Quantitative Assessment of Clinician Assistance During Dynamic Rehabilitation Using Force Sensitive Resistors

Background: Neuromodulation using epidural electrical stimulation (EES) has shown functional restoration in humans with chronic spinal cord injury (SCI). EES during body weight supported treadmill training (BWSTT) enhanced stepping performance in clinical trial participants with paraplegia. Unfortunately, tools are lacking in availability to quantify clinician assistance during BWSTT with and without EES. Force sensitive resistors (FSRs) have previously quantified clinician assistance during static standing; however, dynamic tasks have not been addressed.Objective: To determine the validity of FSRs in measurements of force and duration to quantify clinician assistance and participant progression during BWSTT with EES in participants with SCI.Design: A feasibility study to determine the effectiveness of EES to restore function in individuals with SCI.Methods: Two male participants with chronic SCI were enrolled in a pilot phase clinical trial. Following implantation of an EES system in the lumbosacral spinal cord, both participants underwent 12 months of BWSTT with EES. At monthly intervals, FSRs were positioned on participants' knees to quantity forces applied by clinicians to achieve appropriate mechanics of stepping during BWSTT. The FSRs were validated on the benchtop using a leg model instrumented with a multiaxial load cell as the gold standard. The outcomes included clinician-applied force duration measured by FSR sensors and changes in applied forces indicating progression over the course of rehabilitation.Results: The force sensitive resistors validation revealed a proportional bias in their output. Loading required for maximal assist training exceeded the active range of the FSRs but were capable of capturing changes in clinician assist levels. The FSRs were also temporally responsive which increased utility for accurately assessing training contact time. The FSRs readings were able to capture independent stance for both participants by study end. There was minimal to no applied force bilaterally for participant 1 and unilaterally for participant 2.Conclusions: Clinician assistance applied at the knees as measured through FSRs during dynamic rehabilitation and EES (both on and off) effectively detected point of contact and duration of forces; however, it lacks accuracy of magnitude assessment. The reduced contact time measured through FSRs related to increased stance duration, which objectively identified independence in stepping during EES-enabled BWSTT following SCI.

Methylation Modification, Alternative Splicing, and Noncoding RNA Play a Role in Cancer Metastasis through Epigenetic Regulation

Metastasis is the leading cause of cancer-related deaths. Understanding the pathogenesis of metastasis at the molecular levels is of great significance for cancer research. However, the molecular diagnosis or treatment of cancer metastasis is limited. Accumulating and growing evidence shows that epigenetic changes are present in all human cancers, and epigenetic regulation is an indispensable factor to promote tumor metastasis. With the deepening of research and the advancement of technology, the function and mechanism of epigenetic regulation, including DNA methylation, histone/RNA modification, and precursor messenger RNA alternative splicing and noncoding RNAs, has become more increasingly clear. At present, the application of epigenetic therapies in tumor treatment is becoming a feasible therapeutic route. In this review, we looked for the key molecules in epigenetic regulation and discuss their relative regulating mechanisms in cancer metastasis. Furthermore, we highlight promising therapeutic strategies, including monitoring serum DNA for diagnostic purposes and early phase clinical trial therapies that target DNA and histone methylation. This may also be beneficial in finding new targets for further prognosis and diagnosis of cancer metastasis.

Compliance with dietary guidelines and its relationship with symptoms and clinical outcomes in patients with advanced cancer in early-phase oncology clinical trials.

199 Background: We examined compliance with the Dietary Guidelines for Americans and its association with symptom burden and clinical outcomes in patients with advanced cancer in early-phase clinical trials testing novel immunotherapeutic and targeted agents. Methods: Patients starting an early-phase clinical trial (ECOG-PS = 0-1) were recruited into a prospective, longitudinal design with assessments at baseline and at the end of Cycle 1. Diet and symptom burden were assessed using the validated National Cancer Institute Diet History Questionnaire (NCI-DHQ) and the MD Anderson Symptom Inventory, respectively. Compliance with the Dietary Guidelines for Americans recommendations was measured via the Healthy Eating Index (HEI) (a measure of dietary intake per total energy), computed from NCI-DHQ food group and nutrient scores; higher HEI scores indicate greater compliance with dietary guidance recommendations (possible range = 0–100). Statistical tests included Spearman rank correlations (rho), and Cox proportional hazards models. Results: Among early-phase clinical trial patients [N = 40; 50% female; 80% Non-Hispanic White; 80% ECOG = 1; 36% on trials including an immunotherapeutic agent and 64% on targeted therapy trials; mean age = 55y; mean BMI = 28], mean HEI was 69, compared to 59 for the US general population. The proportion of phase I clinical trial patients who met adequacy guidelines were 80% for whole fruit, 73% for total protein foods, 55% for seafood and plant proteins, 55% for total fruit, 50% for greens and beans, 28% for total vegetables, 15% for fatty acids [(PUFAs + MUFAs)/SFAs ≥2.5], 13% for dairy, and 0% for whole grains. The proportion of patients who met moderation guidelines were 28% for refined grains, 28% for added sugar, 13% for saturated fat, and 0% for sodium. Female patients had higher HEI scores than male patients (73 vs. 65, P = 0.004). Patients who were normal weight (BMI < 25) had higher scores for meeting the moderation in sugar intake guideline than overweight patients (BMI≥25) (7.7 vs. 5.5, P = 0.031). Higher intakes of cooked lean meat from beef, pork, veal, lamb, and game were linked to prolonged overall survival (HR = 0.5, 95%CI = 0.26, 0.96, P = 0.039). In immunotherapy patients, greater compliance with seafood and plant protein recommendations was associated with less fatigue at end of Cycle 1 (rho = -0.7, P = 0.008); in targeted therapy patients, higher glycemic load was associated with worse pain (rho = 0.7, P = 0.004). Conclusions: Diets of these early-phase clinical trial patients overall were congruent with recommendations in the Dietary Guidelines for Americans. However, increasing intakes of whole grains and reducing sodium intakes may be useful dietary goals for this population. Also, dietary factors may influence symptoms, such as fatigue and pain, in early-phase clinical trial patients with advanced cancer.

