The Regulatory Network Involving PcoR, RsaL, and MvaT Coordinates the Quorum-Sensing System in Pseudomonas fluorescens 2P24.

Pseudomonas fluorescens 2P24 is a beneficial plant root-associated microorganism capable of suppressing several soilborne plant diseases. The capacity of P. fluorescens to aggressively colonize the rhizosphere is an important requirement for its biocontrol trait. We previously found that the PcoI/PcoR quorum-sensing system (QS) is involved in regulating the rhizosphere colonization of P. fluorescens. Here, we revealed a sophisticated regulatory network that connects PcoR, RsaL, and MvaT proteins to fine-tune the PcoI/PcoR QS system. Our data showed that PcoR could directly bind to the promoter region of pcoI thereby inducing the PcoI/PcoR QS system, whereas RsaL binds simultaneously with PcoR to the promoter region of pcoI and represses the PcoR-dependent activation of pcoI gene. In addition, RsaL indirectly downregulates the expression of pcoR. Furthermore, we showed that disruption of mvaT enhanced the expression of pcoI, pcoR, and rsaL, whereas MvaT controls the PcoI/PcoR QS in a RsaL-independent manner. Overall, this study elucidates that PcoR, RsaL, and MvaT regulate the PcoI/PcoR QS through a multi-tiered regulatory mechanism and that PcoR is necessary in the RsaL- and MvaT-mediated repression on the expression of pcoI. IMPORTANCE The PcoI/PcoR quorum-sensing system of Pseudomonas fluorescens 2P24 is important for its effective colonization in the plant rhizosphere. Many regulatory elements appear to directly or indirectly influence the QS system. Here, we found a complex regulatory network employing transcriptional factors PcoR, RsaL, and MvaT to influence the expression of the PcoI/PcoR QS in P. fluorescens 2P24. Our results indicate that PcoR and RsaL directly bind to the promoter region of pcoI and then positively and negatively regulate the expression of pcoI, respectively. Furthermore, the H-NS family protein MvaT negatively controls the PcoI/PcoR QS in a RsaL-independent manner. Taken together, our data provide new insights into the interplays between different regulatory elements that fine-tune the QS system of P. fluorescens.

Design of therapeutic education workshops for home haemodialysis in a patient-centered chronic kidney diseases research: a qualitative study.

RATIONALE & OBJECTIVE: A quarter of patients do not receive any information on the modalities of renal remplacement therapy (RRT) before its initiation. In our facility, we provide therapeutic education workshops for all RRT except for home hemodialysis (HHD). The objectives of this study were to identify and describe the needs of CKD patients and caregivers for RRT with HHD and design therapeutic education workshops. SETTING & PARTICIPANTS: Two sequential methods of qualitative data collection were conducted. Interviews with patients treated with HHD and doctors specialized in HHD were performed to define the interview guide followed by semi-structured interviews with the help of HHD patients from our center. ANALYTIC APPROACH: Thematic analysis was conducted and were rooted in the principles of qualitative analysis for social scientists. Data were analyzed by two investigators. Transcribed interviews were entered into RQDA 3.6.1 software for data organization and coding purposes (Version 3.6.1). RESULTS: In total, five interviews were performed. We identified six themes related to the barriers, facilitators, and potential solutions to home dialysis therapy: (1) HHD allows autonomy and freedom with constraints, (2) safety of the care environment, (3) the caregiver and family environment, (4) patient's experience and experiential knowledge, (5) self-care experience and impact on life, and (6) factors that impact the choice of treatment with HHD. We designed therapeutic education workshops in a group of patients and caregivers. CONCLUSIONS: Our study confirmed previous results obtained in literature on the major barriers, facilitators, and potential solutions to HHD including the impact of HHD on the caregiver, the experiences of patients already treated with HHD, and the role of nurses and nephrologists in informing and educating patients. A program to develop patient-to-patient peer mentorship allowing patients to discuss their dialysis experience may be relevant.

How stakeholder engagement influenced a randomized comparative effectiveness trial testing two Diabetes Prevention Program interventions in a Marshallese Pacific Islander Community.

