regionsThis study represented a randomized controlled trial, whereby the tester was not blind to group allocation and the contrast included a passive control group. However, outcomes were based on objective measures. Due to an error in the a-priori sample size calculation, this study was probably underpowered for some outcomes. However, effect sizes of the significant results were higher than the sensitivity power analysis-derived threshold. In addition, the modest reliability of repeated fNIRS measures in some regions hampered a strong interpretation of the results. To optimize the validity of the fNIRS data, we incorporated short-separation channels and accelerometers into the setup and analysis, filtering out movement artefacts and systemic noise as stipulated by recent guidelinesHowever, the fact that weight-shifting capacity in older adults was improved with a single session of training is promising and supports the incorporation of weight-shifting VR-games in fall-prevention programs. Another important finding for the clinical field was that the results were also present in conditions with cognitive distraction, implying robust learning results. Future research is needed to investigate whether enriched weight-shift training can induce sustained neural changes and lead to transfer effects to overall balance capacity in older adults.This study showed that a single training session improved mediolateral weight-shifting capacity in healthy older adults during both ST and DT assessments when compared to a control group without training. The gains were maintained after 24 h and showed short-term transfer to improvement of the limits of stability, although not in the mediolateral direction. The increased HbO | PMC10638445 | |
Materials and methods | PMC10638445 | |||
Participants | chronic musculoskeletal problems, balance impairments, cardiovascular or respiratory disease, diabetes | DIABETES, MAY, NEUROLOGICAL DISORDERS | In total, we recruited forty-three healthy older adults through our local GDPR-proof databases, of which forty were included in the actual study protocol. Participants had to be able to stand upright for a minimum of 5 min without using an aid and were excluded if they presented any medical problems that could influence their performance (e.g. neurological disorders, balance impairments, chronic musculoskeletal problems, cardiovascular or respiratory disease, uncorrected vision, or diabetes). Participants with a Montreal Cognitive Assessment (MoCA) score lower than 26 were excluded. Study information was given before signing the informed consent in accordance with the declaration of Helsinki. Ethical approval was provided by the Ethics Committee Research UZ/KU Leuven (EC Research; S26917; 26 May 2020). | PMC10638445 |
Experimental procedure and tasks | PMC10638445 | |||
Procedure | This randomized controlled trial was pre-registered at clinicaltrials.gov (ID: NCT04594148, first registration: 20/10/2020, including full trial protocol) and consisted of two test sessions at the Movement and Analysis Laboratory Leuven (MALL). Healthy older adults were randomly allocated to either the training (EXP, n = 20) or control group (CTR, n = 20) in a parallel design. Blocked computer-generated randomization was performed by an independent researcher in blocks of four and stratified for gender. The randomization sequence was revealed to the researcher after participant enrollment. On day 1, the EXP received a 25-min weight-shift training intervention within the VR wasp game (see section “ | PMC10638445 | ||
Interventions | Mediolateral weight-shift training was performed via a VR wasp game (see Supplementary Fig. The 25-min training was divided into 10 blocks of 2.5 min with a 30 s rest period in between blocks. A longer break of 2 min was provided after five blocks with the opportunity to rest on a chair. Participants were instructed to hit as many wasps as possible, while maintaining their base of support and initial posture. To make the training more challenging, the wasps were randomly placed at positions higher or lower than the midline and were made bigger or smaller. As such, participants had to pay constant attention to the position and size of the wasp. Verbal feedback and encouragement was provided throughout the training. Participants in the CTR were asked to relax for 25 min, while seated. | PMC10638445 | ||
Weight-shifting assessment | Weight-shifting assessments were performed at pre, post and retention. For this purpose, the wasp game was executed in both single- (ST) and dual-task (DT) conditions. During DT, participants had to perform serial subtractions in threes, while hitting the wasps (see Supplementary Fig. | PMC10638445 | ||
fNIRS assessment | BRAIN | Brain hemodynamics were captured with the continuous wave, single-phase NIRSport2 system (NIRx, Berlin, Germany), with LED wavelengths of 760 and 850 nm and a sampling frequency of 7.81 Hz, following consensus guidelines | PMC10638445 | |
