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Abstract The Illumina Methylation array platform has facilitated countless epigenetic studies on DNA methylation (DNAme) in health and disease, yet relatively few studies have so studied its reliability, i.e., the consistency of repeated measures. Here we investigate the reliability of both type I and type II Infinium probes. We propose a method for excluding unreliable probes based on dynamic thresholds for mean intensity (MI) and ‘unreliability’, estimated by probe-level simulation of the influence of technical noise on methylation β values using the background intensities of negative control probes. We validate our method in several datasets, including newly generated Illumina MethylationEPIC BeadChip v1.0 data from paired whole blood samples taken six weeks apart and technical replicates spanning multiple sample types. Our analysis revealed that specifically probes with low MI exhibit higher β value variability between repeated samples. MI was associated with the number of C-bases in the respective probe sequence and correlated negatively with unreliability scores. The unreliability scores were substantiated through validation in a new EPIC v1.0 (blood and cervix) and a publicly available 450k (blood) dataset, as they effectively captured the variability observed in β values between technical replicates. Finally, despite promising higher robustness, the newer version v2.0 of the MethylationEPIC BeadChip retained a substantial number of probes with poor unreliability scores. To enhance current pre-processing pipelines, we developed an R package to calculate MI and unreliability scores and provide guidance on establishing optimal dynamic score thresholds for a given dataset.

Abstract Background The impact of social frailty on older adults is profound including mortality risk, functional decline, falls, and disability. However, effective strategies that respond to the needs of socially frail older adults are lacking and few studies have unpacked how social determinants operate or how interventions can be adapted during periods requiring social distancing and isolation such as the COVID-19 pandemic. To address these gaps, we conducted a scoping review using JBI methodology to identify interventions that have the best potential to help socially frail older adults (age ≥65 years). Methods We searched MEDLINE, CINAHL (EPSCO), EMBASE and COVID-19 databases and the grey literature. Eligibility criteria were developed using the PICOS framework. Our results were summarized descriptively according to study, patient, intervention and outcome characteristics. Data synthesis involved charting and categorizing identified interventions using a social frailty framework. Results Of 263 included studies, we identified 495 interventions involving ~124,498 older adults who were mostly female. The largest proportion of older adults (40.5%) had a mean age range of 70-79 years. The 495 interventions were spread across four social frailty domains: social resource (40%), self-management (32%), social behavioural activity (28%), and general resource (0.4%). Of these, 189 interventions were effective for improving loneliness, social and health and wellbeing outcomes across psychological self-management, self-management education, leisure activity, physical activity, Information Communication Technology and socially assistive robot interventions. Sixty-three interventions were identified as feasible to be adapted during infectious disease outbreaks (e.g., COVID-19, flu) to help socially frail older adults. Conclusions Our scoping review identified promising interventions with the best potential to help older adults living with social frailty.

Abstract Objectives The objective of this study was to conduct a formative evaluation of the Art Your Service (AYS) arts-based program to determine the program’s potential for improving the social and physical well-being of older adults during the COVID-19 pandemic. Design, settings and participants An online questionnaire was administered to the AYS members who consented to be invited to participate in the study. Questionnaire items consisted of a Likert scale and open-ended questions delivered using an online platform (SurveyMonkey). Participants provided feedback on their perceptions and experiences of the AYS program, such as its impact on their health and well-being during the COVID-19 pandemic, the benefits and challenges of participating, and any suggestions for program improvement. Outcome measures and analysis Quantitative data were analyzed using descriptive statistics (frequencies, means with standard deviations), and open-ended questions (qualitative data) were analyzed using content analysis. Outcomes included participant demographics, perceptions about the program, usability (System Usability Scale [SUS]), eHealth literacy (eHealth Literacy Scale), and social isolation (Lubben Social Network Scale; LSNS-6). Results Program participants revealed consistent patterns of their perceptions and experiences about the program, including a high satisfaction rate (95%) and a perceived positive impact on participants’ health and well-being. The program sessions were perceived to be a well-organized, convenient, and safe way to engage with one another socially during the COVID-19 pandemic. The program usability was also perceived to be high (SUS mean score 86.2). Participants felt a sense of connectedness and had reduced feelings of social isolation. Most participants (75%) reported that the program improved their physical health. Conclusions Findings from this formative evaluation study identified key strengths and opportunities to improve the Art Your Service arts-based program, which can be used to help enhance the program’s functioning and long-term sustainability potential.

Abstract Purpose To identify the nature and extent of the evidence on psychological interventions among individuals with Ehlers-Danlos Syndrome (EDS) and Hypermobility Spectrum Disorder (HSD). Materials and methods Eligible studies reported on psychological interventions for individuals of all ages with EDS and/or HSD. All studies published in English were included, with no restrictions to publication year or status. MEDLINE, CINAHL, EMBASE, and PsycINFO were searched. Two reviewers independently screened studies and abstracted data. Results This scoping review included 10 studies reporting on EDS, HSD, or both. Only cohort studies and case studies were identified. Four studies investigated Cognitive Behavioural Therapy (CBT), one investigated Dialectical Behavioural Therapy (DBT), two investigated psychoeducation, two investigated Intensive Interdisciplinary Pain Treatment (IIPT), and one investigated Acceptance Commitment Therapy (ACT). Interventions targeted pain management, self-destructive behaviours, and related psychological issues (e.g., depression/anxiety). Sample sizes were small (n

Abstract Background Serotonin (5-HT) is a biogenic monoamine with diverse functions in multiple human organs and tissues. During pregnancy, tightly regulated levels of 5-HT in the fetoplacental unit are critical for proper placental functions, fetal development, and programming. Despite being a non-neuronal organ, the placenta expresses a suite of homeostatic proteins, membrane transporters and metabolizing enzymes, to regulate monoamine levels. We hypothesized that placental 5-HT clearance is important for maintaining 5-HT levels in the fetoplacental unit. We therefore investigated placental 5-HT uptake from the umbilical circulation at physiological and supraphysiological levels as well as placental metabolism of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA) and 5-HIAA efflux from trophoblast cells. Methods We employed a systematic approach using advanced organ-, tissue-, and cellular-level models of the human placenta to investigate the transport and metabolism of 5-HT in the fetoplacental unit. Human placentas from uncomplicated term pregnancies were used for perfusion studies, culturing explants, and isolating primary trophoblast cells. Results Using the dually perfused placenta, we observed a high and concentration-dependent placental extraction of 5-HT from the fetal circulation. Subsequently, within the placenta, 5-HT was metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which was then unidirectionally excreted to the maternal circulation. In the explant cultures and primary trophoblast cells, we show concentration- and inhibitor-dependent 5-HT uptake and metabolism and subsequent 5-HIAA release into the media. Droplet digital PCR revealed that the dominant gene in all models was MAO-A, supporting the crucial role of 5-HT metabolism in placental 5-HT clearance. Conclusions Taken together, we present transcriptional and functional evidence that the human placenta has an efficient 5-HT clearance system involving (1) removal of 5-HT from the fetal circulation by OCT3, (2) metabolism to 5-HIAA by MAO-A, and (3) selective 5-HIAA excretion to the maternal circulation via the MRP2 transporter. This synchronized mechanism is critical for regulating 5-HT in the fetoplacental unit; however, it can be compromised by external insults such as antidepressant drugs.

