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Results
PMC10085031
Memorizing repetitions
The number of repetitions needed for memorizing the correct information in the LOW and HIGH conditions were 1.32 (
PMC10085031
Outliers
The numbers of omitted outliers were 1.9 (
PMC10085031
Hindsight bias index
An unpaired
PMC10085031
Percentage of hindsight bias index.
The hindsight bias index (%) was defined as 100 (initial responses-recollection values) / (initial responses—correct information), in which initial responses = numerical value of the initial responses, recollection values = numerical value of the recollection values, and correct information = numerical value of the correct information. “Total,” “Toward” and “Reversed” in the figure indicates the total percentage of distortions, percentage of distorted items for correct information, and the percentage of distorted items against correct information, respectively.
PMC10085031
Ratio of items showing memory distortions
An unpaired
PMC10085031
The percentage of distorted items.
The distorted items (%) were calculated as the distorted items divided by all the items. “Total,” “Toward” and “Reversed” in the figure indicates the total percentage of distortions, the percentage of distorted items for correct information, and the percentage of distorted items against correct information, respectively.
PMC10085031
Discussion
non-delayed recollections
The main finding of this study was that the MLOIE (i.e., the number of items to be remembered) affects the magnitude of hindsight bias, which supports the study’s tentative hypothesis. The larger the number of things to remember, the higher the hindsight bias. This finding is a simple but first reported contribution to the body of knowledge on hindsight bias.Some causes of the hindsight bias have been proposed based on four strategies for recollecting the initial responses: (1) recalling the old belief [We, however, should be aware that these single strategies could not explain the hindsight bias because complex interactions between multiple mechanisms might cause them [Another explanation is that a working memory load during encoding (i.e., keeping remembering a digit number while reading a story) prevents hindsight bias, probably because the working memory load prevents elaborative thinking during encoding, which impedes convincing feelings and prevents “creeping determinism” in recollection [Previous studies had controlled for the strength of the initial responses’ memory trace by the timing of providing correct information and the timing of recollection. This procedure caused delayed recollections to produce a more substantial hindsight bias than non-delayed recollections [It has been reported that hindsight bias induces undesirable risk perceptions and decision-making outcomes for financial investments [The hindsight bias is often viewed as a cognitive limitation producing unwanted results as a by-product of standard information processing and storage methods. Some studies, however, have suggested that the hindsight bias itself might be an adaptive phenomenon that improves the foresight judgments of individuals in a successively changing environment [As a limitation in the present study, we did not measure working memory. Although any dual task was not performed in the present study, there is a possibility that working memory affected the results. Besides, a small sample size could be another limitation. These limitations should be adequately treated in future studies.
PMC10085031
Conclusions
In conclusion, the present study found that the memory load of information encoded (MLOIE) would amplify the magnitude of hindsight bias. The biased recollection degree was higher in the HIGH than the LOW condition, indicating that the memory load amplifies the magnitude of hindsight bias. This suggests that hindsight bias would be mitigated by controlling the memory load when learning information. This knowledge can be practical in reducing incidents caused by hindsight biases.
PMC10085031
Supporting information
PMC10085031
English Hindsight Bias Test (HBT) items.
(DOCX)Click here for additional data file.
PMC10085031
Japanese Hindsight Bias Test (HBT) items.
(DOCX)Click here for additional data file.
PMC10085031
Original data of the hindsight bias index.
(XLSX)Click here for additional data file.
PMC10085031
References
PMC10085031
Background
HAND INFECTION
Although airway management for paramedics has moved away from endotracheal intubation towards extraglottic airway devices in recent years, in the context of COVID-19, endotracheal intubation has seen a revival. Endotracheal intubation has been recommended again under the assumption that it provides better protection against aerosol liberation and infection risk for care providers than extraglottic airway devices accepting an increase in no-flow time and possibly worsen patient outcomes.
PMC10184619
Methods
shockable, VF, non-shockable
SECONDARY
In this manikin study paramedics performed advanced cardiac life support with non-shockable (Non-VF) and shockable rhythms (VF) in four settings: ERC guidelines 2021 (control), COVID-19-guidelines using videolaryngoscopic intubation (COVID-19-intubation), laryngeal mask (COVID-19-Laryngeal-Mask) or a modified laryngeal mask modified with a shower cap (COVID-19-showercap) to reduce aerosol liberation simulated by a fog machine. Primary endpoint was no-flow-time, secondary endpoints included data on airway management as well as the participants‘ subjective assessment of aerosol release using a Likert-scale (0 = no release–10 = maximum release) were collected and statistically compared. Continuous Data was presented as mean ± standard deviation. Interval-scaled Data were presented as median and Q1 and Q3.
PMC10184619
Results
A total of 120 resuscitation scenarios were completed. Compared to control (Non-VF:11 ± 3 s, VF:12 ± 3 s) application of COVID-19-adapted guidelines lead to prolonged no-flow times in all groups (COVID-19-Intubation: Non-VF:17 ± 11 s, VF:19 ± 5 s;p ≤ 0.001; COVID-19-laryngeal-mask: VF:15 ± 5 s,p ≤ 0.01; COVID-19-showercap: VF:15 ± 3 s,p ≤ 0.01). Compared to COVID-19-Intubation, the use of the laryngeal mask and its modification with a showercap both led to a reduction of no-flow-time(COVID-19-laryngeal-mask: Non-VF:p = 0.002;VF:p ≤ 0.001; COVID-19-Showercap: Non-VF:p ≤ 0.001;VF:p = 0.002) due to a reduced duration of intubation (COVID-19-Intubation: Non-VF:40 ± 19 s;VF:33 ± 17 s; both p ≤ 0.01 vs. control, COVID-19-Laryngeal-Mask (Non-VF:15 ± 7 s;VF:13 ± 5 s;p > 0.05) and COVID-19-Shower-cap (Non-VF:15 ± 5 s;VF:17 ± 5 s;p > 0.05). The participants rated aerosol liberation lowest in COVID-19-intubation (median:0;Q1:0,Q3:2;p < 0.001vs.COVID-19-laryngeal-mask and COVID-19-showercap) compared to COVID-19-shower-cap (median:3;Q1:1,Q3:3 p < 0.001vs.COVID-19-laryngeal-mask) or COVID-19-laryngeal-mask (median:9;Q1:6,Q3:8).
PMC10184619
Conclusions
COVID-19-adapted guidelines using videolaryngoscopic intubation lead to a prolongation of no-flow time. The use of a modified laryngeal mask with a shower cap seems to be a suitable compromise combining minimal impact on no-flowtime and reduced aerosol exposure for the involved providers.
PMC10184619
Supplementary Information
The online version contains supplementary material available at 10.1186/s12873-023-00820-y.
PMC10184619
Keywords
Open Access funding enabled and organized by Projekt DEAL.
