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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
Chronic pain measure
As reported previously [
PMC10516978
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, co...
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
Self-reported drug effects
Following FDA guidance [
PMC10516978
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
Physical function measures
Three measures of objective physical performance [
PMC10516978
Cognitive function measures
cognitive functioning [
Three tasks assessed cognitive functioning [
PMC10516978
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 nu...
PMC10516978
Pharmacokinetic analyses
Whole blood samples were collected in standard vacutainer tubes free of additives for participants (
PMC10516978
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
Power analysis
COLD
A power analysis was derived from a prior evaluation of oxycodone and smoked cannabis on cold pressor tests [
PMC10516978
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...
PMC10516978
Results
PMC10516978
QST outcomes
PMC10516978
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 ...
PMC10516978
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
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
Physical functioning outcomes
No significant drug condition main effects on 2-min walking distance, tug time, or stair time (
PMC10516978
Self-reported drug effect outcomes
Overall, drug conditions produced subjective ratings that were significantly different from placebo (Table 
PMC10516978
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
HAP outcomes
A significant main effect of drug condition was observed for enjoyment of study medications (
PMC10516978
Cognitive function
A significant drug condition difference was observed on the circular lights task (
PMC10516978
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
Pharmacokinetics (PK)
Compared to each drug alone, hydromorphone + dronabinol did not significantly impact maximum, or time to maximum THC or hydromorphone concentrations (
PMC10516978
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 cli...
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 da...
PMC10516978
Supplementary information
The online version contains supplementary material available at 10.1038/s41386-023-01597-1.
PMC10516978
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
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: C...
PMC10516978
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 Ca...
PMC10516978
References
PMC10516978
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 ...
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, an...
PMC10133223
Methods
PMC10133223
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) an...
PMC10133223
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 ...
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 ...
PMC10133223
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...
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...
PMC10133223
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
Results
PMC10133223
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 proce...
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...
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. Pati...
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 seve...
PMC10133223
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-023-33982-7.
PMC10133223
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
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...
PMC10133223
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
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
Competing interests
The authors declare no competing interests.
PMC10133223
References
PMC10133223
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
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
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...
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
Trial registration
ClinicalTrials.gov, NCT04001621. Retrospectively registered on June 28, 2019.
PMC10410905
Supplementary Information
The online version contains supplementary material available at 10.1186/s12916-023-02999-0.
PMC10410905
Keywords
PMC10410905
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 ...
PMC10410905
Methods
PMC10410905
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 ...
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 treat...
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 [...
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....
PMC10410905
Results
PMC10410905
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 trastuzu...
PMC10410905
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, dyspep...
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 p...
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
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 (M...
PMC10410905
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 t...
PMC10410905
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
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
Declarations
PMC10410905
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...
PMC10410905
Consent for publication
Not applicable.
PMC10410905
Competing interests
The authors declare that they have no competing interests.
PMC10410905
References
PMC10410905
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 thes...
PMC10422755
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 inpati...
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 an...
PMC10422755
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
Trial registration
Ethical approval was obtained and the trial was registered at the German Clinical Trials Register (DRKS00022136).
PMC10422755
Keywords
PMC10422755
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 dam...
PMC10422755
Methods
PMC10422755
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 year...
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...
PMC10422755
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 w...
PMC10422755
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. Onc...
PMC10422755
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 c...
PMC10422755
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 buildi...
PMC10422755
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 time...
PMC10422755
User activity
PMC10422755