Abstract Background To date, little is known about the sustainability and scalability of MyDiabetesPlan, an eHealth innovation designed to facilitate shared decision-making within diabetes care. To avoid the possibility of its short-lived implementation and promote wider adoption so as to promote patient-centred diabetes care, it is critical to understand MyDiabetesPlan’s sustainability and scalability in order to ensure its long-term impact at a greater scale. We sought to identify the sustainability and scalability potential of MyDiabetesPlan and its limiting factors. Methods Using a concurrent triangulation mixed-methods approach, data were collected from 20 individuals involved in the development and implementation of MyDiabetesPlan. The National Health Services Sustainability Model (NHSSM) and the Innovation Scalability Self-administered Questionnaire (ISSaQ) were administered using a ‘think-aloud’ approach and subsequently, short semi-structured interviews were conducted. Mean aggregate scores and stakeholder-specific scores were generated for the NHSSM and ISSaQ, to quantitatively determine facilitating and limiting factors to sustainability and scalability. Content analysis occurred iteratively with qualitative data, to examine commonalities and differences with the quantitative findings. Results The top facilitating factor to sustaining MyDiabetesPlan was “Staff involvement and training to sustain the process.”, whereas the top limiting factors were: “Adaptability of Improved Process”, “Senior Leadership Engagement” and “Infrastructure for Sustainability”. The top three facilitating factors for scale-up were “Acceptability”, “Development with Theory” and “Consistency with Policy Directives.” Conversely, the top three limiting factors were “Financial and Human Resources”, “Achievable Adoption” and “Broad Reach”. Qualitative findings corroborated the limiting/facilitating factors identified. Conclusions Addressing staff involvement throughout the dynamic care contexts, and resource constraints impacting scale-up can enhance the sustainability and scalability of MyDiabetesPlan . As such, future plans will focus on garnering organizational leadership buy-in and support, which may address the resource constraints associated with sustainability and scalability and improve the capacity for adequate staff involvement. eHealth researchers will be able to prioritize these limiting factors from the outset of their tool development to purposefully optimize its sustainability and scalability performance.

Abstract Background Autoinflammatory diseases, a diverse group of inherited conditions characterized by excessive innate immune activation, have limited therapeutic options. Neuroimmune circuits of the inflammatory reflex control innate immune overactivation and can be stimulated to treat disease using the acetylcholinesterase inhibitor galantamine. Methods We tested the efficacy of galantamine in a rodent model of the prototypical autoinflammatory disease familial Mediterranean fever (FMF). Multiple chronic disease markers were evaluated in animals that received long-term galantamine treatment compared to vehicle. Results Long-term treatment with galantamine attenuated the associated splenomegaly and anemia which are characteristic features of this disease. Further, treatment reduced inflammatory cell infiltration into affected organs and a subcutaneous air pouch. Conclusions These findings suggest that galantamine attenuates chronic inflammation in this mouse model of FMF. Further research is warranted to explore the therapeutic potential of galantamine in FMF and other autoinflammatory diseases.

Abstract Background Numerous studies have reported clinical endpoints following coronary revascularization using bioresorbable vascular scaffolds (BVS), while information about the impact on health-related quality of life is sparse. In this analysis of the German-Austrian ABSORB RegIstRy, the 2 year results concerning quality of life development in a large cohort of patients treated with BVS were reported. Methods Data were collected at baseline as well as 30 days, 6 and 24 months after coronary revascularization using BVS. The EQ-5D score, EQ visual analogue scale (VAS) and Seattle Angina Questionnaire (SAQ) were determined for each time point. Patients were categorized according to the indication for coronary revascularization [acute coronary syndrome (ACS), stable angina pectoris (SAP), silent myocardial ischemia (SMI), or other]. Binary logistic regression analysis was performed to determine factors that predict above-average scores two years after implantation. Results Data from 1317 patients in 88 centres were included. Reasons for revascularization were: ACS (n = 643), SAP (n = 443), SMI (n = 52), and other (n = 179). Mean EQ-5D was significantly increased after six months, while a value comparable to baseline was found two years after implantation. EQ VAS and four of five dimensions of SAQ were significantly improved over baseline at all follow-up surveys. Particularly strong improvements were seen in SAQ scores angina frequency and quality of life. Binary regressions showed different statistically significant predictors in the respective models. Conclusions Following coronary revascularization with BVS strong decrease in self-reported angina frequency and increase of self-reported quality of life were observed with continuous improvements over two years of follow-up. Trial registration ClinicalTrials.gov Identifier: NCT02066623.

Abstract Background Successful guideline implementation depends both on factors extrinsic to guidelines and their intrinsic features. In the Guideline Implementability for Decision Excellence Model (GUIDE-M), “communicating” content (language and format) is one of three core determinants of intrinsic implementability, but is seldom addressed. Our aims were to develop a tool that could be used by guideline developers to optimize language and format during development; identify gaps in this type of guidance in existing resources; and evaluate the perceived need for and usefulness of such a tool among guideline developers. Methods Our mixed-methods design consisted of (1) content development (selection and organization of evidence-based constructs from the GUIDE-M into a prototype Guideline Language and Format Instrument (GLAFI), followed by face validation with guideline developers); (2) document analysis (duplicate) of seven existing guideline tools to measure coverage of GLAFI items and identify new items; and (3) an international survey of guideline developers (corresponding authors of recent Canadian Medical Association or Guidelines International Network database guidelines) to measure perceived importance of language and format, quality of existing resources, and usefulness of a language and format tool. Results GLAFI items were organized into 4 language and 4 format subdomains. In face validation with guideline developers (17 clinicians, 1 methodologist), all agreed that the tool would improve guideline implementability and 93% indicated a desire for regular use. In the existing guideline tool document analysis, only 14/44 (31.8%) GLAFI items were operationalized in at least one tool. We received survey responses from 148/674 (22.0%) contacted guideline authors representing 45 organizations (9 countries). Language was rated as “extremely important” or “important” in determining uptake by 94% of respondents, and format by 84%. Correspondingly, 72% and 70% indicated that their organization would likely use such a tool. Conclusions Optimal language and format are fundamental to guideline implementability but often overlooked. The GLAFI tool operationalizes evidence-based constructs, most of which are absent in existing guideline tools. Guideline developers perceive these concepts to be important and express a willingness to use such a tool. The GLAFI should be further tested and refined with guideline developers and its impact on end-users measured.

Abstract Background Childhood and adolescent overweight and obesity are among the most serious health challenges today. Structured weight reduction programs can be helpful to reduce severe health consequences but evidence is partly scarce. The STARKIDS program aims to improve on some of these limitations and is designed to be a structured, stepwise, digitally supported intervention program for the whole family. It is divided into two intervention steps spanning over 1.5 years and aims at promoting a healthy weight development of children/adolescents with overweight/obesity and an increase in quality of life. Methods The STARKIDS intervention is evaluated in a cluster-randomized study design by comparing it with a control group receiving a one-time structured counselling in the pediatric practice. The study aims to include 1000 families with children/adolescents with overweight/obesity from 100 pediatric practices. The main outcomes are reduction in body mass index percentiles and improvements in children’s/adolescent’s quality of life, secondary outcomes refer to the contents of the intervention such as diet, physical activity, stress, and media habits. All outcomes are measured on three measurement time points: (T0) at baseline/inclusion in the study, (T1) baseline + 12 months which is the end of step 1 of the STARKIDS intervention, and (T2) baseline + 18 months which is the end of step 2 of the STARKIDS intervention. Discussion The stepwise, e-health-supported STARKIDS program is a low-threshold intervention program for families with children/adolescents with overweight/obesity. With the proof of concept, STARKIDS provides the potential to be implemented as a standard care tool for the prevention and intervention of childhood/adolescence obesity in the German health system. Trial registration German Clinical Trials Register (DRKS) DRKS00022813 (acknowledged primary register of the World Health Organization). Registered on 27 November 2020 (Universal Trial Number U1111-1254-9536).

Abstract Background Choosing Wisely (CW) is an international movement comprised of campaigns in more than 20 countries to reduce low-value care (LVC). De-implementation, the reduction or removal of a healthcare practice that offers little to no benefit or causes harm, is an emerging field of research. Little is known about the factors which (i) sustain LVC; and (ii) the magnitude of the problem of LVC. In addition, little is known about the processes of de-implementation, and if and how these processes differ from implementation endeavours. The objective of this study was to explicate the myriad factors which impact the processes and outcomes of de-implementation initiatives that are designed to address national Choosing Wisely campaign recommendations. Methods Semi-structured interviews were conducted with individuals implementing Choosing Wisely Canada recommendations in healthcare settings in four provinces. The interview guide was developed using concepts from the literature and the Implementation Process Model (IPM) as a framework. All interviews were conducted virtually, recorded, and transcribed verbatim. Data were analysed using thematic analysis. Findings Seventeen Choosing Wisely team members were interviewed. Participants identified numerous provider factors, most notably habit, which sustain LVC. Contrary to reporting in recent studies, the majority of LVC in the sample was not ‘patient facing’; therefore, patients were not a significant driver for the LVC, nor a barrier to reducing it. Participants detailed aspects of the magnitude of the problems of LVC, providing insight into the complexities and nuances of harm, resources and prevalence. Harm from potential or common infections, reactions, or overtreatment was viewed as the most significant types of harm. Unique factors influencing the processes of de-implementation reported were: influence of Choosing Wisely campaigns, availability of data, lack of targets and hard-coded interventions. Conclusions This study explicates factors ranging from those which impact the maintenance of LVC to factors that impact the success of de-implementation interventions intended to reduce them. The findings draw attention to the significance of unintentional factors, highlight the importance of understanding the impact of harm and resources to reduce LVC and illuminate the overstated impact of patients in de-implementation literature. These findings illustrate the complexities of de-implementation.

