Health Research Funding Research Articles

Evidence of commitment to research partnerships? Results of two web reviews

BackgroundPartnerships between academic researchers and health system leadership are often promoted by health research funding agencies as an important strategy in helping ensure that funded research is relevant and the results used. While potential benefits of such partnerships have been identified, there is limited guidance in the scientific literature for either healthcare organisations or researchers on how to select, build and manage effective research partnerships. Our main research objective was to explore the health system perspective on partnerships with researchers with a focus on issues related to the design and organisation of the health system and services. Two structured web reviews were conducted as one component of this larger study.MethodsTwo separate structured web reviews were conducted using structured data extraction tools. The first review focused on sites of health research bodies and those providing information on health system management and knowledge translation (n = 38) to identify what guidance to support partnerships might be available on websites commonly accessed by health leaders and researchers. The second reviewed sites from all health ‘regions’ in Canada (n = 64) to determine what criteria and standards were currently used in guiding decisions to engage in research partnerships; phone follow-up ensured all relevant information was collected.ResultsAbsence of guidance on partnerships between research institutions and health system leaders was found. In the first review, absence of guidance on research partnerships and knowledge coproduction was striking and in contrast with coverage of other forms of collaboration such as patient/community engagement. In the second review, little evidence of criteria and standards regarding research partnerships was found. Difficulties in finding appropriate contact information for those responsible for research and obtaining a response were commonly experienced.ConclusionGuidance related to health system partnerships with academic researchers is lacking on websites that should promote and support such collaborations. Health region websites provide little evidence of partnership criteria and often do not make contact information to research leaders within health systems readily available; this may hinder partnership development between health systems and academia.

A realist review of community engagement with health research

Introduction: Community engagement is increasingly recognized as a critical aspect of global health. Recent years have seen an expansion of community engagement activities linked to health research, but debates and inconsistencies remain about the aims of different types of engagement, mechanisms underpinning their implementation and impact, and influential contextual factors. Greater commitment to and consistency around community engagement by health research programs, implementers and funders requires a more coherent evidence base. This realist review is designed to improve our understanding of how and why community engagement contributes to intended and unintended outcomes (including research and ethical outcomes) in different contexts. Given the breadth and diversity of the literature on community engagement in health research, the review will initially focus on malaria research in low- and middle-income countries (LMICs) and draw on wider global health literature where needed. Methods and analysis: Community engagement in practice is often a complex set of interventions. We will conduct a realist review – a theory driven approach to evidence synthesis – to provide explanations for how and why community engagement with health research produces the pattern of outcomes observed across different contexts of application. We will consolidate evidence from a range of documents, including qualitative, quantitative and mixed method studies. The review will follow several stages: devising an initial programme theory, searching evidence, selecting appropriate documents, extracting data, synthesizing and refining the programme theory, and reiteration of these steps as needed. Ethics and dissemination: A formal ethics review is not required for this literature review. Findings will be disseminated in a peer reviewed journal, through national and international conferences, and through a set of short briefings tailored for audiences with an interest in community engagement. Outputs and presentations will be informed by and feed into our network of community engagement experts. PROSPERO registration number: CRD42019125687

Genome-Wide Chromosomal Instability by Cell-Free DNA Sequencing Predicts Patient Survival in Metastatic Breast Cancer

Background: Cell-free DNA (cfDNA) could well recapitulate the genomic features of tumor with minimal invasion. We aimed to evaluate the prognostic value of genome-wide chromosomal instability derived from cfDNA in patients with metastatic breast cancer (MBC). Methods: We retrospectively identified 65 patients with MBC who were intended to change line of therapy and had blood draw for cfDNA. We performed low-coverage whole-genome sequencing of cfDNA from plasma, and chromosomal instability was analyzed and represented by chromosomal instability (CIN) score. Findings: 32 (53.3%) samples resulted to have high CIN score, with similar clinicopathologic characteristics relative to patients with low CIN. Different subtypes of MBC exhibit remarkably diverse copy number profiles. High CIN score was associated with significantly shorter overall survival after blood draw, median 21.2 months (95% CI 14.1-28.3) versus not reached (P=0.006). Besides, patients with high CIN had worse progression free survival compared with the low CIN group (median 7.3 vs 11.0 months, P=0.034). CIN score remained an independent prognostic factor in multivariate analysis (hazard ratio, 3.563; 95%CI, 1.481 to 8.572; P=0.005). Interpretation: Genome-wide chromosomal instability tracking by cfDNA is reliable and predicts survival in patients with MBC. Funding Statement: This study was supported by National Natural Science Foundation of China (81874122, 81772490), National Key R&D Program of China (2018YFC0115204), the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (Grants 2017-I2M-3-004 and 2019-I2M-1-003), and Capital’s Funds for Health Improvement and Research (CFH2018-4-4024). Declaration of Interests: Ziliang Qian is a salaried employee of Prophet Genomics Inc., a provider of cancer genome-based diagnostic testing. The remaining authors declare no conflict of interest. Ethics Approval Statement: Use of patients’ clinicopathologic data and cfDNA draws were approved by institutional review board, and written informed consent was obtained from all patients.

