Empowering the Participant Voice (EPV): Design and implementation of collaborative infrastructure to collect research participant experience feedback at scale.

Empowering the Participant Voice (EPV) is an NCATS-funded six-CTSA collaboration to develop, demonstrate, and disseminate a low-cost infrastructure for collecting timely feedback from research participants, fostering trust, and providing data for improving clinical translational research. EPV leverages the validated Research Participant Perception Survey (RPPS) and the popular REDCap electronic data-capture platform. This report describes the development of infrastructure designed to overcome identified institutional barriers to routinely collecting participant feedback using RPPS and demonstration use cases. Sites engaged local stakeholders iteratively, incorporating feedback about anticipated value and potential concerns into project design. The team defined common standards and operations, developed software, and produced a detailed planning and implementation Guide. By May 2023, 2,575 participants diverse in age, race, ethnicity, and sex had responded to approximately 13,850 survey invitations (18.6%); 29% of responses included free-text comments. EPV infrastructure enabled sites to routinely access local and multi-site research participant experience data on an interactive analytics dashboard. The EPV learning collaborative continues to test initiatives to improve survey reach and optimize infrastructure and process. Broad uptake of EPV will expand the evidence base, enable hypothesis generation, and drive research-on-research locally and nationally to enhance the clinical research enterprise.

Addressing Signal Drift and Screening for Detection of Biomarkers with Carbon Nanotube Transistors.

Electrical biosensors, including transistor-based devices (i.e., BioFETs), have the potential to offer versatile biomarker detection in a simple, low-cost, scalable, and point-of-care manner. Semiconducting carbon nanotubes (CNTs) are among the most explored nanomaterial candidates for BioFETs due to their high electrical sensitivity and compatibility with diverse fabrication approaches. However, when operating in solutions at biologically relevant ionic strengths, CNT-based BioFETs suffer from debilitating levels of signal drift and charge screening, which are often unaccounted for or sidestepped (but not addressed) by testing in diluted solutions. In this work, we present an ultrasensitive CNT-based BioFET called the D4-TFT, an immunoassay with an electrical readout, which overcomes charge screening and drift-related limitations of BioFETs. In high ionic strength solution (1X PBS), the D4-TFT repeatedly and stably detects subfemtomolar biomarker concentrations in a point-of-care form factor by increasing the sensing distance in solution (Debye length) and mitigating signal drift effects. Debye length screening and biofouling effects are overcome using a poly(ethylene glycol)-like polymer brush interface (POEGMA) above the device into which antibodies are printed. Simultaneous testing of a control device having no antibodies printed over the CNT channel confirms successful detection of the target biomarker via an on-current shift caused by antibody sandwich formation. Drift in the target signal is mitigated by a combination of: (1) maximizing sensitivity by appropriate passivation alongside the polymer brush coating; (2) using a stable electrical testing configuration; and (3) enforcing a rigorous testing methodology that relies on infrequent DC sweeps rather than static or AC measurements. These improvements are realized in a relatively simple device using printed CNTs and antibodies for a low-cost, versatile platform for the ongoing pursuit of point-of-care BioFETs.

Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for patients with rare disease in a publicly funded health care system: A prospective cohort study.

PURPOSE: To evaluate the diagnostic utility of publicly funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases. METHODS: We prospectively enrolled 297 probands who met eligibility criteria and received ES across 5 sites in Ontario, Canada, and extracted data from medical records and clinician surveys. Using the Fryback and Thornbury Efficacy Framework, we assessed diagnostic accuracy by examining laboratory interpretation of results and assessed diagnostic thinking by examining the clinical interpretation of results and whether clinical-molecular diagnoses would have been achieved via alternative hypothetical molecular tests. RESULTS: Laboratories reported 105 molecular diagnoses and 165 uncertain results in known and novel genes. Of these, clinicians interpreted 102 of 105 (97%) molecular diagnoses and 6 of 165 (4%) uncertain results as clinical-molecular diagnoses. The 108 clinical-molecular diagnoses were in 104 families (35% diagnostic yield). Each eligibility criteria resulted in diagnostic yields of 30% to 40%, and higher yields were achieved when >2 eligibility criteria were met (up to 45%). Hypothetical tests would have identified 61% of clinical-molecular diagnoses. CONCLUSION: We demonstrate robustness in eligibility criteria and high clinical validity of laboratory results from ES testing. The importance of ES was highlighted by the potential 40% of patients that would have gone undiagnosed without this test.

Solution Processed Schottky Diodes Enabled by Silicon Carbide Nanowires for Harsh Environment Applications.