Abstract Background There is recognition that the overuse of procedures, testing, and medications constitutes low-value care which strains the healthcare system and, in some circumstances, can cause unnecessary stress and harm for patients. Initiatives across dozens of countries have raised awareness about the harms of low-value care but have had mixed success and the levels of reductions realized have been modest. Similar to the complex drivers of implementation processes, there is a limited understanding of the individual and social behavioral aspects of de-implementation. While researchers have begun to use theory to elucidate the dynamics of de-implementation, the research remains largely atheoretical. The use of theory supports the understanding of how and why interventions succeed or fail and what key factors predict success. The purpose of this scoping review was to identify and characterize the use of theoretical approaches used to understand and/or explain what influences efforts to reduce low-value care. Methods We conducted a review of MEDLINE, EMBASE, CINAHL, and Scopus databases from inception to June 2021. Building on previous research, 43 key terms were used to search the literature. The database searches identified 1998 unique articles for which titles and abstracts were screened for inclusion; 232 items were selected for full-text review. Results Forty-eight studies met the inclusion criteria. Over half of the included articles were published in the last 2 years. The Theoretical Domains Framework (TDF) was the most commonly used determinant framework (n = 22). Of studies that used classic theories, the majority used the Theory of Planned Behavior (n = 6). For implementation theories, Normalization Process Theory and COM-B were used (n = 7). Theories or frameworks were used primarily to identify determinants (n = 37) and inform data analysis (n = 31). Eleven types of low-value care were examined in the included studies, with prescribing practices (e.g., overuse, polypharmacy, and appropriate prescribing) targeted most frequently. Conclusions This scoping review provides a rigorous, comprehensive, and extensive synthesis of theoretical approaches used to understand and/or explain what factors influence efforts to reduce low-value care. The results of this review can provide direction and insight for future primary research to support de-implementation and the reduction of low-value care.

Abstract Background Little is known about the clinical value of Insulin-like growth factor-binding protein-7 (IGFBP7), a cellular senescence marker, in an elderly general population with multiple co-morbidities and high prevalence of asymptomatic cardiovascular ventricular dysfunction. Inflammation and fibrosis are hallmarks of cardiac aging and remodelling. Therefore, we assessed the clinical performance of IGFBP7 and two other biomarkers reflecting these pathogenic pathways, the growth differentiation factor-15 (GFD-15) and amino-terminal propeptide of type I procollagen (P1NP), for their association with cardiac phenotypes and outcomes in the PREDICTOR study. Methods 2001 community-dwelling subjects aged 65–84 years who had undergone centrally-read echocardiography, were selected through administrative registries. Atrial fibrillation (AF) and 4 echocardiographic patterns were assessed: E/e’ (> 8), enlarged left atrial area, left ventricular hypertrophy (LVH) and reduced midwall circumference shortening (MFS). All-cause and cardiovascular mortality and hospitalization were recorded over a median follow-up of 10.6 years. Results IGFBP7 and GDF-15, but not P1NP, were independently associated with prevalent AF and echocardiographic variables after adjusting for age and sex. After adjustment for clinical risk factors and cardiac patterns or NT-proBNP and hsTnT, both IGFBP7 and GDF-15 independently predicted all-cause mortality, hazard ratios 2.13[1.08–4.22] and 2.03[1.62–2.56] per unit increase of Ln-transformed markers, respectively. Conclusions In a community-based elderly cohort, IGFBP7 and GDF-15 appear associated to cardiac alterations as well as to 10-year risk of all-cause mortality.

Abstract Background There is general scarcity of research on key elements of implementation processes and the factors which impact implementation success. Implementation of healthcare interventions is a complex process. Tools to support implementation can facilitate this process and improve effectiveness of the interventions and clinical outcomes. Understanding the impact of implementation support tools is a critical aspect of this process. The objective of this study was to solicit knowledge and agreement from relevant implementation science and knowledge translation healthcare experts in order to develop a process model of key elements in the implementation process. Methods A two round, modified Delphi study involving international experts in knowledge translation and implementation (researchers, scientists, professors, decision-makers) was conducted. Participants rated and commented on all aspects of the process model, including the organization, content, scope, and structure. Delphi questions rated at 75% agreement or lower were reviewed and revised. Qualitative comments supported the restructuring and refinement. A second-round survey followed the same process as Round 1. Results Fifty-four experts participated in Round 1, and 32 experts participated in Round 2. Twelve percent (n = 6) of the Round 1 questions did not reach agreement. Key themes for revision and refinement were: stakeholder engagement throughout the process, iterative nature of the implementation process; importance of context; and importance of using guiding theories or frameworks. The process model was revised and refined based on the quantitative and qualitative data and reassessed by the experts in Round 2. Agreement was achieved on all items in Round 2 and the Delphi concluded. Additional feedback was obtained regarding terminology, target users and definition of the implementation process. Conclusions High levels of agreement were attained for all sub-domains, elements, and sub-elements of the Implementation Process Model. This model will be used to develop an Implementation Support Tool to be used by healthcare providers to facilitate effective implementation and improved clinical outcomes.

Abstract Background Biallelic loss-of-function variants in NCF1 lead to reactive oxygen species deficiency and chronic granulomatous disease (CGD). Heterozygosity for the p.Arg90His variant in NCF1 has been associated with susceptibility to systemic lupus erythematosus, rheumatoid arthritis, and Sjögren’s syndrome in adult patients. This study demonstrates the association of the homozygous p.Arg90His variant with interferonopathy with features of autoinflammation and autoimmunity in a pediatric patient. Case presentation A 5-year old female of Indian ancestry with early-onset recurrent fever and headache, and persistently elevated antinuclear, anti-Ro, and anti-La antibodies was found to carry the homozygous p.Arg90His variant in NCF1 through exome sequencing. Her unaffected parents and three other siblings were carriers for the mutant allele. Because the presence of two NCF1 pseudogenes, this variant was confirmed by independent genotyping methods. Her intracellular neutrophil oxidative burst and NCF1 expression levels were normal, and no clinical features of CGD were apparent. Gene expression analysis in peripheral blood detected an interferon gene expression signature, which was further supported by cytokine analyses of supernatants of cultured patient’s cells. These findings suggested that her inflammatory disease is at least in part mediated by type I interferons. While her fever episodes responded well to systemic steroids, treatment with the JAK inhibitor tofacitinib resulted in decreased serum ferritin levels and reduced frequency of fevers. Conclusion Homozygosity for p.Arg90His in NCF1 should be considered contributory in young patients with an atypical systemic inflammatory antecedent phenotype that may evolve into autoimmunity later in life. The complex genomic organization of NCF1 poses a difficulty for high-throughput genotyping techniques and variants in this gene should be carefully evaluated when using the next generation and Sanger sequencing technologies. The p.Arg90His variant is found at a variable allele frequency in different populations, and is higher in people of South East Asian ancestry. In complex genetic diseases such as SLE, other rare and common susceptibility alleles might be necessary for the full disease expressivity.