PMC10184619
Background
infection
INFECTION
Based on experience with SARS-CoV-1, the resuscitation guidelines were adapted to mitigate the risk of infection for the rescuers, while accepting an increase in no-flow time and possibly worse patient outcomes [
PMC10184619
Methods
shockable, OHCA
Ethical approval for this study (Ethical Committee No 2021-414-f-S) was granted on July, 2th 2021 by the Ethical Committee of the University Hospital of Muenster, Muenster, Germany (Chairperson Prof W.E. Berdel). The study was performed at a training center for paramedics in Bielefeld, Germany in August 2021 (‘Studieninstitut für kommunale Verwaltung Westfalen-Lippe, Fachbereich Medizin und Rettungswesen’). This manuscript adheres to the applicable CONSORT guidelines. After providing written informed consent, 60 paramedics were randomly allocated into 30 fixed teams, simulating the crew of an ambulance, and asked to perform a basic-life-support (BLS) OHCA scenario according to the guidelines of the European Resuscitation Council (ERC) 2021 [ The laryngeal mask modified with a shower capFollowing the training, the previously formed teams were randomised via balanced randomization into two groups to investigate the effects on each initial rhythm: The first group completed the three scenarios of ERC COVID-19-adapted guidelines with a shockable, the second group with a non-shockable rhythm using each of the previously trained airway devices [ Flowchart of the group allocation processThe target for the participants was to achieve the highest possible resuscitation quality with regard to protection specificities due to the COVID-19 pandemic [The Laerdal Resusci Anne QCPR manikin (Laerdal Medical GmbH, Lilienthalstr.5, 82,178 Puchheim, Germany, To visualize the simulated aerosol release, the breathing system of the Laerdal Resusci Anne QCPR manikin was modified using the ‚Look Tiny Cx fog machine‘ (Look Solutions GmbH & Co. KG, Bünteweg 33, DE-30,989 Gehrden, Data were transmitted via WLAN to the SimPad PLUS (SimPad PLUS, Laerdal Medical 2016, The duration of each scenario was limited to 5 min. During the COVID-19 scenarios, participants wore PPE as recommended in the COVID-19-adapted guidelines (FFP3 mask (equivalent to the US N95 standard), eye and face protection, long-sleeved gown, and gloves) [After completion of all scenarios, the participants were asked to anonymously provide information on their subjective assessment of the amount of aerosol release (0 = no release – 10 = maximum release) and the feeling of safety using the different airway devices (safe, rather safe, rather unsafe, unsafe), the assessment of the quality of the different resuscitation scenarios with regard to the shortest possible no-flow time (good quality, rather good quality, rather bad quality, bad quality) and optimal protection of the rescuer (good protection, rather good protection, rather bad protection, bad protection).The primary outcome was no-flow time, defined as time without chest compressions. Secondary outcomes were the established quality indicators of resuscitation as mentioned above as well as the results of the participants survey on rescuer safety.
PMC10184619
Analysis
SAID
STATA version 16 (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC.) was used for statistical analyses. The sample size was calculated with a standardized tolerance limit of one standard deviation and no difference, 20 participants were required for a power = 0.8 with a significance level of 0.05. Mean difference between outcomes for the scenarios within the COVID-19 groups and compared to control group are adjusted for the correlation between measures obtained by the same team by using mixed models. We performed a non-inferiority analysis in which one scenario is said to be non-inferior to reference scenario if the lower limit of 95% confidence interval of the mean differences is less than half a standard deviation of the outcome for the reference scenario. The statistical evaluation of the provider survey was performed with the Friedman- and Wilcoxon–test. The significance level was set at P ≤ 0.05.
PMC10184619
Discussion
infection, OHCA, vomiting, SAD
INFECTION, WASTED, COMPLICATIONS
The present paper compares no-flow time and established quality indicators of resuscitation as well as aerosol release using COVID-19 resuscitation guidelines including three different airway management strategies in accordance with the ERC-2021 using a simulation model [Over the last decade, the impact of different airway management strategies on outcomes following OHCA has been investigated in various studies [Since the insertion of SAD is easy to both learn and put into practice for non-medical emergency service personnel, their use is widespread in Europe. Due to the relevant risk of release of infectious aerosols, airway interventions in patients with COVID-19 are associated with a significant risk of infection. Especially during face mask and supraglottic airway ventilation, intubation, extubation, and cardiopulmonary resuscitation, an increased aerosolization could be observed [SAD manufacturers should consider incorporating the shower cap concept into their SAD and prospective studies should evaluate this concept with regard to complications such as obstructing access to the airway in situations such as vomiting, an additional risk be a unnoticed tear in the shower cap, which may lead to a false sense of safety, different head-shapes, patients with a large beard or additional wasted plastic for times when an SAD is placed but CPR is not being performed. In addition, an SAD modified with a shower cap could represent a further building block not only in the context of prehospital resuscitation or difficult airway protection but also for anaesthesia.
PMC10184619
Limitations
As the influence of the different airway devices on key performance indicators of resuscitation was investigated, the application of the PPE was not part of the study, but obviously leads to a further prolongation of no-flow time [
PMC10184619
Conclusions
The present study shows that the COVID-19-adapted guidelines using ETI led to a prolongation of the no-flow time, which markedly worsened the overall quality of resuscitation. These effects can be attenuated using an SAD. Although the influence of airway management on the outcome of resuscitation and the transmission of Sars-CoV-2 is critically discussed, the use of a modified LMA with a shower cap seems to be suitable to ensure optimal resuscitation quality and to reduced aerosol exposure at the same time.
PMC10184619
Acknowledgements
The authors would like to thank Marvin Deslandes for revision and Helge Myklebust and Laerdal Medical for kindly providing the ’Shower-cap’ concept.
PMC10184619
Authors’ contributions
TB
SSS has been involved in acquisition of data, drafting the manuscript, revising it critically for important intellectual content, gave final approval of the version to be published and gave the Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. SL has been involved in acquisition of data, drafting the manuscript, revising it critically for important intellectual content, gave final approval of the version to be published and gave the Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. EL has been involved in acquisition of data, revising the manuscript critically for important intellectual content, gave final approval of the version to be published and gave the Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. TB has been involved in acquisition of data, revising the manuscript critically for important intellectual content, gave final approval of the version to be published and gave the Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DK has been involved in acquisition of data, revising the manuscript critically for important intellectual content, gave final approval of the version to be published and gave the Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DT has been involved in acquisition of data, revising the manuscript critically for important intellectual content, gave final approval of the version to be published and gave the Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MW has been involved in acquisition of data, revising the manuscript critically for important intellectual content, gave final approval of the version to be published and gave the Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. OS has made substantial contributions to conception and design, analysis and interpretation of data, revising the manuscript critically for important intellectual content, gave final approval of the version to be published and gave the Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. SWR has made substantial contributions to conception and design, interpretation of data, drafting the manuscript and revising it critically for important intellectual content, gave final approval of the version to be published and gave the Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. KCT has made substantial contributions to conception and design, interpretation of data, drafting the manuscript and revising it critically for important intellectual content, gave final approval of the version to be published and gave the Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. GJ has made substantial contributions to conception and design, acquisition and interpretation of data, drafting the manuscript and revising it critically for important intellectual content, gave final approval of the version to be published and gave the Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
PMC10184619
Funding
No funding was obtained for this study.Open Access funding enabled and organized by Projekt DEAL.
PMC10184619
Data Availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
PMC10184619
Declarations
PMC10184619
Ethics approval and consent to participate
Ethical approval for this study (Ethical Committee No 2021-414-f-S) was granted on July, 2th 2021 by the Ethical Committee of the University Hospital of Muenster, Muenster, Germany (Chairperson Prof W.E. Berdel). All methods were carried out in accordance with relevant guidelines and regulations in Ethics declaration section. Informed consent was obtained from all participants.
PMC10184619
Consent for publication
Not applicable.
