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Conclusion | This study suggests that video-based SA training for laparoscopic novices has a positive impact on performance and error rate. SA training should thus be included as one aspect besides simulation and real cases in a multimodal curriculum to improve the efficiency of laparoscopic surgical skills training.
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Supplementary Information | The online version contains supplementary material available at 10.1007/s00464-023-10006-z. | PMC10234874 |
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Keywords | cognitive skills | Open Access funding enabled and organized by Projekt DEAL.Minimally invasive surgery (MIS) has replaced open procedures as the gold standard in many areas of surgery. This includes simple procedures, such as laparoscopic appendectomy or cholecystectomy [The paradigm shift in training methodology toward a competency-based approach is a consequence of increased demands for patient safety. Errors can typically occur more often during surgical training, especially during complex procedures [Currently, resident surgeons usually spend a considerable amount of time assisting and watching experienced surgeons during residency. However, the assisting residents react to the surgeon’s commands and do not necessarily make individual decisions or get involved in planning the next steps, despite being active members of the operating team. Nonetheless, these hours of assisting are of utmost importance. Actively paying attention is crucial to maximizing training effects. This skill of being aware of the current surgical step and anatomical structures at risk will be referred to as “situational awareness” (SA) in this manuscript. In its original definition, SA describes the ability to process information effectively. It depends on general cognitive skills, such as attention, (working) memory and multitasking. SA can be divided into three levels. (1) Perception of key elements in the environment. (2) Recognition of the importance of the key elements and involvement in the current situation. (3) A look into the future and the prediction of a possible outcome for the current situation. Transferred to the OR for a basic procedure, such as laparoscopic cholecystectomy (LC), those three steps could be (1) perception of the preparation status of the cystic duct, (2) recognition that the visualization of the Calot triangle is crucial before clipping and cutting and being aware that anatomical variations of vessels can be present, and (3) if the criteria of the critical view of safety are not met, severe damage of the biliary tree and hepatic blood vessels is at risk. Just as with other mental skills, SA warrants dedicated training to be effective. In addition, it has been shown that SA training for surgeons can reduce errors [ | PMC10234874 |
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Materials and methods | PMC10234874 |
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Setting and participants | This study was conducted as a voluntary elective course for medical students in their clinical (3rd to 6th) years at the Medical Faculty of the University of Heidelberg, Germany. The course took place at the MIS Training Center of the Department of General, Visceral and Transplant Surgery. Only laparoscopy-naïve students were included. Students with more than 2 h of prior laparoscopic training were excluded. All participants were informed about the type, extent, and purpose of the study, as well as the possibility to withdraw their consent at any time without disadvantages. SA training was implemented via video clips of recorded LC. Active participation, a fundamental element of SA training, was achieved with interceptive questions (see below). These questions demanded from the participants to distinguish different tissues in the current situation and predict possible outcomes of actions. This type of video-based SA training with interceptive questions was developed following the SA training already described in the literature [ | PMC10234874 |
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Study design | This was a prospective, single-center, two-arm, blinded, parallel-group randomized trial. Randomization was performed by a computer-based program and kept safe in sealed opaque and numbered envelopes. There was structured training for the tutors rating the same video clips to ensure inter-rater quality. In order to avoid bias through the tutors by heterogeneity, only two tutors conducted the majority of the trial. | PMC10234874 |
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SA training | The intention of the intervention was to train SA. According to Endsley [Extract of the intervention training for situational awareness during LCThe SA training within the curriculum comprised three parts of video sessions. Each video session consisted of two parts:Distinction between the cystic artery, bile duct, and connective tissue during dissection of the Calot triangle.Perception of whether the gallbladder will perforate during its removal from the liver bed. | PMC10234874 |
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Baseline | Prior to training, all participants completed a questionnaire about relevant previous experiences. Questions involved prior experience in the OR, especially in general laparoscopic procedures and open cholecystectomy along with personal characteristics that may be associated with higher performance in (laparoscopic) surgery. Enquired characteristics comprised sports, playing a musical instrument, and playing video games, as done previously[ | PMC10234874 |
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Pre-test | After an introduction to LC via touch surgery, a validated serious game [CONSORT Flow diagram of the study design | PMC10234874 |
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Post-test | The post-test was performed under the same conditions as the pre-test. At the end of the training, all participants completed another questionnaire evaluating the training, focusing on cognitive training. | PMC10234874 |
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Study hypothesis | The difference in the OSATS score was defined as the primary outcome.HH | PMC10234874 |
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Sample size calculation | The sample size determination was calculated with a t test, assumptions from experiences of previous studies and the results of the pilot study. The assumptions made were a significance level of 5%, a standard deviation of 13 and a group difference of 10 points on the OSATS score. Accounting for a drop-out rate of 25%, a sample size of 68 was calculated. Analysis was planned to achieve a power of 80%. | PMC10234874 |
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Statistical analysis | Statistical analysis was performed using R [ | PMC10234874 |
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Primary outcome | REGRESSION | Confirmative testing was performed looking for superiority in the OSATS score at the post-test.As predefined in the protocol, a stepwise linear regression was used to test the hypothesis. Possible influencing variables were selected beforehand. These were ranked by relevance and significance and gradually removed during model establishment. This was carried out using stepwise regression, identifying the smallest statistically significant model. | PMC10234874 |
