Production and use of rapid responses during the COVID-19 pandemic in Quebec (Canada): perspectives from evidence synthesis producers and decision makers.

BACKGROUND: The COVID-19 pandemic has required evidence to be made available more rapidly than usual, in order to meet the needs of decision makers in a timely manner. These exceptional circumstances have caused significant challenges for organizations and teams responsible for evidence synthesis. They had to adapt to provide rapid responses to support decision-making. This study aimed to document (1) the challenges and adaptations made to produce rapid responses during the pandemic, (2) their perceived usefulness, reported use and factors influencing their use and (3) the methodological adaptations made to produce rapid responses. METHODS: A qualitative study was conducted in 2021 with eight organizations in the health and social services system in Quebec (Canada), including three institutes with a provincial mandate. Data collection included focus groups (n = 9 groups in 8 organizations with 64 participants), interviews with decision makers (n = 12), and a document analysis of COVID-19 rapid responses (n = 128). A thematic analysis of qualitative data (objectives 1 and 2) and a descriptive analysis of documents (objective 3) were conducted. RESULTS: The results highlight the teams and organizations' agility to deal with the many challenges encountered during the pandemic (e.g., increased their workloads, adoption of new technological tools or work processes, improved collaboration, development of scientific monitoring, adaptation of evidence synthesis methodologies and products). The challenge of balancing rigor and speed was reported by teams and organizations. When available at the right time, rapid responses have been reported as a useful tool for informing or justifying decisions in a context of uncertainty. Several factors that may influence their use were identified (e.g., clearly identify needs, interactions with producers, perceived rigor and credibility, precise and feasible recommendations). Certain trends in the methodological approaches used to speed up the evidence synthesis process were identified. CONCLUSIONS: This study documented rapid responses producers' experiences during the COVID-19 pandemic in Quebec, and decision makers who requested, consulted, or used these products. Potential areas of improvements are identified such as reinforce coordination, improve communication loops, clarify guidelines or methodological benchmarks, and enhance utility of rapid response products for decision makers.

Substrate promiscuity of Dicer toward precursors of the let-7 family and their 3'-end modifications.

The human let-7 miRNA family consists of thirteen members that play critical roles in many biological processes, including development timing and tumor suppression, and their levels are disrupted in several diseases. Dicer is the endoribonuclease responsible for processing the precursor miRNA (pre-miRNA) to yield the mature miRNA, and thereby plays a crucial role in controlling the cellular levels of let-7 miRNAs. It is well established that the sequence and structural features of pre-miRNA hairpins such as the 5'-phosphate, the apical loop, and the 2-nt 3'-overhang are important for the processing activity of Dicer. Exceptionally, nine precursors of the let-7 family (pre-let-7) contain a 1-nt 3'-overhang and get mono-uridylated in vivo, presumably to allow efficient processing by Dicer. Pre-let-7 are also oligo-uridylated in vivo to promote their degradation and likely prevent their efficient processing by Dicer. In this study, we systematically investigated the impact of sequence and structural features of all human let-7 pre-miRNAs, including their 3'-end modifications, on Dicer binding and processing. Through the combination of SHAPE structural probing, in vitro binding and kinetic studies using purified human Dicer, we show that despite structural discrepancies among pre-let-7 RNAs, Dicer exhibits remarkable promiscuity in binding and cleaving these substrates. Moreover, the 1- or 2-nt 3'-overhang, 3'-mono-uridylation, and 3'-oligo-uridylation of pre-let-7 substrates appear to have little effect on Dicer binding and cleavage rates. Thus, this study extends current knowledge regarding the broad substrate specificity of Dicer and provides novel insight regarding the effect of 3'-modifications on binding and cleavage by Dicer.

Perceptions and Preoccupations of Patients and Physicians Regarding Use of Medical Cannabis as an Intervention Against Chronic Musculoskeletal Pain: Results from a Qualitative Study.