Abstract Background The scale-up of evidence-based innovations is required to reduce waste and inequities in health and social services (HSS). However, it often tends to be a top-down process initiated by policy makers, and the values of the intended beneficiaries are forgotten. Involving multiple stakeholders including patients and the public in the scaling-up process is thus essential but highly complex. We propose to identify relevant strategies for meaningfully and equitably involving patients and the public in the science and practice of scaling up in HSS. Methods We will adapt our overall method from the RAND/UCLA Appropriateness Method. Following this, we will perform a two-prong study design (knowledge synthesis and Delphi study) grounded in an integrated knowledge translation approach. This approach involves extensive participation of a network of stakeholders interested in patient and public involvement (PPI) in scaling up and a multidisciplinary steering committee. We will conduct a systematic scoping review following the methodology recommended in the Joanna Briggs Institute Reviewers Manual. We will use the following eligibility criteria: (1) participants—any stakeholder involved in creating or testing a strategy for PPI; (2) intervention—any PPI strategy proposed for scaling-up initiatives; (3) comparator—no restriction; (4) outcomes: any process or outcome metrics related to PPI; and (5) setting—HSS. We will search electronic databases (e.g., Medline, Web of Science, Sociological Abstract) from inception onwards, hand search relevant websites, screen the reference lists of included records, and consult experts in the field. Two reviewers will independently select and extract eligible studies. We will summarize data quantitatively and qualitatively and report results using the PRISMA extension for Scoping Reviews (PRISMA-ScR) checklist. We will conduct an online Delphi survey to achieve consensus on the relevant strategies for PPI in scaling-up initiatives in HSS. Participants will include stakeholders from low-, middle-, and high-income countries. We anticipate that three rounds will allow an acceptable degree of agreement on research priorities. Discussion Our findings will advance understanding of how to meaningfully and equitably involve patients and the public in scaling-up initiatives for sustainable HSS. Systematic review registration We registered this protocol with the Open Science Framework on August 19, 2020 ( https://osf.io/zqpx7/ ).

Abstract Objective To assess the quality of recommendations from 161 clinical practice guidelines (CPGs) using AGREE-REX-D (Appraisal of Guidelines REsearch and Evaluation-Recommendations Excellence Draft). Design Cross-sectional study Setting International CPG community. Participants Three hundred twenty-two international CPG developers, users, and researchers. Intervention Participants were assigned to appraise one of 161 CPGs selected for the study using the AGREE-REX-D tool Main outcome measures AGREE-REX-D scores of 161 CPGs (7-point scale, maximum 7). Results Recommendations from 161 CPGs were appraised by 322 participants using the AGREE-REX-D. CPGs were developed by 67 different organizations. The total overall average score of the CPG recommendations was 4.23 (standard deviation (SD) = 1.14). AGREE-REX-D items that scored the highest were (mean; SD): evidence (5.51; 1.14), clinical relevance (5.95; SD 0.8), and patients/population relevance (4.87; SD 1.33), while the lowest scores were observed for the policy values (3.44; SD 1.53), local applicability (3,56; SD 1.47), and resources, tools, and capacity (3.49; SD 1.44) items. CPGs developed by government-supported organizations and developed in the UK and Canada had significantly higher recommendation quality scores with the AGREE-REX-D tool (p < 0.05) than their comparators. Conclusions We found that there is significant room for improvement of some CPGs such as the considerations of patient/population values, policy values, local applicability and resources, tools, and capacity. These findings may be considered a baseline upon which to measure future improvements in the quality of CPGs.

Abstract Background Positive impacts of quality improvement initiatives on health care and services have not been substantial. Knowledge translation (KT) strategies (tools, products and interventions) strive to facilitate the uptake of knowledge thereby the potential to improve care, but there is little guidance on how to develop them. Existing KT guidance or planning tools fall short in operationalizing all aspects of KT practice activities conducted by knowledge users (researchers, clinicians, patients, decision-makers), and most do not consider their variable needs or to deliver recommendations that are most relevant and useful for them. Methods We conducted a 3-phase study. In phase 1, we used several sources to develop a conceptual framework for creating optimized Knowledge-activated Tools (KaT) (consultation with our integrated KT team, the use of existing KT models and frameworks, findings of a systematic review of multimorbidity interventions and a literature review and document analysis on existing KT guidance tools). In phase 2, we invited KT experts to participate in a Delphi study to refine and evaluate the conceptual KaT framework. In phase 3, we administered an online survey to knowledge users (researchers, clinicians, decision-makers, trainees) to evaluate the potential usefulness of an online mock-up version of the KaT framework. Results We developed the conceptual KaT framework, and iteratively refined it with 35 KT experts in a 3-round Delphi study. The final framework represents the blueprint for what is needed to create KT strategies. Feedback from 201 researcher, clinician, decision-maker and trainee knowledge users on the potential need and usefulness of an online, interactive version of KaT indicated that they liked the idea of it (mean score 4.36 on a 5-point Likert scale) and its proposed features (mean score range 4.30–4.79). Conclusions Our findings suggest that mostly Canadian KT experts and knowledge users perceived the KaT framework and the future development of an online, interactive version to be important and needed. We anticipate that the KaT framework will provide clarity for knowledge users about how to identify their KT needs and what activities can address these needs, and to help streamline the process of these activities to facilitate efficient uptake of knowledge.

Abstract Background Sensitive and reliable molecular diagnostics is needed to guide therapeutic decisions for cancer patients. Although less material becomes available for testing, genetic markers are rapidly expanding. Simultaneous detection of predictive markers, including mutations, gene amplifications and MSI, will save valuable material, time and costs. Methods Using a single-molecule molecular inversion probe (smMIP)-based targeted next-generation sequencing (NGS) approach, we developed an NGS panel allowing detection of predictive mutations in 33 genes, gene amplifications of 13 genes and microsatellite instability (MSI) by the evaluation of 55 microsatellite markers. The panel was designed to target all clinically relevant single and multiple nucleotide mutations in routinely available lung cancer, colorectal cancer, melanoma, and gastro-intestinal stromal tumor samples, but is useful for a broader set of tumor types. Results The smMIP-based NGS panel was successfully validated and cut-off values were established for reliable gene amplification analysis (i.e. relative coverage ≥3) and MSI detection (≥30% unstable loci). After validation, 728 routine diagnostic tumor samples including a broad range of tumor types were sequenced with sufficient sensitivity (2.4% drop-out), including samples with low DNA input (

Abstract Background Preoperative chemoradiotherapy is the recommended standard of care for patients with local advanced rectal cancer. However, it remains unclear, whether a prolonged time interval to surgery results in an increased perioperative morbidity, reduced TME quality or better pathological response. Aim of this study was to determine the time interval for best pathological response and perioperative outcome compared to current recommended interval of 6 to 8 weeks. Methods This is a retrospective analysis of the German StuDoQ|Rectalcarcinoma registry. Patients were grouped for the time intervals of “less than 6 weeks”, “6 to 8 weeks”, “8 to 10 weeks” and “more than 10 weeks”. Primary endpoint was pathological response, secondary endpoint TME quality and complications according to Clavien-Dindo classification. Results Due to our inclusion criteria (preoperative chemoradiation, surgery in curative intention, M0), 1.809 of 9.560 patients were suitable for analysis. We observed a trend for increased rates of pathological complete response (pCR: ypT0ypN0) and pathological good response (pGR: ypT0-1ypN0) for groups with a prolonged time interval which was not significant. Ultimately, it led to a steady state of pCR (16.5%) and pGR (22.6%) in “8 to 10” and “more than 10” weeks. We were not able to observe any differences between the subgroups in perioperative morbidity, proportion of rectal extirpation (for cancer of the lower third) or difference in TME quality. Conclusion A prolonged time interval between neoadjuvant chemoradiation can be performed, as the rate of pCR seems to be increased without influencing perioperative morbidity.

Abstract Background Promoting the collection and use of health related outcome measures (HROM) in daily practice has long been a goal for improving and assessing the effectiveness of care provided to patients. However, there has been a lack of consensus on what criteria to use to select outcomes or instruments, particularly in the context of primary health care settings where patients present with multiple concurrent health conditions and interventions are whole-health and person-focused. The purpose of this proposed study is to undertake a formal consensus exercise to establish criteria for selecting HROM (including patient-reported (PRO or PROM), observer-reported (ObsR)), clinician-reported (ClinRO) and performance related outcomes (PerfO) for use in shared decision-making, or in assessing, screening or monitoring health status in primary health care settings. Methods A Delphi consensus online survey will be developed. Criteria for the Delphi panel participants to consider were selected from a targeted literature search. These initial criteria (n = 35) were grouped into four categories within which items will be presented in the Delphi survey, with the option to suggest additional items. Panel members invited to participate will include primary health care practitioners and administrators, policy-makers, researchers, and experts in HROM development; patients will be excluded. Standard Delphi methodology will be employed with an expectation of at least 3 rounds to achieve consensus (75% agreement). As the final list of criteria for selecting HROM emerges, panel members will be asked to provide opinions about potential weighting of items. The Delphi survey was approved by the Ethics Committee in the Faculty of Health Sciences at McMaster University. Discussion Previous literature establishing criteria for selecting HROM were developed with a focus on patient reported outcomes, psychological/ behavioural outcomes or outcomes for minimum core outcome sets in clinical trials. Although helpful, these criteria may not be applicable and feasible for application in a primary health care context where patients with multi-morbidity and complex interventions are typical and the constraints of providing health services differ from those in research studies. The findings from this Delphi consensus study will address a gap for establishing consensus on criteria for selecting HROM for use across primary health care settings.