BACKGROUND: Marshallese face significant health disparities, with particularly high rates of type 2 diabetes. Engaging stakeholders in the research process is essential to reduce health inequities. METHODS: A community- and patient-engaged research approach was used to involve community Marshallese stakeholders in a randomized comparative effectiveness trial testing two Diabetes Prevention Program interventions. RESULTS: The article outlines the engagement process and the specific influence that stakeholders had on the research planning and implementation, discussing the areas of agreement and disagreement between community and patient stakeholders and academic investigators and documenting changes to the research protocol. CONCLUSION: The article provides an example of methods that can be used to design and conduct a randomized controlled trial testing with a population who has been underrepresented in research and suffered significant historical trauma.

Are Publicly Funded Health Databases Geographically Detailed and Timely Enough to Support Patient-Centered Outcomes Research?

Emerging health care research paradigms such as comparative effectiveness research (CER), patient-centered outcome research (PCOR), and precision medicine (PM) share one ultimate goal: constructing evidence to provide the right treatment to the right patient at the right time. We argue that to succeed at this goal, it is crucial to have both timely access to individual-level data and fine geographic granularity in the data. Existing data will continue to be an important resource for observational studies as new data sources are developed. We examined widely used publicly funded health databases and population-based survey systems and found four ways they could be improved to better support the new research paradigms: (1) finer and more consistent geographic granularity, (2) more complete geographic coverage of the US population, (3) shorter time from data collection to data release, and (4) improved environments for restricted data access. We believe that existing data sources, if utilized optimally, and newly developed data infrastructures will both play a key role in expanding our insight into what treatments, at what time, work for each patient.

Patient-centred outcomes research: brave new world meets old institutional policies.

Background: Engaging patients across the research trajectory supports research that is generalizable, high quality, timely and actionable. However, this approach comes with challenges and opportunities as investigators and engaged patient stakeholders encounter institutional policies around patient engagement, privacy and research participant protection. Objective: To describe the resolution and impact of quandaries arising when patient stakeholders' values and preferences conflicted with institutional policies. Methods: Case study from a Patient-Centered Outcomes Research Institute-funded trial. Results: The first example focuses on the tension between the health care organization's requirements for background checks for all patient advisors and the funders' requirement to engage hard-to-reach populations. To create an environment of mutual trust and respect with patient stakeholders, the research team decided against imposing background checks. All 53 patient and parent advisors have served continuously for 2 years and meeting attendance exceeds 95%. The second example describes parent stakeholders' role in revising a letter informing patients about a privacy violation. Among 49 families affected by and informed about this violation, 35 (71%) agreed to participate. The third example focuses on how patient stakeholder preferences about study reminders conflict with the 1996 Health Insurance Portability and Accountability Act rules. While patient stakeholders strongly endorsed text message reminders, regulations and technology do not permit reminders with enough detail to ensure clarity. Although retention rates exceeded 90%, attendance at study appointments was below 75% and below 60% for minority and low socio-economic status families. Conclusion: Patient engagement positively impacts research. Resolving conflicts between patient-engaged research and existing institutional policies and regulations would allow this impact to become fully realized.

The Head and Neck Cancer Patient Concern Inventory© : Patient Concerns' Prevalence, Dental Concerns' Impact, and Relationships of Concerns with Quality of Life Measures.

