Chronic knee pain (CKP) affects a large number of adults, many of whom do not receive best-practice care and are at high risk for unnecessary surgery.The aim of this study was to investigate the effect of the Hinge Health 12-week digital care program (DCP) for CKP on knee pain and function, with secondary outcomes of surgery interest and satisfaction, at 12 weeks and 6 months after starting the program.Individuals with CKP were recruited onto the 12-week program, comprising sensor-guided physical exercises, weekly education, activity tracking, and psychosocial support such as personal coaching and cognitive behavioral therapy (CBT). We used a single-arm design with assessment of outcomes at baseline, 12 weeks, and 6 months after starting the program. We used a linear mixed effects model with Tukey contrasts to compare timepoints and report intention-to-treat statistics with last observation carried forward.P<.001) and 10 points , respectively. Significant reductions of 57%  and 51%  in visual analog scale (VAS) knee pain and stiffness, respectively, were observed at 12 weeks, as well as a 67% reduction in surgery interest . Average satisfaction at week 12 was 9.2 out of 10. Critically, all improvements were maintained at 6 months at similar or greater magnitude.The cohort consisted of 41 individuals . Between baseline and week 12, participants reported clinically significant improvements in the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain and Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form (KOOS-PS) function scales of 16 points (95% CI 12-21, Participants on the Hinge Health DCP for CKP showed substantial clinical improvements that were maintained 6 months after enrolling in the program. This shows that DCPs carry strong potential to deliver evidence-based, cost-effective care to those suffering from CKP. Chronic knee pain (CKP) is one of the most common health conditions  and is aThe lack of widespread best-practice conservative care for those suffering from CKP drives patients toward total knee arthroplasty (TKA), an expensive intervention which almost doubled in rate between 2000 and 2010 in the United States . FurtherA digital care program (DCP), whereby each facet of evidence-based care is digitized, aims to deliver care more efficiently, effectively, and in a way that would improve outcomes while decreasing costs. In particular, a DCP for CKP administered remotely would allow patients access to the program at any time and place, provide a single touchpoint for every aspect of care, enable rich data collection on patient behavior and progress, and drastically reduce the marginal cost of additional patients receiving treatment. Furthermore, as poor adherence can limit long-term effectiveness of a program for CKP , a DCP iThe American College of Rheumatology recommends those suffering from CKP to participate in cardiovascular and strengthening exercise, self-management training, psychosocial intervention, and weight loss for overweight patients . In lineThe aims of this study were to (1) determine the change in pain and function between baseline and follow-up (week 12 and 6 months) in participants in the 12-week Hinge Health DCP and (2) assess changes in surgery interest and patient satisfaction between baseline and follow-up.We used a single-arm design with patient-reported outcome measures (PROMs) collected before starting the program (“baseline”), at the end of the 12-week program, and at 6 months after starting the program.The 12-week Hinge Health DCP was deployed at two sites in the United States, both of which compensated Hinge Health for the deployment. All potential participants were employees of a self-insured employer, covered by their medical plan. Potential participants were recruited by email, letters mailed to their home address, and fliers posted in the workplace, and were screened for inclusion by Web-based questionnaire. For inclusion, subjects had to provide written informed consent, have lived with knee pain for at least 3 months in the past 12 months, and had to meet at least 2 of the following additional inclusion criteria derived from the American College of Rheumatology criteria for OA of the knee [An a priori sample size calculation was performed for comparing the primary outcomes of pain and function. Using an alpha level of .05, a power of 0.8, and a medium effect size of 0.5, 33 subjects were needed. Recruitment of 41 participants accounted for a potential dropout rate of 20% over the course of the study. As there were a limited number of places available on the program, we invited eligible applicants on a first come, first serve basis. Users were not compensated for their time, but could participate in the program free of charge.The Hinge Health DCP is a 12-week program  which aiParticipants had a weekly exercise repetitions goal for sensor-guided exercises, which increased over the course of the program. Approximately 15 min of stretching and strengthening exercise for 3-4 days per week was sufficient to reach their weekly goal. Specifically, we provided the following sensor-guided exercises: standing quad stretch (pulling heel toward buttocks), seated quad stretch (pull leg toward chest), half squats, forward lunges, leg raise , seated leg raise , and hamstring stretch . The app tracked the execution of the exercises and provided real-time feedback to the user to ensure that the exercises were performed correctly. Before starting a new exercise, a narrated video showed correct execution, and this video remained available to the participant throughout the program. Crucially, the sensors afforded an objective avenue to monitor adherence.Education articles were presented once per week, for a total of 12 education articles, each requiring approximately 10-20 min of reading. Each article consisted of approximately 6 pages, and we tracked consumption of each page. A piece of education was marked complete if the participant reached the final page of the article.Participants were asked to log their pain and stiffness symptoms on a visual analog scale (VAS) at least twice a week, alongside any treatments they had been using for their knee. Participants were prompted to fill out questionnaires at predetermined timepoints in order to track PROMs. The specific timepoints for each PROM are outlined below.A self-report activity tracker helped log any physical activity they performed during the week, encouraging at least three 30-min sessions per week of low-impact exercise.pacing activity levels), whereas others were provided based on data provided by users: the weight loss CBT for participants with a body mass index >25 kg/m2; the coping with pain CBT for users with a score greater than 30 on the pain catastrophizing scale; the low mood and anxiety CBT for participants with a score of 10 or higher on the Hospital Anxiety and Depression Scale (HADS), respectively.CBT modules were provided. One was provided to all users . Participants communicated with the coach through the tablet app, phone, SMS, or email. The participants could initiate a conversation at any time and the coach would respond within the same day. Moreover, the coach sent weekly messages to introduce the week’s education, provide feedback on completed CBT modules, send an overview of the participant’s performance in the previous week, and encourage the user to attend to their weekly goals on Wednesdays and Fridays, if the participant was behind on their goals.We used the Knee Injury and Osteoarthritis Outcome Score (KOOS) 9-question pain subscale ,35, as wParticipants reported on their knee pain and function by completing VAS questions at baseline (screening) and twice per week during the program, asking “Over the past 24 h how bad was your knee pain?” and “Over the past 24 h how bad was your knee stiffness?” respectively. The left pole was set to 0 and contained the text “none,” and the right pole was set to 100 and contained the text “worst imaginable.” Unlike other PROMs, VAS reports were optional in the app. To assess overall satisfaction with the program, we asked “On a scale of 0-10, how likely is it that you would recommend the Hinge Health program to a friend or colleague?” at week 6 and week 12. We tracked participants’ self-reported likelihood of undergoing knee surgery at baseline (screening), week 6, and week 12 of the program by asking “On a scale from 0 to 10, how interested are you in knee surgery?” All secondary outcomes were also assessed at 6-month timepoint.intention-to-treat statistics with last observation carried forward. We used a linear mixed effects model implemented through LME4 [P value. P values <.05 were considered significant. We also examined the per protocol results. Due to the low dropout rate, these results were not meaningfully different from the intention-to-treat results and are therefore not reported here.We report ugh LME4  and implugh LME4  in the s2, and predominantly female. At baseline, 66% (27/41) of users were not doing any physical therapy-style exercise and 54% (22/41) were active 90 min or less per week including walking, suggesting a predominantly sedentary lifestyle. There were no significant differences in any of the demographics or baseline data between those who completed the PROMs at 6 months and those who did not .Demographics of participants are presented in Engagement across each of the relevant goals provided to participants in the program are shown in P<.001) that were maintained at 6 months . Knee function also significantly improved at 12 weeks  and was maintained at 6 months .Participants reported highly significant improvements on the KOOS pain subscale (P<.001) and 51% reduction in knee stiffness (P<.001). These improvements were maintained at 6 months for both knee pain  and stiffness .Between baseline and week 12, participants reported a 57% reduction in knee pain (P<.001). At 6 months participants still expressed low interest in surgery . Of the 17 participants at high risk of surgery at baseline—defined as a surgery interest of 5 or higher—by week 12 only 3 remained at high risk. At 6 months, still only 3 remained at high risk for surgery, 2 of whom also were at high surgery risk at week 12, and 1 of whom had moved into the high-risk category between week 12 and 6 months.Surgery interest significantly decreased over the course of the program from 3.5 out of 10 at baseline to 1.2 out of 10 at 12 weeks . By 6 months, the average rating was 9.3 (SD 1.1).Although CKP is a common cause of severe chronic pain and disability affecting millions of individuals, accessible comprehensive treatment programs that address multiple components of care are lacking. The challenges to effectively delivering a program involving physical therapy, education, and psychosocial support are diverse and substantial—including time constraints on primary care appointments, paucity of reimbursement for education, and lack of awareness of the psychosocial risk factors that impact outcomes for CKP. Moreover, there are significant practical and cost barriers faced by the patient—such as traveling to physical therapy appointments, large patient costs, sourcing and paying for childcare, or having to seek out education and psychosocial support on their own. Finally, tracking outcomes and program adherence is difficult if not impossible in the traditional outpatient setting, and there is a distinct lack of technology-enabled solutions for patients. The results of this study demonstrated that the Hinge Health 12-week DCP for individuals with CKP produced clinically and statistically significant improvements in knee pain, stiffness, and function that lasted over a period of 6 months following initiation of the 12-week program, and were accompanied by a significant reduction in surgery interest as well as high satisfaction. Furthermore, the digitization of exercise therapy allowed for precise tracking of participation and adherence, showing that on average participants completed exercise therapy between 3 and 4 days each week.Participants’ KOOS pain and function