Abstract Background In sub-Saharan Africa, 58% of adults living with HIV are women. In Uganda, HIV prevalence is 8.3% for women compared to 6.1% for men. Access to antiretroviral therapy (ART) and prevention of mother to child transmission (PMTCT) programs have enabled women living with HIV (WLWH) to have children with minimal risk of perinatal transmission. Nevertheless, pregnant WLWH face many challenges. We explored women’s perceptions of how they cope with the challenges of pregnancy and the postpartum period as HIV-infected women. Methods We conducted semi-structured interviews with postpartum WLWH accessing ART who had a pregnancy within 2 years prior to recruitment between February–August, 2014. Childbearing associated stressors and coping strategies were discussed. We used content analysis to identify major themes and NVivo 10 software facilitated data analysis. Results Twenty women were interviewed with median age 33 (IQR: 28–35) years, CD4 cell count 677 cells/mm3 (IQR: 440–767), number of live births 4 (IQR: 2–6), and number of living children 3 (IQR: 2–4.3). We summarize five identified coping strategies within a socio-ecological framework according to Bronfenbrenner’s Ecological Model. Coping strategies on the individual level included acceptance of self and HIV status, and self-reliance. On the interpersonal level, participants reported coping through support from partners, family, and friends. On the organizational level, participants reported coping through HIV-related healthcare delivery and system supports. At the community level, women reported coping through support from church and spirituality. Conclusions The results highlight coping strategies used by WLWH to manage the myriad challenges faced during pregnancy and the postpartum period. Intervention programs for WLWH must emphasize psychosocial care and incorporate strategies that address psychosocial challenges in the HIV care package in order to optimize well-being. Additionally policies that support networks of WLWH should be put in place and funding support should be provided through existing funding mechanisms in order to respond to the needs and challenges of WLWH. Programmes that support WLWH for economic empowerment and improved livelihoods should be strengthened across all regions in the country.

Abstract Background A knowledge synthesis attempts to summarize all pertinent studies on a specific question, can improve the understanding of inconsistencies in diverse evidence, and can identify gaps in research evidence to define future research agendas. Knowledge synthesis activities in healthcare have largely focused on systematic reviews of interventions. However, a wider range of synthesis methods has emerged in the last decade addressing different types of questions (e.g., realist synthesis to explore mediating mechanisms and moderators of interventions). Many different knowledge synthesis methods exist in the literature across multiple disciplines, but locating these, particularly for qualitative research, present challenges. There is a need for a comprehensive manual for synthesis methods (quantitative/qualitative or mixed), outlining how these methods are related, and how to match the most appropriate knowledge synthesis method to answer a research question. The objectives of this scoping review are to: 1) conduct a systematic search of the literature for knowledge synthesis methods across multi-disciplinary fields; 2) compare and contrast the different knowledge synthesis methods; and, 3) map out the specific steps to conducting the knowledge syntheses to inform the development of a knowledge synthesis methods manual/tool. Methods We will search relevant electronic databases (e.g., MEDLINE, CINAHL), grey literature, and discipline-based listservs. The scoping review will consider all study designs including qualitative and quantitative methodologies (excluding economic analysis or clinical practice guideline development), and identify knowledge synthesis methods across the disciplines of health, education, sociology, and philosophy. Two reviewers will pilot-test the screening criteria and data abstraction forms, and will independently screen the literature and abstract the data. A three-step synthesis process will be used to map the literature to our objectives. Discussion This project represents the first attempt to broadly and systematically identify, define and classify knowledge synthesis methods (i.e., less traditional knowledge synthesis methods). We anticipate that our results will lead to an accepted taxonomy for less traditional knowledge synthesis methods, and to the development and implementation of a methods manual for these reviews which will be relevant to a wide range of knowledge users, including researchers, funders, and journal editors.

Abstract Background Osteoporosis affects over 200 million people worldwide at a high cost to healthcare systems. Although guidelines on assessing and managing osteoporosis are available, many patients are not receiving appropriate diagnostic testing or treatment. Findings from a systematic review of osteoporosis interventions, a series of mixed-methods studies, and advice from experts in osteoporosis and human-factors engineering were used collectively to develop a multicomponent tool (targeted to family physicians and patients at risk for osteoporosis) that may support clinical decision making in osteoporosis disease management at the point of care. Methods A three-phased approach will be used to evaluate the osteoporosis tool. In phase 1, the tool will be implemented in three family practices. It will involve ensuring optimal functioning of the tool while minimizing disruption to usual practice. In phase 2, the tool will be pilot tested in a quasi-experimental interrupted time series (ITS) design to determine if it can improve osteoporosis disease management at the point of care. Phase 3 will involve conducting a qualitative postintervention follow-up study to better understand participants' experiences and perceived utility of the tool and readiness to adopt the tool at the point of care. Discussion The osteoporosis tool has the potential to make several contributions to the development and evaluation of complex, chronic disease interventions, such as the inclusion of an implementation strategy prior to conducting an evaluation study. Anticipated benefits of the tool may be to increase awareness for patients about osteoporosis and its associated risks and provide an opportunity to discuss a management plan with their physician, which may all facilitate patient self-management.

Abstract Background Research has shown that the long term management of food allergy is suboptimal. Our study aims to provide direction for improvement, by evaluating food allergy management from the perspective of, food allergic patients or their caregivers, and allergists in selected outpatient settings in Ontario. Methods This two-part study included an anonymous questionnaire completed by patients or their caregivers in allergy clinics, and a qualitative interview with allergists. In Part A, food allergic patients or their caregivers were surveyed about information they received on food allergy, their level of confidence with self-management, and their learning needs. In Part B, allergists were interviewed about teaching priorities and the challenges and strategies that currently exist in food allergy management. The questionnaire was developed and piloted at the Hamilton Health Sciences Corporation-McMaster University Medical Center Site. Using convenience sampling, participants were recruited from 6 allergy clinics in 5 Ontario cities. Patients of any age with food allergy who were evaluated by an allergist were considered for inclusion. Quantitative data was analyzed using descriptive statistics and frequency analysis. Audio recorded interviews with allergists were transcribed verbatim and analyzed using content analysis of grounded theory methodology. Results Ninety-two food allergic families in the care of 6 allergists in Toronto, Hamilton, London, Kitchener, and Kingston participated in the study. Key areas requiring improvement in food allergy management were identified: 33% of families were not shown how to use an epinephrine auto-injector with a trainer, only 57% were asked to demonstrate an auto-injector, despite being on average at their 5th visit, and only about 30% felt very confident about when and how to give an auto-injector. Fifty percent of families did not receive sufficient information on medical identification and 21% did not receive information about support groups. Interviews with allergists revealed limitations in time and nursing resources. Conclusions Our study highlights the educational gaps and overall experiences of food allergic families in Ontario, and the challenges faced by the allergists managing them.

Abstract Background Knowledge translation (KT) is a rapidly growing field that is becoming an integral part of research protocols. Methods This meeting report describes one group's experience at the 2009 KT Canada Summer Institute in developing an end-of-grant KT plan for a randomized control trial proposal. Results Included is a discussion of the process, challenges, and recommendations from the trainee's perspective in developing an end-of-grant KT plan. Conclusion New researchers should consider developing an end-of-grant KT plan with strategies that move beyond passive dissemination to incorporate innovative means of collaboration with the end user to craft the message, package the information, and share the research findings with end users.