PURPOSE: The Patient Concern Inventory© (PCI) is a clinical tool of self-reported patient concerns to be used by the clinician to structure the patient-oncologist visit. It was developed in the United Kingdom to address the issues of quality of life (QOL) in head and neck cancer (HNC) patients. The purpose of the study reported here was to determine the prevalence of PCI© items, the associations between PCI© items and QOL, and to explore the importance of oral/dental issues in the patient's well-being. METHODS: The PCI© and the University of Washington (UW-QOLv4) instruments were self-administered by an HNC population in a cross-sectional study. Following an a priori sample size estimate, consecutive HNC patients attending at the University of Florida's Oral Medicine and the ENT Clinics had the study described, eligibility assessed, and if eligible, were invited to participate in the study. Participants completed the PCI© and UW-QOL. PCI© issues prevalence was determined, and for those with a ≥10% prevalence: 1) Fisher's exact test was used to test for statistical differences between treatments, and 2) multivariable regression was used to test each of the prevalent PCI© issues across four QOL measures, health in the last 7 days, overall QOL in the last 7 days, and the physical and social domain scores. RESULTS: Twenty of 45 PCI© issues had a prevalence ≥10%. Of the 15 prevalent items statistically associated with a QOL measure, four issues are the clinical responsibility of the dental profession: 1) chewing/eating, 2) dental health/teeth, 3) mouth opening, and 4) salivation. An additional four (eight total, 50%) are of clinical concern for dental clinicians: 5) pain in head/neck, 6) swallowing, 7) speech/voice/being understood, and 8) taste. CONCLUSIONS: Dental concerns represent almost half of all PCI© concerns observed in 10% or more of the sample patients. Prosthodontists should support our maxillofacial prosthodontics specialists in joining other oral oncologists and advocate for comprehensive, integrated dental support for HNC patients by assuring dental involvement/inclusion with the multidisciplinary oncology team and a research agenda to established best patient-centered outcomes.

Oncology Nurses Can Build Patient-Centered Outcomes Research Partnerships.

Nurses can inform and lead patient-centered outcomes research (PCOR) projects that address care-related questions prioritized by patients. However, PCOR projects may fail to materialize because time constraints create barrier.

Facilitators and Barriers to Patient-Centered Outcomes Research Partnership Sustainability in the United States.

PURPOSE: Engaging patients in research can enhance relevance and accelerate implementation of findings. Despite investment in patient-centered outcomes research (PCOR), short-term funding cannot maintain such efforts beyond the program timeframe. Sustained interaction between researchers, practitioners, patients, and other stakeholders is needed to sustain use of evidence-based practices and achieve maximum benefit. While previous literature describes components of public health program sustainability, such factors do not necessarily apply to the partnerships that implement those programs, and facilitators are likely to differ across disciplines. We sought to determine facilitators and barriers to PCOR partnership sustainability from participant experiences with sustainable and unsustainable community-academic partnerships across the United States. METHODS: From 2017 to 2019, a collaboration representing public health institutes, community-based organizations, and academic organizations convened PCOR partnership members in virtual focus groups and conducted qualitative analysis to identify facilitators and barriers to partnership sustainability. A grounded theory framework, which applied a combination of a priori codes (barriers, facilitators, sustainable, not sustainable) and open coding, guided participant selection, data collection, and analysis across all project stages. RESULTS: There was no single definition of partnership sustainability. Common facilitators of sustainability were investing time in relationships, connector role to promote communication and trust, equal power dynamics, shared motivation for participation, partnership institutionalization, and reciprocity. Barriers to partnership sustainability included external factors influencing participation and operations, funding-related challenges, and lack of institutionalization. CONCLUSIONS: PCOR partnerships should incorporate an early and ongoing focus on relationship development through intentional efforts to collaborate with specific partners and stakeholders according to the goals of the research. This would allow more patients to access the evidence-based practices resulting from research investments.

Applying a Commercialization-Readiness Framework to Optimize Value for Achieving Sustainability of an Electronic Health Data Research Network and Its Data Capabilities: The SAFTINet Experience.

