The protocol of a randomized trial is the foundation for study planning, conduct, reporting, and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. Herein, we systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomized trial. We completed a scoping review and developed a project specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (harms, outcomes, nonpharmacological treatment) and other reporting guidelines (Template for Intervention Description and Replication [TIDieR]). The potential modifications were rated in a 3-round Delphi survey followed by a consensus meeting. Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of 2 new protocol items, revision to 5 items, deletion/merger of 5 items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open-science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct, and reporting. The updated SPIRIT 2025 statement consists of an evidence based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrollment, interventions, and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policy makers, regulators, and other reviewers.
Radiofrequency ablation (RFA) offers localized and minimally invasive treatment of small-to-medium sized inoperable tumors. In RFA, tissue is ablated with high temperatures obtained from electrodes (needles) inserted percutaneously or via an open surgery into the target. RFA treatments are generally not planned in a systematic way, and do not account for nearby organs-at-risk (OARs), potentially leading to sub-optimal treatments and inconsistent treatment quality. We therefore develop a mathematical framework to design RFA treatment plans that provide complete ablation while minimizing healthy tissue damage. Borrowing techniques from radiosurgery inverse planning, we design a two-stage approach where we first identify needle positions and orientations, called needle orientation optimization, and then compute the treatment time for optimal thermal dose delivery, called thermal dose optimization. Several different damage models are used to determine both target and OAR damage. We present numerical results on three clinical case studies. Our findings indicate a need for high source voltage for short tip length (conducting portion of the needle) or fewer needles, and low source voltage for long tip length or more needles to achieve full coverage. Further, more needles yields a larger ablation volume and consequently more OAR damage. Finally, the choice of damage model impacts the source voltage, tip length, and needle quantity.
Abstract Background The COMET-ICE trial demonstrated that sotrovimab clinically and statistically significantly reduces the risk of all-cause > 24-h hospitalization or death due to any cause among patients with COVID-19 at high risk of disease progression. Patient-reported outcomes are important to capture symptom burden of COVID-19 and assess treatment effectiveness. This study investigated symptoms and their impact over the acute phase of COVID-19 infection among patients on sotrovimab versus placebo. Methods Randomized (1:1), double-blind, multicenter, placebo-controlled, phase 2/3 study in 57 centers across five countries. Participants were non-hospitalized patients with symptomatic, mild-to-moderate COVID-19 and ≥ 1 baseline risk factor for disease progression (aged ≥ 55 years or ≥ 1 of the following: diabetes requiring medication, obesity, chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, or moderate-to-severe asthma). An intravenous infusion of sotrovimab 500 mg or placebo was administered on Day 1. The FLU-PRO Plus questionnaire was administered once-daily with 24-h recall from Day 1–21, and at Day 29. Intensity and duration of COVID-19 symptoms were determined from area under the curve (AUC) and mean change in total and individual domain scores through Days 7, 14, and 21. Time to symptom alleviation was assessed. Results In total, 1057 patients were randomized to sotrovimab (n = 528) or placebo (n = 529). At Day 7, mean decrease in FLU-PRO Plus total score (measured by AUC) was statistically significantly greater for patients on sotrovimab (–3.05 [95% confidence interval (CI) –3.27 to –2.83]) than placebo (–1.98 [95% CI –2.20 to –1.76]; difference –1.07 [95% CI –1.38 to –0.76]; p < 0.001). Significant differences were also observed at Days 14 and 21. A more rapid decline in symptom severity was observed with sotrovimab versus placebo through Week 1 and the first 21 days post-treatment. By Day 21, 41% of patients on sotrovimab and 34% on placebo reported symptom resolution. In a post-hoc analysis, median time to symptom alleviation was 4 and 6 days, respectively. Conclusions Sotrovimab provides significant and rapid improvements in patient-reported COVID-19 symptoms, as measured by the FLU-PRO Plus. These results further show the benefits of sotrovimab in alleviating symptoms among high-risk patients with COVID-19. Trial registration ClinicalTrials.Gov: NCT04545060 ( https://clinicaltrials.gov/ct2/show/NCT04545060 ). Date of registration: September 10, 2020 (retrospectively registered).
Ultra-high field (UHF) imaging studies have provided critical observations that contribute to our understanding of the pathophysiology of mental illnesses. The neurochemical imaging needs in psychiatry that were unmet at lower fields are now being addressed. The primary added value brought by UHF imaging for psychiatric research is the ability to make robust observations with smaller samples; this has been highly valuable for "perturb-and-measure" studies involving electroconvulsive therapy and pharmacological challenges. In some cases, the reduced scanning time at UHF has enabled more comprehensive multimodal acquisitions. While we are still far from developing routine clinical UHF applications, this speaks to the lack of demand for diagnostic imaging in psychiatric practice, rather than challenges at UHF per se. UHF imaging has the potential to put normative approaches into practice for clinical neurochemistry in psychiatry. We need concerted efforts toward method sharing, data pooling, and improved access to accelerate the pursuit of this goal.