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Secondary outcomes | Exploratory analysis was performed by looking for group differences in the post-test of the GOALS Score, the error score, and the total procedure time in minutes. These analyses were performed using the unpaired t tests with equal variances. The individual sub-items of the error score were analyzed with Chi-Square test. Since the study was conducted as a clinical elective course, it was evaluated in detail at the end. General factors, such as supervision, and the different training mediums were evaluated. Furthermore, the cognitive training was evaluated on the perceived expedience of cognitive training, the extent of subjective learning effect, and the level of concentration during training. A digital graphic scale ranging from 1 to 100 was provided for answering. The responses were evaluated via Pearson correlation analysis. Group differences were calculated using the Mann–Whitney | PMC10234874 |
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Results | Data from 61 students were available for analysis. A detailed overview of baseline characteristics is provided in Table Demographic data*Absolute (in percent) | PMC10234874 |
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Primary outcome | REGRESSION | The SA intervention resulted in a significant improvement in performance measured with the OSATS score (SA: 67.0 ± 11.5 versus control: 59.1 ± 14.0, Linear regression model with post-test OSATS score as the dependent variableBold values indicate group significantly impacts performance | PMC10234874 |
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Subgroup analysis | ADVERSE EFFECTS | Subgroup analysis did not reveal any unexpected adverse effects attributed to the intervention. Furthermore, no interaction between intervention and subgroup was detected (see supplementary file, Fig. Rainforest plot illustrating subgroup analysis | PMC10234874 |
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Discussion | mistakes | The present randomized study shows that SA training as part of a multimodal training concept can lead to a significant improvement in laparoscopic performance during the early learning curve. The results were consistent in exploratory analyses for additional performance metrics and error rates. Significant group differences appear in favor of the SA-group for the OSATS score, the GOALS score, as well as the error score. These results imply that SA training helps to improve performance. Thus, the primary endpoint of this study was met. Due to the prospective randomized design and rigorous implementation, it can be assumed that the SA training is causal for the difference.The finding that SA training as part of non-technical skills (NTS) training has a positive impact not only on cognitive but also on psychomotor skills is consistent with previous research [The intervention in the present study trained SA and thus an important cognitive function. It led to a reduction in errors in laparoscopic novices. The relationship between lack of SA and the occurrence of errors has been reported in the literature previously [However, despite displaying a superior performance, the SA-group took the same time as the control group to complete the LC. Graafland et al. showed a better response to equipment failure in the SA-trained group, but also found no difference in time required. McCulloch et al. observed an increase in NTS and attitude toward safety during LC, but no change in operating time after the surgeons participated for several months in aviation-style resource management training [The evaluation questionnaire demonstrated that the video clips with SA training were rated more useful and led to higher concentration and learning effects than video clips without SA training. The correlations between the perceived subjective learning effect, level of concentration during training, and the expedience of cognitive training offer the conclusion that only those, who were able to concentrate on the video clips, stated a learning effect. These findings are in line with previous research stating that concentration and attention are crucial to learning effects [The results of the subgroup analysis should be investigated in further studies as they only have explorative character. Various factors and traits influence the acquisition of laparoscopic skills, and this study indicates not all groups benefitted equally from SA training. Male and right-handed participants seem to have benefited from the SA training, but female and left-handed trainees did not benefit equally. Since the participants did not receive any instructions and female participants might perform worse than their male colleagues without instructions [In summary, SA training appears to be a useful complimentary tool to hands-on training in the multimodal training curriculum for novice laparoscopists. At this point, it has yet to be investigated whether SA training for LC can be applied to other, more difficult operations, and to what extent more difficult SA training sessions can provide more experienced surgeons with useful training. It is reasonable to assume that multimedia-based vicarious learning will be adopted by surgeons. A study shows the growing importance of collegial exchange via multimedia posts on social platforms, with a focus on learning through the mistakes and experiences of others [Implementation of SA in the OR might be achieved through interceptive auto-suggestive questions the resident asks herself/himself while assisting and watching. Questions like “What’s going on at the moment?”, “What might happen next?”, and “Do I run into any risks soon?” help train SA. However, whether SA skills learned in a training center are applicable to the OR as well as the feasibility of its implementation and to what extent better SA means better outcomes in terms of mortality and morbidity for patients, needs to be verified in further studies. The feasibility of implementing this multimodal training concept can be difficult in smaller hospitals with limited resources. One way to overcome this problem is to have training centers at larger hospitals offer multimodal training for residents from smaller hospitals.The integration of this study into the elective course came with limitations. Due to administrative reasons, the elective course was supervised by a total of two tutors and three assistants. Also, the MIS training center of the Surgical University Hospital Heidelberg is accessible and in use for various learning and exercise groups and it could not be guaranteed that only a single tutoring session took place at a given time. Despite previous arrangements, inter-rater validity and a generally valid schedule, individual differences in tutoring and distraction cannot be ruled out entirely. Another limitation of this study was that the participants were students. Medical students do not decidedly represent novice surgeons. However, all participants were novices and therefore comparable with each other. Equally limiting was the porcine cadaver liver model, from which no conclusions can be drawn as to whether the recorded increase in surgical performance is also associated with a benefit for alive human patients. On the other hand, the pig cadaver model is a well-established model for LC because of the similar anatomy, and it has already been shown that the technical skills learned can be transferred to humans in the operating room [In conclusion, video-based SA training with a focus on potential errors during the critical steps of LC is beneficial in the early phase of laparoscopy training. Efficient training of novice laparoscopic surgeons is becoming increasingly important and SA training offers a valuable opportunity to add to multimodal training curricula. Video-based SA training could also be integrated into the concept of vicarious learning via social platforms and would thus be easily accessible. Further studies should focus on transferability to the OR and improved patient safety. Additionally, this is one aspect of a comprehensive training curriculum in addition to simulation and guided real cases. | PMC10234874 |
