ABSTRACT
BACKGROUND
Patients and healthcare stakeholders are increasingly becoming engaged in the planning and conduct of biomedical research. However, limited research characterizes this process or ...its impact.
OBJECTIVE
We aimed to characterize patient and stakeholder engagement in the 50 Pilot Projects funded by the Patient-Centered Outcomes Research Institute (PCORI), and identify early contributions and lessons learned.
DESIGN
A self-report instrument was completed by researchers between 6 and 12 months following project initiation.
PARTICIPANTS
Forty-seven principal investigators or their designees (94 % response rate) participated in the study.
MAIN MEASURES
Self-report of types of stakeholders engaged, stages and levels of engagement, facilitators and barriers to engagement, lessons learned, and contributions from engagement were measured.
KEY RESULTS
Most (83 %) reported engaging more than one stakeholder in their project. Among those, the most commonly reported groups were patients (90 %), clinicians (87 %), health system representatives (44 %), caregivers (41 %), and advocacy organizations (41 %). Stakeholders were commonly involved in topic solicitation, question development, study design, and data collection. Many projects engaged stakeholders in data analysis, results interpretation, and dissemination. Commonly reported contributions included changes to project methods, outcomes or goals; improvement of measurement tools; and interpretation of qualitative data. Investigators often identified communication and shared leadership strategies as “critically important” facilitators (53 and 44 % respectively); lack of stakeholder time was the most commonly reported challenge (46 %). Most challenges were only partially resolved. Early lessons learned included the importance of continuous and genuine partnerships, strategic selection of stakeholders, and accommodation of stakeholders’ practical needs.
CONCLUSIONS
PCORI Pilot Projects investigators report engaging a variety of stakeholders across many stages of research, with specific changes to their research attributed to engagement. This study identifies early lessons and barriers that should be addressed to facilitate engagement. While this research suggests potential impact of stakeholder engagement, systematic characterization and evaluation of engagement at multiple stages of research is needed to build the evidence base.
Background
This multi‐institutional retrospective study evaluated the feasibility and safety of endoscopic sex identification in 467 turtles and tortoises, representing 10 species.
Methods
Medical ...records of turtles and tortoises that underwent endoscopic sex identification at the University of Georgia, New England Aquarium and Turtle Conservancy were reviewed for presurgical management, anaesthesia, endoscopic equipment and surgical techniques, endoscopic results and complications.
Results
The majority of animals weighed less than 200 g, were fasted and anaesthetised using an injectable combination of ketamine, dexmedetomidine and morphine or hydromorphone, supplemented by local lidocaine at the prefemoral site. Anaesthetic reversal using atipamezole alone or in combination with naloxone was routine. For uncomplicated procedures, mean total anaesthesia, surgery and recovery times were 22, 4 and 18 minutes, respectively. All animals were placed in lateral recumbency for a prefemoral endoscopic approach to the coelom using a rigid telescope and sterile fluid infusion to visualise the gonads. Sex identification was definitive in 99.4% (n = 464) of the animals. Iatrogenic bladder perforation was the most common complication (n = 5), which necessitated extended anaesthesia and surgical time for repair. Only a single anaesthetic‐related death was reported, which was associated with human error and drug overdose.
Conclusions
This is the first large‐scale study to retrospectively evaluate endoscopic sex identification in multiple chelonian species. Results suggest that endoscopic sexing is a safe, accurate and practical means for sex identification in turtles and tortoises, and represents a valuable tool in their reproductive management.
Background:
Primary tarsometatarsal (TMT) arthrodesis is gaining popularity in the surgical treatment of Lisfranc injuries. However, few studies have evaluated biomechanical effects of TMT ...arthrodesis. The purpose of this study was to compare the kinematics of joints adjacent to the midfoot during simulations of stance before and after sequential arthrodesis of the first, second, and third TMT joints.
