Conflict of interest: JPJ, CG, and SP are owners of US patent application no. 15/532,909 titled "TDP-43-binding polypeptides useful for the treatment of neurodegenerative diseases." JPJ is chief scientific officer of ImStar Therapeutics.

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/).

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The majority of genes associated with breast cancer susceptibility, including BRCA1 and BRCA2 genes, are involved in DNA repair mechanisms. Moreover, among the genes recently associated with an increased susceptibility to breast cancer, four are Fanconi Anemia (FA) genes: FANCD1/BRCA2, FANCJ/BACH1/BRIP1, FANCN/PALB2 and FANCO/RAD51C. FANCA is implicated in DNA repair and has been shown to interact directly with BRCA1. It has been proposed that the formation of FANCA/G (dependent upon the phosphorylation of FANCA) and FANCB/L sub-complexes altogether with FANCM, represent the initial step for DNA repair activation and subsequent formation of other sub-complexes leading to ubiquitination of FANCD2 and FANCI. As only approximately 25% of inherited breast cancers are attributable to BRCA1/2 mutations, FANCA therefore becomes an attractive candidate for breast cancer susceptibility. We thus analyzed FANCA gene in 97 high-risk French Canadian non-BRCA1/2 breast cancer individuals by direct sequencing as well as in 95 healthy control individuals from the same population. Among a total of 85 sequence variants found in either or both series, 28 are coding variants and 19 of them are missense variations leading to amino acid change. Three of the amino acid changes, namely Thr561Met, Cys625Ser and particularly Ser1088Phe, which has been previously reported to be associated with FA, are predicted to be damaging by the SIFT and PolyPhen softwares. cDNA amplification revealed significant expression of 4 alternative splicing events (insertion of an intronic portion of intron 10, and the skipping of exons 11, 30 and 31). In silico analyzes of relevant genomic variants have been performed in order to identify potential variations involved in the expression of these spliced transcripts. Sequence variants in FANCA could therefore be potential spoilers of the Fanconi-BRCA pathway and as a result, they could in turn have an impact in non-BRCA1/2 breast cancer families.

Policy Points More rigorous methodologies and systematic approaches should be encouraged in the science of scaling. This will help researchers better determine the effectiveness of scaling, guide stakeholders in the scaling process, and ultimately increase the impacts of health innovations. The practice and the science of scaling need to expand worldwide to address complex health conditions such as noncommunicable and chronic diseases. Although most of the scaling experiences described in the literature are occurring in the Global South, most of the authors publishing on it are based in the Global North. As the science of scaling spreads across the world with the aim of reducing health inequities, it is also essential to address the power imbalance in how we do scaling research globally. ContextScaling of effective innovations in health and social care is essential to increase their impact. We aimed to synthesize the evidence base on scaling and identify current knowledge gaps.MethodsWe conducted an umbrella review according to the Joanna Briggs Institute Reviewers’ Manual. We included any type of review that 1) focused on scaling, 2) covered health or social care, and 3) presented a methods section. We searched MEDLINE (Ovid), Embase, PsycINFO (Ovid), CINAHL (EBSCO), Web of Science, The Cochrane Library, Sociological Abstracts (ProQuest), Academic Search Premier (EBSCO), and ProQuest Dissertations & Theses Global from their inception to August 6, 2020. We searched the gray literature using, e.g., Google and WHO‐ExpandNet. We assessed methodological quality with AMSTAR2. Paired reviewers independently selected and extracted eligible reviews and assessed study quality. A narrative synthesis was performed.FindingsOf 24,269 records, 137 unique reviews were included. The quality of the 58 systematic reviews was critically low (n = 42). The most frequent review type was systematic review (n = 58). Most reported on scaling in low‐ and middle‐income countries (n = 59), whereas most first authors were from high‐income countries (n = 114). Most reviews concerned infectious diseases (n = 36) or maternal–child health (n = 28). They mainly focused on interventions (n = 37), barriers and facilitators (n = 29), frameworks (n = 24), scalability (n = 24), and costs (n = 14). The WHO/ExpandNet scaling definition was the definition most frequently used (n = 26). Domains most reported as influencing scaling success were building scaling infrastructure (e.g., creating new service sites) and human resources (e.g., training community health care providers).ConclusionsThe evidence base on scaling is evolving rapidly as reflected by publication trends, the range of focus areas, and diversity of scaling definitions. Our study highlights knowledge gaps around methodology and research infrastructures to facilitate equitable North–South research relationships. Common efforts are needed to ensure scaling expands the impacts of health and social innovations to broader populations.

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Background There is a growing interest in scaling effective health innovations to promote equitable access to high-quality health services worldwide. However, multiple challenges persist in scaling innovations. In this study, we aim to summarize the scaling evidence in the health and social care literature and identify current knowledge gaps. Methods We will conduct a living umbrella review according to the Joanna Briggs Institute Reviewers’ Manual. We will consider all knowledge syntheses addressing scaling in health or social care (e.g., any setting, any clinical area) and conducted in a systematic way. We will search the following electronic databases: MEDLINE (Ovid), Embase, PsychINFO (Ovid), CINAHL (EBSCO), Web of Science, The Cochrane Library, Sociological Abstract (Proquest), Academic Search Premier (EBSCO), and Proquest Dissertations & Theses Global, from inception. Furthermore, we will conduct searches of the grey literature. No restriction regarding date or language will be applied. Each phase of the review will be processed by two independent reviewers. We will develop a data extraction form on Covidence. We will assess the methodological quality of the included reviews using AMSTAR2 and the risk of bias using ROBIS. Results will be presented in tabular form and accompanied by a narrative synthesis covering the traditional themes of scaling science that emerge from the analysis, such as coverage, range, and sustainability, as well as themes less covered in the literature, including reporting guidance, models, tools, barriers, and/or facilitators to scaling innovations, evidence regarding application in high-income or low-income countries, and end-user engagement. We will disseminate the findings via publications and through relevant networks. Discussion The findings of the umbrella review will facilitate access to scaling evidence in the literature and help strengthen the science of scaling for researchers, policy makers, and program managers. Finally, this work will highlight important knowledge gaps and help prioritize future research questions. Systematic review registration This protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on November 11, 2020 (registration number: CRD42020183774).