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Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (MP4 11248 KB)Supplementary file2 (MP4 5251 KB) | PMC10234874 |
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Acknowledgements | The present study is part of Ms. Laura Seifert’s doctoral thesis at Heidelberg University. | PMC10234874 |
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Author contributions | Study conception and design: NF, KKF, and SMW. Acquisition of data: SL, KKF, AS, and FC. Statistical analysis: SL, BL, and KKF. Analysis and interpretation of data: SL, KKF, and NF. Drafting of manuscript: SL and KKF. Critical revision: MSBP and NF. | PMC10234874 |
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Funding | Open Access funding enabled and organized by Projekt DEAL. | PMC10234874 |
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Declarations | PMC10234874 |
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Disclosures | SCHMIDT | Karl-Friedrich Kowalewski, Laura Seifert, Laura Kohlhas, Mona Wanda Schmidt, Seher Ali, Carolyn Fan, Karl Felix Köppinger, Beat Müller-Stich, and Felix Nickel have no conflicts of interest or financial ties to disclose. | PMC10234874 |
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References | PMC10234874 |
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1. Introduction | cancer, tumor | CANCER, TUMOR | Curcumin is a natural ingredient with antioxidant effects, widely studied as a treatment for various types of cancer. However, its effects on ultraviolet radiation have not been fully explored. The effects of single or daily application of 0.1–100 μM curcumin on cell apoptosis in ultraviolet B (UVB)-induced mice were tested using an experimental double-blind posttest design with a control group and two research models: a single application of curcumin before a single UVB exposure and daily application of curcumin for 7 days before a single UVB exposure on the seventh day. Apoptotic cells were counted using a tunnel system kit. The number of apoptotic cells under a single or daily application of curcumin for 7 days was significantly lower than that of the UVB controls (Curcumin is a polyphenolic compound extracted from turmeric (Topical curcumin at a dose of 30 µM can induce apoptosis in several tumor cells, thereby reducing cell cycle progression and preventing the growth of cancer cells [This study aimed to explore the preventive effect of topical curcumin on UVB-induced mice by histopathologically examining the number of apoptotic cells using two different study designs. The first group was applied with topical curcumin in four concentrations once, followed by a single UVB exposure. The second group was applied with topical curcumin in four concentrations once daily for 7 consecutive days, followed by a single UVB exposure. Biopsy was then performed to determine the number of apoptotic cells. The optimal number of applications and concentration were also determined for the potential use of topical curcumin as a photoprotective agent. | PMC9824043 |
3. Discussion | inflammation, death, tumor necrosis, ultraviolet exposure-induced apoptosis | TUMOR NECROSIS, INFLAMMATION, AUTOIMMUNE DISEASES, MALIGNANCIES, OXIDATIVE STRESS, DISEASES | Cell apoptosis or programmed cell death serves as an integral part of cellular homeostasis. An increase in the abnormal viability of cells influenced by endogenous or exogenous factors can lead to the development of various diseases, most prominently malignancies and autoimmune diseases. The protein family BCL-2 is responsible for regulating cellular apoptosis balance through pro-apoptotic and pro-survival members and thus serves as a basis for potential therapeutic developments for various diseases [The usefulness of curcumin has long been explored, and the compound is associated with modulation on various pathways. Special interest has been directed to the autophagy or degradation of supernumerary or dysfunctional components within cells, in which curcumin inhibits the formation of reactive oxygen species (ROS) and acts as an antioxidant agent [Minimal differences in apoptotic cell count were observed among the three curcumin concentrations of 0.1, 1, and 10 μM in single application with subsequent UVB radiation. However, a drastic decrease was found when the concentration was increased to 100 μM. In addition, the highest concentration (100 μM) yielded the lowest number of apoptotic cells after daily use for 7 consecutive days, providing the best result in this study. Although an increase in application and concentration seemed to result in an overall low apoptotic cell count, the single application of the low concentrations of 0.1 and 1 μM was superior compared with their daily application. We have yet to establish the reason behind this phenomenon. However, we hypothesized that this phenomenon may be related to the biphasic effect of curcumin on the oxidation of post-prandial chylomicrons and its biphasic hormetic response on proteasome activity and heat-shock protein synthesis in human keratinocytes [The protective effect of curcumin in this research was supported by other experimental studies. Li et al. [In the current study, we observed that the application of topical curcumin gave a protective effect against ultraviolet exposure-induced apoptosis in mice. However, this study has limitations because it did not examine the markers of oxidative stress (reactive oxygen species, hydrogen peroxide, and malondialdehyde) and inflammation (cyclooxygenase-2, interleukin, prostaglandin E2, tumor necrosis factor-alpha, and nitric oxide) that may have an effect on the process of apoptosis. | PMC9824043 |
4. Methods | PMC9824043 |
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4.1. Study Design and Subject | ALBINO | The study was a double-blind experimental posttest design with a control group, conducted at the Hasanuddin University Animal Laboratory, Makassar, Indonesia. Healthy male Swiss albino mice aged 6–9 weeks and weighing 20–30 g were maintained under a temperature of 28 °C ± 2 °C and humidity of 50% ± 10% for a minimum of 1 week. All mice were shaved on the back regularly during the research.The topical preparation was curcumin purchased from Sigma-Aldrich, Inc. (St Louis, MO, USA). It was diluted in acetone at concentrations of 0.1 μM, 1 μM, 10 μM, and 100 μM. The UVB lamp source was 10 FS-40-T12 fluorescent sun lamps with a spectrum of 280–340 nm and a peak emission of 314 nm. The UVB lights were calibrated with a FLUX radiometer. | PMC9824043 |
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4.2. Study Protocol | Two experimental models were used: a single application of various curcumin concentrations before a single UVB exposure and daily application of various curcumin doses for 7 days before a single UVB exposure on the seventh day. The mice were randomly allocated to 11 groups, each containing five mice. Group 1 received no treatment, group 2 received only UVB irradiation, and group 3 received acetone and UVB irradiation. Groups 4–7 received topical curcumin applications with concentrations of 0.1 µM, 1 µM, 10 µM, and 100 µM, respectively, with a dose of 2 µL/cm | PMC9824043 |
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4.3. Cell Apoptosis Activity Examination | The apoptotic cells among the squamous epithelial cells in all epidermis layers were counted histopathologically using the Apo-BrdU-IHC Kit TUNEL System (Biovision | PMC9824043 |
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4.4. Data Analysis | Data analysis was conducted using SPSS 18.0 for Windows (SPSS Inc. Chicago, IL, USA). The statistical tests used were one-way ANOVA for comparison between groups in each experimental design and the | PMC9824043 |
