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Harms | All participants underwent a comprehensive evaluation of their intra-oral hard and soft tissues at baseline and follow-up. At the 12-month (T3) follow-up period, there was no harm reported or observed as a result of either intervention, confirming their safety and tolerance. Furthermore, no participant was removed from the trial on the basis that their oral hygiene proved to be unsatisfactory, requiring their fixed orthodontic appliances to be removed. | PMC10803043 |
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Discussion | tooth brush, bleeding, hyperplasia, ’s mouth, gingivitis, caries, tooth brushing, orthodontic | BLEEDING, DEMINERALIZATION, HYPERPLASIA, GINGIVITIS, CARIES, BLIND, COMPLICATIONS | To date, no long-term RCT designed to evaluate the impact of MT versus PT in an orthodontic population has been reported, while more recent studies have once again only reported short-term (<8 weeks) evaluations [A key requirement of any participant undergoing fixed appliance therapy is the need to maintain optimal oral hygiene. Furthermore, the long-term nature of orthodontic treatment increases the likelihood of both hard (enamel demineralization, with white spot lesions or caries) and soft (gingivitis, hyperplasia, and periodontal pocketing/attachment loss) tissue complications, in the absence of this optimal cleaning. Thus regular tooth brushing becomes essential, and with the availability of PT and their inherent appeal, there is a need for robust clinical evidence of their effectiveness over both the short term but perhaps more importantly, the long term [A further strength of the current trial was that following the initial protocol registration with the International Standard Randomised Controlled Trials Centre, no protocol deviations were reported, thus minimizing the risk of bias, through e.g. selective reporting. Furthermore, the trial sample retained its power, with appropriate allowance being made for potential drop-outs, with the observed rate being consistent with previous studies in the same field [The present trial could detect no difference in three primary outcomes (GI, PI, and BoP), at any of the time points from 1 to 12 months, in participants undergoing comprehensive fixed appliance therapy in both arches, in terms of the toothbrush type. These findings do not support the superiority of a specific PT in maintaining optimal health when compared with an MT for those wearing orthodontic appliances. The findings are in contrast with a number of previous studies, which as highlighted above, are at risk of bias, with significant limitations, and perhaps most importantly, fail to take into account the long-term nature of orthodontic treatment. In a recent trial, designed to quantify the duration of tooth brushing, with MT and PT, in children with fixed appliances, no differences were detected in their effectiveness, with a reported brushing time of approximately 3 min [This study did find a significant interaction between the toothbrush type, the follow-up period, and specific tooth in the participant’s mouth. Specifically, an increase was observed in the GI, PI, and BoP at 1 month, which was reduced during the subsequent follow-up periods, with the exception of the lower incisor and posterior molar regions, where the scores remained high. The latter reflects well in terms of the more recently described concept of some bleeding being commensurate with periodontal health [While every effort was made in the design and execution of the current randomized clinical trial to address the many shortcomings in the present literature, nevertheless, there are inherent limitations. The trial was based in a single-hospital setting, and therefore, its findings may not be generalizable. The study was not double-blind, as participants were clearly aware of the choice of tooth brush to be used. However, the operator and outcome assessment, along with the data analysis, were all performed blind.The specific powered toothbrush selected for the present study used a sonic triple clean head, and alternatives are now available, which may be more effective [ | PMC10803043 |
Conclusions | orthodontic | PLAQUE | No differences have been found between a manual and sonic-powered toothbrush in controlling plaque and gingival health in participants undergoing fixed orthodontic treatment in either the short term or long term. | PMC10803043 |
Acknowledgements | We would like to acknowledge the support of the staff within the Hospital in helping to facilitate this research. We would like to thank Colgate-Palmolive (USA), for helping to support funding for the trial. | PMC10803043 |
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Author Contributions | Ama Johal (CRediT contribution not specified), Muftah Shagmani (Investigation-Equal, Methodology-Supporting, Writing – review & editing-Supporting), Ian Arad (Conceptualization-Supporting, Investigation-Supporting, Methodology-Supporting, Writing – review & editing-Supporting), Omar Alfuraih (Investigation-Supporting, Methodology-Equal, Writing – review & editing-Equal) | PMC10803043 |
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Conflict of interest | The authors declare that there is no conflict of interest. | PMC10803043 |
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Data availability | The data underlying this article will be shared on reasonable request to the corresponding author. | PMC10803043 |
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References | PMC10803043 |
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Background | knee osteoarthritis | KNEE OSTEOARTHRITIS | A randomized clinical trial assessing plasma rich in growth factors (PRGF) versus hyaluronic acid for knee osteoarthritis was published in 2012 (sponsor trial ID BTI-01-EC/07/ART). Evidence of misreporting was discovered following access to unpublished materials. In accordance with the principles of the Restoring Invisible and Abandoned Trials (RIAT) initiative, we sought to re-analyse Study PRGF based on the unpublished trial materials. | PMC9850713 |
Methods | Reanalysis was made possible primarily based on two unpublished study documents (original trial protocol and final report) obtained from the authors of the original publication. A call to action, calling on the authors to correct the original publication, was publicly issued. The involved ethics committee was repeatedly approached and extensive discussion with the authors ensued. After no agreement to correct the paper was reached, we embarked on this restoration. Reanalysis was focused on providing updated analyses for efficacy and safety. | PMC9850713 |
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Results | pain | SECONDARY | The efficacy of PRGF was not statistically different from hyaluronic acid for any prespecified primary or secondary efficacy outcomes. For the primary endpoint, the percent of patients on PRGF compared to hyaluronic acid with a decrease >40% in WOMAC pain subscale score was 5.4% higher; 95% confidence interval (CI) −10.4% to 21.3%; | PMC9850713 |
Conclusions | This reanalysis of Study PRGF found no clinically or statistically significant benefit from PRGF compared to hyaluronic acid. The restoration of Study PRGF shows the urgency of important changes to trial reporting and oversight practices. In the future, timely access to all clinical trial documents is needed to minimize the risk of reporting bias. Similarly, ethics committees should be ready to intervene whenever a case of potential misconduct arises. | PMC9850713 |
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Trial registration | This is a RIAT project, whose original trial was approved and registered on 19 December 2007 by the Ethics Committee of the Basque Country, Spain, as BTI-01-EC/07/ART. | PMC9850713 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s13063-022-07049-3. | PMC9850713 |
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Keywords | PMC9850713 |
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Background | KNEE OSTEOARTHRITIS | There is substantial concern within the scientific community about the profusion of incompletely reported and misreported studies. Projects such as the Restoring Invisible & Abandoned Trials (RIAT) initiative (In this article, we present the results of our RIAT reanalysis of a clinical trial on plasma rich in growth factors (PRGF) known as BTI-01-EC/07/ART, hereafter referred to as Study PRGF. The original study was sponsored by BTI Biotechnology Institute (BTI). We acknowledge the work of the original investigators. This double-blind, randomized controlled trial was designed to assess the efficacy and safety of PRGF compared with hyaluronic acid for adults suffering from symptomatic knee osteoarthritis. It was reported in Chronologically, on 8 January 2019, the RIAT researchers asked the study’s corresponding author for the related protocol, final report and Ethics Committee resolutions, which were granted on 14 January 2019. Once the dossier was reviewed, the RIAT researchers wrote again on 21 January 2019 to explain in detail every detected concern, asking for clarification. From that time on, two phone calls and twelve emails were exchanged. In accordance with RIAT procedures, the RIAT researchers made public on 27 March 2019 the need to correct the article and simultaneously informed the contact author about this ‘call to action’ [Study PRGF was a multicentre, 24-week, double-blind, randomized controlled trial [ | PMC9850713 |