Diffusion gradient nonlinearity bias correction reduces bias of breast cancer bone metastasis ADC values.

Health Research Fund of Central Denmark Region. Diffusion gradient nonlinearity (DGNL) bias causes apparent diffusion coefficient (ADC) values to drop with increasing superior-inferior (SI) isocenter offset. This is a concern when performing quantitative diffusion-weighted imaging (DWI). To investigate if DGNL ADC bias can be corrected in breast cancer bone metastases using a clinical DWI protocol and an online correction algorithm. Prospective. A diffusion phantom (Model 128, High Precision Devices, Boulder, CO) was used for in vitro validation. Twenty-three women with bone-metastasizing breast cancer were enrolled to assess DGNL correction in vivo. DWI was performed on a 1.5T MRI system as single-shot, spin-echo, echo-planar imaging with short-tau inversion recovery (STIR) fat-saturation. ADC maps with and without DGNL correction were created from the b50 and b800 images. Uncorrected and DGNL-corrected ADC values were measured in phantom and bone metastases by placing regions of interest on b800 images and copying them to the ADC map. The SI offset was recorded. In all, 79 bone metastases were assessed. ADC values with and without DGNL correction were compared at 14 cm SI offset using a two-tailed t-test. In the diffusion phantom, DGNL correction increased SI offset, where ADC bias was lower than 5%, from 7.3-13.8 cm. Of the 23 patients examined, six had no metastases in the covered regions. In the remaining patients, bias of uncorrected bone metastasis ADC values was 19.1% (95% confidence interval [CI]: 15.4-22.9%) at 14 cm SI offset. After DGNL correction, ADC bias was significantly reduced to 3.5% (95% CI: 0.7-6.3%, P < 0.001), thus reducing bias due to DGNL by 82%. Online DGNL correction corrects DGNL ADC value bias and allows increased station lengths in the SI direction. 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:904-911.

Lessons learned from a health authority research capacity-building initiative.

Health systems worldwide are under pressure to deliver better care to more people with increasingly complex needs within constrained budgets. Research capacity building has been shown to help alleviate these challenges and is underway at hospitals and health authorities across the country; however, approaches vary widely and little exists in the Canadian literature to share experience and best practices. This article describes how a health authority in British Columbia, Canada, implemented and evaluated a 5-year research capacity-building program in partnership with a provincial health research funder. We offer lessons learned for those leading similar innovation-focused change management initiatives, including vision and buy in, complexity thinking, infrastructure, leadership, and coalition development. We suggest that collective learning and building a more robust research capacity-building literature can help health organizations and their partners take significant steps toward integrating research and care for a more effective, efficient, and patient-centred health system.

Publicly funded clinical research in Canada.

Clinical research is funded by industry, governments, charities, and hospitals. It is important to know the economic commitment of the various funding bodies, but until now there has been no national source available which provides these data. We surveyed the major funders to provide such a measure. There is evidence that government and charity funding of medical research is a trigger for private sector research investment; therefore, tracking all sources of funding for clinical research will provide policy-makers with an overall picture of health research funding. These data support policy decision-making related to clinical research in Canada.

Abstract 1081: Smad3 silences neutrophil anticancer activity in the tumor microenvironment