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5. Conclusions | Topical curcumin can act as a photoprotective agent by preventing cell apoptosis in UVB-induced mice. In terms of daily application and increasing concentration, 100 μM curcumin treatment was associated with the smallest number of histopathologically observed apoptotic cells after a single UVB exposure. However, at low concentrations, a single application of curcumin was more beneficial than daily application. Further studies, especially using concentrations lower than 0.1 μM, are warranted to prove this hypothesis. | PMC9824043 |
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Author Contributions | Conceptualization, K.D., M.N.M. and I.Y.; methodology, U.A.M., I.J.P. and M.F.; software, I.J.P. and M.F.; validation, K.D., M.N.M. and U.A.M.; formal analysis, I.J.P. and M.F.; investigation, K.D.; resources, K.D.; data curation, I.J.P. and M.F.; writing—original draft preparation, K.D.; writing—review and editing, K.D., U.A.M. and M.F.; visualization, I.J.P., U.A.M. and M.F.; supervision, M.N.M. and I.Y.; project administration, K.D. and M.F.; funding acquisition, K.D. and I.J.P. All authors have read and agreed to the published version of the manuscript. | PMC9824043 |
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Institutional Review Board Statement | This study obtained ethics approval from the local ethics committee board (UH07100058). | PMC9824043 |
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Informed Consent Statement | Not applicable. | PMC9824043 |
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Data Availability Statement | The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC9824043 |
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Conflicts of Interest | The authors declare no conflict of interest. | PMC9824043 |
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Sample Availability | Samples of the compounds are available from the authors. | PMC9824043 |
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References | Induction of apoptosis in UVB-irradiated mice. Pretreatment with topical curcumin before UVB irradiation prevented apoptosis in both experimental models.Apoptotic cells, indicated by brown staining in the nuclei (arrow), at 400× magnification under an Olympus Type CX-31 microscope, in the UVB-only group with majority apoptosis cells (Comparison of apoptotic cell count between one-time and seven-time curcumin application before single 343-mJ UVB exposure.Note: * Significant; SD, Standard deviation. | PMC9824043 |
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Background | impairment of primary Osteoarthritis | OSTEOARTHRITIS OF THE KNEE | This primary analysis evaluated the “PREVenting the impairment of primary Osteoarthritis by high-impact long-term Physical exercise regimen—Psychological Adherence Program” (PrevOP-PAP), designed to support patients with osteoarthritis of the knee (OAK) to engage in regular moderate-to-vigorous physical activity (MVPA) to reduce OAK symptoms (WOMAC scores). Theory-based on the health action process approach (HAPA), the intervention targeted volitional precursors of MVPA change: action and coping planning, maintenance and recovery self-efficacy, action control, and social network formation. We hypothesized that compared to an active control condition, increases in MVPA at the end of the 12-month intervention would translate into lower WOMAC scores at 24 months in the intervention condition. | PMC10318642 |
Methods | Participants with radiographically verified moderate OAK ( | PMC10318642 |
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Results | MVPA (12 months) did not mediate effects of the PrevOP-PAP on WOMAC scores (24 months). Compared to the active control condition, WOMAC scores (24 months) were lower in the intervention condition, but this effect did not remain stable in sensitivity analyses ( | PMC10318642 |
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Conclusions | Compared to an active control condition, the PrevOP-PAP did not produce reliable effects on WOMAC scores and none on preceding MVPA. Of the HAPA-proposed volitional precursors, only action planning was sustainably increased. Future interventions should use m-health applications to digitally support long-term changes in proposed volitional precursors of MVPA change. | PMC10318642 |
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Trial registration | German Clinical Trials Register; | PMC10318642 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12891-023-06661-x. | PMC10318642 |
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Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10318642 |
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Background | age-related disease, pain | OSTEOARTHRITIS OF THE KNEE | Osteoarthritis of the knee (OAK) is a highly prevalent, progressive, age-related disease that causes pain and stiffness of the affected joint, causing reductions in individuals’ quality of life [Although patients with OAK report strong intentions to adapt their lifestyles to relieve severity or slow progression of OAK symptoms [The HAPA also considers contextual barriers (e.g., environmental conditions such as rainy weather) and facilitators to behavior change [There has been extensive research on PA in patients with OAK, however, only few intervention programs were theory-based [Furthermore, most HAPA-based interventions so far have addressed contextual facilitators or barriers indirectly, for instance, as part of action or coping planning strategies where participants identify (alone or with others) good opportunities to act or barriers that keep them from implementing the planned behavior [In addition, current RCTs with patients with OAK mainly focus on shorter-term effects [ | PMC10318642 |
Research question and hypotheses | In a population of individuals with moderate OAK, the present study addresses the following primary research question: Is there an indirect effect of a HAPA-based psychological intervention (PrevOP-PAP intervention), consisting of a motivational intervention and a volitional intervention including network formation, on participants’ OAK symptoms (WOMAC) via MVPA when compared to an active control condition receiving the motivational intervention only [ | PMC10318642 |
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Method | PMC10318642 |
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Procedure, randomization, and design | TIDieR | The PrevOP-PAP was an unblinded randomized controlled trial embedded in a parallel group design with the PrevOP-PAP crossed within the same sample of the PrevOP-Main Medical Trial (PrevOP-MMT; preregistered at [Consolidated Standards of Reporting Trials (CONSORT) diagram depicting participant flow through the studyThe PrevOP-MMT tested a high-impact long-term physical exercise regimen with resistive vibration exercise (PrevOP-MMT high-impact exercise condition) against a low-impact long-term exercise regimen with walking exercise (PrevOP-MMT low-impact exercise condition) and an unstructured, non-monitored exercise control group (PrevOP-MMT active control condition). The PrevOP-MMT high-impact exercise condition and PrevOP-MMT low-impact exercise condition received structured and monitored training for 12 months, which was followed up by a home-based-mobility maintenance program (see trial registration [The PrevOP-PAP was crossed with the PrevOP-MMT (see below and additional file; Additional Figure Individuals interested in study participation were informed about the study and screened for inclusion and exclusion criteria in an initial telephone interview and during