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Methods | We reassessed the data of Study PRGF in accordance with the RIAT recommendations. To this purpose and apart from the involved published article, we used as principal sources the following documents: (1) full original protocol, (2) ethics committee approval resolution, (3) final study report (summary version). All of them were accessed on request from the contact author of the original publication. Other related documents (Statistical Plan Analysis, study database, set of documents reviewed by the Ethics Committee and alleged final report dated November 2011) were also requested from the study authors with no response from their side.According to RIAT recommended procedures [ | PMC9850713 |
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Interventions | ®, pain | INFILTRATION, INFILTRATED | Each included participant was randomized to receive infiltrations of the affected knee (3 injections on a weekly basis) with either PRGF-Endoret® (BTI) or hyaluronic acid (Euflexxa®, Copenhagen, Denmark). PRGF-Endoret® was prepared from autologous peripheral blood at each treatment visit by following subsequent steps of blood extraction, centrifugation and plasma fractioning. Plasma rich in platelets without leukocytes was then pipetted and activated with calcium chloride before infiltrated. Compliance was not considered a useful outcome to be estimated due to the fact that both interventions were administered by the researchers. Acetaminophen intake, the only permitted medication for pain relief throughout the trial period, was registered during the trial. | PMC9850713 |
Sample size | pain | Sample size calculation was initially stated in the protocol based on the original main outcome, the percentage of patients with a decrease >40% in the score in the WOMAC pain subscale at the final visit with respect to baseline (which is similar to a pain improvement >40%). Null hypothesis was set as no difference in that outcome between both interventions. A statistical power of 80% and | PMC9850713 |
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Randomization and blinding | INFILTRATION, INFILTRATING | A stratified randomization in blocks of four was performed by using a specific software developed by GlaxoSmithKline (C4 Study Design Pack). Each centre was considered as one stratum. Randomized numbers were generated and assigned to participants, which were subsequently allocated to one study group, PRGF or hyaluronic acid. Sealed envelopes were used to conceal treatment allocation until the moment before applying the treatment.Both participants and independent outcome assessors remained blinded to treatment assignment. Clinical researchers were not blinded due to relevant differences between both interventions in terms of appearance and viscosity. As for participants, peripheral blood was drawn from all patients regardless their assigned treatment and the infiltration area was hidden while the injection was given. Outcome assessors were not involved in infiltrating included participants. | PMC9850713 |
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Outcomes | INFILTRATION | According to the original protocol, participants were expected to be assessed 1, 2, and 6 months after the last treatment infiltration for the following outcomes: | PMC9850713 |
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Primary efficacy outcome | pain | The prespecified primary efficacy outcome was a clinically significant improvement in pain, measured as the percentage of patients with a decrease >40% in the score in the WOMAC pain subscale at the final visit with respect to baseline. This outcome was not presented in the published article but only in the unpublished final report. | PMC9850713 |
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Safety outcomes | ADVERSE EVENTS, ADVERSE EVENT, COMPLICATIONS | A record of complications and/or adverse events with imputation scale was performed. In accordance with the protocol, any sort of circumstances considered by researchers as an adverse event was to be recorded in detail in the booklet, including surgical or postsurgical complications. Non-severe adverse events or those not considered as related to interventions were expected to be listed within the annual report and/or final report. | PMC9850713 |
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Statistical analysis | SECONDARY | With regard to the statistical analysis, RIAT investigators adhere to the original protocol procedures linked only to primary and secondary prespecified outcomes. A database was created to register and extract data from every endpoint described in the study protocol, including a statistical analysis when needed [Efficacy analyses were prespecified to be conducted using a Missing values were jointly dealt by the sponsor, lead researcher and statistician to decide on the last meaningful data (probably a The final unpublished report was used as the main source of data for all outcomes except the non-preplanned primary outcome and use of acetaminophen, as data for these variables were only available in the article publication. | PMC9850713 |
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Discussion | PMC9850713 |
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Main findings and contrast with original published article | knee osteoarthritis, pain | ADVERSE EVENTS, SECONDARY, KNEE OSTEOARTHRITIS | Our RIAT appraisal of Study PRGF underlined that no substantial differences in pain relief and other efficacy estimates were proved when adult participants with knee osteoarthritis were treated with plasma rich in growth factors or hyaluronic acid. As far as safety is concerned, there is no sound evidence about a different profile between both interventions, while some data on type and persistent adverse events make advisable further research. This analysis is well aligned with the final report authored by Sánchez and colleagues but it is not the case concerning the published article in We assessed and reported the Study PRGF in accordance with the original protocol, which had no amendments reported by the study authors or the corresponding ethics committee. The re-assessment of the dossier has shown a marked discrepancy in the main efficacy outcome based on the fact that unlike study authors, in the analysis the RIAT investigators stuck to the protocol and original final report. A specific section in the protocol devoted to ethical considerations (page 35) clearly stated that ‘no changes or deviations of the protocol will be permitted without evidence of approval’. However, the authors reported a non-approved main efficacy outcome, which should be seen as a protocol major change, reaching statistically significant differences in favour of the investigational product. It has been previously described that changes to endpoints can compromise the scientific integrity of a trial, leading to misguided research and suboptimal patient care [Our re-analysis has shown in detail how an inappropriate shift in a primary outcome can dramatically influence final results. In this sense, it should be noted that the original statistical analysis was performed by the own trial sponsor, which stresses the need to rely on fully independent bodies for this crucial task.Other issues such as secondary outcomes reported but not pre-specified and vice versa and the unexpected change in the analysis plan from a per-protocol to an intention-to-treat strategy were also identified. Theoretically, such a switch might have come from the journal review process or a late realization from the original team that intention-to-treat was most appropriate. However, the change should have been explained and justified in the original work, as should the switch of the primary outcome from 40% to 50% reduction. Interestingly, as Table With regard to harms caused by the interventions, inconsistencies between text and figures appeared on persistent symptoms. Finally, the study authors failed to report their conflicts of interest in the authorship and publication of this article. In particular, one of them (EA) was the Scientific Director of the BTI Biotechnology Institute, manufacturer of PRGF-Endoret®, and others (JJA, SP, GO) were employees of the company [ | PMC9850713 |
Agreements and disagreements with other studies | Beyond the clinical trial carried out by Sánchez et al. [When studies are examined individually, there are important and repeated weaknesses: no randomization [ | PMC9850713 |
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RIAT procedures | osteoarthritis | OSTEOARTHRITIS, OSTEOARTHRITIS | Compared to previous exercises, basically represented by the Study 329 [Following the RIAT principles, the study authors were offered from the beginning the possibility to correct themselves all detected inaccuracies. A call to action was publicly issued and sent to the study authors [The Osteoarthritis Research Society International (OARSI) assessed in 2000 the optimal cut-offs to be applied for the OARSI responder criteria regarding several settings, including knee intra-articular specific drugs for osteoarthritis [And fourth, we would be pleased if our experience led to a deep reflection on the future role of ethics committees, reinforcing their commitment with the best practices in research. To fulfil this important mission over the entire life of a clinical trial, these committees would need adequate and well-trained resources, as well as the ability to take action when a case of malpractice is detected. | PMC9850713 |