scores improved by clinically significant 16 and 10 points, respectively, at the end of the 12-week program. Similarly, VAS pain and stiffness scores improved by clinically significant 58% and 50% at the end of the 12-week program. These improvements are greater than or of similar magnitude to other treatment programs that have shown efficacy for CKP, including a 12-week graded physical activity exercise program which found improvements in WOMAC pain and function of 25% and 22%, respectively, immediately after program completion ; an 8-weThe clinically significant improvements in KOOS pain and function in this study were maintained at 6 months after starting the program, with improvements of 18 and 14 points, respectively. Similarly, the improvements in VAS pain and stiffness scores were maintained, with improvements of 60% and 58% at the 6-month timepoint, respectively. These results suggest strong maintenance of effect of the program. Similar long-term effects have been reported in other intervention programs of similar length ,12,39-41The results of this study demonstrate that the Hinge Health DCP shows promise for providing participants with a program to effectively manage their CKP condition. However, this study has several limitations. This was a single-arm study without blinding of the participants, and thus any placebo effect, for example, due to simply being accepted into the program, or regression to the mean was not able to be evaluated. Future work with a more rigorous study design such as a randomized, controlled trial as compared with standard care or multiple baseline trial will be needed to better understand the effect of the program as compared with standard care. Although the sample size was relatively small, the results demonstrated large effect sizes for primary outcomes which showed highly significant results and should be confirmed in larger future studies.The study enrolled participants with self-reported CKP, but did not require a physician-diagnosis of knee OA. However, our recruitment questionnaire utilized questions specific to clinical diagnosis for knee OA derived from the American College of Rheumatology criteria for OA of the knee , and ourP<.001) and stiffness . Deyle et al [Study results showed good subject engagement with exercise and education. However, due to the comprehensive nature of the program, it is not possible to determine if all components of the program are integral to the study results. As shown in le et al ,40,49, tThe results of this study demonstrated clinically and statistically significant improvements in pain, function, and stiffness following a 12-week digitally based program designed to address multiple components of care for CKP. Although the initial results with this program are promising, future research will be needed to understand the long-term effects of the program. Due to the adaptability of the system, future work may also investigate the effect of a similar program on other chronic pain conditions such as lower back pain.In conclusion, the results of this pilot study of the 12-week digital Hinge Health DCP demonstrate improvements in knee pain, stiffness, and function which were maintained to 6 months after enrollment into the program. The program greatly reduced surgery interest in participants, providing strong evidence that the program may be an effective intervention to delay or significantly reduce the incidence of more invasive and costly treatments for CKP such as surgery.


Secondary school students  responded to a subjective outcome evaluation form to assess their views of the program, workers , and perceived effectiveness of the program. Results showed that high proportions of the respondents had positive perceptions of the program and the instructors, and more than four-fifths of the respondents regarded the program as helpful to them. While schools admitting students with different academic abilities and hours did not differ in the subjective outcome evaluation ratings, subjective evaluation ratings for workers were highest, followed by ratings for the program and perceived effectiveness. The present study replicates the previously reported findings and provides additional support for the effectiveness of the Tier 1 Program of the Project P.A.T.H.S.  in Hong Kong.


Over the last two decades, there has been a concerted effort in North America to organize medical physicists’ clinical training programs along more structured and formal lines. This effort has been prompted by the Commission on Accreditation of Medical Physics Education Programs (CAMPEP) which has now accredited about 90 residency programs. Initially the accreditation focused on standardized and higher quality clinical physics training; the development of rounded professionals who can function at a high level in a multidisciplinary environment was recognized as a priority of a radiation oncology physics residency only lately. In this report, we identify and discuss the implementation of, and the essential components of, a radiation oncology physics residency designed to produce knowledgeable and effective clinical physicists for today's safety‐conscious and collaborative work environment. Our approach is that of inverse planning, by now familiar to all radiation oncology physicists, in which objectives and constraints are identified prior to the design of the program. Our inverse planning objectives not only include those associated with traditional residencies , but also encompass those other attributes essential for success in a modern radiation therapy clinic. These attributes include formal training in management skills and leadership, teaching and communication skills, and knowledge of error management techniques and patient safety. The constraints in our optimization exercise are associated with the limited duration of a residency and the training resources available. Without compromising the knowledge and skills needed for clinical tasks, we have successfully applied the model to the University of Calgary's two‐year residency program. The program requires 3840 hours of overall commitment from the trainee, of which 7%–10% is spent in obtaining formal training in nontechnical “soft skills”.PACS number(s): 01.40 Di, 01.40.gb, 87.10‐e Code of Ethics for the American Association of Physicists in Medicine in 2009, and the Report of Task Group 159: Recommended ethics curriculum for medical physics graduate and residency programs in 2010. The American Board of Radiology Foundation released its online Ethics and Professionalism Program in 2011.With the recent requirement by the American Board of Radiology that candidates for the certification examination must have completed a CAMPEP accredited residency, there has been a concerted effort across the continent to formalize both the structure of residency programs themselves as well as the standards against which they are assessed. On a similar timescale, there has been increasing emphasis on topics such as ethics and professionalism and patient safety. The AAPM published the Report of Task Group 109: Clearly, the primary focus of a medical physics residency program is, and should continue to be, to develop a high level of clinical physics competency in the graduating resident.The CanMEDS Physician Competency Framework describes the knowledge, skills and abilities that specialist physicians need for better patient outcomes. The framework is based on the seven roles that all physicians need to have, to be better doctors: Medical Expert, Communicator, Collaborator, Manager, Health Advocate, Scholar, and Professional.More recently the American Board of Radiology has listed six essential competencies for maintenance of certification for both physicians and physicists: medical knowledge; patient care and procedural skills; interpersonal and communication skills; professionalism; practice‐based learning and improvement; systems‐based practice. While these competencies are currently only expected to be exhibited at the time of recertification, can it be more than a matter of time before the graduating resident will be required to provide evidence of grounding in these competencies? Indeed, these core competencies are now receiving prominence in the AAPM's Report 249, the latest revision of the Guidelines for medical physics residency programs.http://www.astro.org/Meetings-and-Events/Pilot-Leadership-Course/Course-Program/Course-Curriculum.aspx). LeadershipMore recently still the American Society for Radiation Oncology has introduced a Disciplines of Leadership course for members who already have or aspire to leadership roles in Radiation Oncology .http://www.ucalgary.ca/rop/). The University of Calgary is a comprehensive university offering the full range of undergraduate and graduate degrees including medicine. In addition to a CAMPEP accredited Residency Program, accredited MSc and PhD programs were also offered.At the time of development of the residency program described here, the Medical Physics Department at the cancer center supported the treatment of approximately 2400 new patients per year on nine megavoltage units. Most modern treatment techniques, including low‐ and high‐dose‐rate brachytherapy, IGRT, TBI and motion management, were — and still are — routinely available. There were 11 medical physicists in the Department, all certified by the Canadian College of Physicists in Medicine and all of whom had an academic appointment at some level within the Department of Oncology and/or Department of Physics and Astronomy at the University of Calgary .To comply with CAMPEP requirements for accreditation of a residency program. The development described here was undertaken in 2007 prior to the introduction of the new CAMPEP standards . This knowledge must be organized into strategically planned curricula and linked to specific objectives. Finally, incorporating regular and rigorous assessment will determine the degree to which an individual attains the required level of knowledge and performance. The major courses and practica listed below systematically improve both knowledge and skill by progressing upward on Miller's pyramidFortunately, we can use, as the required knowledge base, the plethora of published literature in medical physics in the forms of review articles, task group reports from the AAPM, and other procedure specific documents (MDPH 711(/712)* — Clinical Competency 1 (/2): These structured courses extend over the first (/second) year of the residency and consist of rotations through areas of clinical physics, with extensive reading lists, under the supervision of faculty. Rigorous oral evaluations take place throughout these courses.MDPH 731* — Radiation Oncology Physics Tutorials: This course requires the resident to prepare written answers to 120 preset questions published by the Canadian College of Physicists in Medicine as part of the certification process in Radiation Oncology Physics in Canada. The course is conducted in a tutorial setting, with examinations and evaluations carried out periodically.MDPH 741 * — Treatment Planning: This course has three components. The first component is the observation of simulation and localization under the supervision of a radiation oncologist. The second component is an in‐depth study of treatment planning physics. Human anatomy and physiology is refreshed by using Web‐based tools (such as free YouTube lectures from UC Berkley website). The final component involves following 10 patients through their entire radiation therapy course, from immobilization to treatment delivery. The resident's progress is evaluated throughout the course with regular written and oral exams.The graduating resident will be expected to have acquired more extensive hands‐on experience with the technology and techniques of modern radiotherapy than can be gained during the clinical competency courses which provide merely an overview. The acquisition of critical clinical skills is accomplished through several mechanisms. Firstly, all residents take responsibility, under