PMC10184619
Competing interests
The authors declare that they have no competing interests.
PMC10184619
Abbreviations
StatesVentricular Fibrillation, Respiratory Syndrome
Basic Life-SupportCardiopulmonary ResuscitationCorona-Virus-Disease 2019Endotracheal IntubationEuropean Resuscitation Council 2021Extraglottic Airway DevicesFiltering Face Piece 3Laryngeal Mask AirwayOut-of-Hospital Cardiac ArrestPersonal Protective EquipmentSevere Acute Respiratory Syndrome Corona-Virus 1United StatesVentricular Fibrillation
PMC10184619
References
PMC10184619
Background
prostate cancer, Prostate
DISEASE, PROSTATE CANCER, PROSTATE
Isolated local failure (ILF) can occur in patients who initially receive definitive radiation therapy for prostate cancer. Salvage therapy for ILF includes high dose rate (HDR) brachytherapy. Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) can accurately detect ILF and can exclude extraprostatic disease. Lutetium-177 PSMA Radioligand Therapy (RLT) is a novel treatment for prostate cancer that can target prostate cancer accurately, while sparing radiation dose to normal tissues.
PMC10116658
Methods
toxicity, prostate cancer
DNA DAMAGE, PROSTATE CANCER, PROSTATE
ROADSTER is a phase I/II randomized, single-institution study. Patients with an ILF of prostate cancer after definitive initial radiation therapy are eligible. The ILF will be confirmed with biopsy, magnetic resonance imaging (MRI) and PSMA PET. Patients will be randomized between HDR brachytherapy in two fractions (a standard of care salvage treatment at our institution) (cohort 1) or one treatment of intravenous Lutetium-177 PSMA RLT, followed by one fraction of HDR brachytherapy (cohort 2). The primary endpoints for the phase I portion of the study (n = 12) will be feasibility, defined as 10 or more patients completing the study protocol within 24 months of study activation; and safety, defined as zero or one patients in cohort 2 experiencing grade 3 or higher toxicity in the first 6 months post-treatment. If feasibility and safety are achieved, the study will expand to a phase II study (n = 30 total) where preliminary efficacy data will be evaluated. Secondary endpoints include changes in prostate specific antigen levels, acute toxicity, changes in quality of life, and changes in translational biomarkers. Translational endpoints will include interrogation of blood, urine, and tissue for markers of DNA damage and immune activation with each treatment.
PMC10116658
Discussion
ROADSTER explores a novel salvage therapy for ILF after primary radiotherapy with combined Lutetium-177 PSMA RLT and HDR brachytherapy. The randomized phase I/II design will provide a contemporaneous patient population treated with HDR alone to facilitate assessment of feasibility, tolerability, and biologic effects of this novel therapy.
PMC10116658
Trial registration
NCT05230251 (ClinicalTrials.gov).
PMC10116658
Keywords
PMC10116658
Background
toxicity, prostate, Prostate cancer, prostate cancer deaths, prostate cancer
DISEASE, PROSTATE CANCER RECURRENT, DNA DAMAGE, PROSTATE, PROSTATE CANCER, PROSTATE CANCER
Prostate cancer is a major male health issue, with over 1.4 million new cases of prostate cancer diagnosed and 375,000 new prostate cancer deaths in 2020 worldwide [There are several potentially curative treatment options for patients with ILF, including salvage radical prostatectomy (RP), as well as prostate directed ablative therapies such as cryotherapy, high intensity focused ultrasound (HIFU), and salvage radiotherapy options such as stereotactic body radiation therapy (SBRT), low dose rate (LDR) brachytherapy or high dose rate (HDR) brachytherapy. In a recent meta-analysis comparing these options, the chances of recurrence-free survival (RFS) were similar, with approximately half of patients with durable disease control with the different salvage techniques [Prostate-specific membrane antigen positron emission tomography (PSMA PET) has been used more recently as a tool to detect prostate cancer recurrence after radiation treatments. In this setting, PSMA PET has been shown to change the management plan in a majority of patients when compared to the management plan based on conventional imaging alone [Lu-177 PSMA RLT emits beta particles with a maximum energy of 497 keV, which limits the range of these particles in tissue to less than 2 mm [We hypothesized that a theragnostic combination targeting PSMA may improve outcomes and reduce toxicity in men with suspected ILF after definitive radiotherapy. Specifically, use of a diagnostic PSMA-targeting agent will improve our ability to select men with a high probability of ILF. The use of a PSMA-targeting RLT would then allow the selective treatment of the site of ILF as well as potential extra-prostatic disease not detectable even with the diagnostic PSMA PET imaging. In ROADSTER, we aim to assess safety and feasibility of adding Lu-177 PSMA RLT in combination with HDR brachytherapy for ILF after definitive radiotherapy. A randomized phase I/II design will be used to provide a contemporaneous cohort of men treated with our institutional standard salvage therapy of two fractions of HDR. Translational endpoints will include acquisition of liquid and tissue biospecimens for the assessment of response biomarkers and assessment of DNA damage and immune activation among the two cohorts.
PMC10116658
Methods
PMC10116658
Inclusion and exclusion criteria
prostate cancer, prostate
PROSTATE CANCER, PROSTATE, PROSTATIC DISEASE
Patients with suspected ILF after radiation will be recruited. Patients must have a BCF per Phoenix criteria at least two years after initial prostate cancer treatment, an intra-prostatic lesion with PSMA PET avidity (Standard Uptake Value (SUV) of 3.0 or greater on a diagnostic PSMA PET/CT), and no evidence of extra prostatic disease.All patients are required to have a prostate biopsy to confirm ILF at the time of enrolment and have no contraindications for HDR brachytherapy, general anaesthesia, PSMA PET/MRI or Lu-177 PSMA RLT. Contraindications for these procedures include having inadequate marrow function (absolute neutrophil count less than 1.5 × 10
PMC10116658
Baseline assessment
toxicity, D.L., Prostate Cancer, prostate cancer
PROSTATE CANCER, PROSTATE CANCER
Patients will be required to complete baseline assessments of toxicity by CTCAE v4.0, quality of life (QoL) related to prostate cancer by the Expanded Prostate Cancer Index Composite (EPIC), and baseline bloodwork to assess marrow, renal and hepatic function. Baseline bloodwork and urine samples will be collected as liquid biomarkers for future biomarker analysis. A hybrid PSMA PET/MRI will be done prior to randomization. As part of the PET/MRI, delayed PET images of the pelvis will be acquired at least 60 min after the PSMA ligand injection. MR images of the pelvis will be acquired, including T2 weighted, diffusion weighted, and dynamic contrast enhanced sequences. Imaging will be read by a certified Nuclear Medicine specialist (D.L.) experienced in PSMA PET/MRI and PET/CT interpretation using established interpretation schemes [
PMC10116658
Treatment
tumor, CTVp
PRIMARY TUMOR, TUMOR, PROSTATE, DISEASE
The trial schema is given in Fig.  ROADSTER trial schemaBrachytherapy will be performed using transrectal ultrasound (TRUS) guidance, under general anesthesia in a dedicated brachytherapy suite, with intraoperative planning. Pre-procedure PSMA PET/MR images will be fused with intra-operative TRUS images using an in-house developed surface-based deformable algorithm to accurately delineate the areas of ILF. For each HDR brachytherapy treatment, 10.5 Gy will be prescribed to the entire prostate, with a focal boost to 13.5 Gy to the clinical target volume of the primary tumor (CTVp), as defined by the gross tumor volume (GTV) on all available images with a 5 mm expansion to account for microscopic disease. Details on brachytherapy planning objectives are found in Table  Dose objectives for a single HDR brachytherapy treatment Lu-177 PSMA RLT will be delivered in the Department of Nuclear Medicine as per local practice. One dose of 6.8 GBq of Lu-177 PSMA RLT will be administered intravenously, which will deliver an estimated tumor dose of 13.6–40.8 Gy, given the estimated dose of 2–6 Gy per GBq that has been reported in the literature [Figure  Representative images of the first ROADSTER patient enrolled on cohort 2Figures  Post Lu-177 PSMA RLT SPECT/CT imagesFigures 
PMC10116658
Primary and secondary endpoints
toxicity
SECONDARY
ROADSTER is a phase I/II, randomized controlled trial with safety and feasibility as primary outcomes. The planned accrual for the phase I portion of the study will be 12 patients: six patients in cohort 1 and six patients in cohort 2. Safety of each cohort will be declared if no more than one patient in each cohort experiences a grade 3 or higher CTCAE V4.0 toxicity at 6 weeks or 6 months post-treatment. Feasibility will be declared if 10 or more of the planned 12 patients are successfully accrued and complete the study as per protocol within 24 months of activation. If the initial accrual of 12 men across both cohorts demonstrates both safety and feasibility, the study will expand to the phase II portion, in which 30 men in total will be enrolled and randomized between these two cohorts. Sample sizes were chosen to support measuring the safety and feasibility of this study in the phase 1 and 2 portions. No formal statistical sample size calculation was performed.Secondary endpoints will include biochemical response, defined as a decrease of PSA by 50% from the baseline level; acute toxicity, defined by changes in CTCAE v4.0 scores; and changes in EPIC QoL scores. These secondary endpoints will be assessed at baseline, 6 weeks after treatment and 6 months after treatment.