Cognitive assessment and other descriptors | sarcopenia | SARCOPENIA | After the experimental procedures on day 2, participants performed a descriptive test battery. We used the MoCA for assessment of cognitive ability. Other questionnaires included the Falls Efficacy Scale International (FES-I) to assess concern about falling, the sarcopenia questionnaire (SARC-F) and the Pittsburgh Sleep Quality Index (PSQI) capturing sleep quality and quantity over the last month and the night in between assessment day 1 and 2. | PMC10638445 |
Data processing | PMC10638445 | |||
Weight-shifting data | Matlab 2018b (Mathworks, MA, USA) was used to process the CoM data as calculated in real time within the D-Flow software | PMC10638445 | ||
fNIRS data | CORTEX | fNIRS data were imported into Matlab (version 2018b, Mathworks, MA, USA) and analyzed using the NIRS toolbox (open access; Visually checking raw signals and resampling signals to 5 Hz. Converting raw signals into optical density using the Beer–Lambert law for which a partial path length correction factor of 0.1 was used. Running a general linear model (GLM) with the autoregressive iteratively reweighted least squares (AR-IRLS) method Averaging channels per hemisphere for each ROI, as determined within fOLD, and the human motor area template for separating the PMC and SMA Calculating relative oxygenated hemoglobin (HbOfNIRS lay-out with regions of interest (ROIs) according to fOLD toolbox, with a specificity level of 50%. The prefrontal cortex (PFC) is represented by the blue colored connections to the channels, the frontal eye fields (FEF) by the green channels, the supplementary motor area (SMA) by the orange channels, the premotor cortex (PMC) by the purple channels, and the somatosensory cortex (SSC) by the yellow channels. The channels situated at the midline were excluded (indicated by black crosses), and ROIs were analyzed for each hemisphere separately.As HbO | PMC10638445 | |
Statistical analysis | An a-priori sample size calculation (see clinicaltrials.gov, ID: NCT04594148) determined that we required 40 participants (20 per group). However, during data analyses, an error was found in that calculation, so an additional sensitivity power analysis was performed. From this, we determined that our sample of 40 is sufficient to detect effect sizes SAS (Version 9.4 of the SAS System for Windows, SAS Institute Inc., Cary, NC, USA) and SPSS (IBM SPSS Statistics, Version 26) was used for data analysis, including all participants. Participant characteristics as well as behavioral and cortical outcomes at baseline were compared between groups with an independent To explain the training effects, Pearson’s correlations between changes in ST weight-shifting speed (pre-post, pre-retention) and participant characteristics (age, MoCA, FES, SARC-F, PSQI, baseline MiniBEST) were calculated, resulting in 12 comparisons. As well, an exploratory correlational analysis (without correction for multiple comparisons) was carried out between changes in cortical hemodynamics for the ROIs that displayed significant interaction effects and weight-shifting performance. | PMC10638445 | ||
Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-46645-4. | PMC10638445 | ||
Acknowledgements | A special word of thanks is direction towards Marie Bogaerts, Annelien Loverix, Hanne Vandenbossche and Ella Copermans for their crucial involvement during data collection. Above all, the authors are grateful for the enthusiastic contributions of all participants, without whom this study would not have been possible. The work was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement (grant number 721577), the Research Foundation Flanders (FWO) (grant number: G0A5619N), and NWO/ZonMw (Rubicon; 452020220). | PMC10638445 | ||
Author contributions | RECRUITMENT | V.R. was responsible for the recruitment, data collection, data analysis and writing of the manuscript. N.D. contributed to the data and statistical analysis. F.H. helped with the data collection and data analysis. C.M. contributed to the sample size calculation and manuscript revisions. S.V. provided the infrastructure of the research lab and contributed to the manuscript revisions. A.N. was responsible for obtaining the funding for the project, and contributed to the design, analysis and writing of the manuscript. J.-J.O. contributed to the data analysis and writing of the manuscript. | PMC10638445 | |
Data availability | The datasets generated for this study will be made available upon reasonable request, which should be directed to the corresponding author. | PMC10638445 | ||
Competing interests | The authors declare no competing interests. | PMC10638445 | ||
References | PMC10638445 | |||
Objectives | DIE, EH | ENDOMETRIAL HYPERPLASIA | To compare the effectiveness of dienogest (DIE) and norethisterone acetate (NETA) regimens in the treatment of endometrial hyperplasia (EH) without atypia. | PMC10348941 |