supervision, for routine quality control on accelerators, simulators, and other equipment over the full two years of the residency. After a short introduction period, each resident is assigned a routine clinical task such as quality control of one of the linear accelerators. Every resident contributes to annual quality control. Rotation around clinical tasks is encouraged and expected to maximize the exposure of the resident to the range of equipment and techniques in the clinic. Secondly, two formal numbered and structured University of Calgary project courses are required components of the residency. Lastly four practica are taken over the two summers of the residency.712/722*. Two to three short term clinical projects are completed during each course extending over the first (/second) year of the program. Projects with immediate clinical relevance, such as a contribution to the commissioning of a new machine, and with clearly defined objectives are offered by the faculty. The projects culminate in written reports, oral presentations, and occasionally a journal publication. The resident's performance is formally evaluated against the objectives established at the commencement of each project.MDPH Clinical experience is augmented by four structured supervised practica, taken over the two summers of the program: two in treatment planning and another two in diagnostic imaging. There were three reasons for incorporating a post‐PhD Diploma program within the two‐year residency. The first was to formalize recognition of the faculty for their contributions to this advanced level of training and the associated demands on the faculty. For the purposes of academic promotion and career progression, contributions to numbered courses in the University of Calgary calendar carry much more weight than ad hoc informal teaching activities. Secondly, as described below, it was necessary to formalize the relationship between the residency program and the UofC in order to access the heavily oversubscribed Masters in Business Administration courses required to meet Objective 3. Finally, alignment with University standards enforces a degree of rigor on both faculty and trainees in terms of timely completion of the individual course requirements, thorough documentation and evaluations both by, and of, the trainee.A Diploma program at the University of Calgary requires equivalent of 10 credit courses . The courses described under Objective 1 above (and identified by *) constituted six of the required eight courses, with the two remaining being the business courses described below. While incorporation of the post‐PhD Diploma did confer benefits on the residency program, it came with its own constraints such as scheduling courses in synchrony with the University's semester system. It was felt that adequate exposure to treatment planning and the many imaging devices necessary for modern radiotherapy could not be accomplished within the constraints of the Diploma structure. For that reason, two practica were scheduled for each of the two summers of the residency program.Introduction to these management topics is addressed primarily through the two graduate business courses offered through the University of Calgary's Haskayne School of Business Masters in Business Administration program.HROD 793* — Business Negotiations: The major concepts and theories of negotiation, dynamics of interpersonal and intergroup conflict, and analysis of negotiation strategies and individuals’ styles are discussed, along with simulations and applications from various areas.HROD 789* — Optimizing Team Dynamics is designed for those who will be leading or working in teams in environments where success depends on effective teamwork and the ability of team members to integrate disparate knowledge bases.Participants in these courses include leaders from industry and government, as well as from the health care sector. MBA courses in most universities are oversubscribed and hence do not accept “walk‐ins”. Approval of the Post‐PhD, Diploma program followed by negotiation with the Business School led to the allocation of guaranteed slots for our residents.Systematic treatment of errors and uncertainties have evolved only recently from cross marriage from safety and reliability engineering. However, it has received little attention in the training programs of not just medical physicists, and has been identified as a major shortcoming in allied residencies’ models.The course has been described elsewhere.http://tlc.ucalgary.ca/teaching/programs/isw). Many of our trainees were sufficiently motivated to pursue the University of Calgary teaching certificate which requires further study, culminating in an assessment of the resident's teaching skills in a classroom setting. Following completion of the Instructional Skills Workshop, the resident is then assigned to teach about 20 to 36 hours of graduate classroom teaching, , and teaching other professionals.Residents are required to take an Instructional Skills Workshop through the University of Calgary  course was developed to engage trainees in these topics and included role playing to demonstrate some of the more common pitfalls when practicing these activities.The program has included all the components listed above since 2007, with the exception of the “soft skills workshop” which was added in 2012. The presence of structure through the university system provides a framework for formal evaluations and improvements to the training program for most of the components. All components are evaluated by the residents and any comments made are used to modify the program when possible. We conclude from both formal and informal evaluations that the program has been well received by the residents.Reconfiguring this residency program, whilst maintaining a solid core of clinical competency development, was predicated on several premises. Firstly, faculty who engage in training should be formally recognized for such activities. This is particularly important for junior staff seeking career progression and is best accomplished through university calendar courses that are evaluated according to university procedures.The clinical physicist may discharge many of her duties alone, such as machine quality control and plan checking. While these core activities are necessary to maintain safety and qualityNext, training programs need to acknowledge ethical behavior and professionalism as fundamental attributes of medical professionals.Finally, education and training of others, whether it be through in‐services, graduate level courses or resident mentoring, are expected as important activities of the majority of medical physicists. Only 20% of internal medicine residency program formally train their residents in teaching skills;A constraint that was not identified at the start of development of this program was the additional financial burden of enrolling in a university program. This was the price of meeting optimization Objectives 2 and 3. The cost of the post‐PhD Diploma embedded in the residency program is approximately $10,000 over two years, with most of this fee resulting from the two MBA courses ($8000). Applicants to the program have to decide whether or not the additional features of this program justify the additional cost. However, to put this cost in today's education and training context for medical physics, a Certificate program, lasting a year or less, costs between $8000 and $15,000, while the residency component of a Doctorate in Medical Physics Program has similar costs for the resident, however, per year. Providing exposure to residents regarding formal management skills and decision‐making processes during a training program opens new venues where an enthused trainee can hone his/her skills by going through a full professional degree program such as MBA. Moreover, if in future the medical physics discipline needs to incorporate the leadership and management skills as part of a formal degree program, one can extend the residency program to a three‐year MBA/Post‐PhD diploma.A program has been developed and implemented which met the tested and tried objectives from medicine and allied residenciesCreative Commons Attribution 4.0 International License.This work is licensed under a


In particular a methodof direct computation of arrays of Franck-Condon factors for “Morse”molecules by numerical integration using an electronic computer program was described andnn-Runge  and N2+(∏u−A2Πu)  systems.In the present paper further results from the use of this program are presented for bandsystems of a number of diatomic oxides.eω, exe,re, μAυωmaxfor both states of the transition involved. The notation is standard [1Π–X1Σ+)SiO: (A1Σ–A1Π)MgO: (B1Σ–X1Σ)MgO: (B1Σ–X1Σ)SrO: (A2Σ+–X2Σ+)AlO:(A2Δ–X2Δ)VO: (Aβ:(B2Π–X2Π)NOγ:(A2Σ+–X2Π)NOsomeof which  are of importance in the spectra of stellar envelopes[The computations were performed upon the 704 electronic digital computer of the NationalBureau of Standards using a program written by Miss I. Stegun and Miss R. Zucker of thecomputation laboratory. The input data for this program arestandard . The tranvelopes andothenvelopes.υmax entries correspond to the highestspectroscopically identified vibrational level of the electronic state involved.The basic input data for these transitions is listed in The eight Franck-Condon factor arrays appear in Most of the band systems reported here were studied because of a need to interpret in ourlaboratories spectra produced by shock excitation of powdered oxides .As has It was pointed out in (I) that the prime limitation in the use of such tables is therealism of the Morse model for the respective molecular potentials involved. Such tables as2 to 9 are therefore to some extent interim results to be used until comparable tablesderived from wavefunctions from numerical “real” molecular potentials becomeavailable [er, the narrower is the primary parabola and thefewer subsidiary loci, while the larger Δer the widerthe primary parabola and the more subsidiary loci. Both extremes, and some intermediatecases, are to be seen in er is largest (0.26A) in the case of theNOβ system for which the primary parabola is wide and its vertexis far removed from the origin. The O2 Schumann-Runge system [1Σ–X1Σ) system has a narrowprimary locus. TheA10(A2Σ+–X2Σ+) system(Δer=0.049A) is a somewhat similar, though lessextreme case.The profiles of primary and subsidiary Condon loci are indicated. They exhibit the samegeneral patterns as were noted in (I); viz: the smallerΔe system  is a comv′, v″ plane) of theseloci has obvious important applications to the definitive identifications of bands. Somepreliminary remarks were made in (I) on a study of the geometry of the loci which iselaborated upon more fully elsewhere [Knowledge of the profiles  and other states of N2 and In addition to the results quoted in (I) and in this paper, the computer program has alsobeen used to evaluate e system,the N2+u system and a nuu system. It alsoIn the case of SiO, where an analytic method has also been used to compute a limited array(for application to shock tube spectra) agreemen


This paper reports the results of a qualitative study that explored the administration and implementation of the Tier 1 Program (Secondary 1 Curriculum) of the Project P.A.T.H.S. The case study method was used to explore perceptions of the teachers and the project coordinator of program effectiveness, and to identify various factors for program success. A school admitting high academic achievers was selected, and site visits, as well as individual and focus group interviews, were conducted with the program coordinator, social worker, and course teachers. The results suggested that clear vision and program goals, high quality of curriculum, helpful leadership, positive teacher attitude, and strong administrative support are factors for program success. Analyzing the data enables the researchers to understand the characteristics of a successful program as well as the interplay among factors for producing success.


