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QST methods | chronic pain, acute pain, pain | CHRONIC PAIN, COLD | A number of sensory pain measures were included in this study to quantify acute pain (i.e., threshold responses, temporal summation of pain, cold pressor testing, and conditioned pain modulation), and as a model of chronic pain (i.e., capsaicin [10% topical cream]). | PMC10516978 |
Acute pain measures | pain | All thermal and pressure pain testing was conducted over two trials to obtain consistent readings; trial results were averaged for each measure. | PMC10516978 |
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Chronic pain measure | As reported previously [ | PMC10516978 |
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Global QST outcomes | pain | COLD, CENTRAL SENSITIZATION, SENSITIVITY | Two global QST outcomes were derived from the full testing battery: (1) Central Sensitization (average Z-scores of thermal and mechanical temporal summations, conditioned pain modulation, and after-sensation ratings) and (2) General Sensitivity (average Z-scores of pressure and thermal thresholds, thermal tolerance, cold pressor threshold and tolerance), with higher values representing greater sensitization and sensitivity, respectively. | PMC10516978 |
Clinical pain severity | pain | Clinical pain severity rating was collected at every time point using an online (delivered via Qualtrics) 0–100 Visual Analog Scale (VAS) [ | PMC10516978 |
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Self-reported drug effects | Following FDA guidance [ | PMC10516978 |
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HAP measures | The primary HAP outcome was whether participants achieved (yes/no) a post-drug exposure rating of ≥60 on the 0-100 VAS High scale [ | PMC10516978 |
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Physical function measures | Three measures of objective physical performance [ | PMC10516978 |
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Cognitive function measures | cognitive functioning [ | Three tasks assessed cognitive functioning [ | PMC10516978 |
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Adverse events (AEs) | Participants were asked whether they experienced any side effects of the study medication throughout the session. Reported AEs were documented and classified according to severity (i.e., mild, moderate, and severe) and relatedness (i.e., unrelated, possibly, probably, and definitely). Primary outcomes were the total number of related AEs, collapsed across severity, as well as the number of related AEs rated as mild, moderate, or severe. | PMC10516978 |
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Pharmacokinetic analyses | Whole blood samples were collected in standard vacutainer tubes free of additives for participants ( | PMC10516978 |
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Study medications | BLIND | Oral hydromorphone (4 mg, Sky Pharma), dronabinol (10 mg; Akorn), and placebo were overencapsulated using size 00 gelcaps to blind drug condition to participants and experimenters. Hydromorphone was chosen as a prototypical opioid with limited differential CYP450 metabolism [ | PMC10516978 |
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Power analysis | COLD | A power analysis was derived from a prior evaluation of oxycodone and smoked cannabis on cold pressor tests [ | PMC10516978 |
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Data analytic plan | REGRESSION | Primary outcomes (i.e., peak or trough ratings post-drug administration) as a function of drug were examined with mixed-effects models for continuous outcomes, generalized estimating equations (GEE) for dichotomous outcomes, and multinomial logistic regression for nominal categorical outcomes (i.e., response option for study medication enjoyment was “yes,” “no,” and “no effect”). Chi-square analysis was conducted when GEE models did not converge. Drug conditions were compared using Tukey post-hoc tests. Analyses were replicated using area under the curve (AUC) analysis and including body mass index (BMI) as a covariate. Findings did not significantly change so only primary findings with peak effect analysis without controlling for BMI are reported. Sex did not moderate any study outcomes, so only main effects are reported. Main data analyses were conducted by an independent biostatistician who did not participate in outcome assessments. For all analysis SAS version 9.4 was used and alpha was set at 0.05, two tailed. | PMC10516978 |
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Results | PMC10516978 |
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QST outcomes | PMC10516978 |
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Quantitative sensory testing (QST) outcomes. | COLD | Data show results from the cold pressor task (top) and global QST measures (bottom), as a function of study condition (x-axis). Medication conditions were Placebo + Placebo (Plc + Plc), oral hydromorphone 4 mg + placebo (Hydro + Plc), and hydromorphone 4 mg combined with oral dronabinol 10 mg (Hydro + Drnb). Line that connect bars represents a significant difference in post-hoc comparison and error bars represent SEM. | PMC10516978 |
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Chronic pain outcomes | primary hyperalgesia, pain | HEAT | There was a significant main effect of drug on heat pain threshold in the zone of primary hyperalgesia sensitized by capsaicin ( | PMC10516978 |
Global QST outcomes | CENTRAL SENSITIZATION | A significant main effect of drug was revealed on Central Sensitization ( | PMC10516978 |
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Clinical pain severity outcome | pain | Baseline (prior to drug administration) clinical pain severity ratings for each drug condition were: (1) 22.51/100 (placebo); (2) 31.54/100 (hydromorphone); (3) 26.17/100 (dronabinol); and (4) 26.57/100 (hydromorphone + dronabinol). Paired | PMC10516978 |
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Physical functioning outcomes | No significant drug condition main effects on 2-min walking distance, tug time, or stair time ( | PMC10516978 |
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Self-reported drug effect outcomes | Overall, drug conditions produced subjective ratings that were significantly different from placebo (Table | PMC10516978 |
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Participant ratings. | Data show results from participant ratings of Drug, Good, and Bad Effects and percent of participants rating their feeling of High on a VAS 60 or higher during a session, as a function of study condition. Line that connect bars represents a significant difference in post-hoc comparison and error bars represent SEM. | PMC10516978 |