Strengths and limitations | Study PRGF was a randomized controlled trial with a modest sample size, although larger than most studies in its field [Beyond the specific characteristics of the trial, evidence of several protocol violations has been proved over the RIAT process, clearly undermining the results showed by the original journal publication. On the other side, the RIAT development has been feasible due to the access to two major sources of data (protocol and final report) but it must be recognized that our re-analysis was also limited mainly related to the lack of individual participant data. This information was formally requested with no response received from the authors, which has prevented us from presenting results in more detail but also from discarding other potential problems such as data fabrication. Nonetheless, having in mind these limitations, we remain fully confident on the support that the existent data confer to our results. | PMC9850713 |
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Conclusions | knee osteoarthritis | ADVERSE EVENTS, KNEE OSTEOARTHRITIS | In contrast to the original published article by Sánchez and colleagues, our analysis of Study PRGF (originally coded as BTI-01-EC/07/ART) found no statistically significant differences between plasma rich in growth factors and hyaluronic acid in adults with knee osteoarthritis on any of the prespecified outcomes, included the primary efficacy variable. Serious or unexpected adverse events were rare and equally distributed between both interventions. Notwithstanding, further research should focus on finding out the real rate of persistent harms and the particular profile of adverse events linked to each treatment. Health professionals, especially in this case orthopaedic surgeons, but also researchers and decision-makers should be aware of the potential weaknesses in a priori high-quality research. It is highly convenient that all systematic reviews including the present clinical trial update their results in the light of this new evidence. In the same way, any other clinical trial or review based to some extent on the findings of this study is also called to re-assess its conclusions. Also, sharing the imperative demand by many other research teams, health authorities are strongly encouraged to make compulsory free access to protocols and raw data supporting subsequent publications.As Le Noury and colleagues rightly stated in their pioneering report [ | PMC9850713 |
Acknowledgements | The authors would like to thank the RIAT Support Center ( | PMC9850713 |
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Authors’ contributions | Conception of the work, acquisition of data and database creation: LCS. Database quality assessment and content review: JE, LL and MGV. Data analysis and interpretation: all authors. Drafting the work and revising it critically for important intellectual content, final approval of the version to be published: all authors. All authors agree to be accountable for all aspects of the work. LCS is the guarantor. | PMC9850713 |
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Funding | No specific funding has been received for this work. | PMC9850713 |
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Availability of data and materials | All data for which the RIAT authors are directly responsible are included in this published article and its supplementary information files. This RIAT project has used third-party data to generate part of the results presented in the study, which cannot be made openly available. In agreement with the | PMC9850713 |
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Declarations | PMC9850713 |
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Ethics approval and consent to participate | The original version of this restored trial was approved by the Ethics Committee of the Basque Country, Spain, on 19 December 2007 (BTI-01-EC/07/ART). | PMC9850713 |
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Consent for publication | According to the original publication of this restored trial, all patients provided written consent before entry into the study. | PMC9850713 |
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Competing interests | The RIAT authors declare that they have no competing interests. | PMC9850713 |
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References | PMC9850713 |
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Background | RECRUITMENT | Global workforce challenges faced by health care providers are linked to low levels of job satisfaction, recruitment, retention, and well-being, with detrimental impacts on patient care outcomes. Resilience-building programs can provide support for staff who endure highly stressful environments, enhance resilience, and support recruitment and retention, with web-based formats being key to increasing accessibility. | PMC9975925 |
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Objective | We aimed to examine participants’ engagement with a newly developed Resilience Enhancement Online Training for Nurses (REsOluTioN), explore its acceptability, and compare levels of resilience and psychological well-being in nurses who completed REsOluTioN with those who did not. | PMC9975925 |
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Methods | MAY | We carried out a pilot randomized trial (1:1), conducted at a single site (mental health and community trust in South England) between August 2021 and May 2022. Local research ethics approvals were obtained. Nurses were invited to participate and were randomly assigned to a waitlist group or REsOluTioN group. Training lasted for 4 weeks, consisting of prereading, web-based facilitated sessions, and mentorship support. We evaluated trial engagement, acceptability of training, and pre-post changes in resilience, measured by the Brief Resilience Scale, and psychological well-being, measured by the Warwick Edinburgh Mental Wellbeing Scale. Qualitative participant feedback was collected. Consolidated Standards of Reporting Trials 2010 extension guidelines for reporting pilot and feasibility trials were used. | PMC9975925 |
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Results | Of 108 participants recruited, 93 completed the study. Participants’ mean age was 44 (SD 10.85) years. Most participants were female (n=95, 88.8%), White (n=95, 88.8%), and worked in community settings (n=91, 85.0%). Sixteen facilitated and 150 mentoring sessions took place. Most REsOluTioN program participants reported the sessions helped improve their resilience (n=24, 72.8%), self-confidence (n=24, 72.7%), ability to provide good patient care (n=25, 75.8%), relationships with colleagues (n=24, 72.7%), and communication skills (n=25, 75.8%). No statistically significant differences between training and control groups and time on well-being ( | PMC9975925 |
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Conclusions | The REsOluTioN program was acceptable, engaging, perceived as useful, and nurses were keen for it to be implemented to optimize resilience, psychological health, communication, and workplace environments. The study has evidenced that it is acceptable to implement web-based resilience programs with similar design features within busy health care settings, indicating a need for similar programs to be carefully evaluated. Mentorship support may also be a key in optimizing resilience. Trial limitations include small sample size and reduced statistical power; a multicenter randomized controlled trial could test effectiveness of the training on a larger scale. | PMC9975925 |
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Trial Registration | ClinicalTrials.gov NCT05074563; https://clinicaltrials.gov/ct2/show/NCT05074563 | PMC9975925 |
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International Registered Report Identifier (IRRID) | RR2-10.2196/37015 | PMC9975925 |
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Introduction | PMC9975925 |
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Overview | RECRUITMENT | The ongoing global workforce challenges facing health care providers are well documented and are linked to low levels of job satisfaction, recruitment, retention, and staff well-being, with detrimental impacts on patient care outcomes [The development of evidence-based strategies to improve the psychological well-being of health care staff and mitigate against burnout has been cited as a key priority [Several resilience-enhancement programs have been developed for health care professionals, using both group and individual programs, delivered in a range of contexts and using blended models of delivery [As a result of the need for targeted resilience-enhancement programs within the nursing setting, this paper reports on a pilot randomized controlled trial (RCT) that was designed to evaluate a web-based resilience-enhancement program for nurses [ | PMC9975925 |