Methods | DIE, irregular uterine bleeding | ENDOMETRIAL HYPERPLASIA WITHOUT ATYPIA | Participants were premenopausal women with irregular uterine bleeding, and endometrial hyperplasia without atypia on endometrial biopsy. Enrolled patients were randomly allocated into two groups: group I got DIE 2 mg/day (orally Visanne) for 14 days (10th to the 25th day of cycle) while group II received between the 16th and 25th day of the cycle, norethisterone acetate (NETA) 15 mg/d (orally Primolut Nor) was administered for 10 days. Both groups continued the therapy for six months. | PMC10348941 |
Results | DIE | REGRESSION | The DIE group showed a higher resolution (32.7%) and regression (57.7%) than NETA group (31% & 37.9%, respectively) with significant regression ( | PMC10348941 |
Conclusion | REGRESSION | If used as first-line treatment, Dienogest produces a better rate of regression and a lower incidence of hysterectomy than Norethisterone Acetate does when used in EH without atypia. | PMC10348941 | |
Keywords | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). | PMC10348941 | ||
What does this study add to the clinical work | PMC10348941 | |||
Introduction | irregular uterine hemorrhage, endometrial cancer, endometriosis, hyperplasia, DIE, cancer, endometrial hyperplasia, amenorrhea, weight gain, acne | ENDOMETRIAL CANCER, ENDOMETRIOSIS, HYPERPLASIA, CELLULAR ATYPIA, ENDOMETRIAL HYPERPLASIA, CANCER, ENDOMETRIAL HYPERPLASIA, ACNE, CYTOLOGIC ATYPIA | Endometrial hyperplasia, which may lead to endometrial cancer or coexist with it, is characterized by an excessive growth of the endometrial glands [Although this ailment is often detected during the postmenopausal stage, it may occur at any age as long as the person is exposed to estrogen. The most significant risk factor for the development of endometrial cancer from hyperplasia is hyperplasia with cellular atypia. The most prevalent indication of endometrial hyperplasia is irregular uterine hemorrhage [In 80% of instances, simple hyperplasia that is left untreated heals on its own; in 19% of cases, it persists; and in 1% of cases, it turns into cancer. However, the chance of developing cancer rises when cytologic atypia is present [The progestin's mode of action for treating hyperplasia involves pseudo-decidualization, a decrease in the number of endometrial glands, and their anti-estrogenic activities [Progestin is proven to be useful in treating endometrial hyperplasia, however the side effects of progestin medications, particularly older second-generation medications, include weight gain, mood changes, acne, amenorrhea, and negative vascular consequences. [Dienogest (DIE), a fourth-class oral progestin from a new generation, combines the pharmacologic characteristics of progestin derivatives with those of 19-norprogestins. It has potent progestogenic impacts without androgenic, mineralocorticoid, or glucocorticoid activities, making it particularly useful for the cure of endometriosis [Our research compares the efficacy of DIE and norethisterone acetate (NETA) regimens for treating EH without atypia. | PMC10348941 |
Patients and methods | PMC10348941 | |||
Study design and inclusion criteria | endometrial hyperplasia, abnormal endometrial thickness, abnormal uterine hemorrhage | ENDOMETRIAL HYPERPLASIA, ABNORMAL UTERINE HEMORRHAGE, ENDOMETRIAL HYPERPLASIA WITHOUT ATYPIA | A prospective controlled study of premenopausal women between the ages of 41 and 53 who were hospitalized to the Obstetrics and Gynecology Department at Zagazig University between January 2020 and October 2021 with abnormal uterine hemorrhage and persistent pelvic discomfort participated in an interventional prospective study (Fig. Flow chart of studied patientsParticipants in the research had abnormal endometrial thickness (more than 12 mm) on transvaginal ultrasonography and endometrial hyperplasia without atypia on endometrial biopsy (according to the WHO endometrial hyperplasia criteria) [ | PMC10348941 |
Exclusion criteria | liver, kidney, heart, diabetes, AUB, breast cancers, hyperplasia | ABNORMAL UTERINE BLEEDING, BREAST CANCER, HYPERPLASIA, LEIOMYOMA, THROMBOEMBOLIC DISEASE | However, those with localized endometrial lesions like leiomyoma or atypical or complicated hyperplasia who have had hormone treatment within the last six months are at higher risk and other causes of abnormal uterine bleeding (AUB) like adnexal swellings and genital and breast cancers were excluded. Also, patients with liver, kidney, heart, diabetes, thromboembolic diseases or steroid therapy were ineligible.Outcomes of therapeutic treatment of EH for six months | PMC10348941 |
