Context: An evidence base that addresses issues of complexity and context is urgently needed for large-system transformation (LST) and health care reform. Fundamental conceptual and methodological challenges also must be addressed. The Saskatchewan Ministry of Health in Canada requested a six-month synthesis project to guide four major policy development and strategy initiatives focused on patient-and family-centered care, primary health care renewal, quality improvement, and surgical wait lists. The aims of the review were to analyze examples of successful and less successful transformation initiatives, to synthesize knowledge of the underlying mechanisms, to clarify the role of government, and to outline options for evaluation. Methods:We used realist review, whose working assumption is that a particular intervention triggers particular mechanisms of change. Mechanisms may be more or less effective in producing their intended outcomes, depending on their interaction with various contextual factors. We explain the variations in outcome as the interplay between context and mechanisms. We nested this analytic approach in a macro framing of complex adaptive systems (CAS). Findings:Our rapid realist review identified five "simple rules" of LST that were likely to enhance the success of the target initiatives: (1) blend designated leadership with distributed leadership; (2) establish feedback loops; (3) attend to history; (4) engage physicians; and (5) include patients and families. These principles play out differently in different contexts affecting human Conclusions:Realist review methodology can be applied in combination with a complex system lens on published literature to produce a knowledge synthesis that informs a prospective change effort in large-system transformation. A collaborative process engaging both research producers and research users contributes to local applications of universal principles and mid-range theories, as well as to a more robust knowledge base for applied research. We conclude with suggestions for the future development of synthesis and evaluation methods.
Fibroblast growth factor stimulates proliferation and subsequent differentiation of precursor cells isolated from the neuroepithelium of embryonic day 10 mice in vitro. Here we show that fibroblast growth factor-induced proliferation is dependent on the presence of insulin-like growth factors (IGFs) and that IGF-I is endogenously produced by the neuroepithelial cells. Blocking of endogenous IGF-I activity with anti-IGF-I antibodies results in complete inhibition of fibroblast growth factor-mediated proliferation and in cell death. IGF-I alone acts as a survival agent. These observations correlate with the detection of transcripts for IGF-I and basic fibroblast growth factor in freshly isolated neuroepithelium and are consistent with an autocrine action of these factors in early brain development in vivo.We have employed a serum-and insulin-free assay to examine the relative effects of IGFs and FGFs on neural precursor proliferation and find that the proliferation of precursors observed with bFGF is markedly enhanced by insulin and the IGFs, with tIGF
BackgroundThere is a growing emphasis in public health on the importance of evidence-based interventions to improve population health and reduce health inequities. Equally important is the need for knowledge about how to implement these interventions successfully. Yet, a gap remains between the development of evidence-based public health interventions and their successful implementation. Conventional systematic reviews have been conducted on effective implementation in health care, but few in public health, so their relevance to public health is unclear. In most reviews, stringent inclusion criteria have excluded entire bodies of evidence that may be relevant for policy makers, program planners, and practitioners to understand implementation in the unique public health context. Realist synthesis is a theory-driven methodology that draws on diverse data from different study designs to explain how and why observed outcomes occur in different contexts and thus may be more appropriate for public health.MethodsThis paper presents a realist review protocol to answer the research question: Why are some public health interventions successfully implemented and others not? Based on a review of implementation theories and frameworks, we developed an initial program theory, adapted for public health from the Consolidated Framework for Implementation Research, to explain the implementation outcomes of public health interventions within particular contexts. This will guide us through the review process, which comprises eight iterative steps based on established realist review guidelines and quality standards. We aim to refine this initial theory into a ‘final’ realist program theory that explains important context-mechanism-outcome configurations in the successful implementation of public health interventions.DiscussionDeveloping new public health interventions is costly and policy windows that support their implementation can be short lived. Ineffective implementation wastes scarce resources and is neither affordable nor sustainable. Public health interventions that are not implemented will not have their intended effects on improving population health and promoting health equity. This synthesis will provide evidence to support effective implementation of public health interventions taking into account the variable context of interventions. A series of knowledge translation products specific to the needs of knowledge users will be developed to provide implementation support.Systematic review registrationPROSPERO CRD42015030052Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-016-0229-1) contains supplementary material, which is available to authorized users.
The successful implementation of an MDP approach to PHC requires moving away from physician-driven care. This can only be achieved once there is a change in the underlying structures, values, power relations, and roles defined by the health care system and the community at large, where physicians are traditionally ranked above other care providers. The CBPAR methodology allows community members and the health-related professionals who serve them to take ownership of the research and to critically reflect on iterative cycles of evaluation. This provides an opportunity for practitioners to implement relevant changes based on internally generated analyses.