CONTEXT: Sustaining electronic health data networks and maximizing return on federal investment in their development is essential for achieving national data insight goals for transforming health care. However, crossing the business model chasm from grant funding to self-sustaining viability is challenging. CASE DESCRIPTION: This paper presents lessons learned in seeking the sustainability of the Scalable Architecture for Federated Translational Inquiries Network (SAFTINet), and electronic health data network involving over 50 primary care practices in three states. SAFTINet was developed with funding from the Agency for Healthcare Research and Quality to create a multi-state network for comparative effectiveness research (CER) involving safety-net patients. METHODS: Three analyses were performed: (1) a product gap analysis of alternative data sources; (2) a Strengths-Weaknesses-Opportunities-Threat (SWOT) analysis of SAFTINet in the context of competing alternatives; and (3) a customer discovery process involving approximately 150 SAFTINet stakeholders to identify SAFTINet's sustaining value proposition for health services researchers, clinical data partners, and policy makers. FINDINGS: The results of this business model analysis informed SAFTINet's sustainability strategy. The fundamental high-level product needs were similar between the three primary customer segments: credible data, efficient and easy to use, and relevance to their daily work or 'jobs to be done'. However, how these benefits needed to be minimally demonstrated varied by customer such that different supporting evidence was required. MAJOR THEMES: The SAFTINet experience illustrates that commercialization-readiness and business model methods can be used to identify multi-sided value propositions for sustaining electronic health data networks and their data capabilities as drivers of health care transformation.

Developing a team science workshop for early-career investigators.

INTRODUCTION: High impact biomedical research is increasingly conducted by large, transdisciplinary, multisite teams in an increasingly collaborative environment. Thriving in this environment requires robust teamwork skills, which are not acquired automatically in the course of traditional scientific education. Team science skills training does exist, but most is directed at clinical care teams, not research teams, and little is focused on the specific training needs of early-career investigators, whose early team leadership experiences may shape their career trajectories positively or negatively. Our research indicated a need for team science training designed specifically for early-career investigators. METHODS: To address this need, we designed and delivered a 2-day workshop focused on teaching team science skills to early-career investigators. We operationalized team science competencies, sought the advice of team science experts, and performed a needs assessment composed of a survey and a qualitative study. Through these multiple approaches, we identified and grouped training priorities into three broad training areas and developed four robust, hands-on workshop sessions. RESULTS: Attendees comprised 30 pre- and post-doc fellows (TL1) and early-career faculty (KL2 and K12). We assessed impact with a pre- and post-workshop survey adapted from the Team Skills Scale. Results from the pre- and post-test Wilcoxon signed-rank analysis (n = 25) showed statistically significant improvement in team science skills and confidence. Open-ended responses indicated that the workshop focus was appropriate and well targeted to the trainees' needs. CONCLUSIONS: Although team science education is still very much in its infancy, these results suggest that training targeted to early-career investigators improves team skills and may foster improved collaboration.

Delivering Patient Data to Patients Themselves.

Physicians need nearly a decade of training to understand complex patient data such as laboratory tests and genomic data. How can these data possibly be delivered to patients in ways that they can understand and use?

Single-subject classification of presymptomatic frontotemporal dementia mutation carriers using multimodal MRI.

Background: Classification models based on magnetic resonance imaging (MRI) may aid early diagnosis of frontotemporal dementia (FTD) but have only been applied in established FTD cases. Detection of FTD patients in earlier disease stages, such as presymptomatic mutation carriers, may further advance early diagnosis and treatment. In this study, we aim to distinguish presymptomatic FTD mutation carriers from controls on an individual level using multimodal MRI-based classification. Methods: Anatomical MRI, diffusion tensor imaging (DTI) and resting-state functional MRI data were collected in 55 presymptomatic FTD mutation carriers (8 microtubule-associated protein Tau, 35 progranulin, and 12 chromosome 9 open reading frame 72) and 48 familial controls. We calculated grey and white matter density features from anatomical MRI scans, diffusivity features from DTI, and functional connectivity features from resting-state functional MRI. These features were applied in a recently introduced multimodal behavioural variant FTD (bvFTD) classification model, and were subsequently used to train and test unimodal and multimodal carrier-control models. Classification performance was quantified using area under the receiver operator characteristic curves (AUC). Results: The bvFTD model was not able to separate presymptomatic carriers from controls beyond chance level (AUC = 0.570, p = 0.11). In contrast, one unimodal and several multimodal carrier-control models performed significantly better than chance level. The unimodal model included the radial diffusivity feature and had an AUC of 0.646 (p = 0.021). The best multimodal model combined radial diffusivity and white matter density features (AUC = 0.680, p = 0.005). Conclusions: FTD mutation carriers can be separated from controls with a modest AUC even before symptom-onset, using a newly created carrier-control classification model, while this was not possible using a recent bvFTD classification model. A multimodal MRI-based classification score may therefore be a useful biomarker to aid earlier FTD diagnosis. The exclusive selection of white matter features in the best performing model suggests that the earliest FTD-related pathological processes occur in white matter.