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HAP outcomes | A significant main effect of drug condition was observed for enjoyment of study medications ( | PMC10516978 |
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Cognitive function | A significant drug condition difference was observed on the circular lights task ( | PMC10516978 |
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Adverse events (AEs) | Study-related AEs were documented in 52 (35.1%) sessions and experienced by 26 (70.3%) participants. No serious AEs occurred. Compared with placebo, active drug dosing produced more mild and moderate AEs ( | PMC10516978 |
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Pharmacokinetics (PK) | Compared to each drug alone, hydromorphone + dronabinol did not significantly impact maximum, or time to maximum THC or hydromorphone concentrations ( | PMC10516978 |
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Discussion | pain | CHRONIC PAIN | The present study rigorously and comprehensively evaluated the effects of co-administering dronabinol (10 mg) and hydromorphone (4 mg) on evoked and clinical pain, self-reported drug effects, HAP metrics, physical and cognitive functioning, and AEs in patients with chronic pain. Overall, our findings reveal limited clinical benefits, and suggest that co-administering dronabinol (10 mg) with hydromorphone (4 mg) to this clinical population demonstrated a slightly enhanced risk for use along with elevated risk for AEs in the combined condition. These findings were consistent across sexes (see online supplement Table We found that although hydromorphone + dronabinol was associated with significant analgesia on several QST outcomes, it was not different than hydromorphone by itself, indicating no added benefit of the combination at the doses tested. We also found that none of the drug conditions significantly changed ratings of clinical pain severity. Overall, these findings are consistent with previous laboratory studies with healthy adults demonstrating limited additive benefit of combined cannabinoids and opioids on analgesia [To our knowledge, the present study is the first to evaluate the individual and combined effects of dronabinol and hydromorphone on clinically-relevant standardized physical testing measures [Relative to hydromorphone, dronabinol significantly increased the percent of participants who rated feeling High ≥ 60, a cutoff discussed by HAP experts as a metric of future risk. This value is higher than what was observed in prior studies [Despite several strengths, the present study had a number of limitations. First, only a single dose of hydromorphone and dronabinol was used, precluding dose-dependent examinations. A more parametric, dose-dependent design was considered but rejected due to concerns about feasibility of completing numerous sessions given that participants were older adults with chronic pain. In lieu of that design, the study assessed the highest cannabinoid dose tested by our prior research to provide maximal opportunity to detect the presence of any effect (whereas it would be more challenging to infer whether lack of effect smaller doses represented true lack of effect or a dose-related issue). The more definitive test for this line of research would be a full dose-dependent evaluation. In addition, the average participant age was >60 years old, which has been associated with changes in drug metabolism that may have impacted results. Third, use of an oral synthetic THC formulation may limit the data generalizability. Many advocates for the synergistic properties of cannabis prefer different routes of administration (e.g., inhalation) arguing that the whole, natural cannabis flower produces different effects than THC alone and could interact with opioids or produce analgesia in ways we do not yet fully understand. Fourth, although necessary for safety purposes, the hydromorphone condition was unrandomized which may have introduced order effects. Fifth, a longer walking test (6-min vs. 2-min) may have increased clinical pain levels and revealed more nuances in physical performance, but was shortened due to participant burden. Lastly, we focused on the acute effects of dronabinol and hydromorphone co-administration, and thus we cannot inform the long-term use of these two drugs on clinical outcomes, side effects, and HAP. | PMC10516978 |
Conclusion | CHRONIC PAIN | To our knowledge, this is the only laboratory study to examine the independent and combined effects of doses of dronabinol (10 mg) and hydromorphone (4 mg) that are within the range that can be prescribed therapeutically on a comprehensive array of clinically-relevant outcomes in individuals with chronic pain. These data extend our prior research with healthy adults by providing further evidence that combining dronabinol with hydromorphone for analgesia and physical function yields little benefit in a clinical cohort. The doses tested for dronabinol did not improve hydromorphone’s analgesic profile but did increase ratings of High, as well as negative side effects, and AEs. Finally, any significant analgesic effect observed following dronabinol + hydromorphone appeared to be driven by the hydromorphone, negating dronabinol enhancement of analgesia at the dose tested. | PMC10516978 |
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Supplementary information | The online version contains supplementary material available at 10.1038/s41386-023-01597-1. | PMC10516978 |
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Acknowledgements | JENSEN | The study team thanks Deborah Fashole-Luke, Bryan Herrera, Katie Smith, Jenna Pelly, Sydney Jensen, Savannah King, Alex Kearson, Jim Stone, Sana Rehman, Leticia Nanda, and Dr. Annie Umbricht for their assistance with study sessions and Paul Nuzzo with his assistance conducting data analyses. | PMC10516978 |
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Author contributions | ASH | Conceptualization: CMC, KED, RV, ASH, TJS. Methodology: CMC, KED, RV, ASH, CJM. Investigation: CMC, CJM, CLB, ASH, TJS, RV, KED. Visualization: CJM, KED, KRH. Formal analysis: CJM. Funding acquisition: CMC, KED. Project administration: CMC, KED. Supervision: CMC, CJM, CLB, ASH, TJS, RV, KED. Writing – original draft: CJM, CMC, KRH. Writing – review & editing: CMC, CJM, KRH, CLB, ASH, TJS, RV, KED. | PMC10516978 |
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Funding | KED | ABUSE | This study was supported by grant funding from the National Institute on Drug Abuse (NIDA) R01DA042751 (KED and CMC), R01DA040644 (KED and CMC), R01DA035246 (KED), T32NS070201 (KRH), and F32DA04939302 (CJM). | PMC10516978 |