A pituitary adenylate cyclase-activating polypeptide (PACAP)-specific receptor, PAC1R, is coupled with multiple signal transduction pathways including stimulation of adenylate cyclase, phospholipase C and extracellular-signal regulated kinase (ERK)1/2. PAC1R has been shown to exert its long-lasting and potent signals via β-arrestin1 and β-arrestin2. However, the precise roles of the two β-arrestin isoforms in PACAP-PAC1R signaling remain unclear. Here we examined the interaction between the two β-arrestin isoforms and PAC1R, β-arrestin-dependent PAC1R subcellular localization and ERK1/2 activation. Upon PACAP stimulation, although PAC1R similarly interacted with β-arrestin1 and β-arrestin2 in HEK293T cells, the complex of PAC1R and β-arrestin2 was translocated from the cell surface into cytosol, but that of β-arrestin1 remained in the cell surface regions in HeLa cells and mouse primary cultured neurons. Silencing of β-arrestin2 blocked PACAP-induced PAC1R internalization and ERK1/2 phosphorylation, but silencing of β-arrestin1 increased ERK1/2 phosphorylation. These results show that β-arrestin1 and β-arrestin2 exert differential actions on PAC1R internalization and PAC1R-dependent ERK1/2 activation, and suggest that the two β-arrestin isoforms may be involved in fine and precise tuning of the PAC1R signaling pathways. Pituitary adenylate cyclase-activating polypeptide (PACAP)  is a mulPAC1R belongs to a class B G protein-coupled receptor (GPCR) family, which couples to Gs and Gq proteins and can stimulate several transduction pathways such as adenylate cyclase, phospholipase C, intracellular calcium increase, p38 and/or extracellular-signal regulated kinase (ERK)1/2 signaling pathway , 17. PreThe PACAP-induced ERK1/2 signaling pathway is considered to have two major pathways, the G protein-dependent signaling pathway leading to inositol phosphate (IP) accumulation and calcium release, and the G protein-independent signaling pathway that involves recruitment of β-arrestins . May et Two nonvisual β-arrestins, β-arrestin1 (arrestin2) and β-arrestin2 (arrestin3), together with two retinal isoforms, visual arrestin (arrestin1) and cone arrestin (arrestin4), belong to a superfamily of scaffolding proteins and act as multifunctional adaptor proteins that regulate GPCR signaling pathway –23. β-ArLyu et al. have previously identified distinct C terminus regions of PAC1R that are required for signal transduction (adenylyl cyclase and phospholipase C responses) and receptor internalization . HomologIn this study, we have addressed the roles of the two β-arrestin isoforms that regulates PAC1R internalization and trafficking as well as their involvement in the ERK1/2 activation.PACAP (PACAP-38) was purchased from Peptide Institute . H89 and CMPD101 were purchased from Tocris Bioscience . D-sphingosine and Concanavarin A (ConA) were purchased from Sigma-Aldrich  and Pitstop 2 (ab120687) was purchased from Abcam .PAC1R cDNA (accession ID: NM_001199635) was subcloned into the pFN21A vector  at SgfI and PmeI restriction sites. Arginine vasopressin receptor (AVPR2), β-arrestin1 and β-arrestin2 cDNAs were purchased from Flexi ORF clone book . For construction of NanoBiT system (Promega) to detect protein-protein interaction between PAC1R and the two β-arrestin isoforms, the PAC1R cDNA was subcloned into the pFC36K vector to generate PAC1R-SmBiT and the β-arrestin1 and β-arrestin2 cDNAs were into both the pFN33K and pFC34K vectors to generate both N-terminal and C-terminal LgBiT-fused β-arrestin1 and 2  using SgfI plus PmeI or EcoICRI restriction sites. As AVPR2 is known to interact with β-arrestin2 .We examined whether β-arrestin1 and β-arrestin2 are implicated in the PAC1R internalization by time-lapse cell imaging to visualize PAC1R and the two β-arrestin isoforms coupling and translocation in HeLa cells. At as early as 3 min after 1 μM PACAP stimulation, the NanoBiT signals from β-arrestin1 and β-arrestin2 (β-arrestin1-LgBiT and LgBiT-β-arrestin2) co-expressed with PAC1R-SmBiT were clearly detectable and localized around the plasma membrane and cytoplasm. At 15 min or later, however, the signal from PAC1R-β-arrestin1 complex remained localized around the plasma membrane, whereas that from PAC1R-β-arrestin2 complex localized predominantly at the cytoplasm  Movies. To confirm the PAC1R and β-arrestin coupling in more biologically relevant cells, we also used mouse primary cultured cortical neurons. PACAP increased the luciferase luminescence with similar dose-dependency and time-course in cortical neurons infected with PAC1R-SmBiT-pQM512B lentivirus in combination with either β-arrestin1-LgBiT-pQM512B or LgBiT-β-arrestin2-pQM512B lentiviruses . These dWe examined whether β-arrestin1 and β-arrestin2 are implicated in the PAC1R internalization. The β-arrestin1 and β-arrestin2 siRNAs effectively decreased the respective β-arrestin levels to less than 35% in HEK293T cells . The intWe addressed whether β-arrestin2 is also implicated in the PACAP-induced ERK1/2 activation in HEK293T cells . In the In the present study, we have investigated PAC1R internalization that depends on β-arrestin1 and β-arrestin2 using the NanoBiT system, HaloTag technology and siRNA-mediated silencing of endogenous β-arrestins in HEK293T cells, HeLa cells and primary cultured cortical neurons. For this purpose, we used time-lapse luminescence microscopy and processed the images to detect intracellular translocation. In addition, we examined the roles of β-arrestin1 and β-arrestin2 involved in the PACAP-stimulated PAC1R-mediated prolonged ERK1/2 activation relevant to the PAC1R internalization.Here we showed that PACAP-stimulated PAC1R interacted with β-arrestin1 and β-arrestin2 with similar PACAP dose- and time-dependency and that subcellular distribution of the PAC1R and β-arrestin2 complex changed time-dependently, whereas the complex with β-arrestin1 seemed to remain at the cell surface regions. We also showed that silencing of β-arrestin2 significantly reduced PACAP-induced PAC1R internalization and prolonged ERK1/2 activation, but silencing of β-arrestin1 did not affect PAC1R internalization and rather increased ERK1/2 phosphorylation. Moreover, we found evidence suggesting that PACAP-induced ERK1/2 phosphorylation was dependent on PAC1R internalization using inhibitors of clathrin-mediated endocytosis, ConA and Pitstop2. Taken together, these results suggest that β-arrestin2 but not β-arrestin1 is critically involved in the PAC1R endocytosis and subsequent activation of the ERK1/2 signalosome. These findings contribute to the mechanistic understanding of previous studies showing that PAC1R endocytosis is implicated in the PACAP-increased ERK1/2 activation , 27. HowIn recent studies, accumulating evidence suggests that β-arrestin1 and β-arrestin2 have distinct roles in various GPCR signaling events , 36–39. In the current study, we observed that silencing of β-arrestin2 inhibits prolonged ERK1/2 activation (25 min after PACAP stimulation), whereas, in contrast, β-arrestin1 siRNA increases ERK1/2 activation (3 min after PACAP stimulation) in HEK293T cells. The same reciprocal activity of the two β-arrestin isoforms on ERK1/2 activation has been demonstrated for the angiotensin II type 1A receptor-mediated activation of ERK1/2, which is increased under β-arrestin1 silencing but is eliminated under β-arrestin2 silencing in HEK-293 cells . In cont2 receptor is expected to have the potential to correct both positive and cognitive symptoms of schizophrenia [The finding of the β-arrestin-mediated signaling implicated signaling-biased ligands that favor G-protein signaling over arrestin recruitment or vice versa, which proposes therapeutic potential , 42–44. ophrenia . BecauseS1 Fig(A) The immunoprecipitates with antibodies indicated were subjected to immunoblotting with anti-PAC1R and anti-β-arrestin1/2 antibodies.HEK293T cells were stimulated with 1 μM PACAP for 15 min. (TIF)Click here for additional data file.S2 Fig, the protein kinase A inhibitor H89 at 20 μM  or the protein kinase C inhibitor sphingosine at 50 μM  were pretreated for 30 min and PACAP at the indicated concentrations for 60 min before the measurement of luminescence. β-arr1, β-arrestin1; β-arr2, β-arrestin2. Values are mean ± SEM of three independent experiments. *p < 0.05, two-way ANOVA followed by Fisher-PLSD test.HEK293T cells were transfected with the indicated combinations of plasmid vectors. The G-protein coupled receptor kinase 2 and 3 (GRK2/GRK3) inhibitor CMPD101 at 30 μM (TIF)Click here for additional data file.S3 Fig(A-D) Representative images of HEK293T cells transfected with PAC1R-Halo. Cells were treated with clathrin-mediated endocytosis inhibitors, ConA (250 μg/ml) (C) or Pitstop2 (15 μM) (D) were pretreated for 30 min, labeled with Alexa Fluor 488 HaloTag ligand and treated with 1 μM PACAP or saline for 30 min. Scale bar, 10 μm. (E) Quantification of PAC1R-Halo internalization. Scale bar, 10 μm. Values are mean ± SEM of 60 cells obtained from three independent experiments. *p < 0.05, two-way ANOVA followed by Fisher-PLSD test. (F) Representative images of western blots for total and phosphorylated ERK1/2 in HEK293T cells treated with the endocytosis inhibitors and 1 μM PACAP or saline for 25 min. (G) Quantification of phosphorylated ERK1/2 activation by normalizing phosphorylated ERK1/2 levels to total ERK1/2 levels analyzed by western blotting. Values are mean ± SEM of three independent experiments. *p < 0.05, two-way ANOVA followed by Fisher-PLSD test.(TIF)Click here for additional data file.S1 Movie(MP4)Click here for additional data file.S2 Movie(MP4)Click here for additional data file.S3 Movie(MP4)Click here for additional data file.S4 Movie(MP4)Click here for additional data file.