Patient engagement in patient-centered outcomes research: challenges, facilitators and actions to strengthen the field.

AIM: To describe challenges to and facilitators of patient engagement to inform future strategies and suggested actions to strengthen engagement. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Optimization of sagittal and coronal planes with robotic-assisted unicompartmental knee arthroplasty.

BACKGROUND: One of the anatomic goals of total knee arthroplasty (TKA) is optimizing in the coronal and sagittal plane. Accurate alignments of both planes have been correlated to functional outcome and range of motion. There is a paucity of evidence on the accuracy of unicompartmental knee arthroplasty (UKA) in balancing biplanar knee alignment - specifically sagittal plane alignment. Because robotic assisted UKA has an advantage of more accurately manipulating sagittal plane for optimal alignment and kinematics based on pre-operative and intraoperative CT planning we assessed the accuracy. METHODS: We reviewed the clinical and radiographic information of 94 robotic assisted UKA surgeries for balancing of sagittal and coronal knee anatomy using radiographic parameters, such as posterior condylar offset ratio (PCOR), posterior tibial slope (PTS), femoral-tibial angle, and joint line. RESULTS: In the sagittal plane, we found no significant difference between pre and postoperative PCOR values. As planned, PTS was significantly lower after UKA compared to the native knee (4.91° vs 2.28°; p<0.0001). In the coronal plane, there was no significant difference in the joint line however pre and post-operative mechanical axis were significantly different (5.43°±2.58 of varus vs. 2.76°±2.14 of varus; p<0.0001). CONCLUSION: This study attempts to quantify sagittal and coronal plane alignment after robotic assisted UKA. More attention should be paid to the role of sagittal plane alignment after UKA. We believe modifying posterior tibial slope, while maintaining PCOR is fundamental in achieving native kinematics and optimizing range of motion in the sagittal plane. This may be best-accomplished using robotic techniques for UKA.

Patient engagement and study design of PROP UP: A multi-site patient-centered prospective observational study of patients undergoing hepatitis C treatment.

BACKGROUND: New highly efficacious direct-acting antiviral (DAA) therapies are available to treat chronic hepatitis C viral (HCV) infection. Real-world, patient-centered data on harms and benefits associated with these therapies are needed. METHODS: PROP UP is a multi-center prospective observational study that plans to enroll 1600 patients starting treatment with recently-approved DAA regimens. Informed by extensive input from a HCV patient engagement group who prioritized outcomes most important to them, patient-reported outcomes will be characterized using surveys at five time points: Baseline (T1), treatment week 4 (T2), end of treatment (T3), 12weeks post-treatment (T4), 12months post-treatment (T5). OUTCOMES: (1) Changes in side effects, functioning, pre-existing conditions, and out-of-pocket costs during therapy (T1 vs T2/T3); (2) Medication adherence in relation to a history of mental health/substance abuse, treatment regimens, pill burden, reasons for missed doses, and cure rates; (3) Short term impact of cure on functioning and amelioration of symptoms (T1 vs T4); (4) Long-term treatment harms or benefits of cure on symptoms, side effects, pre-existing conditions, and functioning (T1 vs T5). Similarities between regimens will be examined where comparisons are appropriate and meaningful. CONCLUSION: PROP UP complements previous clinical trials by focusing on patient-reported outcomes in a representative sample of patients treated in clinical practice, by collaborating with a patient engagement group, by characterizing the experiences of vulnerable subgroups, and by investigating long-term harms and benefits of treatments. PROP UP is designed to provide novel and detailed information to support informed decision-making for patients and providers contemplating HCV treatment (PCORI CER-1408-20,660; NCT02601820).

Methods for Incorporating Stakeholder Engagement into Clinical Trial Design.