Competing interests | DemeRx | ASH | The investigators have no relevant conflicts of interest to disclose. In the past 3 years, KED has received honoraria for advisory board work for the Canopy Corporation and consulted with Mind Med, Inc., and DemeRx. ASH receives partial salary support from Ashley Addiction Treatment. RV has been a paid consultant to Canopy Health Innovations and received honoraria for advisory board work from MyMD Pharmaceuticals, Mira1a Pharmaceuticals, Syqe Medical Ltd, Radicle Science Inc., and WebMD. CLB has received grant funding from Canopy Growth Corporation and Pear Therapeutics. | PMC10516978 |
References | PMC10516978 |
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Subject terms | bleeding, perforation, oesophageal ESD, oesophageal ESD-associated | ADVERSE EVENTS, STRICTURE, ULCERS, BLEEDING | There are significant risks of adverse events following oesophageal endoscopic submucosal dissection (ESD), such as stricture, delayed bleeding and perforation. Therefore, it is necessary to protect artificial ulcers and promote the healing process. The current study was performed to investigate the protective role of a novel gel against oesophageal ESD-associated wounds. This was a multicentre, randomized, single-blind, controlled trial that recruited participants who underwent oesophageal ESD in four hospitals in China. Participants were randomly assigned to the control or experimental group in a 1:1 ratio and the gel was used after ESD in the latter. Masking of the study group allocations was only attempted for participants. The participants were instructed to report any adverse events on post-ESD days 1, 14, and 30. Moreover, repeat endoscopy was performed at the 2-week follow-up to confirm wound healing. Among the 92 recruited patients, 81 completed the study. In the experimental group, the healing rates were significantly higher than those in the control group (83.89 ± 9.51% vs. 73.28 ± 17.81%, | PMC10133223 |
Introduction | STRICTURES, ESOPHAGEAL NEOPLASMS, DIGESTIVE SYSTEM NEOPLASM | Endoscopic submucosal dissection (ESD) is a popular intervention for digestive system neoplasms. Moreover, ESD is used to perform en bloc resection of entire oesophageal neoplasms, contributing to a precise pathological assessmentCurrently, endoscopic balloon dilatation, stent placement, oral steroid administration, and endoscopic steroid injection have been used prophylactically for strictures after ESDWe designed a novel gel consisting of a colloidal and fixative solution, to protect artificial wounds after oesophageal ESD. The colloidal solution is composed of poloxamers and sodium alginate, whereas the fixative solution contains calcium chloride. Poloxamers are synthetic nonionic triblock copolymers (PEO–PPO–PEO) of polyethylene oxide, and the most notable features of poloxamers include their temperature-dependent self-assembly and thermo-reversibilityIn this multicentre, randomized, single-blind trial, we investigated the effectiveness and safety of a novel gel designed to protect oesophageal wounds resulting from ESD. | PMC10133223 |
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Methods | PMC10133223 |
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Study design | This multicentre, randomized, single-blind trial performed in four hospitals in China investigated the efficacy and safety of a novel protective gel applied after oesophageal ESD. The study protocol was approved by the ethics committee of Zhejiang University School of Medicine First Affiliated Hospital (PRO20200140) and was executed in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local regulations. This trial was registered on | PMC10133223 |
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Participants | coagulative dysfunction, hepatic or renal failure, tumours, infection, cardiopulmonary dysfunction | TUMOURS, INFECTION, SYSTEMIC DISEASE | The study included adults who underwent oesophageal ESD between December 2020 and November 2021 across four participating hospitals. The inclusion criteria were as follows: (1) age 18–80 years, (2) underwent oesophageal ESD successfully, (3) first resection of the same lesion and (4) written consent provided for study participation. The exclusion criteria were as follows: (1) diagnosis of active infection or severe systemic diseases, (2) diagnosis of coagulative dysfunction, hepatic or renal failure, or cardiopulmonary dysfunction, (3) diagnosis of other tumours, (4) a history of oesophageal surgery or radiotherapy, (5) inability to complete the ESD operation, (6) pregnancy, (7) glucocorticoid therapy in the past 6 weeks and (8) refusal to participate in the study. | PMC10133223 |
Randomization and masking | BLIND | Using a random number table, participants were randomly divided into the control and experimental groups at a 1:1 ratio. Sequence generation, participant enrolment, and assignment were performed by three different individuals who were not involved in the rest of this clinical trial. In this single blind trial, masking of the allocations was only attempted for participants in this study. | PMC10133223 |
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Procedures | dysphagia, bleeding, oesophageal ESD, fever, upper gastrointestinal endoscope, chest pain, perforation, ulcer | DYSPHAGIA, BLEEDING, ULCER | In the control group, participants only underwent a standard oesophageal ESD procedure, whereas those from the experimental group underwent application of this new gel after oesophageal ESD. ESD was performed by experienced endoscopists at each participating institution. For the ESD procedure, an upper gastrointestinal endoscope (GIF-Q260J Endoscope, Olympus, Tokyo, Japan) and a dual knife (Olympus, Tokyo, Japan) were used. The lesion was marked using dots, created by a dual knife. The lesion was lifted by injection into the submucosal layer by a solution stained using indigo carmine, and then submucosal dissection was performed.Hangzhou Yingjian Bioscience & Technology Co., Ltd provided the protective gel for free. This gel consists of colloidal and fixative solutions. The colloidal solution contains poloxamers, sodium alginate, and beta-glucan, whereas the fixative solution consists of calcium chloride. In the experimental group, after oesophageal ESD, the colloidal solution was first spread onto the ulcer, followed by the fixative solution.Following ESD, participants were instructed to report any discomfort, such as fever, chest pain, or dysphagia, on post-ESD days 1, 14, and 30. A repeat endoscopy was performed, during the 2-week follow-up, to confirm resection site healing, assess gel status, and detect any delayed bleeding, perforation, or dysphagia (Fig. Study design. Participants were randomly divided into the control and experimental groups at a 1:1 ratio. In the control group, participants only underwent a standard oesophageal ESD procedure, whereas those from the experimental group underwent application of the gel after oesophageal ESD. A repeat endoscopy was performed, during the 2-week follow-up. Participants were instructed to report any discomfort on post-ESD days 1, 14, and 30. ESD, endoscopic submucosal dissection. | PMC10133223 |