Primary health-care professionals play an important role in the treatment and prevention of Sexually Transmitted Infections (STI). Continuing Medical Education (CME)-courses can influence the knowledge and behavior of health-care professionals concerning STI. We performed a prospective cohort study to evaluate if the individual and online e-learning program “The STI-consultation”, which uses the Commitment-to-Change (CtC)-method, is able to improve the knowledge, attitude and behavior of Dutch General Practitioners (GPs), concerning the STI-consultation. This e-learning program is an individual, accredited, online CME-program, which is freely available for all GPs and GP-trainees in the Netherlands.In total 2192 participants completed the questionnaire before completing the e-learning program and 249 participants completed the follow-up questionnaire after completing the e-learning program. The effect of the program on their knowledge, attitude and behavior concerning the STI-consultation was evaluated.In total 193 participants formulated 601 learning points that matched the learning objectives of the program. The knowledge and attitude of the participants improved, which persisted up to two years after completing the program. Another 179 participants formulated a total of 261 intended changes concerning the sexual history taking, additional investigation and treatment of STI, 97.2% of these changes was partially or fully implemented in daily practice. Also, 114 participants formulated a total of 180 “unintended” changes in daily practice. These changes concerned the attitude of participants towards STI and the working conditions concerning the STI-consultation.The individual, online e-learning program “The STI-consultation”, which uses the CtC-method, has a small but lasting, positive effect on the knowledge, attitude, and behavior of GPs concerning the STI-consultation.The online version of this article (doi:10.1186/s12875-017-0625-1) contains supplementary material, which is available to authorized users. Since the incidence of sexually transmitted infections (STI) is rising, the pressure on health-care systems is increasing and the health of many (young) people is at risk –4. PrimaThe knowledge and behavior of general practitioners (GPs) concerning STI can be influenced by continuing medical education (CME)-programs . The goaTo achieve a behavioral change following a CME-course, the Commitment-to-Change (CtC)-method seems a useful addition –15. In tTo date, little attention has been devoted to the effect of the CtC-method in e-learning programs. Although e-learning programs for CME are able to improve knowledge and induce changes in behavior , there aWhen intending to improve the knowledge concerning STI and the sexual history taking-behavior of health-care professionals, a behavioral change has to be achieved. The aim of the present paper is to evaluate if the individual, online e-learning module “The STI-consultation”, using the CtC-method, has a lasting, positive effect on the knowledge, attitude, and behavior of GP’s concerning the STI-consultation.In the Netherlands, GPs perform 270,000 STI-consultations per year, accounting for 70% of the STI-consultations , 18. CMEThe individual e-learning program “The STI-consultation”, which uses the CtC-method, was created by the NHG in co-operation with the Dutch expertise-center “STI-aids Netherlands” and the department of General Practice of the Academic Medical Centre-University of Amsterdam. The content e-learning program was based on the content of the NHG-guideline “The STI-consultation” . The e-lChanging the behavior of health-care professionals in daily practice requires three stages of change: confrontation with activities that trigger the consideration of change (priming), experiencing strategies to motivate or facilitate the change (focusing), and maintaining the behavioral change by means of a supportive activity (follow-up) –28. The The e-learning program “The STI-consultation” was freely accessible for all Dutch GPs to allow the full population of GPs to participate in the study. The data for this project were collected among GPs that had completed the program. Data were collected since the e-learning program became available in September 2013 and the data-collection was completed in September 2015. In total 2387 GPs completed the e-learning program, 2203 participants gave permission to collect their data  to “very applicable” (4). After completing the program, participants were asked to indicate their three most important learning points and their intended change for daily practice both in reaction to what they had learned in the e-learning program.Two years after the introduction of the e-learning program, in October 2015, participants received an evaluation questionnaire. In total 287 participants completed this questionnaire, 36 participants had to be excluded because of missing data and two participants had to be excluded because of double participation. The responses of 249  participants were used for analysis. The questionnaire again contained the eleven questions from the quickscan. Participants who formulated intended changes were asked to what extent they had succeeded to implement their intended changes in daily practice. Participants were also asked if they had implemented any “unintended” changes in daily practice. These “unintended” changes were defined as changes that participants made in daily practice in reaction to what they had learned during the e-learning program, without the intention of making the particular change directly after completing the e-learning program. The intended changes and the “unintended” changes were compared to evaluate whether the content of the changes differed.To evaluate if completing the e-learning program contributed to a change in the knowledge and attitude of participants towards STI, before —and after-scores on the quickscan were compared. To evaluate if scores changed over time since completing the program we compared groups based on time since completing the program .The learning points, intended changes and implemented changes in daily practice were analyzed by matching them to the specific learning objectives of the e-learning program [see Additional file T-test. Nominal values are displayed in cross tables and analyzed using the chi-square test. A p-value of <0.05 was considered statistically significant.For normally distributed, continuous variables the mean (+/− standard deviation) was calculated. Differences in means between different groups were analyzed by means of ANOVA with the post-hoc Bonferroni-method. Differences in scores over time, were analyzed using the paired sample Because of the high amount of non-responders in the study we only analyzed the data available to us.All statistical analyses were performed using SPSS version 22 .Table There were no significant differences present between participants who completed the e-learning program less than one year ago and participants who completed the e-learning program more than one year ago (data not shown).Of the 2203 participants who completed the e-learning program, 193 participants (8.8%) together formulated a total of 601 learning points. Most learning points concerned sexual history taking (28.1%), additional investigation (27.5%), and the treatment of patients with STI (17.5%) .In total 179 participants (8.2%) intended to make a total of 261 changes in daily practice Table . Most inParticipants that formulated intended changes, reported that 34.3% of the intended changes was fully implemented, 62.9% was partially implemented, and 2.8% was not implemented. Reasons for partially or not implementing the intended changes concerned forgetting the intended changes (50.0%), small amount of consultation for STI in daily practice (21.4%), time pressure (14.3%), shame or resistance to talk about STI (7.1%), and the costs of STI-tests (7.1%).“I do not make a phone-call anymore when a patient has a question about STI, but I want to see the patient in my office, so I can more easily ask the right questions.” (participant)“We extended the duration of a STI-consultation from 20 minutes to 30 minutes. Quality-improvement!” (participant)In total 114 participants made a total of 180 “unintended” changes in daily practice. These changes mostly concerned the sexual history taking (41.7%), the additional investigation (31.7%), and a change in the working conditions of the STI-consultation (9.4%). Participants described the change in the working conditions concerning the STI-consultation, as:“It was an interesting CME-course, and it seems like much information has stayed with me.”(participant).This study shows that the individual online e-learning program “The STI-consultation”, which uses the CtC-method, is able to positively influence the knowledge, attitude, and behaviour of GPs concerning the STI-consultation. This positive influence remains up to two years after completing the e-learning program. Participants also noted that the e-learning program had a lasting influence on their knowledge: “In sexual history taking, I try to focus more on the sexual behavior of the patient, instead of asking if a patient is homosexual (behavior versus identity)”. (participant).Our results indicate that after completing the program, the knowledge and attitude of participants improved and that they changed their behaviour, both by means of intended and “unintended” changes. Remarkable is the finding that, although the amounts are small, the “unintended” changes relatively often concern the working conditions of the STI-consultation and the attitude of participants towards sexuality, STI and sexual history taking, when compared to the intended changes, such as became clear from this remark: Our findings suggest that, next to the traditional forms of CME, individual and online forms are effective in improving STI-knowledge and attitudes of health-care professionals. This supports the findings of previous research on the effectivity of internet-based CME and CME for STI , 9. Sinc“The videotaped case-studies are a nice way to support the sexual history taking of doctors.” (participant).The videotaped case-studies are an important