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Study Aim | The aim of this paper is to report on the implementation and evaluation of the REsOluTioN pilot RCT. Specific study objectives were to (1) explore participants’ engagement with the REsOluTioN trial, assessed by the number of nurses recruited to it; (2) explore the acceptability of the REsOluTioN program, assessed by participant retention numbers and data on how the training impacted participants’ views on resilience, communication, clinical practice, and workplace relationships; and (3) compare levels of resilience and psychological well-being in nurses who completed REsOluTioN program with nurses who did not (waitlist control arm). | PMC9975925 |
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Methods | PMC9975925 |
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Trial Design and Setting | The study was a 1:1 two-armed pilot randomized trial. It was conducted in a mental health and community National Health Service (NHS) trust in the South of England. | PMC9975925 |
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Ethical Considerations | The Oxford Brookes University Faculty Research Ethics Committee (F.20.01.12.1, dated August 22, 2021) reviewed and approved the trial protocol. Other necessary local research and development office approvals were obtained from the Oxford Health NHS Foundation Trust Research and Development Department (21/HRA/1418). The trial protocol was registered on ClinicalTrials.gov (NCT05074563). Consolidated Standards of Reporting Trials (CONSORT) 2010 extension guidelines for pilot and feasibility trials were used [ | PMC9975925 |
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Recruitment | We invited nonagency nurses of different levels of seniority, working across a wide range of clinical settings from the participating NHS trust to participate. We used posters on the participating trust’s website, social media platforms, and meetings with nursing staff, research delivery teams, and trust communications teams to promote the study. The participating trust’s chief nurse also shared information about the trial with all nurses employed by the trust, using email communications and web-based meeting forums. Nurses who were interested in taking part were provided with a Qualtrics survey web link that contained a study information sheet and consent form. Upon providing consent, they were asked to provide demographic information and complete a prestudy survey ( | PMC9975925 |
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The REsOluTioN Program | The REsOluTioN program was hosted on the Totara learning management system (version 12), via the Learning and Development information technology team at the participating trust. The web-based training was conducted over 4 weeks and covered weekly modules on (1) building hardiness and maintaining a positive outlook, (2) intellectual flexibility and emotional intelligence, (3) reflective and critical thinking, and (4) achieving life balance and enabling spirituality.A blended synchronous and asynchronous learning approach was used, which included (1) web-based 4×120 minutes large-group facilitated sessions on the weekly modules led by experienced senior nurses and other senior multidisciplinary health care staff; (2) 4×30 minute independent preparatory learning on the module topics prior to the large-group facilitated sessions; and (3) 8 small group mentoring sessions led by senior nurses and delivered between 30 and 60 minutes at flexible timings, twice weekly.Both large-group facilitated sessions and mentor meetings were delivered via Teams (Microsoft Corp). Learning materials in the form of PowerPoint presentations, instructional videos created by the study team, case examples, and peer-reviewed journal articles were used. The facilitated sessions also included group discussions and breakout activities. More about the content and delivery of REsOluTioN program is found elsewhere [ | PMC9975925 |
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Waitlist Control | Nurses who were randomized to the control arm were allocated to a waitlist for 6 weeks. After 6 weeks, participants from both arms were asked to complete a poststudy survey ( | PMC9975925 |
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Outcomes | The following outcome data were collected: (1) | PMC9975925 |
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Data Management | All data were deidentified using study codes and stored in password-protected Excel (Microsoft Corp) spreadsheets that were accessed by authorized team members only. We followed the university’s policies and General Data Protection Regulation requirements for data storage. | PMC9975925 |
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Sample Size | The limitations of the pilot study design, as well as finite resource availability, determined our sample size. The study objective was to afford a preliminary comparison of training outcomes, and due to funding constraints and the pressures imposed by COVID-19, we aimed to recruit between 60 and 100 participants; this was deemed appropriate for a pilot study of this nature [ | PMC9975925 |
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Randomization and Blinding | An independent team member who was not involved in the conduct of the trial, delivery of the REsOluTioN program, or data analysis implemented the randomization and allocation. For randomization, we used a computer-generated random number sequence. For allocation concealment, we used sequentially numbered opaque-sealed envelopes that were opened only after entering the name of each participant on the envelope. A team member who was involved in data analysis was blinded to the group allocation. However, participants were not blinded to group allocation due to the nature of the training. | PMC9975925 |
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Statistical Methods | Participants’ demographic characteristics and acceptability outcomes (completers or noncompleters) were descriptively analyzed. Depending on the normality of the data, resilience and psychological well-being measures were presented as means (SD) or medians (IQR). Intention-to-treat analysis was carried out to examine outcomes. Data from participants who withdrew from the study and who were lost to follow up (n=14, 13.1%) were imputed using the expectation maximization technique. We used ANOVA to evaluate any differences in resilience and psychological well-being between arms at 6 weeks. All analyses were undertaken in SPSS statistics software (version 22.0; IBM Corp) [ | PMC9975925 |
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Results | PMC9975925 |
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Overview | A CONSORT diagram detailing the flow of participants through the pilot trial is presented in Consolidated Standards of Reporting Trials (CONSORT) flow diagram depicting flow of participants through the pilot trial. | PMC9975925 |
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Participant Engagement and Retention | MAY | Between August 2021 and May 2022, a total of 134 nurses expressed an interest in participating in the study. Of 134, a total of 108 completed the web-based consent process and prestudy survey. One participant was excluded on the basis of eligibility as he/she was a nursing student rather than an employed member of staff. Consented participants (n=107) were randomly assigned to the waitlist control (n=51) or REsOluTioN program (n=56). Nine participants withdrew from the REsOluTioN group prior to the intervention starting due to changing work commitments or annual leave requirements, which meant that they were unable to be allocated to a training cohort. At 6 weeks post enrollment, 93 participants had completed the poststudy survey, as 5 were lost to follow up and did not complete (2 in the waiting list group and 3 in the REsOluTioN group). When comparing participants who completed the study with those who withdrew or were lost to follow-up, there were no significant differences in terms of baseline demographic characteristics age (t | PMC9975925 |
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Acceptability of the REsOluTioN Program | RECRUITMENT | Participants were allocated to waitlist control and REsOluTioN groups in 4 consecutive cohorts during the recruitment period. Cohort 1 had 14 people in the waitlist control and 6 in the REsOluTioN group, cohort 2 had 2 and 4, cohort 3 had 13 and 11, and cohort 4 had 22 and 26 participants, respectively. A total of 150 mentoring sessions and 16 facilitated sessions took place across the 4 cohorts. No mentors or facilitators reported the length of the sessions, but the mentoring sessions lasted between 30 minutes to 1 hour depending upon the number of participants allocated to the mentor, while the large-group facilitated sessions lasted up to 2 hours. Thus, the sessions were acceptable in terms of delivery and duration. The participant retention rate at 6 weeks was 96% (44/47) in the REsOluTioN group; of these, 33 (75%) participants provided extra feedback on the REsOluTioN program via an additional survey.Of the participants who completed the poststudy evaluation of the REsOluTioN program (n=33), the majority thought that both the web-based workplace resilience training (n=30, 90.9%) and mentoring (n=29, 87.9%) had been useful; a minority felt that their participation in the training program had not impacted on their experience or outlook toward clinical practice (n=7, 21.2%). Participants felt that participation