Statistical analysis | EVENTS, SEPARATION | The sample size was calculated based on the primary studies. The treatment difference assumption was mainly based on another studyAdverse events were organized by our study group and presented as the number and proportion of patients. For other surgical information, the surgical time was defined as the interval between the start and completion of oesophageal ESD. The cutting time was the interval between the start of the resection and complete separation of the specimen. Moreover, the protective gel injection time and the wound coverage by gel were also calculated among the experimental groups.The results are presented as the mean ± standard deviation or counts (percentages). The t-test was used for data analysis. All | PMC10133223 |
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Ethics approval | All study procedures were approved by the ethics committee of Zhejiang University School of Medicine First Affiliated Hospital (PRO20200140). The authors have obtained informed consent from all subjects and/or their legal guardian(s). | PMC10133223 |
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Results | PMC10133223 |
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Study flow | ulcer | SECONDARY, ULCER | In this study, 92 patients were screened and considered eligible between December 2, 2020, and November 03, 2021. Among them, 46 individuals were randomly assigned to the control group, whereas the other 46 individuals were assigned to the experimental group. Overall, 81 (88.0%) of 92 patients completed the whole process and were included in the efficacy analysis, while the remaining 11 (12.0%) patients were lost to follow-up and discontinued the study. All 92 individuals were included in the safety analysis (Fig. Trial profile. The primary outcome (the healing rate) and secondary outcomes (ulcer area 14 days later, absolute change of ulcer area, and the wound characteristics in endoscopic re-evaluation 14 days after ESD) were assessed in the population completing the whole process. The safety analyses were measured among all the patients who were randomly assigned and completed the oesophageal ESD. ESD, endoscopic submucosal dissection. | PMC10133223 |
Evaluation of ulcer healing | ulcer | ULCER | Assessed from the endoscopic re-evaluation 2 weeks after oesophageal ESD, the remaining ulcer area was much larger in the control group than in the experimental group (1.80 ± 1.32 cmArtificial wounds detected from endoscopy. ( | PMC10133223 |
Adverse events | chest pain, fever, abdominal pain | ADVERSE EVENTS, ADVERSE EVENT | On the first day after oesophageal ESD, 11 (23.9%) patients in the control group, and 19 (41.3%) patients in the experimental group, showed signs of adverse events, most of which were fever, chest pain, or abdominal pain (Table Adverse events.Data are n/N (%). The adverse events of the day after endoscopy were measured among all the patients who were randomly assigned and completed the endoscopic submucosal dissection. And the follow-up 14 days later or 30 days later only measured the participants that continued the study. | PMC10133223 |
Discussion | oesophageal perforation, bleeding, fibrosis, postoperative stricture | OESOPHAGEAL PERFORATION, BLEEDING, INFILTRATION, ADVERSE EVENTS, GASTROINTESTINAL BLEEDING, ULCERS, FIBROSIS, ESOPHAGEAL STRICTURES, OESOPHAGEAL STRICTURE, STRICTURE, ESOPHAGEAL NEOPLASMS, POSTOPERATIVE STRICTURE | In this multicentre, randomized, single-blind trial, we validated the potential of our novel protective gel as an effective and safe therapeutic agent for artificial wounds after oesophageal ESD. The healing rates of ulcers treated with this protective gel were much higher than those observed in the control group. Patients treated with the gel also had less severe wounds as determined by repeat endoscopy. Additionally, we observed no severe adverse events related to gel application that were reported during the 1-month follow-up. Therefore, our findings suggest that this kind of protective gel should be assessed as a potential treatment for patients receiving oesophageal ESD.ESD has enabled the en bloc resection of large-sized superficial oesophageal neoplasms, but it carries the risk of causing oesophageal stricture, bleeding, and perforationDuring the wound healing process, the infiltration of inflammatory cells, excessive collagen formation, and disorganized fibrosis might play a role in stricture formationCurrently, steroid administration and repeated endoscopic balloon dilatation are common interventions for preventing oesophageal strictures. However, it was reported that intralesional steroid injections could inhibit the healing process and cause oesophageal perforation and gastrointestinal bleeding. Systemic administration increases the risk of immunosuppression and osteoporosisAs mentioned above, advanced strategies such as cell sheets or mineral sheets have been proposed to protect wounds. However, some of them are time-consuming, while others require high technical expertiseAdmittedly, there are some limitations in this study. First, most of the former studies have indicated that postoperative stricture formed after 14 days | PMC10133223 |
Conclusion | ulcer | ADVERSE EVENTS, ULCER | In conclusion, this multicentre, randomized, single-blind trial emphasizes the effectiveness, convenience, and safety of our novel protective gel when applied over wounds following oesophageal ESD. It could be applied to cover more than 90% of the ulcer area within approximately three minutes. More importantly, no severe relative adverse events were reported during the 1-month follow-up. Therefore, we recommend using this protective gel as a prophylactic intervention to promote ulcer healing and protect the ulcer bed after oesophageal ESD. | PMC10133223 |
Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-33982-7. | PMC10133223 |
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Acknowledgements | We would like to thank all the investigators who cooperated in recruiting patients at participating institutions. We would like to thank Hangzhou Yingjian Bioscience & Technology Co.,Ltd that provided the protective gel for free. | PMC10133223 |