feature of the e-learning program. Previous research shows that both the use of the movies or videotaped case-studies and role models are able to contribute to the process of acquiring knowledge and changing attitude , 38, 39.In this study we have also seen that participants formulated intended changes for daily practice, of which 97.2% was partly or fully implemented in daily practice. This does not only support the findings of previous research performed on the use of the CtC-method in traditional CME-courses –15, but Our study is performed in a large study population of over 2000 GPs. Additionally, we were able to analyze the effect of the e-learning program up to two years after the program was completed, showing that changes induced by individual e-learning can have a long-term effect.Our study is limited by the use of self-reported data of the participants, possibly leading to socially desirable answers. Especially the self-reported data on behavioural changes in daily practice may be subject to self-report bias, leading to the under-report of behaviour that may be considered as non-desirable by the participants and over-report of behaviour that may be considered as desirable by participants . AdditioOur results provide insight in the effectiveness of individual, online CME-courses. Since online CME-courses are gaining popularity , 9, it iIndividual e-learning programs, especially with the addition of CTC, are an effective method for CME, not only for improving and maintaining the knowledge and attitude of health-care professionals, but also for improving their behaviour in daily practice. By offering an individual e-learning program that participants can complete in their own environment and at their own pace, a barrier for completing a CME course on STI may be taken away, also offering the opportunity to improve the knowledge and attitude of the health-care professional concerning STI and sexual history taking.Additional file 1:Learning objectives for the e-learning program “The STI-consultation”, presented per competence-area (translated from Dutch). This file contains the learning objectives for the e-learning program “The STI-consultation”, presented per competence-area. The content of this file was based on the “Program plan e-learning “The STI-consultation” (Programmaplan PIN “Het soa-consult”). (DOCX 23 kb)Additional file 2:English-language version of the questionnaire used in the study (translated from Dutch). This file contains the English-language version of the questionnaire used in the study. The content of this file was translated from the original questionnaire used in our study. (DOC 27 kb)


The clinical research enterprise is not producing the evidence decision makers arguably need in a timely and cost effective manner; research currently involves the use of labor-intensive parallel systems that are separate from clinical care. The emergence of pragmatic clinical trials (PCTs) poses a possible solution: these large-scale trials are embedded within routine clinical care and often involve cluster randomization of hospitals, clinics, primary care providers, etc. Interventions can be implemented by health system personnel through usual communication channels and quality improvement infrastructure, and data collected as part of routine clinical care. However, experience with these trials is nascent and best practices regarding design operational, analytic, and reporting methodologies are undeveloped.To strengthen the national capacity to implement cost-effective, large-scale PCTs, the Common Fund of the National Institutes of Health created the Health Care Systems Research Collaboratory (Collaboratory) to support the design, execution, and dissemination of a series of demonstration projects using a pragmatic research design.In this article, we will describe the Collaboratory, highlight some of the challenges encountered and solutions developed thus far, and discuss remaining barriers and opportunities for large-scale evidence generation using PCTs.A planning phase is critical, and even with careful planning, new challenges arise during execution; comparisons between arms can be complicated by unanticipated changes. Early and ongoing engagement with both health care system leaders and front-line clinicians is critical for success. There is also marked uncertainty when applying existing ethical and regulatory frameworks to PCTS, and using existing electronic health records for data capture adds complexity. High-quality evidence regarding the risks and benefits of treatments is lacking across a multitude of clinical specialties –7, and tPragmatic clinical trials (PCTs) are trials that use data collected in the electronic health record (EHR) as part of routine care, or are “embedded” in routine care, and are a foundational component of such a system. By their nature, PCTs are designed to show real-word effectiveness in broad, generalizable patient groups  . These Phttp://rethinkingclinicaltrials.org/). While embedded PCTs hold great promise and much work has been done to describe the continuum of pragmatic versus explanatory trials for considerations in the design phase of PCTs , 14, infAlthough there have been numerous publications describing nuanced challenges and solutions encountered in the conduct of specific Demonstration Projects, this is the first to widen the focus and describe the NIH Collaboratory more generally. We build on the knowledge created by the Cores to review important generalizable lessons learned over the first four years since the Collaboratory was established. We also discuss the remaining opportunities and challenges for the Collaboratory and its forthcoming projects, and for the medical community more broadly regarding PCTs to power a learning health system.Cores were created to explore key elements of PCTs: electronic health records; phenotypes, data standards and data quality; patient-reported outcomes; health care systems interactions; ethics & regulatory; biostatistics and study design; and stakeholder engagement. The Collaboratory Coordinating Center  at the Duke Clinical Research Institute  serves 3 roles: (1) to provide support to the demonstration projects to help ensure success; (2) to cull experiences and create generalizable solutions regarding challenges in designing, conducting, and disseminating results from PCTs; and (3) to disseminate lessons learned, tools, and other resources to the broader community, including the creation of a Knowledge Repository and the Living Textbook of Pragmatic Clinical Trials: Rethinking Clinical Trials.To provide expertise to the NIH Collaboratory Demonstration Projects, the following working groups, or There have been two funding opportunities so far, one in 2012 and one in 2014, and we expect another funding opportunity in 2017 to support 10 additional PCTs. In 2012, seven demonstration projects were funded  has been critical. The Collaboratory’s success depends entirely on the willingness of investigators to share their challenges in real time with the rest of the network, including the NIH staff. This differs from many research enterprises, in which investigators often feel motivated to present an image of perfection to everyone outside of their project and especially to the sponsors. The Collaboratory projects were selected with the understanding that they would generate challenges that the research community must learn to overcome. The transformation of challenges into lessons learned that are then shared with the broader community is a direct result of the good faith, generosity, and candor of the Collaboratory demonstration project investigators and their health system partners.The information regarding lessons learned was gleaned from a number of sources. The Collaboratory held yearly Steering Committee meetings  in which all the Principal Investigators (PIs) gather to share their experience and knowledge through interviews and presentations. Members of the Coordinating Center interview each of the PIs at these meetings to gather lessons learned, and each PI presents lessons learned at a general session followed by an opportunity for discussion. Leaders of each of the Cores also hold monthly calls with the PIs and their teams to discuss problems and explore solutions, and these lessons are gathered as a part of minutes from the call. In addition, all the PIs and some members of their teams are authors on this paper.As one of the Collaboratory investigators said, nothing is “plug and play” in a PCT within a healthcare system. In all the Collaboratory demonstration projects, there were important changes made to the protocol during the planning phase as a result of further engagement with stakeholders, consultation with other experts, and collection of pilot data.In one of the first seven planning projects funded—the Blood Pressure Medication Timing Study (BPMedTime)—the ultimate sample size needed was determined to be 5000 versus the original 1000 subjects in order to detect a lower effect rate than anticipated. Because this new sample size was too large to be feasible within the budgetary constraints of the funding mechanism, the BPMedTime trial was not transitioned to the implementation phase; however, all of the other demonstration projects were moved forward.Because PCTs occur in the dynamic environment of one or more healthcare systems, changes can arise that require modification of the protocols or how they are implemented. Leadership changes, staff turnover, and new local or national policies can all require a change of plan. For example, after experiencing issues with study implementation, the STOP CRC research team partnered with practice improvement facilitators who were trained in the plan-do-study-act (PDSA) method . The facCollaboratory PCTs are conducted in real-world settings and leverage the existing infrastructure  of healthcare systems to answer clinical questions of importance to patients, providers, payers, and other stakeholders. In these PCTs, the data originate from the healthcare systems EHR and include proprietary information, so strong and trusting partnerships are needed between investigators and healthcare system leaders . While hData are collected during