Methods:
Ten midtibia cadaveric specimens were loaded on a 6-degree-of-freedom robotic gait simulator. Motion capture cameras were used to collect joint kinematics throughout simulations of the stance phase. Simulations were performed for the intact and sequential arthrodesis conditions of the first, second, and third TMT joints. The sagittal, coronal, and transverse plane rotational kinematics of the intact condition were compared to kinematics after each sequential arthrodesis condition.
Results:
Sequential arthrodesis of the first and second TMT joints had no significant effect on ankle, subtalar, talonavicular, and first metatarsophalangeal joint motion during simulated stance when compared to the intact condition. In contrast, inclusion of the third TMT joint into the sequential arthrodesis significantly increased subtalar inversion (P = .032) in late stance and increased range of motion values in the ankle and subtalar joints by 2.1 degrees (P = .009) and 2.8 degrees (P = .014), respectively.
Conclusion:
Sequential primary arthrodesis induced changes to ankle and adjacent joint kinematics during stance phase simulations, although not until the third TMT joint was included into the primary arthrodesis. The significant changes to kinematics due to arthrodesis of the first, second, and third TMT joints were small.
Clinical Relevance:
The minimal changes in sagittal, coronal, and transverse plane rotational kinematics support the positive clinical outcomes reported in the literature for primary partial arthrodesis of Lisfranc injuries. The inclusion of the third TMT joint should be done judiciously.
The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are fatal lysosomal storage disorders caused by mutations in the HEXA and HEXB genes, respectively. These mutations cause ...dysfunction of the lysosomal enzyme β-N-acetylhexosaminidase A (HexA) and accumulation of GM2 ganglioside (GM2) with ensuing neurodegeneration, and death by 5 years of age. Until recently, the most successful therapy was achieved by intracranial co-delivery of monocistronic adeno-associated viral (AAV) vectors encoding Hex alpha and beta-subunits in animal models of SD. The blood-brain barrier crossing properties of AAV9 enables systemic gene therapy; however, the requirement of co-delivery of two monocistronic AAV vectors to overexpress the heterodimeric HexA protein has prevented the use of this approach. To address this need, we developed multiple AAV constructs encoding simultaneously HEXA and HEXB using AAV9 and AAV-PHP.B and tested their therapeutic efficacy in 4- to 6-week-old SD mice after systemic administration. Survival and biochemical outcomes revealed superiority of the AAV vector design using a bidirectional CBA promoter with equivalent dose-dependent outcomes for both capsids. AAV-treated mice performed normally in tests of motor function, CNS GM2 ganglioside levels were significantly reduced, and survival increased by >4-fold with some animals surviving past 2 years of age.
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Tay-Sachs and Sandhoff diseases are caused by mutations in the HEXA and HEXB genes, respectively, which impact the activity of the heterodimeric lysosomal enzyme β-hexosaminidase A, and result in the accumulation of GM2 ganglioside in CNS. HexA is the only isozyme in human that hydrolyzes GM2 ganglioside, and co-expression of both proteins is necessary to produce high enzyme levels for cross-correction. An AAV9 vector expressing both proteins from a central promoter was administered systemically in Sandhoff mice and shown to reduce GM2 ganglioside levels, improve behavioral performance, and extend median survival to 634 days.
Abstract
Uridylation-dependent RNA decay is a widespread eukaryotic pathway modulating RNA homeostasis. Terminal uridylyltransferases (Tutases) add untemplated uridyl residues to RNA 3′-ends, marking ...them for degradation by the U-specific exonuclease Dis3L2. In Schizosaccharomyces pombe, Cid1 uridylates a variety of RNAs. In this study, we investigate the prevalence and impact of uridylation-dependent RNA decay in S. pombe by transcriptionally profiling cid1 and dis3L2 deletion strains. We found that the exonuclease Dis3L2 represents a bottleneck in uridylation-dependent mRNA decay, whereas Cid1 plays a redundant role that can be complemented by other Tutases. Deletion of dis3L2 elicits a cellular stress response, upregulating transcription of genes involved in protein folding and degradation. Misfolded proteins accumulate in both deletion strains, yet only trigger a strong stress response in dis3L2 deficient cells. While a deletion of cid1 increases sensitivity to protein misfolding stress, a dis3L2 deletion showed no increased sensitivity or was even protective. We furthermore show that uridylyl- and adenylyltransferases cooperate to generate a 5′-NxAUUAAAA-3′ RNA motif on dak2 mRNA. Our studies elucidate the role of uridylation-dependent RNA decay as part of a global mRNA surveillance, and we found that perturbation of this pathway leads to the accumulation of misfolded proteins and elicits cellular stress responses.