Abstract Background Working with patients and health care providers to co-design health interventions is gaining global prominence. While co-design of interventions is important for all patients, it is particularly important for older adults who often experience multiple and complex chronic conditions. Persona-scenarios have been used by designers of technology applications. The purpose of this paper is to explore how a modified approach to the persona-scenario method was used to co-design a complex primary health care intervention (Health TAPESTRY) by and for older adults and providers and the value added of this approach. Methods The persona-scenario method involved patient and clinician participants from two academically-linked primary care practices. Local prospective volunteers and community service providers (e.g., home care services, support services) were also recruited. Persona-scenario workshops were facilitated by researchers experienced in qualitative methods. Working mostly in homogenous pairs, participants created a fictitious but authentic persona that represented people like themselves. Core components of the Health TAPESTRY intervention were described. Then, participants created a story (scenario) involving their persona and an aspect of the proposed Health TAPESTRY program (e.g., volunteer roles). Two stages of analysis involved descriptive identification of themes, followed by an interpretive phase to extract possible actions and products related to ideas in each theme. Results Fourteen persona-scenario workshops were held involving patients (n = 15), healthcare providers/community care providers (n = 29), community service providers (n = 12), and volunteers (n = 14). Fifty themes emerged under four Health TAPESTRY components and a fifth category - patient. Eight cross cutting themes highlighted areas integral to the intervention. In total, 414 actions were identified and 406 products were extracted under the themes, of which 44.8% of the products (n = 182) were novel. The remaining 224 had been considered by the research team. Conclusions The persona-scenario method drew out feasible novel ideas from stakeholders, which expanded on the research team’s original ideas and highlighted interactions among components and stakeholder groups. Many ideas were integrated into the Health TAPESTRY program’s design and implementation. Persona-scenario method added significant value worthy of the added time it required. This method presents a promising alternative to active engagement of multiple stakeholders in the co-design of complex interventions.

Abstract Background It is important to identify biomarkers associated with BRCA mutation in women with early breast cancer (BC) to improve early identification of mutation carriers. Thus, in this study, we examined the protein expression of claudin (CLDN) 3, CLDN4, CLDN7, and E-cadherin. Moreover, we analyzed additional histopathological variables and their associations in familial BC. Methods Immunohistochemical analysis for CLDNs and E-cadherin was performed on 237 BC cases of three different subsets of BC tumors: 62 from BRCA1 mutation carriers, 59 from BRCA2 mutation carriers, and 116 tumors from patients with BRCA wild type (WT) as controls. Histopathological data were also analyzed in the different subgroups. Logistic regression and receiver operation characteristic (ROC) curve were conducted to investigate factors associated with BRCA tumors. Results Expression of CLDN3 positively correlated with BRCA-mutated BC. CLDN3 was expressed in 58% of BRCA1-mutated tumors compared to only 7% in BRCA2-mutated tumors (p

Abstract Background Telemonitoring services could dramatically improve the care of diabetes patients by enhancing their quality of life while decreasing healthcare expenditures. However, the potential for implementing innovative treatment options in the Austrian public and private health system is not known yet. Thus, we analyzed the readiness to use telemonitoring in diabetes care among Austrian practitioners. Methods We conducted an online survey among a purposive sample of Austrian practitioners (n = 41) using an adapted German version of the practitioner telehealth readiness assessment tool. We assessed three readiness domains for telemonitoring in the context of diabetes care, i.e. core readiness, engagement readiness, and structural readiness, and validated the German tool using principal components analysis. Results Study subjects perceived themselves as open to innovations and also expressed optimistic attitudes towards telemonitoring in general and offering telemonitoring-based services for their patients. Participants achieved a medium average readiness level for telemonitoring (58.2, 95% CI 53.9–62.5) and were thus in a good position to use telemonitoring, although some arguments may adversely affected its use. The top three perceived benefits of telemonitoring were enhanced quality of treatment, better therapy adjustment, and reduced travel and waiting times for patients. The top three barriers were reduced personal communication, practitioner time expenditure and equally placed poor financial compensation as well as data security and privacy issues. Conclusion Our data revealed that Austrian practitioners showed a quite moderate readiness to use telemonitoring in diabetes care. To further advance telemonitoring readiness among all pillars of diabetes care in Austria, joint efforts among healthcare stakeholders are required to overcome existing financial, organizational, and technical obstacles.

Abstract Background The treatment strategies for colorectal cancer located in the right side of the colon have changed dramatically during the last decade. Due to the introduction of complete mesocolic excision (CME) with central ligation of the vessels and systematic lymph node dissection, the long-term survival of affected patients has increased significantly. It has also been proposed that right-sided colon resection can be performed laparoscopically with the same extent of resection and equal long-term results. Methods A retrospective evaluation of a prospectively expanded database on right-sided colorectal cancer or adenoma treated at the University Hospital of Wuerzburg between 2009 and 2016 was performed. All patients underwent CME. This data was analyzed alone and in comparison to the published data describing laparoscopic right-sided colon resection for colon cancer. Results The database contains 279 patients, who underwent right-sided colon resection due to colorectal cancer or colorectal adenoma (255 open; 24 laparoscopic). Operation data (time, length of stay, time on ICU) was equal or superior to laparoscopy, which is comparable to the published results. Surprisingly, the surrogate parameter for correct CME (the number of removed lymph nodes) was significantly higher in the open group. In a subgroup analysis only including patients who were feasible for laparoscopic resection and had been operated with an open procedure by an experienced surgeon, operation time was significantly shorter and the number of removed lymph nodes is significantly higher in the open group. Conclusion So far, several studies demonstrate that laparoscopic right-sided colon resection is comparable to open resection. Our data suggests that a consequent CME during an open operation leads to significantly more removed lymph nodes than in laparoscopically resected patients and in several so far published data of open control groups from Europe. Further prospective randomized trials comparing the long-term outcome are urgently needed before laparoscopy for right-sided colon resection can be recommended ubiquitously.

Abstract Background Systematic reviews are infrequently used by health care managers (HCMs) and policy-makers (PMs) in decision-making. HCMs and PMs co-developed and tested novel systematic review of effects formats to increase their use. Methods A three-phased approach was used to evaluate the determinants to uptake of systematic reviews of effects and the usability of an innovative and a traditional systematic review of effects format. In phase 1, survey and interviews were conducted with HCMs and PMs in four Canadian provinces to determine perceptions of a traditional systematic review format. In phase 2, systematic review format prototypes were created by HCMs and PMs via Conceptboard©. In phase 3, prototypes underwent usability testing by HCMs and PMs. Results Two hundred two participants (80 HCMs, 122 PMs) completed the phase 1 survey. Respondents reported that inadequate format (Mdn = 4; IQR = 4; range = 1–7) and content (Mdn = 4; IQR = 3; range = 1–7) influenced their use of systematic reviews. Most respondents (76%; n = 136/180) reported they would be more likely to use systematic reviews if the format was modified. Findings from 11 interviews (5 HCMs, 6 PMs) revealed that participants preferred systematic reviews of effects that were easy to access and read and provided more information on intervention effectiveness and less information on review methodology. The mean System Usability Scale (SUS) score was 55.7 (standard deviation [SD] 17.2) for the traditional format; a SUS score

Abstract Background In 2013, Health Quality Ontario introduced stroke quality-based procedures (QBPs) to promote use of evidence-based practices for patients with stroke in Ontario hospitals. The study purpose was to: (a) describe the knowledge translation (KT) interventions used to support stroke QBP implementation, (b) assess differences in the planned and reported KT interventions by region, and (c) explore determinants perceived to have affected outcomes. Methods A mixed methods approach was used to evaluate: activities, KT interventions, and determinants of stroke QBP implementation. In Phase 1, a document review of regional stroke network work plans was conducted to capture the types of KT activities planned at a regional level; these were mapped to the knowledge to action framework. In Phase 2, we surveyed Ontario hospital staff to identify the KT interventions used to support QBP implementation at an organizational level. Phase 3 involved qualitative interviews with staff to elucidate deeper understanding of survey findings. Results Of the 446 activities identified in the document review, the most common were ‘dissemination’ (24.2%; n = 108), ‘implementation’ (22.6%; n = 101), ‘implementation planning’ (15.0%; n = 67), and ‘knowledge tools’ (10.5%; n = 47). Based on survey data (n = 489), commonly reported KT interventions included: staff educational meetings (43.1%; n = 154), champions (41.5%; n = 148), and staff educational materials (40.6%; n = 145). Survey participants perceived stroke QBP implementation to be successful (median = 5/7; interquartile range = 4–6; range = 1–7; n = 335). Forty-four people (e.g., managers, senior leaders, regional stroke network representatives, and frontline staff) participated in interviews/focus groups. Perceived facilitators to QBP implementation included networks and collaborations with external organizations, leadership engagement, and hospital prioritization of stroke QBP. Perceived barriers included lack of funding, size of the hospital (i.e., too small), lack of resources (i.e., staff and time), and simultaneous implementation of other QBPs. Conclusions Information on the types of activities and KT interventions used to support stroke QBP implementation and the key determinants influencing uptake of stroke QBPs can be used to inform future activities including the development and evaluation of interventions to address barriers and leverage facilitators.