in the web-based training had been important for improving their levels of resilience (n=24, 72.8%), self-confidence (n=24, 72.7%), belief in their ability to provide good patient care (n=25, 75.8%), relationships with work colleagues (n=24, 72.7%), and communication skills with colleagues (n=25, 75.8%).Most participants who completed poststudy evaluation also found the content and sessions helpful (n=29, 87.9%) thought the training delivered an appropriate amount of information (n=27, 81.8%) and that the 4-week duration was about right for training of this type (n=23, 69.7%). The sessions on emotional intelligence and intellectual flexibility were rated most favorably, with 75.8% (n=25) of them indicating that they found it particularly helpful.Analysis of free-text responses from REsOluTioN program participants suggested that they enjoyed opportunities for learning and reflection offered by the training as well as the chance to build networks and interact with colleagues at all levels. Participants indicated that they enjoyed the networking, mentorship, and participatory sessions the most (n=16, 51.5%). However, ringfencing time to attend and engage with the sessions was the most reported challenge due to pressurized working environments. One participant highlighted the need for a cultural shift to support people to take more time for their own well-being. Participants also highlighted organization-wide issues and variability in the way sessions were run as detracting from their overall experience. Evaluation of Resilience Enhancement Online Training for Nurses (REsOluTioN) program–Illustrative quotes.“““““““““ | PMC9975925 |
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Resilience and Psychological Well-being | Mean resilience and psychological well-being scores at baseline and 6 weeks for both groups are presented in Two-way mixed ANOVAs revealed no statistically significant differences between groups and time (baseline and 6 weeks) on resilience scores ( | PMC9975925 |
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Discussion | PMC9975925 |
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Principal Findings | RECRUITMENT | Our findings have shown that nurse participants engaged with REsOluTioN program, as evidenced by the high recruitment rate to the pilot study. The training was acceptable to nurses working in frontline clinical settings; this is demonstrated by the large number of participants who enrolled in and completed the study. While a small number of participants withdrew from the study or were lost to follow-up, the majority of these withdrew prior to the training commencing due to changing work commitments, meaning that they were no longer able to join a cohort. Participant feedback demonstrated that most participants clearly valued the importance of protecting their resilience within the workplace. Most participants were receptive toward the REsOluTioN program and reported that they felt it was an important tool for helping to enhance their resilience, confidence, patient care provision, and relationships with work colleagues; this demonstrates the potential application of web-based resilience tools for this population group. Overall, the REsOluTioN program was well received and identified a desire from nurses for web-based resilience training tools to be implemented as a way of optimizing resilience, psychological health, communication practices, and the workplace environment. Though there were no significant differences between REsOluTioN and waitlist control groups at 6 weeks in terms of resilience and psychological well-being, these results must be considered alongside the small sample size, due to the pilot nature of the trial. | PMC9975925 |
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Comparison With Prior Work | Our findings have highlighted the potential need for resilience-enhancement programs for nurses working in highly stressful working conditions. This pilot trial was carried out across an NHS trust in South England during the height of the COVID-19 pandemic, when pressures on health care staff were extremely high, with nurses having considerable demands on their time and multiple conflicting priorities [The REsOluTioN pilot trial has shown that web-based resilience-enhancement programs appear acceptable to nurses working across a range of health care settings. This is evidenced by the low dropout rate of participants who enrolled in the study, which is an indicator of high levels of acceptance [Feedback from participants who enrolled in the training arm indicated that they were satisfied with the different the REsOluTioN program components and that the web-based facilitated and mentorship sessions were well received. This endorsement of the mentorship component of the REsOluTioN program has been evidenced in previous research exploring resilience in nurses [Although no statistically significant mean differences were found in levels of resilience or psychological well-being between the waitlist control and training arms, the small sample size of the pilot study makes it difficult to draw meaningful conclusions from the dataset. Furthermore, resilience and psychological well-being scores were higher in the training arm than the waitlist control arm at the end of the study, suggesting positive trends in the right direction and that the REsOluTioN program may lead to statistically significant outcomes when tested on a larger population. Pilot studies are recommended as the first step in determining information relating to study design, engagement, and acceptability, as | PMC9975925 |
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Strengths and Limitations of the Study | RECRUITMENT | To our knowledge, REsOluTioN was the first web-based training piloted on nurses working during the COVID-19 pandemic and has highlighted many benefits of providing such a resource to nurses working under highly pressurized conditions. In addition, the engagement and acceptability outcomes have been achieved as indicated by the high study recruitment and adherence rates and from the qualitative survey feedback. This confirms that it is possible to implement web-based resilience training programs for nurses within busy workplace environments with successful engagement from nurses.Study limitations include the small sample size, and hence robust conclusions on psychological well-being and resilience outcomes cannot be made. In addition, this study was conducted at only one NHS trust; future studies should be conducted across a range of NHS health and social care settings to increase the generalizability of the findings. Finally, conducting a study during the COVID-19 pandemic may have influenced the findings, as nurses were working under even more pressurized conditions than usual [ | PMC9975925 |
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Conclusions | SB\ZA\101010662\633134 | This pilot RCT has identified the importance of, and need for, tailored resilience-enhancement programs for nurses, who are facing unprecedented workforce pressures and may benefit from additional forms of structured support. The components of the REsOluTioN program were well received, with specific emphasis placed on the mentorship components, suggesting this may be an area of future research focus and practical application.Further, large-scale research is required to test the effectiveness of the REsOluTioN program across real-world health care settings, with the aim of increasing the sustainability, health, and well-being of the nursing workforce in the future.This study is funded by the Burdett Trust for Nursing (SB\ZA\101010662\633134). The authors would like to thank the REsOluTioN session facilitators, mentors, and the learning and development team for their support with the study, as well as all the nurses who participated in this study. CH is supported by the National Institute for Health Research Oxford Health Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NIHR, UK National Health Service, or the UK Department of Health and Social Care.Conflicts of Interest: AC is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP-2017-08-ST2-006), by the NIHR Oxford and Thames Valley Applied Research Collaboration and by the NIHR Oxford Health Biomedical Research Centre (grant BRC-1215-20005). The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health; he has received research, educational and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation, Lundbeck and Angelini Pharma.Preintervention Survey.Postintervention Survey and Evaluation.CONSORT-eHEALTH checklist (V 1.6.2). | PMC9975925 |
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Abbreviations | Consolidated Standards of Reporting TrialsNational Health Servicerandomized controlled trialResilience Enhancement Online Training for Nurses | PMC9975925 |
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Data Availability | The data that support the findings of this study are available from the corresponding author upon reasonable request. | PMC9975925 |
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Abstract | PMC10109527 |