a medical examination by PrevOP-MMT medical personnel at the study center at Charité – Universitätsmedizin Berlin. Prior to the medical examination, participants provided written informed consent.Randomization of participants took place following baseline assessment (month “M”0) and was conducted at the Institute for Clinical Epidemiology and Applied Biometry at Tübingen University Medical Center, using computer-generated random numbers, stratified by sex. Participants were fully informed about randomization procedures and randomly allocated to one of a total of six intervention constellations (see additional file, Additional Figure All participants received a brief motivational intervention following baseline assessment (M0) prior to randomization (see below and [In addition to six medical study visits with physical examinations and radiographic imaging as part of the PrevOP-MMT protocol (at baseline, 3, 6, 9, 12, and 24 months), data were assessed from all participants at baseline (M0), 6 months (month “M”6), 12 months (month “M”12), 18 months (month “M”18), and 24 months (month “M”24) via self-report measures and three one-week accelerometer assessments of daily PA (M0, M12, M24). Self-report measures were assessed via paper–pencil questionnaire booklets at the main study center (Charité – Universitätsmedizin Berlin, Germany; M0, M6; M12; M24) or at participants’ homes (M18) and returned directly to study personnel or mailed to the health pychology lab at Freie Universität Berlin. All data were collected between February 2016 (first assessment) and January 2021 (last assessment). The present report used data relevant for examining the primary research question with assessments at M0, M12, and M24 [The ethics committee of the Charité – Universitätsmedizin Berlin approved this study (EA4/027/15). The present primary analysis report complies with CONSORT guidelines and TIDieR guidelines [ | PMC10318642 |
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Power, recruitment, and inclusion | For the PrevOP-PAP, with an alpha level of 0.05 and a stability factor of 0.68 of the measure to assess the primary outcome (OAK symptoms as measured by the WOMAC [With an expected drop-out rate of 20%, the required sample size increased to Inclusion and exclusion criteria were mostly relevant for the medical PrevOP-MMT and are listed in the additional file (Additional Information | PMC10318642 |
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Masking | PrevOP-PAP intervention content could not be masked for study staff or participants. Study staff were aware of participants’ study group allocation at the beginning of the first intervention session of the PrevOP-PAP. Moreover, data analyses were conducted by N.L., N.K., and R.S. and were also unmasked. | PMC10318642 |
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Intervention content | All intervention contents were delivered in German, derived from theory-based established intervention programs in primary and tertiary prevention settings [ | PMC10318642 |
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Brief motivational intervention | Before randomization, all participants received a brief motivational intervention delivered by trained study staff that consisted of a brochure that participants were asked to read, followed by a brief quiz in form of a cross-word puzzle to test knowledge transfer. The brochure introduced participants to different intensities of PA, providing examples of joint-friendly MVPA and muscle-force strengthening exercises, and MVPA guidelines for persons with OAK [ | PMC10318642 |
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PrevOP-PAP intervention: computer-assisted face-to-face intervention | pain | The computer-assisted face-to-face intervention, again delivered by trained study staff, consisted of an introductory section that reminded participants of the program’s goals, four ensuing sections focussing on outcome expectancies, self-efficacy, goal setting, planning, and a feedback section [Outcome expectancies were addressed by providing participants with a calculated pros-cons difference score of outcomes of regular PA. Participants first indicated how much they agreed with five positive (e.g., less joint stiffness, good for overall health) and five negative (e.g., pain during specific activities, too time-consuming) outcome expectancy statements on 6-point Likert scales (not at all true to completely true). Then scores for pros, cons, and a benefit expectation difference were fed back to participants. In case of con scores being larger than pro scores, trained study staff reviewed concerns with participants and asked them to think of activities associated with less cons (BCT: pros and cons (9.2); [ | PMC10318642 |
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PrevOP-PAP intervention: computer-assisted phone-based intervention and activity calendars | outcome(s | Trained staff (i.e., trained Bachelor’s and Master’s students of psychology employed as students research assistants in the trial) followed a computer-based structured intervention [To increase maintenance self-efficacy and recovery self-efficacy, participants were first asked to review their PA-plan pursuit and indicate a success rate of implementing their PA-specific plan enactment in percent. To do so, participants used their completed activity calendars of the two weeks prior to the phone-based intervention. Participants were then asked to recall positive experiences with implementing their PA plans during the past two weeks. Following this, participants were given the opportunity to revise PA goals and associated action and coping plans or add new ones, up to a maximum of five. This was done in the same manner as in the computer-assisted face-to-face intervention with interventionists recording and reading out the intervention content to participants. If plans were kept, participants were asked to rate their plan-execution self-efficacy anew. At the end of this section, interventionists repeated each kept, altered, or new action plan aloud and asked participants to fill them into a new set of activity calendars. A summary print-out of all action and coping plans generated during the phone-based intervention session was also sent to participants’ homes.Phone-based interventions 3 and 4 had an additional optional component of network creation, when participants were encouraged to identify a sports companion, contact them (phone-based intervention 3) and include these companions (i.e., their initials) into their action plans, creating collaborative implementation intentions (phone-based intervention 4) (BCTs: action planning (1.4), social support (practical) (3.2); [Computer-assisted phone-based interventions lasted between 20 and 60 min. At the end of each intervention session (face-to-face or phone-based) participants rated the quality of the session, were asked if they had any questions, were reminded of the next study appointment, were asked to use the self-regulatory strategies in their daily lives, and were thanked.The final component of the PrevOP-PAP intervention were paper–pencil activity calendars to promote action control and maintenance self-efficacy as well as recovery self-efficacy using BCTs self-monitoring of behavior (2.3), self-monitoring of outcome(s) of behavior (2.4), and feedback on outcome(s) of behavior (2.7) [ | PMC10318642 |
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Measures | The present article used data relevant for the analysis of the pre-registered primary research question under study [ | PMC10318642 |
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OAK symptoms | The primary endpoint was self-reported OAK symptoms at M24 assessed with the WOMAC in its version for OAK administered in German [ | PMC10318642 |