Abstract Tumor microenvironment (TME) is a new therapeutic target for cancer, however it is highly heterogeneous and still largely unknown. Recently, we revealed that Smad3 is essential for TME-driven cancer progression, better understanding of the underlying mechanism may uncover novel therapeutic targets for cancer. Indeed, Smad3-dependent TME (Smad3-TME) is originated from bone marrow, where neutrophils are the most abundant leukocytes but their role in cancer is still controversial. Here, we are the first study to reveal the regulatory role of Smad3 in tumor-associated neutrophils (TAN). Interestingly, we observed that knockout of Smad3 (Smad3-KO) dramatically increased TAN population in mice bearing syngeneic melanoma B16F10 and lung carcinoma LLC, where the anticancer N1 phenotypes were significantly induced in the SMad3-KO TME-isolated TAN. Unexpectedly, adoptive transfer of Smad3-KO bone marrow-derived neutrophils markedly suppressed the progression of LLC-tumor on Smad3-WT mice in vivo, and their enhanced cancer-killing activity was confirmed by co-culture assay in vitro. Furthermore, microarray analysis identified a total of 4416 differentially expressed genes associated with Smad3-KO neutrophils under cancer condition in vitro, but the presence of Smad3 largely decreased the transcriptome diversity; especially on genes associated with virus defense response including an anticancer cytokine IL-28. Silencing of IL-28 significantly reduced the anticancer efficiency of Smad3-KO TAN on LLC-bearing mice in vivo. Mechanistically, we uncovered that IL-28A serves as a direct Smad3 target gene and specifically down-regulated in neutrophils under TGF-β1 or LLC-secretome stimulations; showing by ChIP and dual-luciferase reporter assays in vitro. Thus, targeting Smad3 precisely on TAN may represent as a novel and effective immunotherapy for cancer. Acknowledgments: This study was supported by Lui Che Woo Institute of Innovative Medicine (CARE program), Research Grants Council of Hong Kong (GRF 14117815, 14121816, 14163317, C7018-16G, TRS T12-402/13N), Health and Medical Research Fund (03140486, 14152321), Innovation and Technology Fund of Hong Kong (ITS/068/18), Direct Grant for Research CUHK (2017.002). Note: This abstract was not presented at the meeting. Citation Format: Patrick Ming-Kuen Tang, Philip Chiu-Tsun Tang, Jeff Yat-Fai Chung, Xiao-Ru Huang, Ka-Fai To, Hui-Yao Lan. Smad3 silences neutrophil anticancer activity in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1081.

Abstract 4249: Tumor-infiltrating B lymphocytes may serve as a prognostic biomarker for head and neck squamous carcinoma

Abstract B lymphocytes exert multifaceted functions to produce antibodies in humoral response, present antigen in cell-mediated immunity and suppress immunopathology via anti-inflammatory cytokines. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancers in world. The development and progression of HNSCC is closely related to the dysregulation and evasion of immune system, which enables cancer cells to proliferate and metastasize. In HNSCC, high CD8+ T cell infiltration predicts better patient survival, and the suppressive T cells (Treg) correlates with tumor progression. Nevertheless, the precise role of tumor-infiltrating B lymphocytes (TIL-B) in HNSCC is poorly defined. With a recently published bioinformatics approach, Tumor Immune Estimation Resources (TIMER), comprehensive pan-Cancer analysis was performed on 25 cancer types using the publicly available TCGA database with both survival and RNA-Seq information. Univariate COX regression demonstrates that in lower grade glioma (Hazard Ratio (HR)=830, P=1.3E-06), diffuse large B-cell lymphoma (HR=130, P=0.01), and papillary renal cell carcinoma (HR=15, P=0.02), TIL-B levels are associated with poor survival. Whilst in HNSCC (HR=0.082, P=0.0015), breast invasive carcinoma (HR=0.12, P=0.042), uterine corpus endometrial carcinoma (HR=0.045, P=0.039), cervical carcinoma (HR=0.00049, P=0.022,) and thymoma (HR=1.6E-05, P=0.026), TIL-B levels are associated with better survival. Note that among these 5 cancer types, HNSCC has the lowest P-value, suggesting TIL-B level is likely a good prognostic biomarker for patient outcome in HNSCC. In other 17 cancer types, TIL-B are not related to patient survival (P=n.s.). In HNSCC, clinicopathological analysis shows that the extreme high TIL-B level (top 15% patients with the highest TIL-B level vs. the bottom 15%) is associated with living status (P=0.0047), early AJCC pathological T stage (P=2.71E-04), high differentiation grade (P=5.00E-05), and the absence of perineural invasion (P=8.52E-04). Furthermore, Kaplan-Meier survival curves based on TIL-B level indicate that patients with high TIL-B (top 15%) show longer survival compared with those with low level (bottom 15%; P=0.0005). The median overall survival time is 67.81 months in TIL-B high and 35.91 in TIL-B low group. In conclusion, this study reveals that TIL-B may serve as independent prognostic biomarker for overall survival of HNSCC patients. Acknowledgements: VWYL receives funding supports from the Research Grant Council, HK (General Research Fund: #1711484; #17121616; #14168571; Theme-based Research: T12-401/13-R), Health and Medical Research Fund (HMRF #15160691), the University-Industry Collaboration Program (UIM/329; Innovation and Technology Fund, HK), and the Hong Kong Cancer Fund, HK. YL receives funding (Postdoctoral Hub of UIM/329) from the Innovation and Technology Fund, HK government) This study also receives funding from Lee Hysan Foundation Research Grant &amp; Endowment Fund Research Grant Schemes 2018-2019. Citation Format: Yuchen LIU, Vivain W. Lui. Tumor-infiltrating B lymphocytes may serve as a prognostic biomarker for head and neck squamous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4249.