Silicon carbide nanowires (SiC NWs) exhibit promising features to allow solution-processable electronics to be deployed in harsh environments. By utilizing a nanoscale form of SiC, we were able to disperse the material into liquid solvents, while maintaining the resilience of bulk SiC. This letter reports the fabrication of SiC NW Schottky diodes. Each diode consisted of just one nanowire with an approximate diameter of 160 nm. In addition to analyzing the diode performance, the effects of elevated temperatures and proton irradiation on the current-voltage characteristics of SiC NW Schottky diodes were also examined. The device could maintain similar values for ideality factor, barrier height, and effective Richardson constant upon proton irradiation with a fluence of 1016 ion/cm2 at 873 K. As a result, these metrics have clearly demonstrated the high-temperature tolerance and irradiation resistance of SiC NWs, ultimately indicating that they may provide utility in allowing solution-processable electronics in harsh environments.

"Not-so-popular" orthogonal pairs in genetic code expansion.

During the past decade, genetic code expansion has been proved to be a powerful tool for protein studies and engineering. As the key part, a series of orthogonal pairs have been developed to site-specifically incorporate hundreds of noncanonical amino acids (ncAAs) into proteins by using bacteria, yeast, mammalian cells, animals, or plants as hosts. Among them, the pair of tyrosyl-tRNA synthetase/tRNATyr from Methanococcus jannaschii and the pair of pyrrolysyl-tRNA synthetase/tRNAPyl from Methanosarcina species are the most popular ones. Recently, other "not-so-popular" orthogonal pairs have started to attract attentions, because they can provide more choices of ncAA candidates and are necessary for simultaneous incorporation of multiple ncAAs into a single protein. Here, we summarize the development and applications of those "not-so-popular" orthogonal pairs, providing guidance for studying and engineering proteins.

Hybrid nanomaterial inks for printed resistive temperature sensors with tunable properties to maximize sensitivity.

Nanomaterial-based inks are one of the essential building blocks for printed electronics. Inks consisting of silver nanoparticles have been well received as conductive inks for printed electronics among researchers and industry due to their good electrical performance, relatively low sintering temperature, and wide range of commercial availability. However, homogenous silver nanoparticle inks can lack the appropriate attributes required for robust printed physical sensors. In this work, we demonstrate that fully printed resistive temperature detector (RTD) sensors can benefit from ink hybridization. Specifically, we investigate RTDs printed by aerosol jet printing of hybrid nickel-copper-silver nanoparticle inks. We show that the overall sensitivity of the printed sensors can be enhanced through the introduction of these varied particles due to intentionally incorporated interfacial obstacles within the percolation network. While the temperature coefficient of resistance is decreased, the change in resistance per change in temperature can be maximized through the enhanced scattering provided by nickel and copper particle constituents. We report a sensitivity increase of 300% through utilizing 40% (by volume) mixture of silver and copper/nickel xylene-based inks. The results are corroborated through SEM/EDS analysis to understand the final weight percent of varied elements within the printed thin film. This magnitude of sensitivity opens up the possibility of utilizing printed RTDs for a wider range of sensing applications, where probing electronics are often low-cost.

Imaging Biomarkers in Prostate Stereotactic Body Radiotherapy: A Review and Clinical Trial Protocol.

Advances in imaging have changed prostate radiotherapy through improved biochemical control from focal boost and improved detection of recurrence. These advances are reviewed in the context of prostate stereotactic body radiation therapy (SBRT) and the ARGOS/CLIMBER trial protocol. ARGOS/CLIMBER will evaluate 1) the safety and feasibility of SBRT with focal boost guided by multiparametric MRI (mpMRI) and 18F-PSMA-1007 PET and 2) imaging and laboratory biomarkers for response to SBRT. To date, response to prostate SBRT is most commonly evaluated using the Phoenix Criteria for biochemical failure. The drawbacks of this approach include lack of lesion identification, a high false-positive rate, and delay in identifying treatment failure. Patients in ARGOS/CLIMBER will receive dynamic 18F-PSMA-1007 PET and mpMRI prior to SBRT for treatment planning and at 6 and 24 months after SBRT to assess response. Imaging findings will be correlated with prostate-specific antigen (PSA) and biopsy results, with the goal of early, non-invasive, and accurate identification of treatment failure.

ReGARDD (Regulatory Guidance for Academic Research of Drugs and Devices): The evolution of a collaborative regional CTSA-funded forum and website for regulatory support.