CONTEXT: Lack of engagement with healthcare stakeholders results in missed opportunities to understand translation of evidence into practice. CASE: Stakeholder engagement is a key component of the Comparing Outcomes of Drugs and Appendectomy (CODA) Study, a pragmatic clinical trial funded by PCORI to evaluate the effectiveness of antibiotics versus urgent appendectomy for acute uncomplicated appendicitis. We provide a framework for developing a stakeholder coordinating center (SCC) and describe two examples of how stakeholder engagement can inform study development. FINDINGS: Coordinating engagement activities through the SCC established a commitment to the important partnership with stakeholders. It also facilitated communication and provided a central mechanism for obtaining input on key decisions such as development of patient-centered consent documents and appropriate stopping rules for a specific sub-population of patients with appendicitis. MAJOR THEMES: Translatable lessons include thoughtful planning for engagement, identifying stakeholders with a direct interest in the study conduct and findings, and integration of input received into the decisions that drive the conduct of the study. CONCLUSIONS: Standards for conducting patient-centered research should address the ability to successfully engage patients by demonstrating the capacity to recruit study participants, engage them over the duration of the study, and disseminate findings that are congruent with stakeholder needs. The process of sharing important clinical research findings has improved patient care, and we believe that dissemination of novel engagement strategies can lead to increased success in study design and execution.

Bidirectional Data Collaborations in Distributed Research.

INTRODUCTION: The need for collaborations with bidirectional data exchange within and across distributed research networks has increased. CURRENTLY EXISTING ACTIVITIES: This commentary will present currently publically available activities including the Sentinel Initiative, the Patient-Centered Outcomes Research Network (PCORnet), and the NIH Research Collaboratory. CURRENT TECHNICAL AND GOVERNANCE CHALLENGES: Even with the advances made in this arena, several technical and governance challenges remain including the evolution of clinically rich data sources and modes of care, availability of longitudinal data resources through data linkage, and the processes to share data and link data resources while ensuring privacy and proprietary control of data. PERSPECTIVE: These activities will require enhanced levels of trust between entities involved in the delivery of healthcare (Trust 2.0) in addition to the trust health plans and health systems have with patients (Trust 1.0). Recent public funding announcements and public access to data resources will likely improve the landscape of bidirectional data collaborations in distributed research.

Model for a patient-centered comparative effectiveness research center.

This special report describes the systematic approach the University of Pittsburgh and the University of Pittsburgh Medical Center (UPMC) undertook in creating an infrastructure for comparative effectiveness and patient-centered outcomes research resources. We specifically highlight the administrative structure, communication and training opportunities, stakeholder engagement resources, and support services offered.

Evaluating patient and stakeholder engagement in research: moving from theory to practice.

Despite the growing demand for research that engages stakeholders, there is limited evidence in the literature to demonstrate its value - or return on investment. This gap indicates a general lack of evaluation of engagement activities. To adequately inform engagement activities, we need to further investigate the dividends of engaged research, and how to evaluate these effects. This paper synthesizes the literature on hypothesized impacts of engagement, shares what has been evaluated and identifies steps needed to reduce the gap between engagement's promises and the underlying evidence supporting its practice. This assessment provides explicit guidance for better alignment of engagement's promised benefits with evaluation efforts and identifies specific areas for development of evaluative measures and better reporting processes.

Translating comparative effectiveness research into Medicaid payment policy: views from medical and pharmacy directors.

BACKGROUND: As the USA seeks to expand the conduct and dissemination of comparative effectiveness research (CER), views of key stakeholders will help guide the way. METHODS: We surveyed 60 medical and pharmacy directors from 46 state Medicaid programs. RESULTS: Over 90% felt that CER would lead to better clinical decision-making and overall value within 5 years and were willing to consider cost-effectiveness in setting medical policy. However, perceived poor quality, inconclusive research, restrictive legislative mandates, lack of budget impact and coverage recommendations, and lack of an independent body to interpret study results were major barriers cited to using CER evidence. CONCLUSION: Given the significant resources being invested in CER, it is critical that these barriers are overcome to maximize its usefulness for stakeholders.