PMC10116658
Translational exploratory endpoints
toxicity, tumor, prostate cancer, prostate
TUMOR, DNA DAMAGE, PROSTATE, BLOOD, PROSTATE CANCER
At the time of the second HDR treatment for cohort 1 and the HDR treatment for cohort 2, patients will receive a research prostate biopsy via a transperineal approach under ultrasound guidance. Targeted biopsies of PSMA PET/MR defined lesions will be obtained along with systematic biopsies of the whole gland. These tissue samples are obtained for further translational studies and will assess the effects of HDR brachytherapy in cohort 1 and Lu-177 PSMA RLT in cohort 2 on the prostate cancer ILF.Blood and urine samples will be collected prior to the first treatment, prior to the second treatment, at 6 weeks after the second treatment and at 6 months after the second treatment, in both cohorts 1 and 2. Patients will have serum PSA, marrow function, renal function and hepatic function bloodwork at 6 months after the second treatment in both cohorts. CTCAE v4.0 toxicity scores and EPIC QoL scores will be done at 6 weeks and 6 months after the second treatment as well.Regarding the translational biomarkers, the research biopsy specimens will undergo panel-based deoxyribonucleic acid (DNA) sequencing analysis of commonly altered DNA repair pathway and prostate cancer genes, tumor-associated T-cell receptor deep-sequencing (TCR-seq), as well as PSMA expression and gamma-H2A histone family member X (gamma-H2AX) expression, a marker of radiation-induced DNA damage, by immunohistochemistry. Blood plasma will also undergo circulating tumor DNA (ctDNA) sequencing as well as peripheral blood mononuclear cell (PBMC) analysis with TCR-seq and flow cytometry assessing markers of immune activation and radiation-induced DNA damage (e.g., gamma-H2AX). Finally, urine will be collected for urine tumor DNA (utDNA) sequencing.
PMC10116658
Discussion
tumor, CRPC, occult extra-prostatic disease, toxicity, occult metastatic disease, prostate, prostate HDR, prostate cancer
TUMOR, DISEASE, RECURRENT DISEASE, METASTATIC DISEASE, PROSTATE, SECONDARY, PROSTATE CANCER, CANCER RELAPSE
As a primary outcome, the ROASDTER trial investigates the feasibility and safety of a novel salvage strategy that combines Lu-177 PSMA RLT with HDR brachytherapy in patients with proven radiorecurrent ILF with no signs of metastatic disease. By adding Lu-177 PSMA RLT as a systemic therapy early in the course of cancer relapse, occult metastatic disease may be treated early, potentially reducing rates of systemic progression, which is the most frequent pattern of relapse in this setting [Given the physical and biological characteristics of Lu-177 PSMA RLT, we hypothesize this may have an improved toxicity profile compared with other salvage therapy options. Specifically, in a comprehensive meta-analysis of salvage therapy options, there were lower severe genitourinary (GU) toxicity rates amongst the radiation salvage options compared with the non-radiation options. The severe GU toxicity rates for SBRT, LDR brachytherapy, and HDR brachytherapy were 5.6%, 9.1%, and 9.6%, respectively, while the severe GU toxicity rates for cryotherapy, RP and HIFU were 15%, 21%, and 23%, respectively [As a secondary outcome, this trial investigates disease control associated with a standard salvage treatment option, involving two fractions of prostate HDR brachytherapy, in the PSMA-PET era. Most of the salvage data in the literature precedes PSMA PET use and the ROADSTER trial may provide a new benchmark by using PSMA PET as a screening tool to select patients with lower likelihood of having any occult extra-prostatic disease at the time of diagnosing the ILF. This “stage migration” effect may allow for patients who are included in the trial to have a more favourable recurrence-free survival, with adequate treatment of their ILF site. Moreover, PSMA PET and MR data together may allow for more accurate definition of the recurrent disease in the prostate at the time of HDR prostate brachytherapy boost with a focused boost to the lesion and better OAR sparing [Additional outcomes in ROADSTER trial include translational studies, assessing the effects of Lu-177 PSMA RLT and HDR brachytherapy on the radiorecurrent prostate cancer. Tissue, blood, and urine biospecimens will be collected at during the study. These biospecimens will be interrogated to characterize effects on tumor and normal tissue radiation injury and immune activation and to assess for potential biomarkers of response or toxicity after Lu-177 PSMA RLT and HDR brachytherapy.While out of scope for the current trial protocol, which is focused on safety and feasibility endpoints, our practice for men receiving salvage brachytherapy includes long term biochemical and clinical monitoring. Future plans will include examination of long-term disease control and side effects in this population.While there are several Lu-177 PSMA RLT trials ongoing for patients with CRPC, there are only a few studies that are incorporating Lu-177 PSMA RLT in metastatic castrate sensitive prostate cancer (CSPC): (NCT04720157; NCT04443062; NCT05079698; NCT04343885; and NCT03828838) [In summary, the ROADSTER trial is a randomized phase I/II trial investigating safety, feasibility and early efficacy of a novel salvage treatment strategy involving Lu-177 PSMA RLT in conjunction with whole prostate HDR brachytherapy with a focused boost. The randomized phase I/II design will provide a contemporaneous patient population treated with HDR alone to facilitate assessment of feasibility, tolerability, and biologic effects of this novel therapy. Access to MR and PSMA PET imaging will allow for localization of the recurrent disease within the prostate, guidance of focal boost delivery at the time of HDR brachytherapy and the precision acquisition of tissue biospecimens from involved and uninvolved prostate for translational science correlative studies.