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Moderate-to-vigorous physical activity (MVPA) | Daily MVPA (in minutes) averaged over one week as assessed with tri-axial accelerometer devices (ActiGraph GT3X, Pensacola, Fl) at M0 and M12 were used in the present analyses. Participants were instructed to wear the devices at their right hip during waking hours for one week at each assessment period. Using an algorithm by Sasaki et al. [ | PMC10318642 |
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HAPA-proposed volitional precursors of MVPA change | All HAPA-defined volitional precursors of MVPA change addressed in the PrevOP-PAP intervention were included in the manipulation checks, including assessments at M0 and M24. They were adapted from prior research [ | PMC10318642 |
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Behavioral intentions and covariates | Behavioral intentions as assessed at M0 and one week after the motivational treatment received by all participants were measured with 4 items (M0 α = 0.81; one week after M0 α = 0.76; [ | PMC10318642 |
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Statistical analyses | SENSITIVITY | Analyses were conducted using R Statistical Software (v4.2.2 [To benefit from full-information maximum likelihood procedures to retain all available data in models and perform analyses with an intent-to-treat approach [Sensitivity analyses for the primary hypothesis test included several groups of covariates: BMI (range in this sample: 19.16 to 45.79 kg/mAs indicated in the study protocol [ | PMC10318642 |
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Results | PMC10318642 |
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Attrition analyses and randomization check | Participants dropping out before M24 ( | PMC10318642 |
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Discussion | This primary analysis report evaluated outcomes of the psychological adherence program PrevOP-PAP that was designed to enhance PA and reduce OAK symptoms (WOMAC) among patients with moderate OAK. The intervention program PrevOP-PAP adopted motivational, volitional, and networking intervention strategies based on the HAPA to support OAK patients’ uptake and maintenance of regular MVPA and reduce OAK symptoms (WOMAC). Intervention effects were contrasted with the PrevOP-PAP active control condition, in which participants only received the motivational intervention. As the primary hypothesis, it was assumed that participants of the PrevOP-PAP intervention condition (compared with participants of the PrevOP-PAP active control condition) would engage in more MVPA at the end of the active intervention phase which would then translate to lower levels of OAK symptoms (WOMAC) at the end of the study period. Present findings did not confirm the proposed intervention effects on overall OAK symptoms (WOMAC) or MVPA. Moreover, MVPA did not mediate the association between the intervention and OAK symptoms (WOMAC). | PMC10318642 |
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Indirect effects of the PrevOP-PAP intervention on OAK symptoms via MVPA | osteoarthritis, pain | OSTEOARTHRITIS, STILL | Compared to the control group, intervention effects on overall OAK symptoms (WOMAC) trended towards a decrease at the end of the study period. Contrary to our hypothesis, this effect did no longer reach statistical significance in sensitivity analyses. Still, exploratory follow-up analyses with different domains of OAK symptoms (WOMAC) as outcomes (i.e., WOMAC-pain, WOMAC-functional limitations, and WOMAC-stiffness) revealed effects of the PrevOP-PAP intervention on pain, but null effects on functional limitations and stiffness at 24 months following study entry. These findings resemble meta-analytic evidence on self-management education programs for osteoarthritis suggesting small – mostly shorter-term – improvements in pain, but no beneficial effects on physical functioning when compared to control groups [ | PMC10318642 |
Effects of the PrevOP-PAP intervention on MVPA and its HAPA-proposed volitional precursors | pain | DISEASE | Importantly, the question arises why participants did not increase their MVPA during the intervention period. On the one hand, increases in intentions to engage in regular MVPA one week after the motivational intervention indicated a successful motivational manipulation for all participants. However, manipulation checks of the PrevOP-PAP intervention yielded only one effect on the HAPA-proposed volitional precursors of MVPA change at the end of the study period. At 24 months following study entry, only action planning showed a significant increase in the PrevOP-PAP intervention condition (vs. PrevOP-PAP active control condition). The finding on intervention effects for action planning is in line with prior findings in the context of cardiac and orthopedic rehabilitation [In this context, coping planning and action control have been highlighted as important additional key intervention components to enhance the effects of action planning [Regarding the null effect on action control, three one-month paper–pencil activity calendar phases delivered throughout the PrevOP-PAP intervention with extended periods of no intervention delivery might not have been sufficient to foster action control in the long run. Future research could implement m-health self-monitoring applications which are permanently available to facilitate continuous and long-term action control.Furthermore, the overall moderate OAK severity and prolonged disease duration in our sample as well as a decrease in pain in the intervention condition might further explain null effects of the PrevOP-PAP intervention on changes in self-efficacy. With decreasing salience of barriers or decreasing barriers, such as pain, over time, increases in behavior-specific self-efficacy become less likely, because self-efficacy is always measured up against perceived difficulties or barriers to act. Also, with regard to the social network formation indicator, i.e., collaborative implementation intentions, the PrevOP-PAP intervention did not yield significant intervention effects and many participants of the intervention condition decided not to participate in the optional network creation intervention. As vicarious experiences and positive affective states experienced in social networks serve as sources of self-efficacy, this might also have affected levels of self-efficacy in our sample [On the other hand, when interpreting null effects on MVPA, it must be noted that participants demonstrated relatively high baseline levels of MVPA (i.e., on average around 47 min per day) when compared to previously reported levels of MVPA among patients with OAK [ | PMC10318642 |