Objective: Explore perceptions and preoccupations regarding use of medical cannabis against chronic musculoskeletal pain, among patients and physicians. Design: Qualitative study using interviews with patients and physicians, based on the Theory of Planned Behavior (TPB). Setting: The study was conducted in Quebec, Canada, in spring 2020. Subjects: We included 27 adult patients and 11 physicians (GPs, anesthesiologists, psychiatrists, and a rheumatologist); the mean age of patients was 48.2 years; 59.3% of patients and 36.4% of physicians were women; 59.3% of patients used no medical cannabis at the time of study; 45.5% of physicians had never authorized it. Methods: Semi-structured interviews were conducted, transcribed and for the qualitative analysis codes were developed in a hybrid, inductive and deductive approach. Guided by the TPB, facilitators and barriers, perceived benefits and harms, and perceived norms that may influence cannabis use or authorization were documented. Results: Although medical cannabis is an interesting avenue for the relief of chronic musculoskeletal pain, doctors and patients agreed that it remained a last line option, due to the lack of scientific evidence regarding its safety and efficacy. The norms surrounding medical cannabis also play an important role in the social and professional acceptance of this therapeutic option. Conclusion: Medical cannabis is seen as a last line option among interventions in the management of chronic pain, and attitudes and prior experiences play a role in the decision to use it. Study results may contribute to improved shared decision making between patients and physicians regarding this option.

Preferences of patients with chronic low back pain about nonsurgical treatments: Results of a discrete choice experiment.

INTRODUCTION: This study aimed to assess patients' preferences of nonsurgical treatments for chronic low back pain (CLBP). METHOD: We conducted a discrete choice experiment (DCE) in Quebec, Canada, in 2018. Seven attributes were included: treatment modality, pain reduction, the onset of treatment efficacy, duration effectiveness, difficulties with daily activities, sleep problems, and knowledge of the patient's body and pain location. Treatment modalities were corticosteroid injections, supervised body-mind physical activities, supervised sports physical activities, physical manipulations, self-management courses, and psychotherapy. Utility levels were estimated using a logit model, a latent class model and a Bayesian hierarchical model. RESULTS: Analyses were conducted on 424 $424$ individuals. According to the Bayesian hierarchical model, the conditional relative importance weights of attributes were as follows: (1) treatment modality (34.79%), (2) pain reduction (18.73%), (3) difficulties with daily activities (11.71%), (4) duration effectiveness (10.06%), (5) sleep problems (10.05%), (6) onset of treatment efficacy (8.60%) and (7) knowledge of the patient's body and pain location (6.06%). According to the latent class model that found six classes of respondents with different behaviours (using Akaike and Bayesian criteria), the treatment modality was the most important attribute for all classes, except for class 4 for which pain reduction was the most important. In addition, classes 2 and 5 refused corticosteroid injections, while psychotherapy was preferred only in class 3. CONCLUSION: Given the preference heterogeneity found in the analysis, it is important that patient preferences are discussed and considered by the physicians. This will help to improve the patient care pathway in a context of a patient-centred model for a disease with growing prevalence. PATIENT OR PUBLIC CONTRIBUTION: A small group of patients was involved in the conception, design and interpretation of data. Participants in the DCE were all CLBP patients.

Mindfulness-based stress reduction to improve depression, pain and high patient global assessment in controlled rheumatoid arthritis.

Objective: The aim was to improve distressing patient-reported outcomes (PROs) that persisted in RA patients with clinically controlled inflammation (controlled RA). Methods: In a pragmatic pilot study, we offered mindfulness-based stress reduction (MBSR), a group intervention, to controlled RA patients who had high (≥16) Centre for Evaluation Studies depression (CES-D) scores and/or patient general assessment of disease activity (PGA) at least 2/10 larger than evaluator general assessment (EGA) (PGA-EGA: Delta). Evaluations before, 6 and 12 months after MBSR included CES-D, PGA, modified HAQ, simple disease activity index (SDAI), anxiety (general anxiety disorder 7; GAD-7), coping strategies (coping with health injuries and problems; CHIP), sleep disturbance and pain. Facilitators and obstacles to recruitment and participation were identified. A subset of patients was interviewed for qualitative analysis of their experience. Results: Out of 306 screened patients, 65 were referred, 39 (60%) agreed and 28 (43%) completed MBSR. Anticipated burden, timing and frequency of group meetings, commuting issues, age extremes and co-morbidities were barriers to participation. Up to 12 months after MBSR, anxiety, depression, emotion-oriented coping, sleep and function significantly improved. Nonetheless, no significant impact was observed on pain, PGA, Delta or SDAI. The interviews revealed that benefits, including integration of effective coping strategies, were maintained. Conclusion: We addressed MBSR feasibility issues and selection of outcomes in controlled RA patients with distressing PROs. For patients who chose to participate in MBSR, lasting benefits were evident for anxiety, depression, sleep and function. Larger studies are required to evaluate the weaker impact of MBSR on RA-related pain and PGA.