Abstract Background For women living with HIV (WLWH) in low- and middle-income countries, World Health Organization (WHO) infant feeding guidelines now recommend exclusive breastfeeding until six months followed by mixed feeding until 24 months, alongside lifelong maternal antiretroviral therapy (ART). These recommendations represent the sixth major revision to WHO infant feeding guidelines since 1992. We explored how WLWH in rural Uganda make infant feeding decisions in light of evolving recommendations. Methods We conducted semi-structured interviews with 20 postpartum Ugandan WLWH accessing ART, who reported pregnancy

Abstract Background Chronic diseases are a significant public health concern, particularly in older adults. To address the delivery of health care services to optimally meet the needs of older adults with multiple chronic diseases, Health TAPESTRY (Teams Advancing Patient Experience: Strengthening Quality) uses a novel approach that involves patient home visits by trained volunteers to collect and transmit relevant health information using e-health technology to inform appropriate care from an inter-professional healthcare team. Health TAPESTRY was implemented, pilot tested, and evaluated in a randomized controlled trial (analysis underway). Knowledge translation (KT) interventions such as Health TAPESTRY should involve an investigation of their sustainability and scalability determinants to inform further implementation. However, this is seldom considered in research or considered early enough, so the objectives of this study were to assess the sustainability and scalability potential of Health TAPESTRY from the perspective of the team who developed and pilot-tested it. Methods Our objectives were addressed using a sequential mixed-methods approach involving the administration of a validated, sustainability survey developed by the National Health Service (NHS) to all members of the Health TAPESTRY team who were actively involved in the development, implementation and pilot evaluation of the intervention (Phase 1: n = 38). Mean sustainability scores were calculated to identify the best potential for improvement across sustainability factors. Phase 2 was a qualitative study of interviews with purposively selected Health TAPESTRY team members to gain a more in-depth understanding of the factors that influence the sustainability and scalability Health TAPESTRY. Two independent reviewers coded transcribed interviews and completed a multi-step thematic analysis. Outcomes were participant perceptions of the determinants influencing the sustainability and scalability of Health TAPESTRY. Results Twenty Health TAPESTRY team members (53% response rate) completed the NHS sustainability survey. The overall mean sustainability score was 64.6 (range 22.8–96.8). Important opportunities for improving sustainability were better staff involvement and training, clinical leadership engagement, and infrastructure for sustainability. Interviews with 25 participants (response rate 60%) showed that factors influencing the sustainability and scalability of Health TAPESTRY emerged across two dimensions: I) Health TAPESTRY operations (development and implementation activities undertaken by the central team); and II) the Health TAPESTRY intervention (factors specific to the intervention and its elements). Resource capacity appears to be an important factor to consider for Health TAPESTRY operations as it was identified across both sustainability and scalability factors; and perceived lack of interprofessional team and volunteer resource capacity and the need for stakeholder buy-in are important considerations for the Health TAPESTRY intervention. We used these findings to create actionable recommendations to initiate dialogue among Health TAPESTRY team members to improve the intervention. Conclusions Our study identified sustainability and scalability determinants of the Health TAPESTRY intervention that can be used to optimize its potential for impact. Next steps will involve using findings to inform a guide to facilitate sustainability and scalability of Health TAPESTRY in other jurisdictions considering its adoption. Our findings build on the limited current knowledge of sustainability, and advances KT science related to the sustainability and scalability of KT interventions.

Abstract Background Fungal plant pathogens belonging to the genus Venturia cause damaging scab diseases of members of the Rosaceae. In terms of economic impact, the most important of these are V. inaequalis, which infects apple, and V. pirina, which is a pathogen of European pear. Given that Venturia fungi colonise the sub-cuticular space without penetrating plant cells, it is assumed that effectors that contribute to virulence and determination of host range will be secreted into this plant-pathogen interface. Thus the predicted secretomes of a range of isolates of Venturia with distinct host-ranges were interrogated to reveal putative proteins involved in virulence and pathogenicity. Results Genomes of Venturia pirina (one European pear scab isolate) and Venturia inaequalis (three apple scab, and one loquat scab, isolates) were sequenced and the predicted secretomes of each isolate identified. RNA-Seq was conducted on the apple-specific V. inaequalis isolate Vi1 (in vitro and infected apple leaves) to highlight virulence and pathogenicity components of the secretome. Genes encoding over 600 small secreted proteins (candidate effectors) were identified, most of which are novel to Venturia, with expansion of putative effector families a feature of the genus. Numerous genes with similarity to Leptosphaeria maculans AvrLm6 and the Verticillium spp. Ave1 were identified. Candidates for avirulence effectors with cognate resistance genes involved in race-cultivar specificity were identified, as were putative proteins involved in host-species determination. Candidate effectors were found, on average, to be in regions of relatively low gene-density and in closer proximity to repeats (e.g. transposable elements), compared with core eukaryotic genes. Conclusions Comparative secretomics has revealed candidate effectors from Venturia fungal plant pathogens that attack pome fruit. Effectors that are putative determinants of host range were identified; both those that may be involved in race-cultivar and host-species specificity. Since many of the effector candidates are in close proximity to repetitive sequences this may point to a possible mechanism for the effector gene family expansion observed and a route to diversification via transposition and repeat-induced point mutation.

Abstract Background Scoping reviews are used to identify knowledge gaps, set research agendas, and identify implications for decision-making. The conduct and reporting of scoping reviews is inconsistent in the literature. We conducted a scoping review to identify: papers that utilized and/or described scoping review methods; guidelines for reporting scoping reviews; and studies that assessed the quality of reporting of scoping reviews. Methods We searched nine electronic databases for published and unpublished literature scoping review papers, scoping review methodology, and reporting guidance for scoping reviews. Two independent reviewers screened citations for inclusion. Data abstraction was performed by one reviewer and verified by a second reviewer. Quantitative (e.g. frequencies of methods) and qualitative (i.e. content analysis of the methods) syntheses were conducted. Results After searching 1525 citations and 874 full-text papers, 516 articles were included, of which 494 were scoping reviews. The 494 scoping reviews were disseminated between 1999 and 2014, with 45 % published after 2012. Most of the scoping reviews were conducted in North America (53 %) or Europe (38 %), and reported a public source of funding (64 %). The number of studies included in the scoping reviews ranged from 1 to 2600 (mean of 118). Using the Joanna Briggs Institute methodology guidance for scoping reviews, only 13 % of the scoping reviews reported the use of a protocol, 36 % used two reviewers for selecting citations for inclusion, 29 % used two reviewers for full-text screening, 30 % used two reviewers for data charting, and 43 % used a pre-defined charting form. In most cases, the results of the scoping review were used to identify evidence gaps (85 %), provide recommendations for future research (84 %), or identify strengths and limitations (69 %). We did not identify any guidelines for reporting scoping reviews or studies that assessed the quality of scoping review reporting. Conclusion The number of scoping reviews conducted per year has steadily increased since 2012. Scoping reviews are used to inform research agendas and identify implications for policy or practice. As such, improvements in reporting and conduct are imperative. Further research on scoping review methodology is warranted, and in particular, there is need for a guideline to standardize reporting.