PMC10116658
Acknowledgements
The authors acknowledge the patients who enrolled in this trial and supported this research.
PMC10116658
Authors’ contributions
LCM
AD – Wrote initial draft of manuscript and approved finalized manuscript. GB – Trial concept development and protocol writing. Edited initial draft of manuscript and approved finalized manuscript. LCM – Trial concept development and protocol writing. Edited initial draft of manuscript and approved finalized manuscript. DL – Trial concept development and protocol writing. MM – Trial concept development and protocol writing. JAG – Trial concept development and protocol writing. Edited initial draft of manuscript and approved finalized manuscript. JC – Trial concept development and protocol writing. Edited initial draft of manuscript and approved finalized manuscript. T-Y L – Trial concept development and protocol writing. JT – PET/MRI protocol design. Edited initial draft of manuscript and approved finalized manuscript. DH – Implementation of the HDR brachytherapy protocol. Edited initial draft of manuscript and approved finalized manuscript. KS – Trial concept development and protocol writing. JH – Trial concept development and protocol writing. VV - Trial concept development and protocol writing. RC – Trial concept development and protocol writing. D D’S – Trial concept development and protocol writing. JB – Trial concept development and protocol writing.
PMC10116658
Funding
This trial was funded with support from the London Health Sciences Foundation. The London Health Sciences Foundation did not contribute to the study design; the collection, management, analysis and interpretation of data; writing of the report; or the decision to submit the report for publication.
PMC10116658
Data Availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
PMC10116658
Declarations
PMC10116658
Competing interests
CCSRI, CRS, MM
LCM
AD – none. GB – Industry Advisory Boards and Speaking – Tolmar, Trelstar, and Advanced Accelerator Applications; Industry Research – Siemens, and Invicro; Leadership – OICR Clinical Lead Clinical Translation Program, and OH-CCO PET Steering Committee; Research Funding – OICR, CIHR, and CCSRI. LCM – none. DL – none. MM – none. JAG – none. JC – none. T-Y L – none. JT – Industry Research – Siemens, Cubresa, and Invicro; Research Funding – NSERC, CFI, DoD, CRS, OICR, CIHR. DH – none. KS – none. JH – none. VV – none. RJC – none. DD?S – none. JB – none.
PMC10116658
Ethics approval and consent to participate
This study has been approved by the Western University Health Sciences Research Ethics Board (Project ID: 120132) and will be conducted in accordance with the principles of the Declaration of Helsinki. Western University, located in London, Ontario, Canada, is the University partner of the London Health Sciences Centre, the academic hospital system of London, Ontario and the surrounding region. Patients will give their informed consent voluntarily to participate in this trial.
PMC10116658
Consent to publish
Patients will give their consent voluntarily to have the results published.
PMC10116658
References
PMC10116658
Subject terms
VF, glaucoma, Retinal nerve fiber layer
GLAUCOMA SUSPECT, GLAUCOMA
This study compared between TEMPO, a new binocular perimeter, with the Humphrey Field Analyzer (HFA). Patients were tested with both TEMPO 24–2 Ambient Interactive Zippy Estimated by Sequential Testing (AIZE)-Rapid and HFA 24–2 Swedish Interactive Threshold Algorithm (SITA)-Fast in a randomized sequence on the same day. Using a mixed-effects model, visual field (VF) parameters and reliability indices were compared. Retinal nerve fiber layer (RNFL) thickness was measured using Cirrus optical coherence tomography (OCT), and coefficient of determinations for VF and OCT parameters were calculated and compared using Akaike information criteria. 740 eyes (including 68 healthy, 262 glaucoma suspects, and 410 glaucoma) of 370 participants were evaluated. No significant differences were seen in mean deviation and visual field index between the two perimeters (P > 0.05). A stronger association between VF mean sensitivity (dB or 1/L) and circumpapillary RNFL was found for TEMPO (adjusted R
PMC10692178
Introduction
fatigue, optic neuropathy, Glaucoma
OPTIC NEUROPATHY, GLAUCOMA
Glaucoma is an optic neuropathy characterized by the gradual loss of retinal ganglion cells and their axons, which can lead to vision lossWe hypothesized that this new technology could reduce testing duration and patient fatigue, minimize variability in test results, and improve the correlation between structural and functional data. The purpose of this study was to compare the TEMPO with the Humphrey field analyzer (HFA), the most widely used automated perimeter.
PMC10692178
Discussion
VF, strabismus, nystagmus, glaucoma, TEMPO
DISEASE, STRABISMUS, NYSTAGMUS, DYSFUNCTION, GLAUCOMA, ANISOMETROPIA
In this study, we prospectively performed VF testing with both TEMPO AIZE-Rapid and HFA Swedish Interactive Threshold Algorithm (SITA)-Fast in a randomized order and identified a stronger structure–function relationship and better reliability indices with TEMPO compared to HFA. TEMPO reduced measurement time by approximately 40% without compromising perimetric performance. Even though the participants were inexperienced with TEMPO prior to the study, it was strongly preferred by patients.Effective glaucoma management necessitates functional and structural exams, and correlating these changes ensures reliable tracking of disease progressionThe average differences in MD, PSD, and VFI between TEMPO and HFA were all within 1 dB. While the mean difference between the measurements was minimal, we observed a trend where the difference increased with the severity of glaucoma (see Supplemental Fig. HFA SITA-Fast and TEMPO AIZE-Rapid have several items in common regarding reliability indices, but there are some differences. First, false positives are calculated by both devices using reaction time. HFA SITA-Fast uses the percentage of stimuli responded to within a minimum reaction time with an adjustment for the average reaction time of the individual patientThis study has several limitations. First, it was based on participants from a tertiary care academic practice, which could introduce certain biases in socio-economic status, demographics, and severity of disease, which could differ from those of patients treated in other settings. This could potentially restrict the generalizability of our findings. Second, the current software is derived from a database that only consists of data from the Japanese population. Regardless of this limitation, HFA and TEMPO exhibited excellent agreement. Third, certain situations, such as conditions of binocular vision dysfunction like strabismus, anisometropia, nystagmus among others, can render binocular open-eye examinations unfeasibleIn conclusion, TEMPO showed a stronger structure–function relationship with Cirrus OCT. Further studies are necessary to evaluate the potential of this binocular VF test for longitudinal monitoring.