Availability of trained professionals to assist researchers navigating regulatory pathways for new drug and device development is limited within academic institutions. We created ReGARDD (Regulatory Guidance for Academic Research of Drugs and Devices), a regional forum initially involving regulatory professionals from four Clinical and Translational Science Award (CTSA)-funded institutions, to build and capitalize on local expertise and to develop a regulatory guidance website geared toward academic researchers. Since 2015, members organized 15 forums covering topics such as FDA premarket submissions, gene therapy, and intellectual property for devices and therapeutics. Through user feedback, targeted surveys, and ongoing iterative processes, we refined and maintained a shared regulatory website, which reached 6000+ users in 2019. Website updates improved navigation to drug versus device topic areas, provided new educational content and videos to address commonly asked questions, and created a portal for posting upcoming training opportunities. Survey respondents rated the website favorably and endorsed expanding ReGARDD as a centralized resource. ReGARDD strengthened the regional regulatory workforce, increased regulatory efficiency, and promulgated best organizational and operational practices. Broad-scale deployment of the ReGARDD model across the CTSA consortium may facilitate the creation of a network of regional forums and reduce gaps in access to regulatory support.

Tritium labelling of two potent dopamine D2 receptor agonists at high specific activity.

An efficient method is described to radiolabel several dopamine D2 receptor agonists with tritium at high specific activity.

Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients.

We conducted an adaptive design single-center pilot trial between October 2017 and November 2018 to determine the safety and efficacy of ultra-short-term perioperative pangenotypic direct acting antiviral (DAA) prophylaxis for deceased hepatitis C virus (HCV)-nucleic acid test (NAT) positive donors to HCV negative kidney recipients (D+/R-). In Group 1, 10 patients received one dose of SOF/VEL (sofusbuvir/velpatasvir) pretransplant and one dose on posttransplant Day 1. In Group 2A (N = 15) and the posttrial validation (Group 2B; N = 25) phase, patients received two additional SOF/VEL doses (total 4) on Days 2 and 3 posttransplant. Development of posttransplant HCV transmission triggered 12-week DAA therapy. For available donor samples (N = 27), median donor viral load was 1.37E + 06 IU/mL (genotype [GT]1a: 70%; GT2: 7%; GT3: 23%). Overall viral transmission rate was 12% (6/50; Group 1:30% [3/10]; Group 2A:13% [2/15]; Group 2B:4% [1/25]). For the 6 viremic patients, 5 (83%) achieved sustained virologic response (3 with first-line DAA therapy; and two after retreatment with second-line DAA). At a median follow-up of 8 months posttransplant, overall patient and allograft survivals were 98%, respectively. The 4-day strategy reduced viral transmission to 7.5% (3/40; 95% confidence interval [CI]: 1.8%-20.5%) and could result in avoidance of prolonged posttransplant DAA therapy for most D+/R - transplants.

Flexible, Print-in-Place 1D-2D Thin-Film Transistors Using Aerosol Jet Printing.

Semiconducting carbon nanotubes (CNTs) printed into thin films offer high electrical performance, significant mechanical stability, and compatibility with low-temperature processing. Yet, the implementation of low-temperature printed devices, such as CNT thin-film transistors (CNT-TFTs), has been hindered by relatively high process temperature requirements imposed by other device layers-dielectrics and contacts. In this work, we overcome temperature constraints and demonstrate 1D-2D thin-film transistors (1D-2D TFTs) in a low-temperature (maximum exposure ≤80 °C) full print-in-place process (i.e., no substrate removal from printer throughout the entire process) using an aerosol jet printer. Semiconducting 1D CNT channels are used with a 2D hexagonal boron nitride (h-BN) gate dielectric and traces of silver nanowires as the conductive electrodes, all deposited using the same printer. The aerosol jet-printed 2D h-BN films were realized via proper ink formulation, such as utilizing the binder hydroxypropyl methylcellulose, which suppresses redispersion between adjacent printed layers. In addition to an ON/OFF current ratio up to 3.5 × 105, channel mobility up to 10.7 cm2·V-1·s-1, and low gate hysteresis, 1D-2D TFTs exhibit extraordinary mechanical stability under bending due to the nanoscale network structure of each layer, with minimal changes in performance after 1000 bending test cycles at 2.1% strain. It is also confirmed that none of the device layers require high-temperature treatment to realize optimal performance. These findings provide an attractive approach toward a cost-effective, direct-write realization of electronics.

TBX3 promotes progression of pre-invasive breast cancer cells by inducing EMT and directly up-regulating SLUG.