Interventions | DIE, abnormal endometrial thickness | STERILE, PROLIFERATIVE, REGRESSION, PATHOLOGY, ATROPHIC | Enrolled patients were randomly allocated into two groups; group I got DIE 2 mg/day (orally Visanne; bayer pharma, Cairo, Egypt) for 14 days (10th to the 25th day of cycle) while Between the 16th and 25th day of the cycle, group II got norethisterone acetate (NETA) 15 mg/d (orally Primolut Nor; Hi Pharma, Cairo, Egypt) for 10 days. Both groups continued the therapy for six months.A list of random numbers created by a computer was used for randomization. The QuickCalcs program was used to create the random number list (GraphPad Software Inc, La Jolla, California). The research supervisor stored the group assigning numbers in an envelope that was sealed.Clinical evaluation and history-taking are performed on all women. In addition, a transvaginal ultrasound was used, and women with abnormal endometrial thickness underwent biopsy using the Pipelle Endometrial Suction Curette (Cooper Surgical Inc., Trumbull, CT 06,611 USA). The Pipelle is a single-use, sterile, plastic, disposable, suction curette consisting of an outer graded sheath and an inner piston for obtaining a histologic biopsy of the uterine mucosa lining or sample extraction of uterine menstrual content for microscopic examination or culturing. The Pipelle had outer diameter (OD) of 3.1 mm and no cervical dilatation needed. The biopsy sample was then examined by the unit of pathology. All women followed-up for six months then the second biopsy and histopathology were done.The pathologic outcomes of endometrial curettages were compared (both during and after therapy, respectively). The outcomes were divided into four groups: advancement (simple EH without atypia), persistence (atrophic, inactive, secretory endometrium), regression (proliferative endometrial) (simple EH atypia, complicated EH atypia, or neither). | PMC10348941 |
Statistical analysis | SD | On an IBM compatible computer, the acquired data were tabulated and analyzed utilizing SPSS (statistical software for social research), version 25 (IBM, Armonk, NY, USA). Quantitative continues group represents by mean ± SD and compared between them by independent t test and paired t test while qualitative represents as number and percentage and is compared between them utilizing chi square test. | PMC10348941 | |
Discussion | Endometrial hyperplasia | ENDOMETRIAL HYPERPLASIA, UTERUS | Endometrial hyperplasia is a widespread condition. Particularly in Arab nations, the uterus is seen as a sign of women and femininity. Her psychological state will be greatly impacted by having her uterus removed. Therefore, every effort must be made to maintain the uterus as much as possible. | PMC10348941 |
Main findings | DIE | To the extent that we are aware, there is insufficient data regarding effect of DIE in EH without atypia and our study is a unique one to compare its effect versus NETA as a conventional treatment of EH. | PMC10348941 | |
Strengths and limitations | The main limitation of research was the small size of study groups, and the factors strengthen the study, the prospective nature of study and use of inclusion and exclusion criteria with coding of the data collected for proper interpretation. | PMC10348941 | ||
Interpretation | irregular bleeding, mastalgia, DIE, cancer, nausea &vomiting | REGRESSION, CANCER | A fourth-generation progestin called DIE was employed in hormone replacement treatment and contraceptive pills [It is well known that progestins speed up the signaling pathways that prevent endometrial cells from undergoing cancer development [A research by Kodama et al. [Ozdegirmenci et al. [In the current study, we used DIE 2 mg/day for 14 days/cycle orally versus NETA 15 mg/day for 10 days/cycle orally in patients with EH without atypia for six months. We found that DIE group showed a higher rate of resolution (38.5%) and regression (57.7%) than NETA group (31% & 37.9%, respectively) with significance regarding regression only (The same results reported by Uysal et al. [Also, our results revealed that side effects of DIE & NETA were comparable between groups with slightly higher rate in NETA group for irregular bleeding, nausea &vomiting and mastalgia. The same finding recorded in Uysal et al. [ | PMC10348941 |
Acknowledgements | PATHOLOGY | Thank you to the pathology and gynecological team for their cooperation. | PMC10348941 | |
Author contribution | EFG: study design, writing and share in gynecological work up of study. HMA: share in gynecological work up of study. HES: collect the study groups and share in writing of study. AMR: share in writing of study and share in gynecological work up of study. | PMC10348941 | ||
Funding | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). The research, writing, and/or publishing of this work were all done without any financial assistance from the authors. | PMC10348941 | ||
Data availability | Data available on reasonable request. | PMC10348941 | ||
Declarations | PMC10348941 | |||
Conflict of interest | No conflicts of interest. | PMC10348941 | ||