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Author contributions | T.Z., X.M. and L.X. contributed equally to this article. Z.S. acted as guarantors of the article. Z.S. and C.Y. conceived and designed the study. T.Z. and L.C. collected and analyzed the data. T.Z. wrote the manuscript. C.D. generated the random allocation sequence. L.X. enrolled participants. X.M., L.X., H.J., J.W., W.L., F.J. and B.L. performed the endoscopy. T.Z., X.M., L.X., H.J., L.C., C.D., L.X., J.W., W.L., B.L., F.J., C.Y. and Z.S. had full access to all the data in the study and had final responsibility for the decision to submit for publication. | PMC10133223 |
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Funding | This work was supported by the Science Technology Department of Zhejiang Province (No 2021C03115 to Z.S., 2019C03040 to X.M.). The funders did not play any role in the study design, data collection and analysis, decisions regarding data release or manuscript preparation. | PMC10133223 |
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Data availability | All the related data is available on reasonable request. The data that support the findings of this study have been deposited in | PMC10133223 |
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Competing interests | The authors declare no competing interests. | PMC10133223 |
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References | PMC10133223 |
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Background | Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer and primary resistance to trastuzumab have a poor clinical outcome and lack good evidence to inform clinical decision. This study investigated the efficacy and safety of pyrotinib plus capecitabine in this population. | PMC10410905 |
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Methods | This phase 2 trial was conducted at 16 sites in China. Patients received oral pyrotinib 400 mg once daily and capecitabine 1000 mg/m | PMC10410905 |
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Results | deaths, diarrhea | DISEASE, ADVERSE EVENT | Between June 2019 and September 2021, 100 patients were enrolled with a median age of 51 years (range, 24–69). All patients had been treated with trastuzumab and 21 (21.0%) patients had prior use of pertuzumab. As of August 31, 2022, the median follow-up duration was 20.1 months (range, 1.3–38.2). The median PFS was 11.8 months (95% confidence interval [CI], 8.4–15.1), which crossed the pre-specified efficacy boundary of 8.0 months. The objective response rate was 70.0% (70/100), with a median duration of response of 13.8 months (95% CI, 10.2–19.3). The disease control rate was 87.0% (87/100). The median overall survival was not reached. The most common grade ≥ 3 treatment-emergent adverse event was diarrhea (24 [24.0%]). No treatment-related deaths occurred. | PMC10410905 |
Conclusions | Pyrotinib plus capecitabine can be considered to be a treatment option in HER2-positive advanced breast cancer patients who have shown primary resistance to trastuzumab. Even in the era of modern anti-HER2 treatments, this clinical setting warrants more investigations to meet unmet needs. | PMC10410905 |
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Trial registration | ClinicalTrials.gov, NCT04001621. Retrospectively registered on June 28, 2019. | PMC10410905 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12916-023-02999-0. | PMC10410905 |
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Keywords | PMC10410905 |
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Background | breast cancers, aggressive disease, breast cancer | SECONDARY, METASTATIC BREAST CANCER, BREAST CANCER | Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is an aggressive disease subtype, which accounts for 15–20% of breast cancers [Definition of primary trastuzumab resistance is derived from and serves for clinical trials, while its value of guiding clinical practice is not clarified. The cutoff to differentiate primary resistance from secondary resistance is not completely consistent in different clinical trials [Primary resistance mostly stands for intrinsic resistance and HER2 independency, while secondary resistance reflects enquired loss of sensitivity or presence of dominant resistant subclones [Pyrotinib is an irreversible pan-HER TKI that targets EGFR, HER2, and HER4. The phase 3 PHOEBE study confirmed the superiority of pyrotinib plus capecitabine over lapatinib plus capecitabine in patients with trastuzumab-taxane-treated, HER2-positive metastatic breast cancer [ | PMC10410905 |
Methods | PMC10410905 |
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Study design and participants | Tumors | ONCOLOGY, METASTATIC BREAST CANCER, TUMORS | This was an investigator-initiated, single-arm, phase 2 trial conducted at 16 sites in China. Patients were included if they were females aged 18–70 years; had pathologically confirmed HER2-positive (score 3 + by immunohistochemistry, or 2 + with positive results of fluorescence in-situ hybridization) locally advanced or metastatic breast cancer; had primary resistance to trastuzumab; had an Eastern Cooperative Oncology Group performance status of 0 or 1; had known hormone receptor status; had an expected survival of ≥ 3 months; had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1 [The study was conducted in accordance with the Declarations of Helsinki and Good Clinical Practice and was approved by the ethics committee of each participating center. Written informed consent was obtained from each patient. The study was registered with ClinicalTrials.gov, NCT04001621. | PMC10410905 |
Procedures | death, Cancer | CANCER, DISEASE PROGRESSION, ADVERSE EVENT, ADVERSE EVENT | Patients received oral pyrotinib 400 mg once daily and oral capecitabine 1000 mg/mImaging examinations were performed every 6 weeks for the first 20 treatment cycles, and every 12 weeks thereafter. Radiological response was assessed by investigators according to RECIST 1.1. For patients who discontinued the study treatment before disease progression or death, subsequent imaging examinations were performed every 12 weeks until the initiation of other anti-cancer therapies, disease progression, or death. OS was followed every 12 weeks until loss to follow-up, death, or completion of the study. Adverse events (AEs) during the study treatment and until 28 days after the last dose of study drug were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. | PMC10410905 |