PMC10692178
Methods
PMC10692178
Participants
Glaucomatous optic neuropathy, glaucomatous VF damage, glaucomatous optic neuropathy, glaucomatous defect, atrophy, glaucoma, Glaucoma
GLAUCOMATOUS OPTIC NEUROPATHY, INTRAOCULAR PRESSURE, PRIMARY ANGLE CLOSURE GLAUCOMA, GLAUCOMA SUSPECT, PRIMARY OPEN-ANGLE GLAUCOMA, ATROPHY, SECONDARY GLAUCOMA, GLAUCOMA, AGE-RELATED MACULAR DEGENERATION, EYE, GLAUCOMA, GLAUCOMA SUSPECT
Participants were recruited from patients at the Shiley Eye Institute, University of California, San Diego. The research protocol followed the tenets of the Declaration of Helsinki and was approved by the University of California, San Diego Institutional Review Board. All study participants provided written informed consent.The participants' eyes were divided into three diagnostic groups: healthy, glaucoma suspect, and glaucoma. Healthy eyes were characterized by intraocular pressure (IOP) ≤ 21 mmHg, normal-appearing optic discs and neuroretinal rims, and normal VF test results defined as PSD within the 95% CI and Glaucoma Hemifield Test (GHT) results within normal limits using SITA 24–2 FAST. Glaucoma suspects were defined as eyes with IOP of ≥ 22 mmHg or glaucomatous-appearing optic discs (glaucomatous optic neuropathy) without repeatable glaucomatous VF damage. Glaucomatous optic neuropathy was defined as excavation, the presence of focal thinning, notching of the neuroretinal rim, or localized or diffuse atrophy of the RNFL by attending physicians based on ophthalmoscopic examination or fundus photographs. Glaucoma was defined as eyes showing at least two reliable (fixation losses and false negatives ≤ 33% and ≤ 15% false positives) and repeatable abnormal (GHT outside normal limits or PSD outside 95% normal limits) VF results using the 24–2 SITA-FAST with similar glaucomatous defect patterns on consecutive testing as evaluated by study investigators. Glaucoma included all types, such as primary open-angle glaucoma, primary angle closure glaucoma, and secondary glaucoma. Eyes were excluded if they had any other ocular or systemic conditions, apart from glaucoma, that could affect VF test results, such as age-related macular degeneration.
PMC10692178
Visual field testing
TEMPO (CREWT Medical Systems, Tokyo, Japan) is the commercial name of the product. It is distinct from the portable head-mounted perimeter device known as imoFor the current study, all patients underwent HFA 24–2 SITA-Fast and TEMPO 24–2 AIZE-Rapid on the same day in a randomized order using Goldmann size III (0.431° visual angle) stimuli. Since the purpose of this study was to compare HFA and TEMPO, no exclusions were made at specific cutoff values for reliability indices (fixation losses, false negatives and false positives) for both devices. The binocular random testing mode was selected for testing with TEMPO. In addition, to evaluate usability for patients, there was a questionnaire, as follows: (1) Which device do you prefer?, (2) Did you have any difficulty with the simultaneous examination of both eyes using the novel device?, (3) Was the screen easy to see?, (4) Was it easy to concentrate?, (5) Was the test time short?. These questions were assessed using a 5-point Likert scale.
PMC10692178
Structure–function relationship
VF, RA, retinal nerve fiber
RNFL was measured using Cirrus spectrum-domain OCT (Carl Zeiss Meditec, Inc, Dublin, CA) Optic Disc Cube 200 × 200 protocol scans. A 3.46 mm diameter circle was automatically placed around the optic disc, providing RNFL thickness globally and in superior, inferior, temporal, and nasal sectors. Coefficient of determination for VF and OCT parameters was calculated and compared using AIC. Age adjusted RA topographic map relating visual field test stimulus locations (left) to OCT-measured retinal nerve fiber layer thickness (right) is shown for a right eye.
PMC10692178
Statistical analysis
VF
Patient and eye characteristics were reported as mean (95% CI) for continuous data and count (percentage) for categorical data. MD, PSD, foveal threshold (FT), and VFI were compared using mixed-effects model between the two perimeters. Reliability indices were illustrated in a kernel density estimate plot to compare the values from two perimeters. Kernel density estimate is a non-parametric way to estimate the probability density function of a random variable. In other words, it provides a smoothed version of a histogram, giving a continuous curve. The Bland-Altmann plot assessed the LoA between the two perimeters. Measurement time for performing VF for both eyes was recorded for each device. It only accounted for the actual examination time and excluded the setup time needed for testing the second eye with HFA. All statistical analyses were performed with Stata software (version 15; StataCorp, College Station, Texas). Statistical significance for tests was set at P ≤ 0.05.
PMC10692178
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-023-48105-5.
PMC10692178
Acknowledgements
DISEASE, EYE
T.N.: C: Topcon (consultant). R.N.W.: Abbvie, Alcon, Allergan, Amydis, Editas, Eyenovia, Iantrek, IOPtic, Implandata, iSTAR Medical, Nicox, Santen, Tenpoint, and Topcon (consultant); National Eye Institute, National Institute for Minority Health and Health Disparities, Centervue (research support); Toromedes, Carl Zeiss Meditec (patent). J.A.: None. C.V.: None. S.M.: National Eye Institute, University of California Tobacco-Related Disease Research Program and an unrestricted grant from Topcon Medical (research support). The sponsor or funding organization had no role in the design or conduct of this research. Research instrument from Topcon Medical.
PMC10692178
Author contributions
Designed and conducted the study: T.N., R.N.W. and S.M. Data collection: T.N. and J.A., Data analysis: T.N. Interpretation: T.N., R.N.W. and S.M. Writing: T.N. and R.N.W. Critical revision: All authors. Manuscript approval: All authors.
PMC10692178
Funding
EYE
Supported by R01EY029058 and R01EY034148 (RNW) from National Institutes of Health/National Eye Institute Grants.
PMC10692178
Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
PMC10692178
Competing interests
The authors declare no competing interests.
PMC10692178
References
PMC10692178
Purpose
MPE
Communicated by Fabio fischetti.To compare fixed transverse textile electrodes (TTE) knitted into a sock versus motor point placed standard gel electrodes (MPE) on peak venous velocity (PVV) and discomfort, during calf neuromuscular electrical stimulation (calf-NMES).
PMC10460736
Methods
NRS, MPE
Ten healthy participants received calf-NMES with increasing intensity until plantar flexion (measurement level I = ML I), and an additional mean 4 mA intensity (ML II), utilizing TTE and MPE. PVV was measured with Doppler ultrasound in the popliteal and femoral veins at baseline, ML I and II. Discomfort was assessed with a numerical rating scale (NRS, 0–10). Significance was set to
PMC10460736
Results
MPE
TTE and MPE both induced significant increases in PVV from baseline to ML I and significantly higher increases to ML II, in both the popliteal and femoral veins (all
PMC10460736
Conclusion
MPE
TTE integrated in a sock produces intensity-dependent increases of popliteal and femoral hemodynamics comparable to MPE, but results in more discomfort at plantar flexion due to higher current required. TTE exhibits in the popliteal vein higher increases of PVV compared to MPE.
PMC10460736
Trial registration
Trial_ID: ISRCTN49260430. Date: 11/01/2022. Retrospectively registered.
PMC10460736
Keywords
Open access funding provided by Karolinska Institute.
PMC10460736
Introduction
fits, MPE, venous stasis, VTE, Venous stasis, venous thromboembolism
SECONDARY, VENOUS STASIS, DEEP VEIN THROMBOSIS (DVT), VENOUS STASIS
Venous stasis is one of the major causes of venous thromboembolism (VTE), which often starts as a deep vein thrombosis (DVT). VTE-prevention targeting venous stasis of the calf include passive compression socks and active mechanical interventions, such as intermittent pneumatic compression and neuromuscular electrical stimulation (NMES), of which the latter today have limited effect due to poor patient compliance (Hajibandeh et al. Previous studies have demonstrated that textile electrodes are well suited for NMES (Gniotek et al. To address the above issues, we designed a novel NMES sock with textile electrodes and tested its efficacy. We believe that such novel NMES sock in the future may have the potential to produce intensity-dependent increases in peak venous velocity (PVV) of both the popliteal and femoral veins, which have been associated with an efficient VTE-prevention (Hajibandeh et al. When using standard gel electrodes, a In this efficacy study, we hypothesized that TTE would result in no difference in effect on hemodynamics and comfort compared to MPE. Thus, the primary aim of this study was to examine whether calf-NMES, using one new TTE-setup with textile electrodes in one-size fits all sock and one established MPE-setup, could both induce significant intensity-dependent increases of PVV in the popliteal and femoral veins related to the current intensity applied. The secondary aim of this study was to explore whether TTE could produce no difference in effect on hemodynamics and comfort compared to the established MPE.