The acquisition of cellular invasiveness by breast epithelial cells and subsequent transition from ductal carcinoma in situ (DCIS) to invasive breast cancer is a critical step in breast cancer progression. Little is known about the molecular dynamics governing this transition. We have previously shown that overexpression of the transcriptional regulator TBX3 in DCIS-like cells increases survival, growth, and invasiveness. To explore this mechanism further and assess direct transcriptional targets of TBX3 in a high-resolution, isoform-specific context, we conducted genome-wide chromatin-immunoprecipitation (ChIP) arrays coupled with transcriptomic analysis. We show that TBX3 regulates several epithelial-mesenchymal transition (EMT)-related genes, including SLUG and TWIST1. Importantly, we demonstrate that TBX3 is a direct regulator of SLUG expression, and SLUG expression is required for TBX3-induced migration and invasion. Assessing TBX3 by immunohistochemistry in early-stage (stage 0 and stage I) breast cancers revealed high expression in low-grade lesions. Within a second independent early-stage non-high-grade cohort, we observed an association between TBX3 level in the DCIS and size of the invasive focus. Additionally, there was a positive correlation between TBX3 and SLUG, and TBX3 and TWIST1 in the invasive carcinoma. Pathway analysis revealed altered expression of several proteases and their inhibitors, consistent with the ability to degrade basement membrane in vivo. These findings strongly suggest the involvement of TBX3 in the promotion of invasiveness and progression of early-stage pre-invasive breast cancer to invasive carcinoma through the low-grade molecular pathway. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

An Institutional Program to Increase Compliance with Clinicaltrials.gov Requirements.

Recent National Institutes of Health policy changes have expanded the number of research studies that must be registered in clinicaltrials.gov beyond the requirements of the Food and Drug Administration Amendments Act of 2007. The International Committee of Medical Journal Editors has also adopted a policy that requires registration of research in a public database. The goal was to increase the transparency of research by reporting the original endpoints of a study, and to discern whether primary endpoints were excluded in subsequent publications. Efforts to increase openness and accountability in clinical trials are likely to strengthen public trust. However, first investigators and study staff must be educated about the requirements, and staff must be prepared to offer support to researchers in navigating the clinicaltrials.gov system. For academic institutions, maintaining compliance requires continuous oversight so that problems can be identified centrally and addressed with investigators. At Wake Forest University Health Sciences, because researchers often did not realize they were out of compliance, we implemented a program to assist them and provide oversight. We introduced standard operating procedures, provided education and assistance to investigators, and engaged leadership about consequences of compliance, resulting in increased budget support for a full-time employee in this role. As a result of these changes, compliance increased from 22% to 92% over 4 months. These approaches may help other institutions become compliant with registration requirements more quickly.

Delivery of the research participant perception survey through the patient portal.

INTRODUCTION: The patient portal may be an effective method for administering surveys regarding participant research experiences but has not been systematically studied. METHODS: We evaluated 4 methods of delivering a research participant perception survey: mailing, phone, email, and patient portal. Participants of research studies were identified (n=4013) and 800 were randomly selected to receive a survey, 200 for each method. Outcomes included response rate, survey completeness, and cost. RESULTS: Among those aged <65 years, response rates did not differ between mail, phone, and patient portal (22%, 29%, 30%, p>0.07). Among these methods, the patient portal was the lowest-cost option. Response rates were significantly lower using email (10%, p<0.01), the lowest-cost option. In contrast, among those aged 65+ years, mail was superior to the electronic methods (p<0.02). CONCLUSIONS: The patient portal was among the most effective ways to reach research participants, and was less expensive than surveys administered by mail or telephone.

Patterned Liquid Metal Contacts for Printed Carbon Nanotube Transistors.

Flexible and stretchable electronics are poised to enable many applications that cannot be realized with traditional, rigid devices. One of the most promising options for low-cost stretchable transistors are printed carbon nanotubes (CNTs). However, a major limiting factor in stretchable CNT devices is the lack of a stable and versatile contact material that forms both the interconnects and contact electrodes. In this work, we introduce the use of eutectic gallium-indium (EGaIn) liquid metal for electrical contacts to printed CNT channels. We analyze thin-film transistors (TFTs) fabricated using two different liquid metal deposition techniques-vacuum-filling polydimethylsiloxane (PDMS) microchannel structures and direct-writing liquid metals on the CNTs. The highest performing CNT-TFT was realized using vacuum-filled microchannel deposition with an in situ annealing temperature of 150 °C. This device exhibited an on/off ratio of more than 104 and on-currents as high as 150 µA/mm-metrics that are on par with other printed CNT-TFTs. Additionally, we observed that at room temperature the contact resistances of the vacuum-filled microchannel structures were 50% lower than those of the direct-write structures, likely due to the poor adhesion between the materials observed during the direct-writing process. The insights gained in this study show that stretchable electronics can be realized using low-cost and solely solution processing techniques. Furthermore, we demonstrate methods that can be used to electrically characterize semiconducting materials as transistors without requiring elevated temperatures or cleanroom processes.