The effects of custom-made foot orthoses on foot pain, foot function, gait function, and free-living walking activities in people with psoriatic arthritis (PsA): a pre-experimental trial.

INTRODUCTION: Foot involvement is a significant concern in psoriatic arthritis (PsA) as it can lead to severe levels of foot pain and disability and reduced mobility and quality of life. Previous studies have shown moderate efficacy for custom-made foot orthoses (CFO) in reducing foot pain and disability in people with rheumatoid arthritis. However, evidence on the efficacy of CFO in people with PsA is lacking. OBJECTIVES: To explore the effects of CFO on foot function, foot and lower limb pain, gait function, and free-living walking activities (FWA) in people with PsA. METHODS: A pre-experimental study including twenty participants with PsA (mean age: 54.10 ± 9.06 years and disease duration: 11.53 ± 10.22 years) was carried out. All the participants received and wore CFO for 7 weeks. Foot and lower limb pain and foot function were measured before and after the intervention using the numerical rating scale (NRS) and the foot function index (FFI). Gait function was assessed by recording spatiotemporal parameters (STPs) during a 10-m walk test using an instrumented gait analysis system (Mobility Lab). Free-living walking activities (step count, free-living cadence, time spent in different ambulatory physical activities (APA)) were recorded over 7 days using an accelerometer-instrumented sock. RESULTS: The FFI reported scores demonstrated severe baseline levels of foot pain (54.46 ± 14.58 %) and disability (46.65 ± 16.14%). Statistically and clinically significant improvements in foot pain and foot function and large effect sizes (Cohen's effect size > 1, p < 0.005) were observed after the intervention period. A strong correlation (r = -0.64, p < 0.01) between the CFO wearing time and foot function was demonstrated. However, no significant changes were found for gait STP or free-living walking activities after 7 weeks of CFO use. CONCLUSION: Results support the clinical and biomechanical plausibility of using CFO in people with PsA to reduce pain and improve foot function. Large-scale and controlled studies are needed to confirm these findings. Moreover, a multidisciplinary approach including the prescription of exercise therapy and physiotherapy combined with CFO could be required to improve STP and promote APA in people with PsA. TRIAL REGISTRATION: ClinicalTrials.gov , NCT05075343 . Retrospectively registered on September 29, 2021.

Spatiotemporal parameters and gait variability in people with psoriatic arthritis (PsA): a cross-sectional study.

BACKGROUND: Foot involvement is a major manifestation of psoriatic arthritis (PsA) and can lead to severe levels of foot pain and disability and impaired functional mobility and quality of life. Gait spatiotemporal parameters (STPs) and gait variability, used as a clinical index of gait stability, have been associated with several adverse health outcomes, including risk of falling, functional decline, and mortality in a wide range of populations. Previous studies showed some alterations in STPs in people with PsA. However, gait variability and the relationships between STPs, gait variability and self-reported foot pain and disability have never been studied in these populations. Body-worn inertial measurement units (IMUs) are gaining interest in measuring gait parameters in clinical settings. OBJECTIVES: To assess STPs and gait variability in people with PsA using IMUs, to explore their relationship with self-reported foot pain and function and to investigate the feasibility of using IMUs to discriminate patient groups based on gait speed-critical values. METHODS: Twenty-one participants with PsA (age: 53.9 ± 8.9 yrs.; median disease duration: 6 yrs) and 21 age- and sex-matched healthy participants (age 54.23 ± 9.3 yrs) were recruited. All the participants performed three 10-m walk test trials at their comfortable speed. STPs and gait variability were recorded and calculated using six body-worn IMUs and Mobility Lab software (APDM®). Foot pain and disability were assessed in participants with PsA using the foot function index (FFI). RESULTS: Cadence, gait speed, stride length, and swing phase were significantly lower, while double support was significantly higher, in the PsA group (p < 0.006). Strong correlations between STPs and the FFI total score were demonstrated (|r| > 0.57, p < 0.006). Gait variability was significantly increased in the PsA group, but it was not correlated with foot pain or function (p < 0.006). Using the IMUs, three subgroups of participants with PsA with clinically meaningful differences in self-reported foot pain and disability were discriminated. CONCLUSION: STPs were significantly altered in participants with PsA, which could be associated with self-reported foot pain and disability. Future studies are required to confirm the increased gait variability highlighted in this study and its potential underlying causes. Using IMUs has been useful to objectively assess foot function in people with PsA. TRIAL REGISTRATION: ClinicalTrials.gov , NCT05075343 , Retrospectively registered on 29 September 2021.