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Objective | sleep behavior disorder, synucleinopathy, RBD, Prodromal | SYNUCLEINOPATHY | Rapid eye movement (REM) sleep behavior disorder (RBD) is widely considered a prodromal synucleinopathy, as most with RBD develop overt synucleinopathy within ~10 years. Accordingly, RBD offers an opportunity to test potential treatments at the earliest stages of synucleinopathy. The North American Prodromal Synucleinopathy (NAPS) Consortium has created a multisite RBD participant, primarily clinic‐based cohort to better understand characteristics at diagnosis, and in future work, identify predictors of phenoconversion, develop synucleinopathy biomarkers, and enable early stage clinical trial enrollment. | PMC10109527 |
Methods | narcolepsy, dementia, RBD, cognitive, motor, sensory, and autonomic function | MULTIPLE SYSTEM ATROPHY, PARKINSON'S DISEASE, NARCOLEPSY | Participants ≥18 years of age with overnight polysomnogram‐confirmed RBD without Parkinson's disease, dementia, multiple system atrophy, or narcolepsy were enrolled from nine sites across North America (8/2018 to 4/2021). Data collection included family/personal history of RBD and standardized assessments of cognitive, motor, sensory, and autonomic function. | PMC10109527 |
Results | Outcomes are primarily reported based on sex (361 total: | PMC10109527 |
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Interpretation | neurological abnormalities, RBD, cognitive, motor, sensory, and autonomic function | These RBD participants, assessed with extensive history, demographic, cognitive, motor, sensory, and autonomic function demonstrated a lack of sex differences and high frequency of concomitant neurological abnormalities. These participants will be valuable for future longitudinal study and neuroprotective clinical trials. | PMC10109527 |
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Introduction | MSA, DLB, sleep behavior disorder, Parkinson's disease, neurodegenerative diseases, synucleinopathies, PD, RBD, Prodromal, muscle atonia | DISORDER, PARKINSON'S DISEASE, NEURODEGENERATIVE DISEASES, DREAM ENACTMENT BEHAVIOR, SYNUCLEINOPATHY, DEMENTIA WITH LEWY BODIES, MULTIPLE SYSTEM ATROPHY, PATHOLOGY, EYE, STAGGERING | The North American Prodromal Synucleinopathy (NAPS) Consortium for Rapid Eye Movement (REM) sleep behavior disorder (RBD) was established to facilitate neuroprotective clinical trials for neurodegenerative diseases characterized by synuclein pathology. Such “synucleinopathies,” including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), affect ~2‐million people in the US, have a staggering economic footprint,RBD is a disorder characterized by a lack of muscle atonia during REM sleep and dream enactment behaviors,Building upon existing RBD research groups (e.g., the International RBD Study Group), | PMC10109527 |
Materials and methods | PMC10109527 |
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Overview | cognitive, motor, autonomic, or sensory domains, neurodegenerative | MAY | A complete methodological description of the NAPS Consortium protocol is published in a separate overview paper (Ju et al. Pending). Briefly, participants >18 years of age with polysomnogram‐confirmed RBD by ICSD‐3 criteriaData collection procedures and practices were rigorously standardized across sites, which included structured interviews and questionnaires on health history, structured neurological, and physical examinations, and an objective test battery of cognitive, motor, autonomic, and sensory functions. If available, a co‐participant (a spouse, family member, or friend who knows the participant well) provided information via structured interviews and written questionnaires. Variables presented in this analysis are detailed below; according to the NAPS1 REDCap database export dated May 26, 2022 prior to complete import into the NAPS2 RAVE database. Biofluid assay data, polysomnograms, data from participants enrolling after April 2021, and data from longitudinal study visits are not presented in this analysis.Based on the clinical evaluation, questionnaires, exam, and objective tests, the clinician at each site (a board‐certified neurologist) completed a standardized, structured assessment to render clinical diagnoses. Determinations were supported by a quarterly, panel‐based adjudication process with three or more NAPS clinicians. Participants were categorized as “RBD+” indicating one or more abnormalities (symptoms, signs, or test results attributable to a neurodegenerative cause) in any of the cognitive, motor, autonomic, or sensory domains ( | PMC10109527 |
RBDSS, obstructive or central) | SLEEP APNEA, RESTLESS LEGS SYNDROME | A NAPS‐specific structured interview queried for RBD symptoms, frequency, severity, treatments, and possible temporal relationship with any antidepressant or other medications. Diagnoses of sleep apnea (obstructive or central), restless legs syndrome, and periodic limb movement were determined during the clinician's structured interview. The severity and frequency of RBD symptoms was assessed by the RBD Severity Scale (RBDSS), | PMC10109527 |
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Other health history and questionnaires | ALZHEIMER | Demographic information and health history (including comprehensive family history) were obtained via structured interview and forms, including those from the Uniform Data Set version 3 (UDS3), from the National Alzheimer Coordinating Center ( | PMC10109527 |
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Neurological test battery | B‐SIT, Impaired orthostatic tolerance, orthostatic intolerance, Hg decrease, orthostatic blood pressure | Participants underwent a broad neurological test battery including objective tests of cognitive, motor, autonomic, and sensory (color vision and smell) function. Cognitive assessments included the psychometric battery from the UDS3 standard and LBD modulesMotor function was assessed via the Timed Up and Go (TUG),Autonomic function was measured with orthostatic blood pressure, in which blood pressure was measured after lying supine for 5 min, then 3 min after standing. Impaired orthostatic tolerance was defined as ≥20 mm Hg decrease in systolic blood pressure and/or a ≥ 10 mm Hg decrease in diastolic blood pressure. Severe orthostatic intolerance was defined as ≥30 mm Hg decrease in systolic blood pressure and/or a ≥ 15 mm Hg decrease in diastolic blood pressure.The Brief Smell Identification Test (B‐SIT; Version A, Sensonics Inc. NJ, USA) | PMC10109527 |
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Statistical analyses | Anxiety, RBDSS, loss of consciousness, Parkinson's Disease Autonomic Function, stress disorder, Parkinson's Disease Rating Scale, Movement Disorder, RBD, arrhythmias/bundle branch block, SCOPA | MOVEMENT DISORDER, OTHER CARDIOVASCULAR DISEASE, PARKINSON'S DISEASE | Statistical analyses were performed with SPSS and GraphPad Prism v9, with alpha at 0.05. Data are presented as mean, standard deviation, number, and percentage of the whole. Data for the whole group (Tables Demographic characteristics.Data are presented as mean ± standard deviation, or raw frequency count with percent of the total number of available responses in parentheses.
RBD and other sleep characteristics.Data are presented as mean ± standard deviation, or raw frequency count with percent of the total number of available responses in parentheses. Other psychotropic/neurologic/sleep‐related medications use include zolpidem, trazodone, cannabidiol, lorazepam, prazosin, ropinirole, donepezil, pimavanserin, diphenhydramine, and gabapentin.RBDSS, RBD Severity Scale; SCOPA, Scales for Outcomes in Parkinson's Disease.
RBD characteristics and sleep outcomes based on antidepressant use.Data are presented as mean ± standard deviation, or raw frequency count with percent of the total number of available responses in parentheses. Data missing on SCOPA, Scales for Outcomes in Parkinson's Disease.
RBD characteristics and sleep outcomes in isolated RBD.Data are presented as mean ± standard deviation, or raw frequency count with percent of the total number of available responses in parentheses. See text for definition of isolated RBD. Other psychotropic/neurologic/sleep‐related medications use include zolpidem, trazodone, cannabidiol, lorazepam, prazosin, ropinirole, donepezil, pimavanserin, diphenhydramine, and gabapentin.SCOPA, Scales for Outcomes in Parkinson's Disease.
General, cardio/cerebrovascular, neurological, and mental health history.Data are presented as mean ± standard deviation, or raw frequency count with percent of the total number of available responses in parentheses. Other cardiovascular disease includes, arrhythmias/bundle branch block (BAI, Beck Anxiety Inventory; BP, blood pressure; LOC, loss of consciousness; PCL‐5, post‐traumatic stress disorder checklist for DSM‐V; PHQ‐9, Patient Health Questionnaire‐9; SCOPA‐AUT, scales for Outcomes in Parkinson's Disease Autonomic Function.
Cognition, motor, autonomic, and sensory function.Data are presented as mean ± standard deviation, or raw frequency count with percent of the total number of available responses in parentheses. Criteria for abnormality: Montreal Cognitive Assessment, Z‐score at or below 1.5 SD based on total score ≤ 25; MDS‐UPDRS part 3, based on total score > 4; Purdue Pegboard, based on total score < 9; Alternate Tap Test, based on total score < 165; Timed Up and Go, based on total time ≥ 13.5 s; Farnsworth‐Munsell Color Vision Test, based on total score > 100; Brief Smell Identification Test, based on total score ≤ 8.BP, blood pressure; MDS‐UPDRS, Movement Disorder Society Unified Parkinson's Disease Rating Scale.