Endpoints | death | DISEASE PROGRESSION, DISEASE | The primary endpoint was PFS, defined as the time from the initiation of study treatment to the first disease progression per RECIST 1.1 or any-cause death, whichever came first.Secondary endpoints included objective response rate (ORR; defined as the proportion of patients with the best response of complete response [CR] or partial response [PR] per RECIST 1.1), duration of response (defined as the time from the first CR or PR to disease progression per RECIST 1.1 in patients with confirmed objective response), disease control rate (DCR; defined as the proportion of patients with the best response of CR, PR, or stable disease per RECIST 1.1), overall survival (OS; defined as the time from the initiation of study treatment to any-cause death), and safety. | PMC10410905 |
Statistical analysis | REGRESSION | Trastuzumab plus vinorelbine was the backbone treatment for trastuzumab-pretreated patients in 2019 in China; thus, the median PFS (5.78 months) of the control group in BOLERO-3 was considered as the historical control in our study [Efficacy and safety were analyzed in all patients with at least one dose of study drug. Continuous variables were expressed as median (range), and categorical variables were expressed as frequency (percentage). The 95% confidence intervals (CIs) of ORR and DCR were calculated using the Clopper-Pearson method. Comparison of ORR was performed between subgroups using the chi-square test. Median PFS and OS were estimated using the Kaplan–Meier method, and their 95% CIs were calculated using the Brookmeyer-Crowley method. Comparison of PFS was performed between subgroups using the Cox proportional hazard regression model. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). Two-sided | PMC10410905 |
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Results | PMC10410905 |
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Efficacy | DISEASE PROGRESSION | By the data cutoff date, 66 (66.0%) of 100 patients had disease progression or died. The median PFS was 11.8 months (95% CI, 8.4–15.1; Fig. Kaplan–Meier curves for progression-free survival. Further analyses showed that the median PFS was 8.2 months (95% CI, 3.0–20.7) in subgroup A (progression during adjuvant trastuzumab; Seven of 100 patients achieved confirmed CR and 63 achieved confirmed PR, with a confirmed ORR of 70.0% (95% CI, 60.0–78.8). Median duration of response was 13.8 months (95% CI, 10.2–19.3). Seven patients with CR were all from subgroup B. The ORR was significantly higher in subgroup B than in subgroups A and C (Additional file Waterfall plot for best percent change in target lesions from baseline among individual patients ( | PMC10410905 |
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Safety | dyspepsia, deaths, Treatment-emergent adverse, anemia | PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME, ANEMIA | Treatment-emergent AEs (TEAEs) are summarized in Table Treatment-emergent adverse eventsData are Twelve (12.0%) of 100 patients had dose reductions of pyrotinib due to AEs, and 37 (37.0%) had dose reductions of capecitabine. Four (4.0%) patients discontinued capecitabine due to increased blood bilirubin, anemia, dyspepsia, and palmar-plantar erythrodysesthesia syndrome, respectively. No AEs leading to discontinuation of pyrotinib occurred. No treatment-related deaths occurred. | PMC10410905 |
Discussion | HER2-positive advanced, breast cancer | To our knowledge, this phase 2 trial was the first positive multicenter study for patients with HER2-positive advanced breast cancer and primary trastuzumab resistance, in contrast to previous failed trials in this clinical setting. The median PFS of 11.8 months met the primary endpoint, significantly longer than the pre-trial hypothesis of 8.0 months in the trial protocol. The combination of pyrotinib and capecitabine was also demonstrated well-tolerated and had no new safety signals in this study.Patients with primary trastuzumab resistance are under-represented in two pivotal phase 3 trials (EMILIA and DESTINY-Breast 03). Even for those who received real second-line treatment in these two trials, they were either primary- or secondary-resistant to trastuzumab. The EMILIA study confirmed the role of T-DM1 in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane when compared with lapatinib plus capecitabine (PFS: 9.6 vs. 6.4 months; hazard ratio, 0.65; Among previous clinical trials focusing on trastuzumab-resistant patients, the definition of primary trastuzumab resistance is not unified, leading to hard indirect comparisons across studies (Additional file Patients who had progression within 12 months of completing adjuvant trastuzumab (subgroup B in our study) are generally included in the trastuzumab-resistant population [The safety profile of pyrotinib plus capecitabine was consistent with results from previous clinical trials [This study has some limitations. First, there might be potential bias due to the single-arm design without control group. In fact, it is very hard to conduct randomized controlled trials since such patients were rare due to advance in early diagnosis and HER2-targeted therapy, and it took us 27 months to enroll 100 patients at 16 sites. In the future, direct comparison between our study treatment and modern treatment option, especially T-DXd, is urgently needed. Second, only Chinese patients were enrolled and the effect of pyrotinib plus capecitabine in other populations needs to be established. Third, the efficacy was assessed by investigators rather than independent review committee. Fourth, due to the small sample size, multivariable analyses were not performed to analyze the independent factors influencing the treatment response and survival. Finally, OS data are not mature yet, which will be reported in the future. | PMC10410905 |
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Conclusions | Pyrotinib plus capecitabine can be considered to be a treatment option in HER2-positive advanced breast cancer patients who have shown primary resistance to trastuzumab. Even in the era of modern anti-HER2 treatments, this clinical setting warrants more investigations to meet unmet needs. | PMC10410905 |
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Acknowledgements | We thank all the patients who participated in this trial and their families. We thank Mian Wei (Medical Manager, Jiangsu Hengrui Pharmaceuticals Co., Ltd) for her input in data interpretation, Yitao Wang (Clinical Statistics Manager, Jiangsu Hengrui Pharmaceuticals Co., Ltd) for statistical support, and Fangzhou Xia (Medical Writer, Jiangsu Hengrui Pharmaceuticals Co., Ltd) for medical writing assistance. | PMC10410905 |