Experiences of Using Cochrane Systematic Reviews by Local HTA Units.

This study evaluated the use of Cochrane systematic reviews (CSRs) by Quebec's local health technology assessment (HTA) units to promote efficiency in hospital decision-making. An online survey was conducted to examine: Characteristics of the HTA units; Knowledge about works and services from the Cochrane Collaboration; Level of satisfaction about the use of CSRs; Facilitating factors and barriers to the implementation of CSRs evidence in a local context; Suggestions to improve the use of CSRs. Data accuracy was checked by 2 independent evaluators. Ten HTA units participated. From their implementation a total of 321 HTA reports were published (49.8% included a SR). Works and services provided by the Cochrane collaboration were very well-known and HTA units were highly satisfied with CSRs (80%-100%). As regards to applicability in HTA and use of CSRs, major strengths were as follow: Useful as resource for search terms and background material; May reduce the workload (eg, brief review instead of full SR); Use to update a current review. Major weaknesses were: Limited use since no CSRs were available for many HTA projects; Difficulty to apply findings to local context; Focused only on efficacy and innocuity; Cannot be used as a substitute to a full HTA report. This study provided a unique context of assessment with a familiar group of producers, users and disseminators of CSRs in hospital setting. Since they generally used other articles from the literature or produce an original SR in complement with CSRs, this led to suggestions to improve their use of CSRs. However, the main limit for the use of CRS in local HTA will remain its lack of contextualisation. As such, this study reinforces the need to consider the notion of complementarity of experimental data informing us about causality and contextual data, allowing decision-making adapted to local issues.

An integrative NMR-SAXS approach for structural determination of large RNAs defines the substrate-free state of a trans-cleaving Neurospora Varkud Satellite ribozyme.

The divide-and-conquer strategy is commonly used for protein structure determination, but its applications to high-resolution structure determination of RNAs have been limited. Here, we introduce an integrative approach based on the divide-and-conquer strategy that was undertaken to determine the solution structure of an RNA model system, the Neurospora VS ribozyme. NMR and SAXS studies were conducted on a minimal trans VS ribozyme as well as several isolated subdomains. A multi-step procedure was used for structure determination that first involved pairing refined NMR structures with SAXS data to obtain structural subensembles of the various subdomains. These subdomain structures were then assembled to build a large set of structural models of the ribozyme, which was subsequently filtered using SAXS data. The resulting NMR-SAXS structural ensemble shares several similarities with the reported crystal structures of the VS ribozyme. However, a local structural difference is observed that affects the global fold by shifting the relative orientation of the two three-way junctions. Thus, this finding highlights a global conformational change associated with substrate binding in the VS ribozyme that is likely critical for its enzymatic activity. Structural studies of other large RNAs should benefit from similar integrative approaches that allow conformational sampling of assembled fragments.

The Accuracy and Precision of Gait Spatio-Temporal Parameters Extracted from an Instrumented Sock during Treadmill and Overground Walking in Healthy Subjects and Patients with a Foot Impairment Secondary to Psoriatic Arthritis.

The objectives of this study were to assess the accuracy and precision of a system combining an IMU-instrumented sock and a validated algorithm for the estimation of the spatio-temporal parameters of gait. A total of 25 healthy participants (HP) and 21 patients with foot impairments secondary to psoriatic arthritis (PsA) performed treadmill walking at three different speeds and overground walking at a comfortable speed. HP performed the assessment over two sessions. The proposed system's estimations of cadence (CAD), gait cycle duration (GCD), gait speed (GS), and stride length (SL) obtained for treadmill walking were validated versus those estimated with a motion capture system. The system was also compared with a well-established multi-IMU-based system for treadmill and overground walking. The results showed a good agreement between the motion capture system and the IMU-instrumented sock in estimating the spatio-temporal parameters during the treadmill walking at normal and fast speeds for both HP and PsA participants. The accuracy of GS and SL obtained from the IMU-instrumented sock was better compared to the established multi-IMU-based system in both groups. The precision (inter-session reliability) of the gait parameter estimations obtained from the IMU-instrumented sock was good to excellent for overground walking and treadmill walking at fast speeds, but moderate-to-good for slow and normal treadmill walking. The proposed IMU-instrumented sock offers a novel form factor addressing the wearability issues of IMUs and could potentially be used to measure spatio-temporal parameters under clinical conditions and free-living conditions.