Application of a Cloud Video Conference Method for Recruiting Healthy Subjects Into an Early-Phase Clinical Trial During the COVID-19 Pandemic

Objective: Our objective is to explore the effect of applying cloud video conferencing methods to the informed consent process in an early-phase clinical trial during the COVID-19 pandemic.Methods: All participants who intended to participate in the trial were informed via a cloud video conference before signing the informed consent forms (ICF). Then, the attitudes of the participants with the cloud video conference and their understanding of the trial were evaluated using a questionnaire when they visited to sign the ICF onsite.Results: A total of 165 subjects participated in the cloud video conference process, and 142 visited the site to sign and date the ICFs at the center during the appointment time. The survey showed that nearly 100% of the subjects evaluated the video-based informed consent process as very good or good and gave correct answers to questions about the trial. Furthermore, 136 (95.8%) subjects believed that the knowledge about the trial derived via the video-based informed consent process was consistent with the onsite reality, and 139 (97.9%) subjects expressed their willingness to participate in an informed consent procedure undertaken through an online video conference.Conclusions: The video-based informed consent process achieved the same effects as an onsite informed consent process. The former saves time and cost of transportation for the subject and exhibits good public acceptance; especially in light of the COVID-19 pandemic, this process is conducive for reducing the risk of subject infection due to travel and would also help avoid crowding on site.

Psilocybin: From Serendipity to Credibility?

Psilocybin has a long history of non-medical use and some seem to infer from this that it has therapeutic utility. Early phase clinical trials with psilocybin are encouraging, but suggest only that larger, multicentre trials are required. These are ongoing but will take many years to complete. Meanwhile, retreat centers offering paid experiences with psilocybin truffles have opened in some countries, often using early phase clinical trial data as a basis for bold, public facing claims. This seems unwise. Early phase trials are not designed for their results to be generalized outside the setting they were undertaken in. To do so risks being misleading. Providing what may be seen as an unregulated drug intervention as a paid service is difficult to reconcile with long-held ethical principles underpinning human research and treatment development that were laid down by the 1947 Nuremberg Code and the 1962 Kefauver Harris Amendments. By using psilocybin before it has been properly tested, retreat centers may be undermining their own credibility and the credibility of the wider field.

Understanding implementability in clinical trials: a pragmatic review and concept map

Background The translation of evidence from clinical trials into practice is complex. One approach to facilitating this translation is to consider the ‘implementability’ of trials as they are designed and conducted. Implementability of trials refers to characteristics of the design, execution and reporting of a late-phase clinical trial that can influence the capacity for the evidence generated by that trial to be implemented. On behalf of the Australian Clinical Trials Alliance (ACTA), the national peak body representing networks of clinician researchers conducting investigator-initiated clinical trials, we conducted a pragmatic literature review to develop a concept map of implementability. Methods Documents were included in the review if they related to the design, conduct and reporting of late-phase clinical trials; described factors that increased or decreased the capacity of trials to be implemented; and were published after 2009 in English. Eligible documents included systematic reviews, guidance documents, tools or primary studies (if other designs were not available). With an expert reference group, we developed a preliminary concept map and conducted a snowballing search based on known relevant papers and websites of key organisations in May 2019. Results Sixty-five resources were included. A final map of 38 concepts was developed covering the domains of validity, relevance and usability across the design, conduct and reporting of a trial. The concepts drew on literature relating to implementation science, consumer engagement, pragmatic trials, reporting, research waste and other fields. No single resource addressed more than ten of the 38 concepts in the map. Conclusions The concept map provides trialists with a tool to think through a range of areas in which practical action could enhance the implementability of their trials. Future work could validate the strength of the associations between the concepts identified and implementability of trials and investigate the effectiveness of steps to address each concept. ACTA will use this concept map to develop guidance for trialists in Australia. Trial registration This review did not include health-related outcomes and was therefore not eligible for registration in the PROSPERO register.

Co-administered antibody improves penetration of antibody–dye conjugate into human cancers with implications for antibody–drug conjugates

Poor tissue penetration remains a major challenge for antibody-based therapeutics of solid tumors, but proper dosing can improve the tissue penetration and thus therapeutic efficacy of these biologics. Due to dose-limiting toxicity of the small molecule payload, antibody-drug conjugates (ADCs) are administered at a much lower dose than their parent antibodies, which further reduces tissue penetration. We conducted an early-phase clinical trial (NCT02415881) and previously reported the safety of an antibody-dye conjugate (panitumumab-IRDye800CW) as primary outcome. Here, we report a retrospective exploratory analysis of the trial to evaluate whether co-administration of an unconjugated antibody could improve the intratumoral distribution of the antibody-dye conjugate in patients. By measuring the multiscale distribution of the antibody-dye conjugate, this study demonstrates improved microscopic antibody distribution without increasing uptake (toxicity) in healthy tissue when co-administered with the parent antibody, supporting further clinical investigation of the co-administration dosing strategy to improve the tumor penetration of ADCs.