A 2 × 2 factorial experiment was conducted to determine the effects of rearing environment (indoor (In) v. outdoor (Out)) and dietary zinc oxide (ZnO) supplementation (0 (-Zn) v. 3100 (+Zn) mg/kg feed) on the response of weaned pigs to a challenge infection with enterotoxigenic Escherichia coli (ETEC). Pigs from the two rearing environments were weaned onto trial diets at 4 weeks of age, moved into conventional accommodation and infected 3 days later with 109 CFU ETEC per os. Faecal ETEC shedding was determined before and after challenge. After 7 days of ETEC infection, all pigs were euthanized for gut lactic acid bacteria (LAB)-to-coliform ratio, pH and small intestine morphological measurements. Both ZnO and outdoor rearing reduced ETEC excretion, and these effects were additive. Outdoor rearing increased small intestine and colon tissue weight. ZnO increased villus height and goblet cell number in the upper small intestine, LAB-to-coliform ratio (through reduced coliforms) in the lower small intestine and proximal colon, and improved growth performance. There were interactive effects of rearing environment and ZnO supplementation on upper small intestine villus height and daily gain, as outdoor rearing conferred advantages on these variables only with ZnO dietary supplementation. Daily gains were 233, 174, 277 and 347 (s.e.m. 27.2) g/day for the In - Zn, Out - Zn, In + Zn and Out + Zn, respectively. These results suggest different, but complementary mechanisms of intestinal health and performance in outdoor-reared pigs and those offered ZnO supplemented diets. The results indicate that the benefits of ZnO to the weaned pig extend beyond suppression of ETEC and appear mediated through altered development of the small intestine mucosa.
Background: All antibodies approved for the treatment of cancer are monoclonal IgGs, and no IgE therapy has yet been tested in humans. The biology of IgE, compared with IgG, offers potential for enhanced immune surveillance and superior effector cell potency against tumor cells. IgE antibodies in preclinical cancer models are not associated with allergic toxicity even in immunocompetent animals, and in vivo efficacy compares favorably with equivalent IgGs. Methods: We conducted a first-in-human first-in-class trial of MOv18, a chimeric monoclonal IgE, in patients with solid tumors expressing folate receptor-alpha, the antigen recognized by this antibody. Antigen expression was deemed positive in the presence of >5% membrane staining of any intensity using the mouse clone BN3.2. Intravenous treatment was administered weekly for 6 weeks, then two-weekly. The trial incorporated pre-treatment skin prick testing with MOv18 IgE, and an ex vivo basophil activation test (BAT) using patient whole blood, with the aim of predicting systemic allergic toxicity and excluding patients at potential risk. Safety, efficacy, markers of immune response, and pharmacokinetics have been evaluated in 24 patients to date, at total doses ranging from 0.07 to 3.0mg. Results: Treatment was well tolerated in almost all patients. The most common toxicity was readily manageable urticaria, without systemic symptoms, signs or tryptase elevation. One patient treated at the 0.5mg dose experienced anaphylaxis, with tryptase elevation, despite a negative pre-dose skin prick test. This was the only patient in the trial with baseline circulating basophils that could be activated by ex vivo exposure to MOv18 IgE. This BAT assay was subsequently used to ensure no further patient with reactive basophils was exposed. Maximum tolerated dose has not yet been reached. Dose-dependent increases in Cmax were observed, and plasma concentrations of 70-100ng/mL achieved at the 1.5mg dose are comparable to typical levels of endogenous IgE. No consistent anti-drug antibody response has been detected. Preliminary evidence of anti-tumor activity was seen in a patient with ovarian cancer at a total MOv18 IgE dose of 0.7mg. Shrinkage of peritoneal metastases was accompanied by a tumor marker reduction meeting Gynecologic Cancer InterGroup criteria for response. Conclusions: These results support for the first time the safety of IgE as a treatment for cancer, and provide preliminary evidence for anti-tumor efficacy of this new therapeutic class. The mechanism of cutaneous toxicity is being investigated. Clinical testing of class-switched IgE versions of approved IgG-based therapeutic antibodies is warranted. Citation Format: James Spicer, Bristi Basu, Ana Montes, Udai Banerji, Rebecca Kristeleit, Gareth J. Veal, Christopher Corrigan, Stephen Till, George Nintos, Timothy Brier, Ionut G. Funingana, Joo Ern Ang, Kam Zaki, Annie Griffin, Claire Barton, Paul Jones, Sarah Mellor, Susan Brook, Katie Stoddart, Christopher Selkirk, Simon Carroll, Heike Lentfer, Natalie Woodman, Amy Pope, Giulia Pellizzari, Mano Nakamura, Kristina M. Ilieva, Atousa Khiabany, Chara Stavraka, Hannah Gould, Jitesh Chauhan, Heather Bax, Sarah Pinder, Debra Josephs, Sophia Karagiannis. Phase 1 trial of MOv18, a first-in-class IgE antibody therapy for cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT141.
The sensitivity specificity of an enzyme-linked immunosorbent assay (ELISA) for the serodiagnosis of strongyloidiasis has been investigated. 45 men with long-standing strongyloidiasis were compared with the same number of age- and sex-matched control subjects. The ELISA detected antibody in 84% of patients with parasitologically proven strongyloidiasis. When the technique was compared with an indirect immunofluorescent assay (IFA), a high correlation coefficient was obtained. Specificity was demonstrated by observing a marked fall in optical density of pooled positive serum after prior incubation with Strongyloides ratti soluble antigen but not after incubation with antigens derived from Ascaris suum or Dirofilaria immitis. The test is simple and offers a useful method for the diagnosis of strongyloidiasis. In these patients it was more reliable than a single parasitological examination of faeces or duodenal contents.
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