Ethical approval | Before enrolling in our trial, we obtained written informed permission from every participant, and they were all free to withdraw at any moment throughout follow-up. The Faculty of Medicine at Zagzig University in Egypt's Institutional Review Board and ethics committee gave their approval to the study's protocol. | PMC10348941 | ||
References | PMC10348941 | |||
Background | obesity | OBESITY | Mandatory calorie labelling in the out-of-home food sector was introduced in England in 2022, and menu pricing strategies that ensure cost is equivalent to portion size (proportional pricing) have been proposed as a policy to reduce obesity. Food delivery app-based platforms now contribute significantly to diet, and evidence suggests that those at a socioeconomic disadvantage may have greater exposure to unhealthy options on these platforms. However, public health policies to improve nutritional quality of food ordered from food delivery apps has received limited examination. | PMC10508026 |
Objective | This experimental study assessed the impact of calorie labelling and proportional pricing on item and meal size selection, calories ordered, and money spent when selecting food and drinks from three outlet types on a virtual delivery app. | PMC10508026 | ||
Methods | SHOP | UK adult participants (N = 1126, 49% female), stratified by gender and education level completed an online study where they ordered items from three branded food and beverage outlets (coffee shop, sandwich outlet, fast food outlet) using a virtual delivery app. Participants were presented food and beverage options with vs. without calorie labels and with value (larger portions are proportionally cheaper) vs. proportional pricing. | PMC10508026 | |
Results | SHOP | Calorie labelling did not influence portion size selection for any outlets, but significantly reduced calories ordered from the coffee shop (-18.95kcals, 95% CI -33.07 to -4.84) and fast food outlet (-54.19kcals, 95% CI -86.04 to -22.33). Proportional pricing reduced the likelihood of choosing a larger beverage from the coffee shop (OR = 0.58, 95% CI 0.45 to 0.75), but was associated with increased calories ordered from the fast food outlet (51.25kcals, 95% CI 19.59 to 82.90). No consistent interactions were observed with participant characteristics, suggesting that effects of calorie labelling and pricing on outcomes were similar across sociodemographic groups. | PMC10508026 | |
Conclusions | Calorie labelling on food delivery platforms may effectively reduce calories ordered. Proportional pricing may be useful in prompting consumers to select smaller portion sizes, although further research in real-world settings will now be valuable. | PMC10508026 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12966-023-01513-2. | PMC10508026 | ||
Keywords | PMC10508026 | |||
Introduction | Globally, there has been an increase in the presence, and use of food delivery platforms [Food prepared outside the home, whether from fast food, takeaway, or full service restaurants is typically greater in energy than food prepared at home [In the UK, public health strategies to improve the nutritional quality of food sold in the out-of-home food sector have been suggested at national and local levels [Non-Governmental Organisations have also urged the UK Government to develop policies to address disproportionate pricing of unhealthy foods [Previous research has assessed the impact of proportional pricing with different foods and beverages in a range of settings and findings are mixed. In a laboratory study, participants were given the option to purchase popcorn with money provided by the researchers [In a study conducted in the Netherlands [It is important to consider how implementing a new policy, such as proportional pricing, would interact with the existing food environment. One study conducted in the US examined the influence of a pricing intervention alongside presence or absence of calorie labelling [Due to the growing popularity of food delivery apps and the need to examine potential interventions to improve dietary choices in this context, the primary aim of the current research was to examine the influence of proportional pricing and calorie labelling interventions, both separately and combined, on portion size choice, calories ordered and monetary value of orders made when selecting food and drinks from three outlet types on a virtual delivery app. Additional aims were to explore whether the effects of proportional pricing and calorie labelling differ according to participant characteristics (i.e. BMI, age, gender, education, ethnicity and food choice motive scores). We hypothesised that there would be a significant impact of pricing strategy, where participants in proportional rather than value pricing conditions would be less likely to choose a larger option, would order fewer calories and spend less money. We also hypothesised that there would be a significant effect of calorie labelling, where participants in calorie labelling conditions would be less likely to choose a larger option, would order fewer calories and would spend less money compared to participants not shown calorie labels. Furthermore, we predicted that the likelihood of choosing smaller options and fewer calories would be most pronounced when participants were provided with both proportional pricing and calorie labels. | PMC10508026 | ||