Strengths and limitations | This study has several strengths. First, this RCT included a long follow-up period up to 24 months post study entry (i.e., 12 months following the intervention period) to elucidate causal mechanisms of the PrevOP-PAP intervention in the long term. The intervention program PrevOP-PAP was based on theoretically-derived health behavior change techniques to allow for testing underlying processes of behavior change [However, some limitations must be acknowledged. Despite the advantages of mediation analyses to understand the causal mechanisms of this complex intervention over time, this modelling approach also comes with drawbacks. Given the complexity of OAK symptoms, it seems likely that further non-hypothesized factors may have explained changes in OAK symptoms over time which, however, were not captured using this theory-guided approach. Future research may apply data-driven approaches such as Bayesian Networks to further elucidate intervention mechanisms of the PrevOP-PAP intervention [Second, intervention delivery and data analyses in this RCT were unmasked due to ethical and practical reasons. Participants were informed that they would be randomly allocated to either the PrevOP-PAP intervention condition or the PrevOP-PAP active control condition and study personnel were aware of delivering the intervention treatment. Masking of statistical analysis is desirable for future RCT evaluation.Third, attrition rates were elevated across two years of the study period (29%) with the majority of participants dropping out during the intervention period within the first year. This may be explained by a high participant burden due to intensive intervention delivery and repeated measurements in crossed psychological PrevOP-PAP and medical PrevOP-MMT trials. However, it must be noted that the sample size of completers in PrevOP-PAP was sufficient to detect the proposed mediation effect with a power of 0.80 as the overall sample size estimation was higher for the PrevOP-MMT. Moreover, we aimed to reduce potential selection effects due to attrition by conducting intent-to-treat analyses with full maximum likelihood estimation and considering potential dropout mechanisms as covariates in our sensitivity analyses [Fourth, despite numerous advantages of the objective assessment of PA, this approach may also have drawbacks. Whereas participants may have increased their engagement in joint-friendly MVPA that are particularly recommended in the context of OAK such as swimming or riding a bike [ | PMC10318642 |
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Conclusions | pain | DISEASE | This psychological adherence program was based on HAPA-derived behavior change techniques and specifically designed for patients with moderate OAK to facilitate the uptake and maintenance of physical activity. Whereas levels of action planning significantly increased following the intervention, primary analyses did not yield beneficial effects of the PrevOP-PAP intervention on physical activity and limited effects on OAK symptoms (WOMAC), i.e., only a decrease in WOMAC-pain at the end of the study period emerged in exploratory follow-up analyses. Resembling meta-analytic findings on self-management programs for OAK, the PrevOP-PAP intervention might thus appear promising for improved disease management (e.g., coping with pain). However, as physical activity did not serve as a mediator of this exploratory finding, underlying mechanisms of improvements in pain still remain unclear. Future research should further investigate which intervention components of the PrevOP-PAP specifically targeted the patients’ pain management. Subsequently, the intervention program could be refined and provided as an m-health application on a large scale for patients with OAK. | PMC10318642 |
Acknowledgements | FRANK | In grateful memory of Dieter Felsenberg.Authors also wish to thank the teams of PrevOP-PAP and PrevOP-MMT for their dedicated work and contributions to the projects: Daniela Lange, Diana Hilda Hohl, Susannah Motter, Luisa Wirth, Lisa Bosch, Theresa Reschke, Annekathrin Teichmann, Eva Marie Keinert, Patrick Klaiber, Ulrike Panse, Nadine Christen, Tim Felsenberg, Martina Kratzsch, Felix Müller, and Frank Touby. | PMC10318642 |
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Protocol version and trial status | This is the primary analyses report as registered with the German Clinical Trials Register on 26 January 2016. No trial registry modifications were undertaken. With regard to the study protocol [ | PMC10318642 |
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Authors’ contributions | RECRUITMENT | N.K. and R.S. (principal investigators of PrevOP-PAP) and N.L. (PrevOP-PAP study researcher): statistical analyses and first draft of the manuscript. J.K., A.D., and S.D.M.: (PrevOP-PAP study researchers): coordination of PrevOP-PAP. G.A. and H.B. (PrevOP-MMT study researchers): coordination of PrevOP-MMT. P.M. (principal trial statistician of PrevOP-PAP and PrevOP-MMT): randomization, power analyses PrevOP-MMT, support in statistical analyses. W.E. (principal investigator of PrevOP-MMT): recruitment of participants, inclusion, medical assessments. All authors contributed to the writing of this manuscript and approved the final version. | PMC10318642 |
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Funding | Open Access funding enabled and organized by Projekt DEAL. This work is part of the overarching OVERLOAD-PrevOP consortium ( | PMC10318642 |
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Availability of data and materials | The datasets generated and analyzed during the current study are available from the corresponding author upon request. | PMC10318642 |
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Declarations | PMC10318642 |
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Ethics approval and consent to participate | The ethics committee of the Charité – Universitätsmedizin Berlin approved this study (EA4/027/15). All procedures were carried out in compliance with the Helsinki Declaration. Before inclusion into the study by PrevOP-MMT medical personnel, written informed consent was obtained from each participant for participation in all study parts (PrevOP-MMT and PrevOP-PAP). Amongst other information, participants were informed: (1) that participation in the study is completely voluntary, (2) that they have the right to withdraw from the trial whenever they desire and that they do not have to state a reason for their decision, (3) that refusal to participate or discontinuation of participation will not have any consequences for the usual care they receive, (4) that their identifying information will be kept strictly confidential (and apart from the remainder of their data), their data being made anonymous by assignment of a pseudonym (i.e., a participant ID-number), (5) that their data will be stored, analyzed, and published in an anonymous form by collaborating study researchers. | PMC10318642 |
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Consent for publication | Not applicable. | PMC10318642 |
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Competing interests | The authors declare no competing interests. | PMC10318642 |
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References | PMC10318642 |
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BACKGROUND | Weight-loss diets often target dietary fat or carbohydrates, macronutrients that are sensed via distinct gut-brain pathways and differentially affect peripheral hormones and metabolism. However, the effects of such diet changes on the human brain are unclear. | PMC10371234 |
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METHODS | obesity | OBESITY | We investigated whether selective isocaloric reductions in dietary fat or carbohydrates altered dopamine D2/3 receptor binding potential (D2BP) and neural activity in brain-reward regions in response to visual food cues in 17 inpatient adults with obesity as compared with a eucaloric baseline diet using a randomized crossover design. | PMC10371234 |
RESULTS | On the fifth day of dietary fat restriction, but not carbohydrate restriction, both D2BP and neural activity to food cues were decreased in brain-reward regions. After the reduced-fat diet, ad libitum intake shifted toward foods high in both fat and carbohydrates. | PMC10371234 |
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CONCLUSION | These results suggest that dietary fat restriction increases tonic dopamine in brain-reward regions and affects food choice in ways that may hamper diet adherence. | PMC10371234 |
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TRIAL REGISTRATION | ClinicalTrials.gov NCT00846040 FUNDING. NIDDK 1ZIADK013037.