Purpose Breast conserving surgery plus accelerated partial breast irradiation is increasingly popular for early-stage breast cancer patients with promising clinical outcomes. However, the identification of the seroma cavity on CT can be challenging, leading to inaccuracy and inconsistency in seroma contouring. For brachytherapy techniques this presents additional challenges. Three-dimensional ultrasound (3DUS) technology will significantly improve target visualization and implant accuracy. In this work, we introduce a robotic 3DUS system with a spatial tracking arm that has great potential for improved visual guidance in breast brachytherapy, and describe the calibration and commissioning process for this system. Materials and Methods The robotic 3DUS system consists of a 3D-printed probe holder, customizable for any commercial ultrasound transducer (BKMedical 8811 for our system), a motor that drives the probe simultaneously both linearly and rotationally to acquire hybrid 3DUS images, an ultrasound transparent TPX plate that supports the probe motion, a spatially-tracked counterbalanced arm, and software for visualization and target segmentation (Figure 1a). The tracking arm consists of five encoded joints, shown in Figure 1a, and allows arm movement to provide sufficient tracking space in clinical use. The linear accuracy of the 3DUS scan was evaluated using a phantom composed of strings separated by 10.00±0.05 mm in three dimensions in a 7.25% isopropyl alcohol solution (22°C). Volume segmentation accuracy was evaluated by imaging and segmenting a sphere (1.2cc) embedded in an ultrasound phantom. Lavenberg-Marquardt based nonlinear regression was used to determine the optimal calibration parameters for each joint, which corrects the rotational deviations of each joint and translational offsets of the end-effector (the transducer). An optical tracking device (Polaris Spectra, Northern Digital Inc., Canada) was used for arm calibration. A total of 202 data points distributed in a 360×650×95mm3 working space were collected, among which, 80% (162 points) were used to calibrate the encoder parameters. The rest were used to evaluate spatial tracking accuracy. Results The 3DUS scanning volume is 5cm × 10cm × scan depth (from 5.2cm to 8.0cm). For a commonly used scan depth (6.0cm), the image resolution is 0.075mm, 0.082mm, and 0.33mm in lateral, axial, and elevational direction, respectively. The mean linear scan accuracy was within 2% in all directions, and the volume segmentation accuracy was 3%, all below TG128 action levels. Mean deviations between the mechanical and optical tracking are 0±0.5mm, 0±0.7mm, and0±0.8mm in three dimensions (plotted in Figure1b), with a mean Euclidean distance of 1.0±0.5mm. Conclusions We have developed, calibrated and commissioned a robotic 3DUS system for breast brachytherapy. The imaging and tracking accuracies were both excellent for clinical use. The spatial tracking arm has exciting potential to achieve rigid registration to other imaging modalities or the implant templates that are used in interstitial partial breast brachytherapy. Acknowledgements The authors would like to thank the support of NSERC and the OICR Imaging Program. Breast conserving surgery plus accelerated partial breast irradiation is increasingly popular for early-stage breast cancer patients with promising clinical outcomes. However, the identification of the seroma cavity on CT can be challenging, leading to inaccuracy and inconsistency in seroma contouring. For brachytherapy techniques this presents additional challenges. Three-dimensional ultrasound (3DUS) technology will significantly improve target visualization and implant accuracy. In this work, we introduce a robotic 3DUS system with a spatial tracking arm that has great potential for improved visual guidance in breast brachytherapy, and describe the calibration and commissioning process for this system. The robotic 3DUS system consists of a 3D-printed probe holder, customizable for any commercial ultrasound transducer (BKMedical 8811 for our system), a motor that drives the probe simultaneously both linearly and rotationally to acquire hybrid 3DUS images, an ultrasound transparent TPX plate that supports the probe motion, a spatially-tracked counterbalanced arm, and software for visualization and target segmentation (Figure 1a). The tracking arm consists of five encoded joints, shown in Figure 1a, and allows arm movement to provide sufficient tracking space in clinical use. The linear accuracy of the 3DUS scan was evaluated using a phantom composed of strings separated by 10.00±0.05 mm in three dimensions in a 7.25% isopropyl alcohol solution (22°C). Volume segmentation accuracy was evaluated by imaging and segmenting a sphere (1.2cc) embedded in an ultrasound phantom. Lavenberg-Marquardt based nonlinear regression was used to determine the optimal calibration parameters for each joint, which corrects the rotational deviations of each joint and translational offsets of the end-effector (the transducer). An optical tracking device (Polaris Spectra, Northern Digital Inc., Canada) was used for arm calibration. A total of 202 data points distributed in a 360×650×95mm3 working space were collected, among which, 80% (162 points) were used to calibrate the encoder parameters. The rest were used to evaluate spatial tracking accuracy. The 3DUS scanning volume is 5cm × 10cm × scan depth (from 5.2cm to 8.0cm). For a commonly used scan depth (6.0cm), the image resolution is 0.075mm, 0.082mm, and 0.33mm in lateral, axial, and elevational direction, respectively. The mean linear scan accuracy was within 2% in all directions, and the volume segmentation accuracy was 3%, all below TG128 action levels. Mean deviations between the mechanical and optical tracking are 0±0.5mm, 0±0.7mm, and0±0.8mm in three dimensions (plotted in Figure1b), with a mean Euclidean distance of 1.0±0.5mm. We have developed, calibrated and commissioned a robotic 3DUS system for breast brachytherapy. The imaging and tracking accuracies were both excellent for clinical use. The spatial tracking arm has exciting potential to achieve rigid registration to other imaging modalities or the implant templates that are used in interstitial partial breast brachytherapy.