the course of routine care, and partnerships must be built with healthcare providers to ensure that the intervention can be added into existing workflows as seamlessly and with as little burden as possible . PhysiciHigh quality PCTs should provide meaningful answers to important clinical questions while protecting the rights and welfare of all research participants (which may include clinicians in the case of cluster-randomized studies) and complying with relevant policies and regulations , 45. As As another example, the data safety monitoring board (DSMB) overseeing the TSOS trial initially wanted to require the team to report every hospitalization as a serious adverse event, but in their cohort of people at risk for post-traumatic stress disorder (PTSD), approximately 15–20% were expected to be re-hospitalized for non-emergent reasons, and some negotiation was required . In the There is clearly an opportunity for more learning and reflection regarding the best way to promote the rights and welfare of research participants in the context of PCTs.In a traditional randomized, controlled trial, it is possible to exert significant control over what happens in the different arms of the trial. Because the demonstration projects are tackling issues that are major public health concerns, such as opioid prescribing and hospital-based infections, competing initiatives are likely to be launched at some of the study sites. Conversely, providers in the experimental arm might resist the intervention due to burden. Providers in the “usual care” arm might voluntarily adopt the trial intervention, especially if there is growing evidence that the intervention is associated with better outcomes. There were a number of opioid reduction related initiatives rolled out during the implementation of PPACT, thereby changing the nature of the underlying usual care. In the words of Lynn DeBar, PI of the PPACT trial: “Our control is not controlled. We can’t control it, and that’s a big challenge .” For anReliance on the EHR for data to support research investigations is challenging for many reasons. First, even when sites are a part of a single corporate entity, local coding varies, and cross-site data standardization is essential. Because no two electronic health record (EHR) systems are alike, the solution requires engagement of local data experts. Tools, such as the ones developed for SPOT do not transfer from one site to another, and local adaptation is necessary. Each health system may have a distinct process or pathway for implementation of an intervention, and a multi-site trial will need to adapt to those. In the case of the SPOT trial, even though all of the sites use Epic, they have different preferred methods for implementing standardized assessment tools, and the investigators needed to adapt to those different preferred pathways.Additionally, because the EHR is optimized for clinical practice and sometimes billing, integrating study-related data elements into the EHR has implications for clinical workflow and compliance. A seemingly small change to the work flow to accommodate a research project likely could have major implications for the IT system. The investigators in LIRE, a study that adds epidemiological benchmarks to lumbar spine imaging reports, found that even minor modifications to reports met with initial resistance since these required allocations of scarce IT resources. Overcoming this sort of hurdle required close coordination with site PIs and local leadership buy-in. Some cases offer a different scenario: for PROVEN, the two corporate partners use a different EHR but with the help of devoted efforts from corporate leadership, were able to add a new record into their EHR system to permit staff to document each time the video was offered and subsequently shown to the patient or family members.As the first round of demonstration projects approach completion, the Collaboratory will continue to identify challenges and lessons learned regarding health care systems interactions, data analysis, interpretation, reporting, and dissemination to inform the next set of demonstration projects and PCTs in general. These lessons will inform other national evidence generation efforts that are underway, such as the Patient-Centered Outcomes Research Network (PCORnet). To understand the full potential of PCTs to advance healthcare, additional knowledge is needed about research designs that were not a part of the first phase of Collaboratory, but may be a part of the second phase:While the 9 Collaboratory trials test a variety of interventions, none involve simple comparisons between two or more alternative medical products or treatments for individual patients. There is an ongoing need to know the comparative effectiveness of currently used individual therapies and the benefits and risks of medical products, and to understand how PCTs might help address these needs. For example, trials that conduct head-to-head comparisons between different classes of drugs for the same condition—e.g., first line treatment for hypertension —could raThe Collaboratory projects all benefitted from research teams that were highly experienced in health services research and clinical trials, and included national leaders in their fields who had deep experience in integration of research into health care delivery. Many of the teams also had experience with their health system partners, and having situation-specific experience was critically important. For example, this experience helped the LIRE investigators understand EHR idiosyncrasies and anticipate challenges, to build upon already established trust, and to leverage previously collected data for pilot purposes. The number of investigators with such backgrounds is small relative to the large number of clinical problems that might benefit from well-designed embedded PCTs. Therefore, it is important to understand what, if any, additional challenges might arise when teams with less experience and expertise, or perhaps more importantly, less familiarity with the host delivery system, attempt to design and conduct a PCT. Experience with this broader population of researcher teams would be useful.Because there are few research teams with the knowledge and experience to conduct successful PCTs, it is critical that experiences and best practices from the Collaboratory and other sources  are translated into education and training to create a larger pool of competent research teams. Teaching people how to conduct PCTs within healthcare systems will require an understanding of how to partner with health care systems and the rapidly changing world of clinical care; the success of a trial depends upon interactions and negotiations with the leaders of healthcare systems of the sort that cannot be taught in a classroom. Thoughtful approaches are needed to develop experience-based learning in the context of existing networks of PCT trialists and to incentivize the few existing experts to devote time to teaching and mentoring.Until we have learned how best to conduct PCTs in different settings and enough research teams have been trained in how to do so, new PCTs could benefit from a core resource to assist in planning and conducting the trials. In the Collaboratory, the demonstration projects benefitted from core expertise within the Coordinating Center during the planning phase. Challenges continued to surface in some of the trials during the implementation phase, underscoring the importance of having a dedicated core resource available throughout the conduct of a PCT. Such a central resource could also be useful for accumulating the knowledge and experience gleaned across multiple PCTs in a wide range of settings, possibly leading to more efficient and informative PCTs in the future.A number of barriers to successful PCTs are associated with how incentives align with health systems, clinicians, and potential sponsors. As healthcare systems become more complex and larger, there are increasing demands to ensure productivity is maintained for the system at large and for clinicians, and it may be more difficult to achieve alignment and to balance clinical obligations with the added work of PCTs. In particular, new mandates on clinician time, such as using EHRs, make it more difficult to add new activities unless it is within the workflow. There is often no clear framework for rewarding or reimbursing clinicians to enable PCTs, especially if time is needed for an intervention that is not directly reimbursed or rewarded. Finally, it may be difficult for clinicians or health systems to envision the direct impact a PCT may have on their practice.In order to make PCTs the norm rather than the exception, cultural changes and incentives are needed. Institutional leadership could make developing, participating in, and leading PCTs part of the strategic planning, which generally emphasizes the importance for professional growth and alignment with health system values. These approaches have been used in the setting of healthcare reform as payments shifted from volume-based care to value-based care, demonstrating behavior changes in both the health systems as well as the clinicians supporting the systems.The NIH Collaboratory is an important part of the overall effort to improve the national capacity to generate evidence to inform healthcare decisions by patients, providers, and payers. Even before the demonstration projects have completed their work, much has been learned. Planning activities are substantial and should be supported as part of a phased approach, such as the planning and implementation phases used by NIH for the Collaboratory. New challenges frequently arise during execution; change is the only constant, and because of this, early and ongoing engagement with all stakeholders is critical. As the new demonstration projects begin, we hope to learn from these lessons and generate others, as there remain opportunities for additional learning in order to make intelligent investments in PCTs. There is also the need to train a new clinical trials workforce, to train reviewers for PCTs, and align interests for all stakeholders to contribute to a national evidence generation system.