Methods | PMC10508026 | |||
Study sample | RECRUITMENT | Participants (final N = 1126) were recruited through the online research platform Prolific [
Adapted consort flowchart of participant recruitment through to completion | PMC10508026 | |
Design | RECRUITMENT | This study used a 2 × 2 between-subjects design. Upon recruitment, participants were randomly assigned to one of four experimental conditions: calorie labels and value pricing; calorie labels and proportional pricing; no calorie labels and value pricing; no calorie labels and proportional pricing. Participants were recruited via the online platform Prolific before being provided with a web link to complete all aspects of the study procedure on Inquisit 6. Randomisation with 1:1:1:1 allocation was performed using the ‘<batch>’ and ‘/subjects’ functions in Inquisit 6. | PMC10508026 | |
Demographic and participant characteristic measures | Online questionnaires collected self-reported data on gender, age, ethnicity, height, weight, and SEP. The primary measure of SEP was the highest educational level achieved, for which there were six options (less than high school, high school completion, college or foundation degree, bachelor’s degree, master’s degree, and doctoral or professional degree). Additional SEP measures collected were subjective social status and equivalised household income. For subjective social status, participants completed the MacArthur Scale of Subjective Social Status (SSS) [ | PMC10508026 | ||
Food choice motives | After completing orders from all three food outlets (described below), participants were presented with subscales of the Food Choice Motives Questionnaire [ | PMC10508026 | ||
Virtual delivery app | HAND PRESENTATION, SHOP | A virtual delivery app (Supplementary material II) was created using the program Inquisit 6, and modelled on a popular UK-based food delivery platform. Three large chain food outlets in the UK (a coffee shop, a sandwich shop, and a fast food outlet) were simulated as they each typically offer products at a larger size with value pricing, and cover a range of food types ordered through delivery apps (i.e., beverages, sandwiches, meals). After completing baseline questionnaires, participants were informed they would be completing hypothetical food and drink orders, and asked to imagine they were going to pay for and receive the items ordered. On the following page, participants were asked to imagine they were ordering a drink from a coffee shop chain at whichever time of day they would usually purchase a drink from a café. There were 21 possible beverages for participants to order. Once participants had chosen their drink, they were asked to select a size (medium or large, except for n = 4 beverages where only a medium was available). Finally, participants specified addition of milk, sugar or sweetener, and other preferences.For the sandwich outlet order, participants were asked to imagine they were ordering a sandwich for lunch. There were 21 possible filling options. Once a choice was made, participants were required to select a size (6-inch or 12-inch) and then make various specifications (bread type, additional fillings, sauce). Participants were then asked if they wanted to see the sides menu. If they selected yes, they were shown the 15 available sides which they could add to their order or continue, before being asked if they wanted to see the drinks menu. If they selected yes, participants were shown the 15 available drinks which they could add to their order or complete their order.For the fast food outlet, participants were asked to imagine they were ordering an evening meal. There were 21 possible main meal component options (e.g. burgers, wraps, chicken dishes). Once participants made their choice, they were asked to specify a meal size (medium or large; for an example screen shot see Fig. Prices, calorie content and presentation of menu items were obtained in 2022 from a major UK food delivery platform. In calorie labelling conditions, each food option had calorie information in the description, and a statement of calorie guidelines visible on the page (“Adults need around 2000kcals a day”). For proportional pricing conditions, prices were calculated for any items with multiple size options. Prices for larger sizes were determined by calculating the percentage increase in kilocalories (herein: kcals) between the smaller and larger size options and translating that into the same percentage increase in price (see supplementary material III for an example).