Integration of ethical considerations into HTA reports: an analysis of integration levels using a systematic review.

OBJECTIVE: To describe the type and level of ethical integration in published health technology assessment (HTA) reports and systematically identify the ethical approaches utilized. METHODS: A literature search was conducted with the Google™ search engine using the keyword "ethic" between 1 January 2015 and 20 August 2019. Only HTA assessment reports with a section on ethics were retained and classified according to their level of ethical integration: no ethical analysis, ethical issues highlighted, assessments according to legal or social norms, and assessments from a moral or axiological perspective-using a qualitative methodology to distinguish such integration. RESULTS: This review yielded 188 reports with a section identified as being on ethics, produced by seventeen HTA agencies in eleven countries. One hundred and thirty-six reports did not develop an ethical analysis, thirty-one highlighted ethical issues, seventeen conducted a norm-based ethical assessment using a descriptive approach grounded in social norms, and four developed an assessment grounded in a moral or axiological perspective. The bioethical "four-principles" framework was used, but mainly for presenting ethical issues and not as a moral framework. CONCLUSIONS: The majority of reports featuring a section on ethics mention ethical considerations without ethical analysis. Ethical issues are grouped with legal, social, and organizational issues and treated as contextual considerations that decision makers should be aware of. When reports present systematic norm-based ethical assessments from a descriptive perspective or ethical assessment based on a moral or axiological perspective, there is a tendency to ground these analyses in frameworks created for the purpose and reliant on a concept of ethics supporting them.

Patient-partner engagement at the Centre de recherche du CHUS in the Province of Québec, Canada: from an intuitive methodology to outreach after three years of implementation.

BACKGROUND: Medical societies and funding agencies strongly recommend that patients be included as partners in research publications and grant applications. Although this "top-down" approach is certainly efficient at forcing this new and desirable type of collaboration, our past experience demonstrated that it often results in an ambiguous relationship as not yet well integrated into the cultures of either patients' or the researchers'. The question our group raised from this observation was: "How to generate a cultural shift toward a fruitful and long-lasting collaboration between patients and researchers? A "bottom-up" approach was key to our stakeholders. The overall objective was to build a trusting and bidirectional-ecosystem between patients and researchers. The specific objectives were to document: 1) the steps that led to the development of the first patient-partner strategic committee within a research center in the Province of Québec; 2) the committee's achievements after 3 years. METHODS: Eighteen volunteer members, 12 patient-partners and 6 clinician/institutional representatives, were invited to represent the six research themes of the Centre de recherche du CHU de Sherbrooke (CRCHUS) (Quebec, Canada). Information on the services offered by Committee was disseminated internally and to external partners. Committee members satisfaction was evaluated. RESULTS: From May 2017 to April 2020, members attended 29 scheduled and 6 ad hoc meetings and contributed to activities requiring over 1000 h of volunteer time in 2018-2019 and 1907 h in the 2019-2020 period. The Committee's implication spanned governance, expertise, and knowledge transfer in research. Participation in these activities increased annually at local, provincial, national and international levels. The Patient-Partner Committee collaborated with various local (n = 7), provincial (n = 6) and national (n = 4) partners. Member satisfaction with the Committee's mandate and format was 100%. CONCLUSIONS: The CRCHUS co-constructed a Patient-Partner Strategic Committee which resulted in meaningful bilateral, trusting and fruitful collaborations between patients, researchers and partners. The "bottom-up" approach - envisioned and implemented by the Committee, where the expertise and the needs of patients complemented those of researchers, foundations, networks and decision-makers - is key to the success of a cultural shift. The CRCHUS Committee created a hub to develop the relevant intrinsic potential aimed at changing the socio-cultural environment of science.

Development of a checklist to guide equity considerations in health technology assessment.