PMC10460736
Materials and methods
PMC10460736
Electrode-setups
MP, MPE
In this study, two different electrode setups for applying NMES to the calf were tested and compared regarding various outcomes. The electrode setups differed regarding electrode- type, and placement and were compared to investigate if textile electrodes knitted in fixed transverse positions in a sock, would yield a non-inferior increase of PVV from baseline compared to standard gel electrodes placed at individual MP.The first electrode setup designated TTE, short for Displaying the transverse textile electrodes. Sock with knitted transverse textile electrodes, the face side (The layers of the transverse textile electrodes. The second electrode setup utilized commercially available standard gel electrodes (Compex Snap, Performance, DJO Global, USA, 5 × 5 cm) manually trimmed to squares sized 3 × 3 cm, to match the size of the TTE. Each standard gel electrode had a snap-on button to which each wire from the NMES-device was attached. The standard electrodes were placed on the skin areas of the calf, one on the medial side and one the lateral side, that required the least NMES current intensity to trigger a calf muscle response, i.e., the “best” MP, as determined by a standard motor point scan. This electrode setup was designated MPE, short for
PMC10460736
Motor point scan
MP
The best MPs were found by scanning one half of the calf at a time (medial/lateral), using the NMES device’s 3 Hz sinusoidal wave motor scan program (Chattanooga Physio constant current generator, DJO Nordic, Malmoe, Sweden). Prior to the MP scan, the side of the calf about to be scanned was covered by a thin layer of conductive gel. A reference electrode (Compex Snap, Performance, DJO Global, USA, 5 × 5 cm) was placed on the contralateral side from the MP scan over the largest circumference of the calf, on a distance from the calf’s midline corresponding to 15% of the calf’s largest circumference. The definition of a MP was the same as in our previous study (Schriwer et al.
PMC10460736
NMES-Settings
MP
For both electrode setups, NMES was applied using the same NMES device as for the MP scan. The NMES stimulation used a biphasic symmetric square wave, meaning that the electrodes continuously were switching polarity so that they alternately, and for equally long durations, served as either anode or cathode. Thus, there was no designated anode or cathode in the electrode setups for this study. Based on previous studies on NMES discomfort, stimulation settings where set to 36 Hz frequency, 200 µs phase duration (400 µs pulse duration), 0.5 s ramp up time and 0.25 s ramp down time (Baker et al.
PMC10460736
NMES Measurement Level I & II
The NMES-device display the current used for the selected stimulation in NMES-levels ranging from 0 to 999, which in a non-linear pulse duration dependent fashion correlate to current amplitudes ranging from 0 to 120 mA. The formula to calculate this correlation may be obtained from the manufacturer (DJO Nordic, Malmoe, Sweden) upon reasonable request, but may not be publicly distributed.When testing the two electrode setups, outcomes were registered at two distinct current intensities, designated Since ML I and ML II could occur at different NMES-levels for different participants, correlating non-linearly to different mA amplitudes for different participants, we deemed the presentation of the testing procedure in mA amplitudes to be too unpractical to be easily reproducible in a clinical setting, since it would require the user to obtain the conversion formula and convert the mA amplitudes back into NMES-levels. Thus, only the NMES-levels are used to describe the different current intensities during the testing procedure, while the current intensities in the results are presented in mA for better relative comparisons in the statistical analysis. The range of increase in current between ML I and ML II is disclosed in the results section.
PMC10460736
Hemodynamic measurements
CONTRACTION
Using a Philips CX50 (2013) Doppler ultrasound machine (Philips Medical Systems, Andover, MA, USA), the widest accessible part of the popliteal and femoral veins was located and visualized in a longitudinal plane before beginning the hemodynamic measurements. The diameters of the veins were calculated at baseline. The diameter of the popliteal vein was 0.90 ± 0.29 cm and of the femoral vein 1.05 ± 0.26 cm. For the two electrode setups (TTE & MPE), PVV was measured in the popliteal and femoral veins at baseline (i.e., electrodes attached but no NMES administered), at ML I, and at ML II. For each subject in the study, all hemodynamic measurements were performed by the same ultrasonographist. During three consecutive NMES-stimulation cycles venous measurements were recorded, and subsequently the peak venous velocity (PVV) was assessed. The measuring tool on the ultrasound machine provided, when using doppler, the ability to save the recordings of blood flow in cm/s and measure the peak venous velocity after the stimulation was complete. The diameter of the vein during the stimulation was not calculated. PVV measurements during three NMES-stimulation cycles were performed and the mean of the three was used for statistical analysis. After analyzing the refill time of the veins, an eight second OFF-time was decided to be used between ON-times for the veins to be adequately refilled with blood before the next upcoming muscle contraction and PVV measurement. To quantify the potential benefit of NMES versus the baseline resting state, for each subject and setting, the percentual increase in PVV at ML I and ML II
PMC10460736
Discomfort
NRS
For each stepwise increase in NMES-levels when testing the two electrode setups, participants were asked to fill in a form to rate their discomfort on a numerical rating scale (NRS) 0–10, where 0 was described to the subject as no discomfort and 10 as the worst imaginable discomfort (Hawker et al.