Ensuring respect for persons in COMPASS: a cluster randomised pragmatic clinical trial.

Cluster randomised clinical trials present unique challenges in meeting ethical obligations to those who are treated at a randomised site. Obtaining informed consent for research within the context of clinical care is one such challenge. In order to solve this problem it is important that an informed consent process be effective and efficient, and that it does not impede the research or the healthcare. The innovative approach to informed consent employed in the COMPASS study demonstrates the feasibility of upholding ethical standards without imposing undue burden on clinical workflows, staff members or patients who may participate in the research by virtue of their presence in a cluster randomised facility. The COMPASS study included 40 randomised sites and compared the effectiveness of a postacute stroke intervention with standard care. Each site provided either the comprehensive postacute stroke intervention or standard care according to the randomisation assignment. Working together, the study team, institutional review board and members of the community designed an ethically appropriate and operationally reasonable consent process which was carried out successfully at all randomised sites. This achievement is noteworthy because it demonstrates how to effectively conduct appropriate informed consent in cluster randomised trials, and because it provides a model that can easily be adapted for other pragmatic studies. With this innovative approach to informed consent, patients have access to the information they need about research occurring where they are seeking care, and medical researchers can conduct their studies without ethical concerns or unreasonable logistical impediments. TRIAL REGISTRATION NUMBER: NCT02588664, recruiting. This article covers the development of consent process that is currentlty being employed in the study.

Drop spreading on a superhydrophobic surface: pinned contact line and bending liquid surface.

In this study, we employ molecular dynamics (MD) simulations to probe the spreading of a drop on a superhydrophobic (SH) surface. The SH surface consists of nanopillars and the drop spreads while being in the Cassie-Baxter (CB) state on the nanopillared surface. Most remarkably, unlike the spreading on non-SH surfaces, we witness that the spreading on SH surfaces is not dominated by the motion of the three-phase contact line (TPCL). Rather, the TPCL remains pinned at the edge of a nanopillar and the spreading is ensured by the liquid surface or the liquid-vapor interface (of this pinned TPCL) bending down and wetting the solid adjacent to the TPCL. Such bending may actually enforce a progressive temporal increase in the instantaneous local contact angle eventually making it equal to or more than 180°. This is in sharp contrast to the classical spreading dynamics, where, with the spreading being dictated by the TPCL motion, the local contact angle always decreases with time. We carry out simulations where the solids supporting the nanopillars have vastly different wettabilities; however, this principle of bending-driven spreading is invariably witnessed. In fact, given the recent experimental study on the rolling of drops on SH surfaces manifesting exactly identical liquid-surface-bending-driven drop motion, we can infer that regardless of the drop size (e.g., nanoscopic or millimetric) or the nature of drop motion (spreading or rolling), the motion of drops in the CB state on SH surfaces is universally driven by the bending of liquid surfaces and not by the motion of the TPCL.

Poly(oligo(ethylene glycol) methyl ether methacrylate) Brushes on High-κ Metal Oxide Dielectric Surfaces for Bioelectrical Environments.

Advances in electronics and life sciences have generated interest in "lab-on-a-chip" systems utilizing complementary metal oxide semiconductor (CMOS) circuitry for low-power, portable, and cost-effective biosensing platforms. Here, we present a simple and reliable approach for coating "high-κ" metal oxide dielectric materials with "non-fouling" (protein- and cell-resistant) poly(oligo(ethylene glycol) methyl ether methacrylate (POEGMA) polymer brushes as biointerfacial coatings to improve their relevance for biosensing applications utilizing advanced electronic components. By using a surface-initiated "grafting from" strategy, POEGMA films were reliably grown on each material, as confirmed by ellipsometric measurements and X-ray photoelectron spectroscopy (XPS) analysis. The electrical behavior of these POEGMA films was also studied to determine the potential impact on surrounding electronic devices, yielding information on relative permittivity and breakdown field for POEGMA in both dry and hydrated states. We show that the incorporation of POEGMA coatings significantly reduced levels of nonspecific protein adsorption compared to uncoated high-κ dielectric oxide surfaces as shown by protein resistance assays. These attributes, combined with the robust dielectric properties of POEGMA brushes on high-κ surfaces open the way to incorporate this protein and cell resistant polymer interface into CMOS devices for biomolecular detection in a complex liquid milieu.