OBJECTIVES: Health technology assessment (HTA) can impact health inequities by informing healthcare priority-setting decisions. This paper presents a novel checklist to guide HTA practitioners looking to include equity considerations in their work: the equity checklist for HTA (ECHTA). The list is pragmatically organized according to the generic HTA phases and can be consulted at each step. METHODS: A first set of items was based on the framework for equity in HTA developed by Culyer and Bombard. After rewording and reorganizing according to five HTA phases, they were complemented by elements emerging from a literature search. Consultations with method experts, decision makers, and stakeholders further refined the items. Further feedback was sought during a presentation of the tool at an international HTA conference. Lastly, the checklist was piloted through all five stages of an HTA. RESULTS: ECHTA proposes elements to be considered at each one of the five HTA phases: Scoping, Evaluation, Recommendations and Conclusions, Knowledge Translation and Implementation, and Reassessment. More than a simple checklist, the tool provides details and examples that guide the evaluators through an analysis in each phase. A pilot test is also presented, which demonstrates the ECHTA's usability and added value. CONCLUSIONS: ECHTA provides guidance for HTA evaluators wishing to ensure that their conclusions do not contribute to inequalities in health. Several points to build upon the current checklist will be addressed by a working group of experts, and further feedback is welcome from evaluators who have used the tool.

In Vitro Selection of Varkud Satellite Ribozyme Variants that Cleave a Modified Stem-Loop Substrate.

In vitro selection is an established approach to create artificial ribozymes with defined activities or to modify the properties of naturally occurring ribozymes. For the Varkud satellite ribozyme of Neurospora, an in vitro selection protocol based on its phosphodiester bond cleavage activity has not been previously reported. Here, we describe a simple protocol for cleavage-based in vitro selection that we recently used to identify variants of the Varkud satellite ribozyme able to target and cleave a non-natural stem-loop substrate derived from the HIV-1 TAR RNA. It allows quick selection of active ribozyme variants from the transcription reaction based on the size of the self-cleavage product without the need for RNA labeling. This results in a streamlined procedure that is easily adaptable to engineer ribozymes with new activities.

How does HTA addresses current social expectations? An international survey.

OBJECTIVES: Integration of ethics into technology assessment in healthcare (HTA) reports is directly linked to the need of decision makers to provide rational grounds justifying their social choices. In a decision-making paradigm, facts and values are intertwined and the social role of HTA reports is to provide relevant information to decision makers. Since 2003, numerous surveys and discussions have addressed different aspects of the integration of ethics into HTA. This study aims to clarify how HTA professionals consider the integration of ethics into HTA, so an international survey was conducted in 2018 and the results are reported here. METHODS: A survey comprising twenty-two questions was designed and carried out from April 2018 to July 2018. Three hundred and twenty-eight HTA agencies from seventy-five countries were invited to participate in this survey. RESULTS: Eighty-nine participants completed the survey, representing a participation rate of twenty-seven percent. As to how HTA reports should fulfill their social role, over 84 percent of respondents agreed upon the necessity to address this role for decision makers, patients, and citizens. At a lower level, the same was found regarding the necessity to make value-judgments explicit in different report sections, including ethical analysis. This contrasts with the response-variability obtained on the status of ethical analysis with the exception of the expertise required. Variability in stakeholder-participation usefulness was also observed. CONCLUSIONS: This study reveals the importance of a three-phase approach, including assessment, contextual data, and recommendations, and highlights the necessity to make explicit value-judgments and have a systematic ethical analysis in order to fulfill HTA's social role in guiding decision makers.

Implementing a fracture follow-up liaison service: perspective of key stakeholders.

Fracture liaison services (FLS) have been shown to prevent efficiently subsequent fragility fractures (FF). However, very few studies have examined their implementation in depth. The purpose of this research was to identify factors influencing the implementation of a FLS at three sites in Quebec, Canada. From 2013 to 2015, individual and group interviews focused on experiences of FLS stakeholders, including implementation committee members, coordinators, and orthopaedic surgeons and their teams. Emerging key implementation factors were triangulated with the FLS patients' clinico-administrative data. The Consolidated Framework for Implementation Research guided the analysis of perceived factors influencing four intervention outputs: investigation of FF risk (using the FRAX score), communication with the participant primary care provider, initiation of anti-osteoporosis medications (when relevant), and referral to organized fall prevention activities (either governmental or community based). Among the 454 FLS patients recruited to the intervention group, 83% were investigated for FF risk, communication with the primary care provider was established for 98% of the participants, 54% initiated medication, and 35% were referred to organized fall prevention activities. Challenges related to restricted rights to prescribe medication and access to organized fall prevention activities were reported. FLS coordinator characteristics to overcome those challenges included self-efficacy beliefs, knowledge of community resources, and professional background. This study highlighted the importance of enabling access to services for subsequent FF prevention, consolidating the coordinator's role to facilitate a more integrated intervention, and involving local leaders to promote the successful implementation of the FLS.