The Nafion was deposited on a graphite electrode and used to avoid “cracking” on the matrix. The TiO2 particle size was an average of 66 nm. FTIR spectroscopy vibration modes of different composites were determined. The electrochemical behavior of the biosensor was studied using electrochemical spectroscopy (EIS) and cyclic voltammetry (CV). The biosensor based on TiO2/NAF/LAC presented the best electro-chemical properties with regard to sensitivity, stability and detection limit after a period of 22 days.Laccase amperometric biosensors were developed to detect the catechol compound. The laccase enzyme (LAC) immobilization was performed on nanostructures of (a) titania (TiO A great number of polyphenolic compounds are byproducts resulting from the large-scale manufacture of several products such as drugs, dyes, pulp, plastic, pesticides and antioxidants ,2,3. SomDue to their good reproducibility, selectivity, high sensitivity, and miniaturization effect, electrochemical techniques, notably amperometric biosensors, stand out as the best candidates for the detection of polyphenols ,11,12,13In recent years, biosensors, modified with oxidoreductase enzymes , have been developed for the detection of phenolic compounds, since phenols can act as electron donors for said enzymes ,14,15,162O2 as a co-substrate or any other external co-factor for its catalysis. Moreover, thermal tolerance is also a positive feature of laccase for biosensor applications. Laccase catalyzes the oxidation of various phenolic compounds with a concomitant reduction of molecular oxygen to water, without the intermediate formation of toxic H2O2. In general, laccase contains four copper atoms classified into type 1 (T1), type 2 (T2), and type 3 (T3), according to their spectroscopic and magnetic properties. T1, the substrate-binding site of the enzyme, is involved in the oxidation of the substrate and the transfer of electrons to the T2/T3 cluster, while T3 is responsible for oxygen uptake and, as a whole, the T2/T3 site is responsible for the reduction of O2 to water /K4[Fe(CN)6] in the presence of 0.1 M KCl at a frequency range of 100 mHz to 100 KHz.Electrochemical Impedance Spectra (EIS) is a powerful tool for studying the interface properties of surface-modified electrodes. The impedance measurements of GE, GE-NAF/LAC, and GE-TiOct) can be obtained by measuring its diameter.) The second is the linear section, which delivers information related to the diffusion process, held in the solution and located at lower frequencies.The curve of EIS presented as “the Nyquist plot” consists of two parts: first is the semicircular section, located at higher frequencies corresponding to the electron-transfer limited process.  at the interface of the electrode  and Kochana (2012) 3−/[Fe(CN)6]4− 1 mM dissolved in 0.1 M KCl at a scan rate of 100 V/s at a range of −0.5 to 0.70 V for the unmodified graphite electrode (GE), as well as with biosensors doped with TiO2.This experiment was carried out in a solution of [Fe(CN)2/NAF/LAC and TiO2/LAC (b and c), which are attributable to the condition of graphite and the semi-conducting properties of TiO2. By contrast, the biosensor NAF/LAC (d) has a very small current peak in the cyclic voltammogram, due to the Nafion being partially surrounded by hydrophobic regions of sulfonate perfluorinated ionomer, which hinders the ion transfer and non-conductive properties of the enzyme as reported in [2/NAF/LAC and TiO2/LAC biosensors exhibit less reversibility and better response in the peak current than the electrode NAF/LAC.In orted in ,44. In aThis behavior can be attributed to the laccase which remained adsorbed in the titania matrix, and therefore did not obstruct the passage of electrons from the electrochemical probe which is consistent with the results of the electrochemical impedance technique .2/LAC (curve c) and TiO2/NAF/LAC (curve d). Curve a exhibits the behavior of the graphite electrode. As expected, there are no redox peaks observed in the absence of laccase, even at a concentration of up to 40 μM of catechol. Nevertheless, a significant increase is seen in the current peak reduction, when the graphite electrode is modified with laccase . This increase in the reduction peak follows the direct lowering of o-quinone, producing the reaction catalyzed by the enzyme on the surface of the electrode [2/NAF/LAC is higher, proving that TiO2 particles play an important role in the transfer of electrons between o-quinone and the electrode surface, as a result of the semi-conductive properties. Such detection is based on the enzymatic oxidation reaction and the subsequent amplification cycle of the recycling of the substrate/analyte on the electrode. The mechanism reaction is presented in 2. Subsequently, 1,2-benzoquinone is electrochemically reduced at appropriate potentials on the biosensor surface. Therefore, the peak current obtained in the process of the electrochemical reduction of 1,2-benzoquinone to catechol is proportional to the concentration of catechol. [lectrode ,6,46. Thatechol. ,47,48,492/LAC and TiO2/NAF/LAC biosensors have been investigated as a function of the concentration of catechol (from 5–150 µM) using the technique of CV with a scan rate 100 mV/s, in PBS . In studies of bioelectrode response, it was observed that the magnitude of the current response increases according to the rising concentration of catechol , these exhibit the same behavior in terms of detection limit 2.5 μM, linear range (1.25–150) and a correlation factor of 0.9944 and 0.9986, respectively. Furthermore, the biosensor TiO2/NAF/LAC presents the best electrochemical response, with a detection limit of 0.75 μM, a wide linear range of 0.75 to 150 μM, and a correlation factor of 0.9966. Similarly, the sensitivity of biosensors was calculated, resulting in 2.6, 2.71 and 2.94 μA/μM to NAF/LAC, TiO2/LAC and TiO2/NAF/LAC, respectively.Based on biosensors NAF/LAC and TiO2/Nafion/laccase presented a 13% higher sensitivity compared to the sensor prepared with Nafion/laccase. This result was due to the inherent biocompatibility of sol-gel–derived titania film and indicative of the biocompatibility of titania/Nafion hydrogel with the enzyme, rendering a substantial improvement in the long-term stability of the biosensor. Additionally, the network structure of the titania/Nafion composite matrix can prevent leaching of the enzyme, which favors the stability of this biosensor [The sensitivity, linear range and detection limit of the enzyme biosensors were tested on the first, seventh, 15th and 22nd days. See the listed results in iosensor .2/LAC and TiO2/NAF/LAC was evaluated through the detection of 40 µM in 0.1 M PBS (pH 6.68) when six successive determinations were made. A relative standard deviation (RSD) of 7%, 9% and 7% was obtained for the biosensors made with NAF/LAC, TiO2/LAC and TiO2/NAF/LAC, respectively, demonstrating that the modifications of the electrodes allow for good reproducibility during measurements, without applying a pretreatment to the biosensors. Moreover, long-term stability is considered one of the key factors in the performance of the biosensors, which is evaluated by measuring the response of 10 µM catechol for 22 days. When the electrodes were not used, they were stored at 4 °C in dry conditions, based on the evidence that the enzymatic biosensors retained their activity at 92%, 87% and 94% for the biosensors made with NAF/LAC, TiO2/LAC and TiO2/NAF/LAC, respectively, after a week. After 22 days, biosensors made with NAF/LAC, TiO2/LAC and TiO2/NAF/LAC retained activities of 58%, 53% and 69%, respectively, indicating good stability of the biosensors, especially the biosensor based on TiO2/NAF/LAC, which shows that the film of titania sol-gel is very efficient in retaining laccase activity.The reproducibility of the biosensors based on NAF/LAC, TiO2/LAC, NAF/LAC and TiO2/NAF/LAC) developed in this research have a good level of sensitivity towards catechol in the order of µA/µM when compared to those reported by other authors in the field who obtained results of µA/mol. By far the best analytical properties were seen in the biosensor TiO2/NAF/LAC. This is due to the semi-conductive properties of TiO2 together with the proposed sol-gel method, which provided a non-aggressive immobilization process of the laccase enzyme, and provided a surrounding biocompatible microenvironment by which it could fulfill its biological activity.The results presented in this work demonstrate that the three biosensors (TiO


Application and selection are based on leadership potential demonstrated in an essay and letters of recommendation. Scholars participate in a curriculum that includes leadership development seminars, workshops, a leadership-focused team project, individual leadership coaching, and active participation at leadership conferences. Seminar topics include defining personal leadership and values, mentoring, emotional intelligence, ethical leadership, difficult conversations, networking, and executive presence. Scholars are exposed to multiple leadership philosophies and styles with the intent that they will integrate the various ideas into their own experience, and develop their own leadership style.The learning principles for the Scholars include a definition of leadership based on the ability to influence, and a research-based model of competencies necessary for effective, ethical leadership. We define health and healthcare leadership for the Feagin Leadership Program as the ability to influence others for the benefit of patients and patient populations. A research-based health leadership model provides the framework for the program. The model is comprised of a core principle of patient-centeredness, and core competencies of critical thinking, emotional intelligence, integrity, selfless service, and teamwork.Since the initiation of the Feagin Leadership Program, we have noticed a positive influence on the Scholars. To evaluate the program’s effect on the Scholars’ leadership development, a Qualtrics survey was distributed to 80 alumni via email. When scholars were asked to contrast their leadership behavior before and after completing the program, they felt that their skills improved in the areas of critical thinking, emotional intelligence, integrity, selfless service, and teamwork. Medical students saw the largest effect in the domains in their ability to motivate others, manage others, and self-awareness. Resident trainees saw the most improvement in their abilities to optimize team dynamics, effectively communicate, motivate others, be self-aware, and self-manage. Lastly, fellows improved their ability to think holistically, effectively communicate, and be resilient.The primary goal of medical education is to train current and future physicians to be equipped with effective clinical and decision-making skills. Unfortunately, there are limited resources focused on developing trainees in the area of leadership. This gap, unfortunately, makes many physicians ill-equipped to cope with the current model of medical practice.In our evaluation, we found that implementation of a structured medical leadership curriculum improved leadership skills in trainees of all levels. This uniquely structured program may serve as a template for other academic institutions in designing curriculum to address this gap in formal medical leadership training. This program has evolved over the past five years, with a curriculum that has adapted not only to the changing demands of medicine, but also based on the evolving field of medical leadership, and alumni feedback. We have also learned that inclusion of a diverse group of medical specialties with different levels of training has enhanced our understanding of leadership across interdisciplinary teams.The Feagin Leadership Program has had a consistent positive influence on its alumni. This effect remained true across different training levels, with interval improvement in critical thinking, emotional intelligence, integrity, selfless service, and teamwork.The authors wish to thank Dr. Kathryn Andolsek, Assistant Dean of Premedical Education, for assistance in the project and her guidance in target journal selection; Donald T. Kirkendall, ELS for his help in preparing the manuscript for submission; and Dr. John A. Feagin, Jr. for his solid core character and leadership that inspired the development of this program.DCT is Chairman, JPD is Executive Director and JHBC serves on the advisory board of the Feagin Leadership Program. JRB is a naval service member and the views expressed in this article don’t reflect the official policy or position of the Department of the Navy. KLA, MHC, RMG, NHW, AA, and JRB have no conflicts of interest to report.