| PMC10109527 |
Results | PMC10109527 |
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Demographics | The participant cohort ( | PMC10109527 |
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neurodegenerative signs, RBD | NEURODEGENERATION | The overall cohort reported mean RBD symptom onset at age 51.1 ± 16.3 (Table With regard to sex differences, RBD symptom onset occurred ~3 years earlier in women than men, a difference that was not statistically significant (48.9 ± 21.0 vs. 51.6 ± 18.1 years of age; Antidepressant usage within the overall population was examined based on participants reporting any history of antidepressant usage (previous or current; no clinically relevant differences were noted when comparing only previous or only current usage) compared to participants with no history of antidepressant usage (Table RBD and sleep‐related outcomes were compared between participants determined to have isolated RBD (i.e., those with no other signs of neurodegeneration) and those with possible neurodegenerative signs (i.e., RBD+; Table | PMC10109527 |
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Health history | anxiety, traumatic brain injury, delusions, hallucinations, Urinary and bowel incontinence, TBI, sexual dysfunction, PTSD, orthostatic hypotension, RBD, depression, apathy/indifference | ORTHOSTATIC HYPOTENSION | The most commonly reported health problems in the cohort (Table Autonomic function, as assessed by SCOPA‐AUT, averaged 13.5 ± 7.8 in the overall cohort, not significantly different between men and women. Urinary and bowel incontinence, as well as orthostatic hypotension were not different between men and women. Men reported a nearly two‐fold higher rate of sexual dysfunction compared to women (68% vs. 37%).Approximately 27% of the cohort reported a history of traumatic brain injury (TBI) occurring on average 31 years ago, which was more common in men (29.2% vs. 16.7%; albeit non‐significant The most common mental health problems were anxiety (39.3%) and depression (recent, <2 years ago, 31.0%; or inactive, >2 years ago, 29.5%). Individuals self‐reporting anxiety and depression averaged 14.4 ± 11.4 and 9.1 ± 6.1 for BAI and PHQ‐9 scores, respectively. However, self‐reported BAI and PHQ‐9 scores in the overall group averaged 8.1 ± 8.8 and 5.2 ± 5.4, respectively, which are scores below clinical thresholds for anxiety or depression (BAI scores <16 indicate mild to no anxiety; PHQ‐9 scores <10 indicate mild to no depression). Considering previously reported associations between PTSD and RBD,The Neuropsychiatric Inventory assessed domains related to delusions, hallucinations, anxiety, and apathy/indifference. This cohort had low rates of current delusions or hallucinations (~4%–5%), whereas anxiety was reported at 22.2% and apathy/indifference at 19.7%. Although men had higher rates in the “apathy/indifference” (22.7% vs. 6.1%; | PMC10109527 |
Neurological test battery results | orthostatic tolerance, Orthostatic hypotension | ORTHOSTATIC HYPOTENSION | The cognitive battery revealed relatively normal mean scores in the overall cohort, with women having better scores in the MoCA (27.1 ± 4.5 vs. men 26.0 ± 5.3; Distribution of scores in primary domains of function. The distribution of individual scores (open circles) with the mean value indicated via the shaded bar and the threshold for abnormality (dotted line) with the percentage of the total cohort falling above/below this threshold and meeting criteria for abnormal function for (A) the Montreal Cognitive Assessment (% abnormal based on Z‐score of 1.5 SD or below after normalization), (B) the MDS‐UPDRS part III (% abnormal based on total score > 4), (C) the Brief Smell Identification Test (% abnormal based on total score ≤ 8), (D) the SCOPA‐AUT (% abnormal based on total score > 13), (E) Farnsworth‐Munsell 100 color vision test (% abnormal based on total score > 100), (F) the Alternate Tap Test for participants dominant hand (% abnormal based on total score < 165).Mean motor test and examination scores were in the normal range (Table A relatively large proportion of participants had autonomic impairment as assessed by orthostatic tolerance testing. Orthostatic hypotension was present in 27.7% of the cohort (defined by a systolic and/or diastolic blood pressure drop of >20/10 mm Hg, respectively, after 3 min of standing), with 13.3% having values in the severe range (i.e., systolic and/or diastolic drop >30/15 mm Hg); there were no differences between men and women.Average FM‐100 scores in non‐color‐blind participants were 143.6 ± 97.6, indicating 74% of the cohort was abnormal, with women showing slightly better mean color vision (119 ± 89 vs. 149 ± 101; | PMC10109527 |
Family history | MSA, DLB, sleep disorders, Systems Atrophy, Parkinson's Disease, neurologic and sleep disorders, PD, neurological diseases, Alzheimer's Disease, Dementia, RBD, AD | DEMENTIA WITH LEWY BODIES, NEUROLOGICAL DISEASE, PARKINSON'S DISEASE, ALZHEIMER'S DISEASE | Participants in this study provided extensive family history information (Fig. Genealogy of known RBD and related neurologic and sleep disorders. Participant (shaded center box) with offspring, sibling, and maternal (m.) and paternal (p.) family members. Non‐shaded circles indicate female sex and non‐shaded squares indicate male sex (shaded squares for participant, cousins and non‐immediate family imply male or female). Rates for RBD, Dementia (including: Alzheimer's Disease (AD), Dementia with Lewy Bodies (DLB), and Dementia NOS [no other symptoms]), Parkinson's Disease (PD), Multiple Systems Atrophy (MSA), other neurological diseases (dz), and other sleep disorders (ds) are listed within each family member. Within the Dementia category, the rate of DLB is indented and indicated. Rates above 1% are bolded for clearer visualization. Note: Raw frequency counts are not embedded due to (1) space constraints, and (2) limitations inherent to these data. All percentages reflect a total sample size of | PMC10109527 |
Discussion | atonia, idiopathic RBD, neurological impairment, neurological abnormalities, RBD | DISEASE | We report characteristics of the initial NAPS Consortium cohort as measured through a standardized, comprehensive clinical assessment. Consistent with previous literature, we found a male preponderance for RBD (~80%),Even across 9 sites, there was a high male:female ratio in our RBD cohort, yet a striking lack of differences between men and women except for younger age of onset and higher antidepressant usage in women. Previous work has described an earlier age of RBD onset in women that can be attributed to previous or current antidepressant usage.Antidepressants are known to cause changes in sleep architecture and polysomnography findings, predominantly during REM sleep (e.g., induce prominent eye movements, suppress REM sleep, and increase REM sleep without atonia, RSWA).“Soft” neurological abnormalities were very common in our cohort (i.e., RBD+ participants; The possible genetic underpinnings of RBD remain ill‐defined. Previous work reported a family history for dream enactment via the RBD1QLimitations in this study include the cross‐sectional and descriptive nature inherent to these data and experimental design. Participants were recruited primarily from clinics offered on a consecutive basis and supplemented with community referrals through the In summary, this multisite dataset represents a coordinated effort to enroll, characterize, and follow a cohort of hundreds of subjects with RBD across North America. Initial results from this current baseline characteristics study already reveal novel insights about sex differences, antidepressant use, heritability, and the breadth and severity of neurological impairment among individuals with idiopathic RBD. Future work is poised to answer critical questions about longitudinal progression of disease, pathophysiological features, biomarkers, and predictors of phenoconversion. Importantly, longitudinal data on this well‐characterized cohort will inform the design of future neuroprotective clinical treatment trials, especially those targeting the earliest phase of synucleinopathy. | PMC10109527 |
Author Contributions | DEH | Conception and design of the study. JEE, MML, ATK, RBP, AP, JFG, EKSL, LKF, JAF, DLB, DEH, AYA, MJH, CHS, JM, SRC, AV, EHD, MGM, DRS, JKLI, BFB, YSJ. Acquisition and analysis of data. JEE, MML, ATK, RBP, AP, JFG, EKSL, LKF, JAF, DLB, DEH, AYA, MJH, CHS, JM, SRC, AV, EHD, MGM, DRS, JKLI, BFB, YSJ. Drafting a significant portion of the manuscript or figures (i.e., a substantial contribution beyond copy editing and approval of the final draft, which is expected of all authors). JEE, MML, ATK, RMP, BFB, YSJ. | PMC10109527 |
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Conflict of Interest | Respicardia, NINDS, Dementia | SCHENCK, LEWY BODY DEMENTIA, BRAIN, FOX, LITTLE, HEART, ALZHEIMER |