| PMC10371234 |
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Introduction | obesity | OBESITY | Among dietary approaches to treat obesity (People with obesity may have reduced dopamine synthetic capacity ( | PMC10371234 |
Results | A subset of individuals for whom metabolic results were previously reported ( | PMC10371234 |
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Only the RF diet decreased activity in brain-reward regions in response to food cues. | CORTEX | Participants rated the pleasantness of a variety of food images during fMRI sessions 4.5 hours after lunch on the fifth day (third inpatient day) of the first eucaloric baseline diet period and on the fifth day of the RC and RF diets. Voxel-wise blood-oxygen-level-dependent (BOLD) responses to food images were compared with fixation within an a priori reward-region mask encompassing orbitofrontal cortex and striatal-pallidal neurocircuit as previously reported (Compared with baseline, only the RF diet resulted in reduced activity in bilateral striatal clusters in caudate and putamen after correction for multiple comparisons as described in Methods ( | PMC10371234 |
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Only the RF diet led to decreased D2BP. | Participants completed PET imaging with the radiolabeled D2-like receptor subtype antagonist [Compared with baseline, the RF diet significantly decreased D2BP in bilateral striatal clusters spanning the left putamen and right caudate/putamen (The cluster where D2BP was decreased during the RF versus the baseline diet was localized to the white/gray matter boundary of striatal nuclei. To rule out potential localization errors due to image misalignment, individual subject alignment data were visually checked independently by 2 members of the study team, and the mean group D2BP by diet condition was verified to map well with the template anatomical image in Talairach space ( | PMC10371234 |
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The RF diet resulted in greater ad libitum intake of foods high in both carbohydrate and fat. | We explored ad libitum food intake for 3 days after the RF and RC diets. Participants selected foods from computerized vending machines stocked with calories in excess of maintenance energy requirements. Average energy intake was (mean ± SEM) 25.9% ± 9.5% greater than the eucaloric baseline diet and was not significantly different following RF versus RC diets ( | PMC10371234 |
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Discussion | weight gain, eating behavior | CAVITY | We previously showed that the RC diet led to widespread metabolic and endocrine changes compared with the eucaloric baseline diet, including increased fat oxidation as well as decreased energy expenditure and decreased daily insulin secretion, whereas the RF diet did not lead to substantial peripheral metabolic or endocrine changes (The most likely interpretation of our data is that the RF diet increased striatal tonic dopamine. This would explain the observed decrease in D2BP because increased endogenous dopamine would be expected to displace the [D2 receptors are located both postsynaptically on nondopaminergic cells within the striatum and presynaptically on cell bodies, axons, and axon terminals of dopaminergic projection neurons (It is unlikely that the observed reduction in D2BP during the RF diet was due to decreased D2-like receptor density because neither dopamine depletion over 2–5 days (An increase in tonic dopamine during the RF diet occurred in conjunction with an increased selection of high-fat, high-carbohydrate foods observed during the subsequent exploratory ad libitum period. Elevations in tonic dopamine alter the balance with phasic dopamine responses (At first glance, our observation that a reduction in BOLD response to food cues during the RF diet occurred alongside a subsequent shift in ad libitum food selections toward high-fat, high-carbohydrate foods appears at odds with the literature on food cue reactivity suggesting a moderate positive association with subsequent weight gain and eating behavior (How could reduction of dietary fat result in increased tonic dopamine in the brain? Dietary fat is detected and signaled to the brain throughout the alimentary canal from taste bud cells in the oral cavity to enteroendocrine and enterocyte cells in the gut (Another potential mechanism for increased brain dopamine during the RF diet involves decreased postprandial plasma triglycerides that peak several hours after a meal in proportion to the amount of fat consumed (Why did the RC diet have no significant effect on brain D2BP or neural activity in response to food cues, as compared with baseline? We found this result surprising particularly because the RC diet significantly decreased daily insulin secretion (How might changes in brain dopamine in response to different diets relate more generally to body weight regulation? Recent mouse data suggest that the effects of brain dopamine may not be isolated to canonical hedonic pathways of food reward. For example, striatal dopamine can also influence downstream hypothalamic nuclei traditionally attributed to control homeostatic feeding and regulate body weight ( | PMC10371234 |
Limitations. | obesity, weight loss | OBESITY | While our interpretation of increased tonic dopamine is supported by relative pharmacokinetic properties of D1/5 and D2-like receptors, and literature on D2-like receptor PET occupancy and fMRI activity, we did not directly measure brain dopamine. Consumption of dietary fat elicits rapid dopaminergic response in reward regions (Ad libitum eating behavior subsequent to the 5-day period of dietary restriction supports our interpretation of increased incentive salience for rewarding foods after the RF diet. However, our study was not specifically powered to detect differences in this exploratory outcome, and analyses were not corrected for multiple comparisons.Our interpretation of the effect of RC and RF diets on brain dopamine is limited to the early stages of initiating reduced-energy diets and does not address long-term changes or adaptations in neurochemistry or reward. Future studies should investigate changes in neurochemistry and reward activity in relation to diet composition over longer periods of weight loss. Furthermore, only adults with obesity were included in the present study. Adults without obesity appear to have a greater capacity to synthesize dopamine (Finally, the number of participants completing neuroimaging scans is relatively small. While we endeavored to collect data on 20 participants based on our prespecified power calculations, analyses ultimately were limited to | PMC10371234 |
Methods | PMC10371234 |
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Experimental model and subject detail | Twenty-one adults provided informed consent to participate in a randomized crossover trial investigating the effects of selective isocaloric reduction of dietary fat versus carbohydrates on macronutrient metabolism, striatal D2BP, and neural activity in response to food stimuli in brain-reward regions (ClinicalTrials.gov, NCT00846040). Study details regarding the primary metabolic outcomes were reported elsewhere ( | PMC10371234 |
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Study details | This study was conducted between February 13, 2009, and October 20, 2014. Volunteers were admitted to the NIH Clinical Center for a 14-day period to receive the eucaloric baseline diet for 5 days. After that, volunteers received either the RC or the RF diet for the next 6 days, followed by 3 days of ad libitum feeding from a computerized vending machine (The CONSORT diagram reiterates enrollment details provided in ref. | PMC10371234 |
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Anthropometrics | Height was measured in centimeters using a wall stadiometer (Seca 242), and weight was measured in kilograms using a digital scale (Scale-Tronix 5702). All measurements were obtained after an overnight fast, while participants were wearing only hospital scrubs. | PMC10371234 |
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Diets | ADVERSE EVENTS | All subjects were confined to the metabolic ward throughout the study without access to outside food. Meals were consumed under observation, and any uneaten food was returned to the kitchen and reweighed. Subsequent meals were adjusted to account for uneaten food as needed. Diets were designed using ProNutra software (version 3.4, Viocare Inc.). Dietary interventions did not result in any adverse events, harm, or unintended effects in any condition. | PMC10371234 |
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Baseline eucaloric diet. | The daily caloric content during the initial out-patient segment and the weight-maintenance phase was based on the resting energy expenditure measured at screening with an activity factor of 1.5. Beginning 2 days before each admission, participants were provided with a weight-maintenance diet using a standard diet composition of 50% carbohydrate, 35% fat, and 15% protein, which continued for the next 5 days. All participants were provided with the standard diet during the first inpatient admission for at least 1 day prior to measuring baseline fMRI and D2BP. Energy and macronutrient intake during the baseline eucaloric diet are presented in | PMC10371234 |
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Reduced energy diets. | During the restricted diet phase (inpatient days 6–11), 30% of baseline calories were removed by selective reduction of either carbohydrate (RC diet) or fat (RF diet) while keeping the other 2 macronutrients unchanged from eucaloric baseline diet. Energy and macronutrient intake during the reduced energy diets are presented in | PMC10371234 |
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