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Authors’ contributions | HL | XH conceived and designed the study. All authors contributed to the acquisition of data. JC, YT, HL, and XH contributed to the analysis and interpretation of data. JC and XH drafted the manuscript. All authors contributed to the critical revision of the manuscript for important intellectual content. XH contributed to the administrative support and study supervision. All authors are accountable for the accuracy and integrity of this work and approved the final version of the manuscript for submission. | PMC10410905 |
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Funding | This work was supported by Jiangsu Hengrui Pharmaceuticals Co., Ltd. The funder provided all the study drugs and participated in data interpretation, but had no role in study design, data collection, or drafting of the manuscript. | PMC10410905 |
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Availability of data and materials | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10410905 |
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Declarations | PMC10410905 |
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Ethics approval and consent to participate | The study was conducted in accordance with the Declarations of Helsinki and Good Clinical Practice and was approved by the ethics committee of each participating center (approval number: 1903198–13, (2019) 2019–270, 2020YJZ11, 2019–029, 2020SR (No. 1), CS2019 (57), 2019KYER (No. 126), 2019155, (2019) ER (No. 22), (2020) RCR (No. 1), (S) ER (No. 2019051), LDYYLL2019-213, BF2019-145–01, SYL-201938–01, ER (R) 2019–235-01, R (2019) ER (No. 3)). All patients provided written informed consent. | PMC10410905 |
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Consent for publication | Not applicable. | PMC10410905 |
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Competing interests | The authors declare that they have no competing interests. | PMC10410905 |
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References | PMC10410905 |
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Background | Robotic therapy and serious gaming support motor learning in neurorehabilitation. Traditional monitor-based gaming outputs cannot adequately represent the third dimension, whereas virtual reality headsets lack the connection to the real world. The use of Augmented Reality (AR) techniques could potentially overcome these issues. The objective of this study was thus to evaluate the usability, feasibility and functionality of a novel arm rehabilitation device for neurorehabilitation | PMC10422755 |
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Methods | stroke, cord injury, paretic impairments | STROKE | The RobExReha system was tested with eleven adult inpatients (mean age: 64.4 ± 11.2 years; diagnoses: 8 stroke, 2 spinal cord injury, 1 Guillain-Barré-Syndrome) who had paretic impairments in their upper limb. Five therapists administered and evaluated the system. Data was compared with a Reference Group (eleven inpatients; mean age: 64.3 ± 9.1 years; diagnoses: 10 stroke, 1 spinal cord injury) who trained with commercially available robotic therapy devices ( | PMC10422755 |
Results | ADVERSE EVENTS | Therapy with the RobExReha system was safe and feasible for patients and therapists, with no serious adverse events being reported. Patients and therapists were generally satisfied with usability. The patients’ usability ratings were significantly higher in the Reference Group for two items of the QUEST: reliability and ease of use. Workload (RTLX) ratings did not differ significantly between the groups. Nearly all patients using the RobExReha system perceived the gaming scenario in AR as functioning adequately despite eight patients having impairments in stereoscopic vision. The therapists valued the system’s approach as interesting and inventive. | PMC10422755 |
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Conclusions | We demonstrated the clinical feasibility of combining a novel robotic upper limb robot with an AR-serious game in a neurorehabilitation setting. To ensure high usability in future applications, a reliable and easy-to-use system that can be used for task-oriented training should be implemented. | PMC10422755 |
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Trial registration | Ethical approval was obtained and the trial was registered at the German Clinical Trials Register (DRKS00022136). | PMC10422755 |
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Keywords | PMC10422755 |
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Background | stoke, upper limb disabilities, Stroke | NEUROLOGICAL DISEASE, STROKE | Neurological rehabilitation is crucial to public health, as a substantial part of the population is affected by neurological diseases throughout their life. Stroke, for example, has a one-year-prevalence of about 1.6% in the German adult population, increasing with age to over 6% in people over the age of 75 [After damage to the central nervous system, neural plasticity enables the brain to adapt in response to motor learning [AR generally has beneficial effects for the learning of spatial tasks [Therefore, in patients with upper limb disabilities due to stoke, our approach was to combine AR with a robotic device to administer a serious gaming therapy. We were also particularly interested if it was possible to create a gaming situation with an easily perceptible depth dimension.The objective of this pilot proof-of-concept study was to evaluate the device’s safety, clinical feasibility, usability, and potential benefits, as recommended by Maciejasz et al. [ | PMC10422755 |
Methods | PMC10422755 |
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User | spasticity, epilepsy, paresis, cord injury, abduction of the shoulder, paresis of the upper limb, fractures, Stereoscopic vision | EPILEPSY, CONTRACTIONS, PARESIS, DER, NEUROLOGICAL DISORDERS | This study had three groups of users: eleven patients (“RobExReha-Patients”) (aged 64.4 ± 11.2 years, range 47–85) and five therapists (“RobExReha-Therapists”) (aged 38.2 ± 16.0 years, range 23–57) who evaluated the RobExReha device and an additional eleven age-matched patients (“Reference Group”) (aged 64.3 ± 9.1 years, range 49–79) were allocated to the reference group (see Table Inclusion criteria for patients were a subacute or chronic paresis of the upper limb due to neurological disorders, preserved language comprehension, ability to communicate, orientation in space and time, ability to sit upright for at least 45 min, and the completion of at least four training sessions with the respective therapy device (RobExReha or Armeo). Further device-related inclusion criteria for the RobExReha-Patients group were ability to reach the clip-in-position of the robotic device at 30° abduction of the shoulder, impairment on the right side, and normal or appropriately corrected vision.We excluded patients with