A discrete choice experiment on preferences of patients with low back pain about non-surgical treatments: identification, refinement and selection of attributes and levels.

Objectives: Hospital-based health technology assessment (HB-HTA) needs to consider all relevant data to help decision making, including patients' preferences. In this study, we comprehensively describe the process of identification, refinement and selection of attributes and levels for a discrete choice experiment (DCE). Methods: A mixed-methods design was used to identify attributes and levels explaining low back pain (LBP) patients' choice for a non-surgical treatment. This design combined a systematic literature review with a patients' focus group, one-on-one interactions with experts and patients, and discussions with stakeholder committee members. Following the patient's focus group, preference exercises were conducted. A consensus about the attributes and levels was researched during discussions with committee members. Results: The literature review yielded 40 attributes to consider in patients' treatment choice. During the focus group, one additional attribute emerged. The preference exercises allowed selecting eight attributes for the DCE. These eight attributes and their levels were discussed and validated by the committee members who helped reframe two levels in one of the attributes and delete one attribute. The final seven attributes were: treatment modality, pain reduction, onset of treatment efficacy, duration of efficacy, difficulty in daily living activities, sleep problem, and knowledge about their body and pain. Conclusion: This study is one of the few to comprehensively describe the selection process of attributes and levels for a DCE. This may help ensure transparency and judge the quality of the decision-making process. In the context of a HB-HTA unit, this strengthens the legitimacy to perform a DCE to better inform decision makers in a patient-centered care approach.

A multi-axial RNA joint with a large range of motion promotes sampling of an active ribozyme conformation.

Investigating the dynamics of structural elements in functional RNAs is important to better understand their mechanism and for engineering RNAs with novel functions. Previously, we performed rational engineering studies with the Varkud satellite (VS) ribozyme and switched its specificity toward non-natural hairpin substrates through modification of a critical kissing-loop interaction (KLI). We identified functional VS ribozyme variants with surrogate KLIs (ribosomal RNA L88/L22 and human immunodeficiency virus-1 TAR/TAR*), but they displayed ∼100-fold lower cleavage activity. Here, we characterized the dynamics of KLIs to correlate dynamic properties with function and improve the activity of designer ribozymes. Using temperature replica exchange molecular dynamics, we determined that the natural KLI in the VS ribozyme supports conformational sampling of its closed and active state, whereas the surrogate KLIs display more restricted motions. Based on in vitro selection, the cleavage activity of a VS ribozyme variant with the TAR/TAR* KLI could be markedly improved by partly destabilizing the KLI but increasing conformation sampling. We formulated a mechanistic model for substrate binding in which the KLI dynamics contribute to formation of the active site. Our model supports the modular nature of RNA in which subdomain structure and dynamics contribute to define the thermodynamics and kinetics relevant to RNA function.

Improving the content validity of the mixed methods appraisal tool: a modified e-Delphi study.

OBJECTIVE: The mixed methods appraisal tool (MMAT) was developed for critically appraising different study designs. This study aimed to improve the content validity of three of the five categories of studies in the MMAT by identifying relevant methodological criteria for appraising the quality of qualitative, survey, and mixed methods studies. STUDY DESIGN AND SETTING: First, we performed a literature review to identify critical appraisal tools and extract methodological criteria. Second, we conducted a two-round modified e-Delphi technique. We asked three method-specific panels of experts to rate the relevance of each criterion on a five-point Likert scale. RESULTS: A total of 383 criteria were extracted from 18 critical appraisal tools and a literature review on the quality of mixed methods studies, and 60 were retained. In the first and second rounds of the e-Delphi, 73 and 56 experts participated, respectively. Consensus was reached for six qualitative criteria, eight survey criteria, and seven mixed methods criteria. These results led to modifications of eight of the 11 MMAT (version 2011) criteria. Specifically, we reformulated two criteria, replaced four, and removed two. Moreover, we added six new criteria. CONCLUSION: Results of this study led to improve the content validity of this tool, revise it, and propose a new version (MMAT version 2018).