Dr. Elliott has received support from the Department of Veteran Affairs, NIH (NHLBI, NIA, NCCIH), Oregon Medical Research Foundation, Portland VA Research Foundation, Eugene & Clarissa Evonuk Foundation in Environmental Physiology, and American Heart Association.Dr. Lim has received support from Department of Veteran Affairs, Department of Defense, NIH (NIMH, NHLBI, NIA, NCCIH, NINDS, NIGMS, NCATS), NSF, Center for Neuroscience & Regenerative Medicine (Henry Jackson Foundation), Oregon Medical Research Foundation, Collins Medical Trust, Brain & Behavior Foundation (NARSAD), American Sleep Medicine Foundation, Hartford Center of Gerontological Excellence, Pacific Northwest National Laboratory, and Portland VA Research Foundation.Allison Keil, Dr. Pelletier, Dr. Forsberg, Jennifer McLeland has no disclosures.Dr. Postuma has received support from the Fonds de Recherche du Quebec – Santé, the Canadian Institutes of Health Research, the Parkinson Society of Canada, the Weston‐Garfield Foundation, the Michael J. Fox Foundation, the Webster Foundation; and personal fees from Takeda, Roche/Prothena, Teva Neurosciences, Novartis Canada, Biogen, Boehringer Ingelheim, Ther‐ anexus, GE HealthCare, Jazz Pharmaceuticals, Abbvie, Jannsen, Otsuko, Phytopharmics, Inception Sciences, and Curasen.Dr. Gagnon has received support from the NIH, the Canadian Institutes of Health Research and the Dr. St. Louis has received support from NIH (NIA, NINDS, and NHLBI), the Michael J. Fox Foundation, Harmony, Inc., and Sunovion, Inc.Dr. Fields has received support from the NIH.Dr. Bliwise has received support from the NIH and has been a Consultant to CliniLabs, Eisai, Ferring, Huxley, Idorsia, and Merck.Dr. Huddleston has received support from NIH (NIA, NINDS, Department of Veteran Affairs, the American Parkinson's Disease Association Center for Advanced Research, the Emory Udall Parkinson's Disease Research Center, the Emory Lewy Body Dementia Association Research Center of Excellence, the Emory Alzheimer's Disease Research Center, the Michael J Fox Foundation, the Georgia Research Alliance, the Bumpus Family Foundation, and the McMahon Family).Dr. Avidan has received consultant fees from Avadel, Merck, Takeda, Eisai, Idorsia, and Harmony, and speaker honoraria from Merck, Eisai, Harmony, and Idorsia.Dr. Howell has received research support from the NIH.Dr. Schenck has received a one‐time speaker honorarium from Eisai, Inc.Dr. Criswell has received support from the NIH and consulting fees from Abbvie and Sio Gene Therapies.Dr. Videnovic has received research support from the NIH and the Michael J Fox Foundation; consultancy fees from Alexion Pharmaceuticals, Biogen, XW Pharma, Jazz.Dr. During has received support from Jazz Pharmaceuticals, Sanofi, Takeda, Rythm Inc., and the Feldman Foundation CA.Dr. Miglis has received support from Jazz Pharmaceuticals, Embr Wave, and Biohaven Pharmaceuticals; Consulting fees from 2nd MD, Infinite MD, and Guidepoint LLC; Payments for CME lectures from MED‐IQ; Royalties from Elsevier Inc.Dr. Shprecher has received support from the Arizona Alzheimer's Consortium, Abbvie, Acadia, Aptinyx, Axovant, Biogen, Eisai, Eli Lilly, Enterin, Neurocrine, Michael J Fox Foundation, NIH, Nuvelution, Theravance, and Teva; consultant fees from Amneal, Forensis, and Neurocrine; speaker honoraria from Acorda, Amneal, Neurocrine, Sunovion, Teva, and US World Meds/Supernus.Dr. Lee‐Iannotti has received support from NIH, Liva Nova, Respicardia, and the Arizona Alzheimer's Consortium. She serves on the Scientific Advisory Board for Jazz Pharmaceuticals, INSPIRE, and Avadel. She is a consultant and speaker for Jazz Pharmaceuticals.Dr. Boeve has served as an investigator for clinical trials sponsored by Alector and Biogen. He serves on the Scientific Advisory Board of the Tau Consortium. He receives support from NIH, the Mayo Clinic Dorothy, and Harry T. Mangurian Jr. Lewy Body Dementia Program, the Little Family Foundation, and the Ted Turner and Family Foundation.Dr. Ju has received support from the NIH and the Centene Corporation contract (P19‐00559) for the Washington University‐Centene ARCH Personalized Medicine Initiative; and compensation for consultant activities for Applied Cognition. | PMC10109527 |
Acknowledgements | The authors would like to express their sincere appreciation and gratitude for the participation of our research subjects, and to the entire NAPS consortium. Financial support from NIH grants R34 AG056639, U19 AG071754, P50 AG016574, P30 AG62677; VA RRD 1K2 RX002947; and Canadian support via Research Chair in Cognitive Decline in Pathological Aging. | PMC10109527 |
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References | PMC10109527 |
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Subject terms | tumors | RESIDUAL DISEASE, TUMORS, HER2-POSITIVE BREAST CANCER | The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease.Neoadjuvant therapies with dual anti-HER2 blockade have proven effective in HER2 | PMC10624889 |
Introduction | tumor, breast cancer | TUMOR, CYTOTOXICITY, HER2-POSITIVE BREAST CANCER, BREAST CANCER | Neoadjuvant treatment escalation approaches with dual anti-human epidermal growth factor receptor 2 (HER2) blockade have been proven effective in early-stage HER2-positive breast cancer, leading to an increase in pathological complete response (pCR) ratesHER2-positive breast cancer is considered an immunogenic tumor, and the host immune response in this breast cancer subtype has been extensively explored due to its known role in modulating the activity of anti-HER2 agents [e.g., through antibody-dependent cellular cytotoxicity (ADCC)]Of note, increased diversity and clonal expansion of B cell receptor (BCR) and TCR repertoires, which can be described with different metrics (Supplementary Fig. Moreover, the achievement of pCR after neoadjuvant treatments is a robust prognostic indicatorIn this retrospective study, we further dissect the heterogeneity of HER2-positive breast cancer by evaluating the characteristics of the BCR and TCR repertoires in the context of two phase III clinical trials, namely NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. Moreover, we explore the impact of BCR and TCR repertoires and diversity measures on treatment response and long-term clinical outcomes. We present a prognostic model integrating baseline immunological and clinical features, as well as treatment response, aimed at identifying distinct prognostic groups in HER2-positive breast cancer patients treated with neoadjuvant therapies. The prognostic stratification of patients and the biological characterization of determinants of prognosis can open the avenue for the implementation of optimized neoadjuvant/post-operative treatment strategies. | PMC10624889 |
Results | PMC10624889 |
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BCR and TCR repertoires in the NeoALTTO and CALGB 40601 trials | tumor | TUMOR, HER2-POSITIVE BREAST CANCER | Aiming at investigating the complexity of the immune response in HER2-positive breast cancer, we explored the diversity of BCR and TCR repertoires in pre-treatment baseline tumor samples. The MiXCR toolIn NeoALTTO, all samples had at least one read mapping to BCR, while one sample did not have any read mapping to TCR. In the CALGB 40601 study, all samples showed reads mapping to both BCR and TCR. As the library size can impact the number of BCR/TCR reads, for the subsequent analyses we normalized the number of BCR/TCR reads by the total number of reads mapping to genes in each sample. The number of reads mapping to TCR was significantly lower than BCR in both studies, and the number of normalized reads and clones were significantly higher in NeoALTTO compared to CALGB 40601 (Supplementary data The proportions of reads mapping to the different immunoglobulin and TCR chains are shown in Supplementary Fig. From here on, we refer to BCR/TCR repertoire characteristics as the global metrics calculated on all reads mapping to chains forming either the BCR or TCR, with clones defined separately for each chain as detailed in the METHODS, representing the whole clonal repertoire.The correlation among different BCR/TCR measures is also shown in Supplementary Figs. Isotypes (IgG, IgA, IgM, IgD, IgE) from BCR heavy chains were also computed (details in METHODS). In both studies, the majority of the BCR heavy chain reads were from IgG, followed by IgA and IgM (Supplementary Fig | PMC10624889 |
BCR and TCR repertoires are heterogeneous according to hormone receptor status and PAM50 subtypes, and correlate with TIL levels | We next explored the association of BCR and TCR repertoires with hormone receptor status, PAM50 subtypes, and TIL levels, scored as % of the intratumoral stroma area following the International TILs Working Group guidelinesAs shown in Fig. | PMC10624889 |
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