Sulfur dioxide is a possible co-injectant with carbon dioxide in the context of geologic sequestration. Because of the potential of SO2 to acidify formation brines, the extent of SO2 dissolution from ...the CO2 phase will determine the viability of co-injection. Pressure-, temperature-, and salinity-adjusted values of the SO2 Henry’s Law constant and fugacity coefficient were determined. They are predicted to decrease with depth, such that the solubility of SO2 is a factor of 0.04 smaller than would be predicted without these adjustments. To explore the potential effects of transport limitations, a nonsteady-state model of SO2 diffusion through a stationary cone-shaped plume of supercritical CO2 was developed. This model represents an end-member scenario of diffusion-controlled dissolution of SO2, to contrast with models of complete phase equilibrium. Simulations for conditions corresponding to storage depths of 0.8−2.4 km revealed that after 1000 years, 65−75% of the SO2 remains in the CO2 phase. This slow release of SO2 would largely mitigate its impact on brine pH. Furthermore, small amounts of SO2 are predicted to have a negligible effect on the critical point of CO2 but will increase phase density by as much as 12% for mixtures containing 5% SO2.
To describe challenges to and facilitators of patient engagement to inform future strategies and suggested actions to strengthen engagement.
Interviews with 19 principal investigators of projects ...funded by the Patient-Centered Outcomes Research Institute and with 33 patients from 18 of the 19 projects.
Facilitators included using existing resources, having clear goals, educating patients and treating patients respectfully. Logistical challenges included extra time and work, institutional barriers and difficulty having meetings. Substantive challenges to selecting, educating and engaging patients, and incorporating feedback were also reported.
To bolster the infrastructure for engagement, we suggest funders, institutions and researchers focus on resources and training for researchers and patients, networks and programs to connect stakeholders and model policies.
Background: Despite growing interest in patient engagement in research, there are few empirical investigations of the nature of engagement and its effects. This information is important, not only to ...inform practical decisions researchers and funders must make, but also to inform discussion of the ethical implications of engaging patients, which has received little attention to date. Methods: The aim of this study was to characterize patient engagement in research funded by the Patient-Centered Outcomes Research Institute (PCORI) as a step toward enhancing current understanding of the nature and effects of engagement and prompting an in-depth consideration of the ethical implications of engaging patients in research. Qualitative interviews were conducted with 19 PCORI-funded principal investigators and with 33 patients engaged in 18 of the same 19 projects. Results: Reasons cited for engaging patients included to enhance relevance and feasibility and to improve dissemination. While engagement occurred at different points during the research, patients were most commonly engaged in reviewing study materials and less commonly engaged at earlier points. Engagement varied by approach, frequency of interaction, and the extent to which patient input changed the research. Impacts of engagement included improving the relevance, feasibility, acceptability, and quality of the research. Conclusion: Our findings on the nature and impacts of engagement have importance not only for practical questions researchers, funders, and patients might raise, but also for several ethical considerations regarding patient engagement related to why patients are engaged, the kinds of patients engaged, when patients are engaged, and how patients are engaged. We discuss our findings in consideration of the main ethical issues they imply, including ethical rationales for engagement, justice-related concerns, and ethical concerns arising from when and how patients are engaged. As efforts to engage patients increase, this discussion provides insights that researchers, funders, and patients may find valuable.
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