PMC10460736
Statistical analysis
NRS
The sample size was determined prior to the start of the experiment based on a pilot study with a difference in PPV between ML I to ML II of 20 cm/s and sigma of 20, with the significance level set at The data were analyzed using SPSS version 27 (IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp.) in cooperation with a statistician. The four tested plateau times, 0.5, 1.5, 3 and 5. seconds, did not demonstrate any statistically significant difference regarding PVV or NRS, regardless of the electrode setup or measurement level. For this reason, the outcome values for PVV and NRS used in the final statistical analysis were based on all values, for all participants, obtained during the four different plateau times. Based on the relatively small number of participants and the Shapiro–Wilk indicating non normal distribution, the non-parametric Wilcoxon signed rank test was chosen to determine if there were any statistically significant differences between medians regarding current intensity (mA), PVV or NRS, for the two electrode setups. The data included some outliers, which were handled both using a rank-based statistics test and by adjusting the values of the outliers to the lowest/highest value within 1.5 times the interquartile range from the first respectively third quartile for the inferential statistics (Altman
PMC10460736
Results
PMC10460736
Current intensities in mA for calf-NMES
MPE
The median (IQR) current intensity required to reach ML I, was significantly lower when using MPE, 16 (7.4) mA, as compared to TTE, 26 (14) mA (Current intensity (mA) required to reach ML I displayed for the TTE and MPE setups. In the boxplot, the length of the box represents IQR, and error bars represent min–max. The black line within boxes represents median. **Indicates a difference with
PMC10460736
Hemodynamics of calf-NMES
PMC10460736
Hemodynamics in the popliteal vein
MPE
The median (IQR) baseline PVV in the popliteal vein was 14.3 (5.4) cm/s. There were significant increases of PVV from baseline to ML I when using both TTE, 29.1 (47.3) cm/s (Hemodynamics in the popliteal vein. Percentual increase of PVV from baseline to ML I and ML II displayed for the TTE and MPE setups. In the boxplot, the length of the box represents IQR, and error bars represent min–max. The black line within boxes represents median. *Indicates a difference with Increasing the current intensity to ML II resulted in significantly higher increases of PVV from baseline as compared to ML I, for both the TTE- and the MPE setups (both
PMC10460736
Hemodynamics in the femoral vein
MPE
The median (IQR) baseline PVV in the femoral vein was 14.2 (3.9) cm/s. PVV exhibited statistically significant increases from baseline to ML I when using both TTE, 21.6 (8.8) cm/s (Hemodynamics in the femoral vein. Percentual increase of PVV from baseline to ML I and ML II for the TTE and MPE setups. In the boxplot, the length of the box represents IQR, and error bars represent min–max and in case of outliers 1.5xIQR. Circles represents outliers. The black line within boxes represents median. **Indicates a difference with The increase in current intensity to ML II caused significantly higher increases of PVV from baseline as compared to ML I, when using both TTE and MPE (both
PMC10460736
Discomfort of calf NMES
NRS, MPE
Using MPE resulted in a statistically significantly lower median NRS (range), 1 (0–3), compared to the use of TTE, NRS 2 (0–7), at ML I (Discomfort of calf NMES. NRS score for the TTE and MPE setups at ML I and ML II. In the boxplot, the length of the box represents IQR, and error bars represent min–max and in case of outliers 1.5 × IQR. Circles represents outliers. The black line within boxes represents median. **Indicates a difference with
PMC10460736
Associations of participant characteristics with outcome
MPE
Female participants, as compared to male participants, required significantly higher current intensity (mA) to produce a plantar flexion, both with TTE and MPE (
PMC10460736
Discussion
Uhl, pelvic fractures, MPE, venous stasis, DVT, VTE, MP
BLOOD CLOTS, EVANS, VENOUS STASIS, DVT
The main finding of this study was that the PVV in both the popliteal and the femoral veins exhibited a dose–response relationship to the current intensity administered to the calf, for both the TTE and the MPE setups. The TTE setup required higher current intensity than the MPE setup to induce a plantar flexion (ML I) and to reach ML II, but also demonstrated superior increases of PVV in the popliteal vein at both ML I and ML II. However, PVV in the femoral vein was equally increased with both setups. Moreover, at ML I, the MPE setup caused less discomfort than the TTE setup. None of the participant characteristics caused more discomfort or significantly altered the increase of PVV.The finding that the PVV in both the popliteal and the femoral vein exhibited significant median increases of 50–100% from baseline to ML I conform with results from earlier studies on NMES (Williams et al. The finding of an intensity-dependent relationship between the current intensity of applied NMES (frequency: 36 Hz) and increased venous return is supported by the literature (Corley et al. The presumable explanation to the observed dependence between current intensity and increased PVV lies in the earlier knowledge that there is a relationship between the current intensity and muscle force production (Flodin et al. An intensity-dependent increase in venous blood flow velocity using calf-NMES is important for the prevention of DVT and VTE, since it may reduce one of their underlying causes, i.e., venous stasis in the lower limbs (Hajibandeh et al. The second most important finding of this study was the identification that the TTE setup, produced an equal or even better hemodynamic response in the popliteal vein compared to the MPE setup. The most plausible explanation to the enhanced hemodynamic response seen would be that the TTE setup required a higher current to reach ML I. This may theoretically have resulted in a broader stimulation over the muscle bulk, activating more muscle fibers as compared to the more focused stimulation resulting from the MPE setup. The TTE setup was configured with electrodes transversely, approximately at the thickest portions of both the lateral and medial gastrocnemius muscle heads, which may be a good electrode placement to cause a broader muscle fiber activation for better venous return (Uhl et al. However, since the determination of when a plantar flexion was performed did not differ between the two electrode setups, another explanation to the observed increased hemodynamic response with TTE may be that the higher current intensity also induced indirect, local effects on blood vessels via the nervous system (Maffiuletti et al. The observation in this study of a more pronounced response of the calf-NMES treatment in the popliteal vein as compared to the femoral vein could most reasonably be explained by two factors. The distance from the calf to the popliteal vein is shorter than to the femoral vein and the diameter of the popliteal vein is smaller as compared to the femoral vein. Thus, changes in peak venous velocity after calf-NMES treatment will be more easily detected in the popliteal as compared to the femoral vein. Another possible influencing factor may be the body position. However, in this study patients were analyzed in the semirecumbent position with the legs horizontal, mimicking a clinical situation in a hospital bed. Thus, the observed increases in venous velocity in the femoral vein may be of importance for patient with eg. Hip- and pelvic fractures, in which blood clots may develop in more proximal veins. However, this conclusion will necessitate further studies.Another aspect to consider when deciding the optimal placement of electrodes is the discomfort of the patients. The observation that the MPE setup exhibited less discomfort at ML I as compared to the TTE setup suggests a better compliance with treatment when electrodes are placed on MP, which is in line with earlier studies (Gobbo 2011). The finding that there was a difference in hemodynamic effect, but no difference in discomfort between the MPE and TTE setup at ML II, on the other hand, suggests that a compromise of several aspects must be taken into account to optimize patient outcome. For example, that compliance to treatment is also affected by the usability of the NMES electrodes. A standardized sock does not require the motor point scan and should therefore increase the usability. However, the issue with discomfort needs to be solved.The great differences in PVV observed, both at baseline and with calf-NMES, are suggestive of vast individual variations, which are supported by earlier studies (Evans et al. A possible limitation of the study is the relatively low number of participants, which hinders conclusions especially on associations between subject characteristics and outcome. Venous velocity, which was assessed with Doppler ultrasound, can be influenced by a number of factors such as venous pressure and vein diameter that were not assessed during stimulation. However, the vein diameter was assessed at baseline and since the stimulation time was so short it is less likely that it affected the blood pressure or the release of cortisol to change the vein diameter. Another limitation is the potentially differing impedances of the TTE and MPE setups, as well as of the skin of the different participants, which is likely to have influenced results. However, we believe that such measurements would have been unreliable considering that manipulation of the calf in the form of ultrasound measurements and NMES, among other factors (Euler et al.
PMC10460736
Conclusion
NMES of the calf increases PVV in an intensity-dependent and clinically relevant manner in both the popliteal and femoral veins using both a TTE
PMC10460736
Acknowledgements
Not applicable.
PMC10460736
Author contributions
PA, JF and RJ wrote the application for the approved ethical permit. RJ, PA, JF, LG, N-KP and CS performed material preparation and created the study protocol. CS and RJ collected and prepared the data for statistical analysis. CS performed the statistical analysis. CS, RJ, JF, and PA wrote the manuscript. All authors read and approved the final manuscript. CS and RJ contributed equally to this work.
PMC10460736
Funding
Open access funding provided by Karolinska Institute. This work was supported by the strategic innovation programs Swelife and Medtech4Health, which are jointly arranged and funded by Sweden´s Innovation Agency (Vinnova), Grant no: 2019-05479 Formas and Energimyndigheten.
PMC10460736