Abstract Background Clinical practice guidelines have the potential to facilitate the implementation of evidence into practice, support clinical decision making, specify beneficial therapeutic approaches, and influence public policy. However, these potential benefits have not been consistently achieved. The limited impact of guidelines can be attributed to organisational constraints, the complexity of the guidelines, and the lack of usability testing or end-user involvement in their development. Implementability has been referred to as the perceived characteristics of guidelines that predict the relative ease of their implementation at the clinical level, but this concept is as yet poorly defined. The objective of our study is to identify guideline attributes that affect uptake in practice by considering evidence from four disciplines (medicine, psychology, management, human factors engineering) to determine the relationship between the perceived characteristics of recommendations and their uptake and to develop a framework of implementability. Methods A realist-review approach to knowledge synthesis will be used to understand attributes of guidelines (e.g., its text and content) and how changing these elements might impact clinical practice and clinical decision making. It also allows for the exploration of 'what works for whom, in what circumstances, and in what respects'. The realist review will be structured according to Pawson's five practical steps in realist reviews: (1) clarifying the scope of the review, (2) determining the search strategy, (3) ensuring proper article selection and study quality assessment, (4) extracting and organising data, and (5) synthesising the evidence and drawing conclusions. Data will be synthesised according to a two-stage analysis: (1) we will extract and define all relevant guideline attributes from the different disciplines, then create a shortlist of unique attributes and investigate their relationships with uptake, and (2) we will compare and contrast the attributes and guideline uptake within each and between the four disciplines to create a robust framework of implementability. Discussion Creating guidelines that are designed to maximise uptake may be a potentially effective and inexpensive way of increasing their impact. However, this is best achieved by a comprehensive framework to inform the design of guidelines drawing on a range of disciplines that study behaviour change. This study will use a customised realist-review approach to synthesising the literature to better understand and operationalise a complex and under-theorised concept.

Abstract Background Low-contact-stress (LCS) mobile-bearing total knee arthroplasty (TKA) (Johnson & Johnson, New Brunswick, NJ; previously: DePuy, Warsawa, USA) provides excellent functional results and wear rates in long-term follow-up analyses. Radiological analysis shows radiolucent lines (RLL) appearing immediately or two years after primary implantation, indicative of poor seat. Investigations proved RLL to be more frequent in uncemented TKA, resulting in a consensus to cement the tibial plateau, but their association with clinical findings and patients discomfort and knee pain is still unknown. Methods 553 patients with 566 low-contact-stress (LCS) total knee prostheses were screened for continuous moderate knee pain. We compared tibial stress shielding classified by Ewald in patients suffering from pain with a matched, pain-free control group on blinded X-rays. We hypothesized a positive correlation between pain and radiolucency and higher frequency of such radiolucent lines in the most medial and most lateral zones of the tibial plateau. Results Twenty-eight patients suffered from knee pain in total. Radiolucencies were detected in 27 of these cases and in six out of 28 matched controls without knee pain. We could demonstrate a significant correlation of knee pain and radiolucencies, which appeared significantly more frequently in the outermost zones of the tibial plateau. Conclusion Our findings suggest that radiolucent lines, representing poor implant seat, about the tibial plateau are associated with knee pain in LCS patients. Radiolucencies are observed more often in noncemented LCS, and cementing the tibial plateau might improve implant seat and reduce both radiolucent lines and associated knee pain.

Abstract Background Osteoporosis affects over 200 million people worldwide at a high cost to healthcare systems. Although guidelines are available, patients are not receiving appropriate diagnostic testing or treatment. Findings from a systematic review of osteoporosis interventions and a series of focus groups were used to develop a functional multifaceted tool that can support clinical decision-making in osteoporosis disease management at the point of care. The objective of our study was to assess how well the prototype met functional goals and usability needs. Methods We conducted a usability study for each component of the tool--the Best Practice Recommendation Prompt (BestPROMPT), the Risk Assessment Questionnaire (RAQ), and the Customised Osteoporosis Education (COPE) sheet--using the framework described by Kushniruk and Patel. All studies consisted of one-on-one sessions with a moderator using a standardised worksheet. Sessions were audio- and video-taped and transcribed verbatim. Data analysis consisted of a combination of qualitative and quantitative analyses. Results In study 1, physicians liked that the BestPROMPT can provide customised recommendations based on risk factors identified from the RAQ. Barriers included lack of time to use the tool, the need to alter clinic workflow to enable point-of-care use, and that the tool may disrupt the real reason for the visit. In study 2, patients completed the RAQ in a mean of 6 minutes, 35 seconds. Of the 42 critical incidents, 60% were navigational and most occurred when the first nine participants were using the stylus pen; no critical incidents were observed with the last six participants that used the touch screen. Patients thought that the RAQ questions were easy to read and understand, but they found it difficult to initiate the questionnaire. Suggestions for improvement included improving aspects of the interface and navigation. The results of study 3 showed that most patients were able to understand and describe sections of the COPE sheet, and all considered discussing the information with their physicians. Suggestions for improvement included simplifying the language and improving the layout. Conclusions Findings from the three studies informed changes to the tool and confirmed the importance of usability testing on all end users to reduce errors, and as an important step in the development process of knowledge translation interventions.

Abstract Background Osteoporosis affects over 200 million people worldwide, and represents a significant cost burden. Although guidelines are available for best practice in osteoporosis, evidence indicates that patients are not receiving appropriate diagnostic testing or treatment according to guidelines. The use of clinical decision support systems (CDSSs) may be one solution because they can facilitate knowledge translation by providing high-quality evidence at the point of care. Findings from a systematic review of osteoporosis interventions and consultation with clinical and human factors engineering experts were used to develop a conceptual model of an osteoporosis tool. We conducted a qualitative study of focus groups to better understand physicians' perceptions of CDSSs and to transform the conceptual osteoporosis tool into a functional prototype that can support clinical decision making in osteoporosis disease management at the point of care. Methods The conceptual design of the osteoporosis tool was tested in 4 progressive focus groups with family physicians and general internists. An iterative strategy was used to qualitatively explore the experiences of physicians with CDSSs; and to find out what features, functions, and evidence should be included in a working prototype. Focus groups were conducted using a semi-structured interview guide using an iterative process where results of the first focus group informed changes to the questions for subsequent focus groups and to the conceptual tool design. Transcripts were transcribed verbatim and analyzed using grounded theory methodology. Results Of the 3 broad categories of themes that were identified, major barriers related to the accuracy and feasibility of extracting bone mineral density test results and medications from the risk assessment questionnaire; using an electronic input device such as a Tablet PC in the waiting room; and the importance of including well-balanced information in the patient education component of the osteoporosis tool. Suggestions for modifying the tool included the addition of a percentile graph showing patients' 10-year risk for osteoporosis or fractures, and ensuring that the tool takes no more than 5 minutes to complete. Conclusions Focus group data revealed the facilitators and barriers to using the osteoporosis tool at the point of care so that it can be optimized to aid physicians in their clinical decision making.

Abstract Background Evaluating the existence and strength of an association between a putative cause and adverse clinical outcome is complex and best done by assessing all available evidence. With the increasing burden of chronic disease, greater time demands on health professionals, and the explosion of information, effective retrieval of best evidence has become both more important and more difficult. Optimal search retrieval can be hampered by a number of obstacles, especially poor search strategies, but using empirically tested methodological search filters can enhance the accuracy of searches for sound evidence concerning etiology. Although such filters have previously been developed for studies of relevance to causation in MEDLINE, no empirically tested search strategy exists for EMBASE. Methods An analytic survey was conducted, comparing hand searches of journals with retrievals from EMBASE for candidate search terms and combinations. 6 research assistants read all issues of 55 journals indexed in EMBASE. All articles were rated using purpose and quality indicators and categorized into clinically relevant original studies, review articles, general papers, or case reports. The original and review articles were then categorized as 'pass' or 'fail' for scientific merit according to explicit criteria in the areas of causation (etiology) and other clinical topics. Candidate search strategies were developed for causation, then run in a subset of 55 EMBASE journals, the retrievals being compared with the hand search data. The sensitivity, specificity, precision, and accuracy of the search strategies were calculated. Results Of the 1489 studies classified as causation, 14% were methodologically sound. When search terms were combined, sensitivity reached 92%. Compared with the best single-term strategy, the best combination of terms resulted in an absolute increase in sensitivity (19%) and specificity (5.2%). Maximizing specificity for combined terms resulted in an increase of 7.1% compared with the single term but this came at an expense of sensitivity (39% absolute decrease). A search strategy that optimized the trade-off between sensitivity and specificity achieved 81.9% for sensitivity and 81.4% for specificity. Conclusion We have discovered search strategies that retrieve high quality studies of causation from EMBASE with high sensitivity, high specificity, or an optimal balance of each.