Example of virtual delivery app | PMC10508026 | |
Other measures | After providing consent, participants were asked to guess the aim of the study. Guesses relating to kcals/calorie information on food choice or food price on food choice were coded as correctly guessed. Aim guessing was coded independently by two authors (AF, RM) and inconsistencies were resolved through discussion or consultation with another author (ER) where necessary (n = 8). Finally, participants were asked questions relating to the representativeness of the virtual app, the typicality of their orders, whether they believed they were influenced by the calorie content or the price of the foods, whether they supported calorie labelling and proportional pricing interventions in the out-of-home food sector, and if they believed either intervention would be successful in helping people to make healthier choices. Throughout the course of the study, there were three attention checks. If any participant failed one of the three attention checks (e.g. How many times have you visited the planet Mars?), their data were excluded from all analyses. | PMC10508026 | ||
Procedure | thirst | After providing consent, participants were randomly assigned to one of the four conditions. Baseline demographic data were collected, and participants completed items on how frequently food apps generally, and the three simulated food outlets in the study, were used by participants. Participants next completed hunger and thirst ratings and following this, took part in the food ordering task for all three outlets (order as above) on the virtual delivery app. A final questionnaire measured food choice motives and additional measures. All questions are shown in Supplementary material IV. Finally, participants were fully debriefed. Participant completed the full study once, and on average, the experiment took approximately 12 min to complete. Data collection took place from the 2nd to the 17th August 2022. | PMC10508026 | |
Analysis | We followed a pre-registered analysis strategy (osf.io/kaju5 [ | PMC10508026 | ||
Primary analyses | REGRESSIONS | Primary outcomes for this study were size choice (medium or large), hypothetical kcals ordered, and hypothetical money spent from each outlet. For each outlet, binary logistic regressions were used to examine the association between calorie labelling condition (present/absent) and pricing condition (proportional/value) as predictors of product size choice. Body Mass Index (BMI), highest level of education (university educated or less than university educated), the five food choice motives, age, gender (male/non-male) and ethnicity (white/non-white) were included as covariates. Multiple linear regressions with robust standard errors (and the same predictors as mentioned above) were used to examine associations between pricing condition and calorie labelling condition with total kcals ordered and total money spent. Results for primary analyses were considered significant at p < .05. For all models we examined the impact of including the interaction between labelling condition and pricing condition as a predictor. All interactions were non-significant, so these were removed from the separate models (i.e. size choice, kcals ordered, hypothetical spend) to minimize model overfitting. | PMC10508026 | |
Unplanned additional analyses | REGRESSION | Data from the three outlets were combined to examine any overall effects of calorie labelling condition and proportional pricing condition across the three outlet types. For size choice, participants were given a score of 0 to 3 according to the number of times they selected a larger portion size. A linear regression model was used to examine associations of calorie labelling condition, pricing condition and their interaction with this outcome. For both kcals ordered and hypothetical spend, mixed ANOVAs were used to observe any main effects of calorie labelling condition, pricing condition and their interaction on the outcomes. In the mixed ANOVAs, the within-subjects factor was the outlet and the between-subjects factors were calorie labelling condition and pricing condition. | PMC10508026 | |
Secondary analyses | INTERACTIONS, SECONDARY | Interactions between participant characteristics (BMI, education, food choice motives, age, gender and ethnicity) and experimental conditions were investigated at a second step in each of the models outlined in the primary analyses. Results for secondary analyses were considered significant at p < .01 to account for multiple testing. | PMC10508026 | |
Sensitivity analyses | SENSITIVITY | Sensitivity analyses (Supplementary Material VI) revealed that results were largely the same whether subjective social status or equivalised household income were used in place of highest education level as a measure of SEP. Additional sensitivity analyses identified no differences in significance for primary findings when participants with a missing BMI (n = 6) were removed (analyses not reported). Changes to primary findings when participants who guessed the aim of the study were removed (n = 98) are reported in the | PMC10508026 |
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