craniotomy, instable fractures, fixated contractions, active implants, epilepsy and severe instabilities, severe spasticity (Modified Ashworth Scale > 3, [Stereoscopic vision was evaluated using the Titmus-Test (Stereo Optical Co., Chicago, IL) but was not a limiting factor for study inclusion. The mean stereoscopic vision of the RobExReha-Patients group was 405 ± 983 arc sec (median: 100 arc sec; range 40–3352 arc sec). With defining the cut-off score for unimpaired stereoscopic vision at 60 arc sec [The five therapists administering the therapy had a working experience of 9.8 ± 8.2 years in neurorehabilitation (min-max: 1–23 y.). They were either physiotherapists (n = 2), a sport therapist (n = 1), a health scientist (n = 1) or a specially trained staff member for robotic upper limb therapy without specific health care profession (n = 1). Two of the therapists were highly trained using other robotic devices daily, and three of them had not regularly used robotic therapy. The technical affinity questionnaire (TA-EG) [
Characteristics of participantsStroke (n = 8)Spinal cord injury (n = 2)Guillain-Barré-Syndrome (n = 1)Stroke (n = 10)Spinal cord injury (n = 1)Time since paresis in days
M: mean, SD: standard deviationAll participants gave informed written consent. Ethics approval was obtained (Ethikkommission der Bayerischen Landesärztekammer) and the study was registered in the German Clinical Trials Register (DRKS00022136). | PMC10422755 |
Technology | The RobExReha robotic system should meet the demand to provide (adaptive) support to the patient, while ensuring a high level of safety. Therefore, the commercially available LBR iiwa robotic arm (KUKA AG, DE) was chosen, which is designed for safe human-robot interactions. The robotic arm was mounted on a cart in a 45° angle and interfaced with the patients’ right arm at the robot flange (see Fig.
Left: subject using the RobExReha system with the HoloLens for the gaming application. Right: arm-robot interface used by a patient during the therapy with the RobExReha system
Arm-robot interface of the RobExReha system: Picture | PMC10422755 |
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Arm-robot interface | To connect the patient’s arm to the robot flange, a mechanical human-machine interface comprising a brace on the upper and lower arm and a counterpart on the robotic flange was developed. The brace consisted of two 3D printed shells (Fig. Subsequently, the steel plate of the brace (Fig. A hand module with a grip hold was attached to the carbon plate that guided the lower arm (see Fig. | PMC10422755 |
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Calibration procedure | shoulder abduction, pain | To calibrate the position of the robot, the shoulder height and upper arm length were manually measured using a measuring tape in the beginning of the first session and entered in the software. At the beginning of each session, the robot moved the flange to the respective clip-in position at 30° shoulder abduction. Once the brace was clipped to the arm, the arm was weighed by the robot to enable the calibration of robotic support. Afterwards, the patient’s specific range of motion (ROM) was evaluated, which consisted of two assessments: the active ROM, in which the patient could actively move the impaired arm, and the passive ROM without pain as guided and determined by the therapist. The passive ROM typically exceeded the active ROM in patients. This differentiation enabled the implementation of two different robotic support modes: (A) The support level was set to a constant level for both ranges, or (B) the support level within the active ROM was set to a constant level while the support of the movement beyond the active ROM increased dynamically until the patient achieved the desired movement. The robot enabled six support levels that were adjustable with increments of 20%, from 0 to 100%. | PMC10422755 |
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Safety features | To ensure the patients’ safety, the robot’s movements were restricted to the respective patient’s passive ROM. An additional safety feature was an automated stop in case the active sum force of all axes exceeded 30 Nm. Moreover, a safety stop button for the supervising therapist was implemented.To give feedback about compensatory movements of the trunk or shoulder girdle, an alert was implemented to notify both therapists and patients if the patient’s shoulder position (i.e., the acromion) left the anticipated position. In case this position deviated more than a predefined threshold from the initial shoulder position, a visual alert was displayed in the gaming environment. Initially, the threshold of this shoulder compensation alert was set to a range of 5 cm around the ideal shoulder position. However, the alert tended to be displayed too early and too frequent and thus interrupted the gaming experience. After increasing the threshold to 7.5 cm, the alert only appeared in cases where a relevant compensatory movement was visually evident for the supervising therapist. The patients reacted adequately by actively correcting the position of their shoulder. | PMC10422755 |
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Gaming scenario | The training setup included an AR-game for HoloLens. The training game was based on a 3D puzzle (see Fig.
View through the HoloLens with the gaming scenario: a blue hand (yellow arrows) could select puzzles pieces. Once a piece was selected, the hand closed (see right figure) and the piece could be moved to the buildingThe difficulty of the game could be adjusted via the distance and size of the building with respect to the hand position, which led to a smaller/greater required travel distance of the patient’s hand to reach the designated spot. This, along with the robotic support level, could be also adjusted while gaming. | PMC10422755 |
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Study protocol | To evaluate the usability and feasibility, the groups used the devices (either directly as a patient or administering the therapy as therapist). After at least four sessions, their experience was evaluated using questionnaires (see Table
Schematic of the structure of this study: the RobExReha-Patients trained 4–5 times with the RobExReha device, while technical and user incidents were reported. After completion of at least four training sessions, the questionnaire evaluation was conducted. The Reference Group only participated in the questionnaire survey and reported their perception of the conventional robotic gaming therapy | PMC10422755 |
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User activity | PMC10422755 |
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