Abstract 1095: Macrophage is a novel and rich source of cancer-associated fibroblasts in the tumor microenvironment

Abstract Background: Cancer-associated fibroblasts (CAF) are highly heterogeneous and their origins are largely unknown. Recently, we revealed that bone marrow-derived macrophages (BMDM) can further differentiate into myofibroblasts locally at the inflammatory site in a Smad3-dependent manner, but its potential role in the tumor microenvironment (TME) is still unexplored. Thus, we hypothesize that tumor-associated macrophages (TAM) may be able to transit into CAF, termed TAM to CAF transition (TAM-CAF), in TME for cancer promotion. Here, we are the first study to discover TAM-CAF as a common phenomenon in cancer. Methods: The evidence of TAM-CAF was confirmed on tumor biopsies from several cancer types including non-small cell lung carcinoma (NSCLC) tissue microarray. The occurrence pattern of TAM-CAF was determined in LysM-Cre/Rosa26-tdTomato mice with syngeneic lung carcinoma LLC by the fate-mapping study. The pathogenic role of TAM-CAF was examined by adoptive transferring of TAM-CAF cells onto LLC-bearing NOD-SCID mice. The regulatory mechanism was further elucidated on Smad3-WT/KO mice in vivo and BMDM in vitro. Results: Interestingly, we observed myofibroblast marker expressing TAM (α-SMA+CD68+) in the tumor biopsies of liver, kidney and lung cancers, which contributed to ~40% of the total CAF and positively associated with the NSCLC mortality. Fate mapping study confirmed the existence of macrophage-derived CAF (α-SMA+ tdTomato+) in LLC-tumor, where the contribution of TAM-CAF on CAF production was progressively increased throughout the tumorigenesis. Furthermore, adoptive transferring of TAM-CAF cells largely promotes tumor progression in LLC-bearing NOD/SCID mice associated with a marked increase of angiogenesis in the TME. Mechanistically, we found that phosphorylation of Smad3 is significantly associated with CAF production in NSCLC-TME (n=120), supported by the dramatic reduction of TAM-CAF in LLC-tumor and BMDM after deletion of Smad3. More importantly, we identified a conserved Smad3 binding site on the 5’UTR of FAP gene by ECR browser and ChIP assay in vitro; revealing its direct regulation on FAP expression at transcriptional level during TAM-CAF. Conclusion: We are the first study to uncover TAM as a rich source of CAF, which is commonly occurred in TME for cancer promotion via a Smad3-dependent mechanism. Thus, TAM-CAF may represent a novel and precision therapeutic target for cancer. Acknowledgments: This study was supported by Lui Che Woo Institute of Innovative Medicine (CARE program), Research Grants Council of Hong Kong (GRF 14117815, 14121816, 14163317, C7018-16G, TRS T12-402/13N), Health and Medical Research Fund (03140486, 14152321), Innovation and Technology Fund of Hong Kong (ITS/068/18), Direct Grant for Research CUHK (2017.002). Citation Format: Philip Chiu-Tsun Tang, Patrick Ming-Kuen Tang, Jeff Yat-Fai Chung, Xiao-Ru Huang, Ka-Fai TO, Hui-Yao LAN. Macrophage is a novel and rich source of cancer-associated fibroblasts in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1095.

Abstract 4933: RAPTOR protein overexpression is predictive of poor clinical outcomes in head and neck squamous cell carcinoma (HNSCC) patients

Abstract Head and neck squamous cell carcinoma (HNSCC) has a high mortality rate, and with rising incidences in Asia. Previously, we demonstrated that the PI3K pathway is the most frequently altered pathway in HNSCC (Lui et al, Cancer Discovery, 2013). However, cumulative PI3K pathway aberrations, nor PIK3CA aberrations, are not associated with clinical outcomes in HNSCC patients (P=n.s.). In this study, we investigate the prognostic significance of RAPTOR (Regulatory associated protein of mTOR), a key component of the PI3K signaling pathway, in HNSCC. To examine the clinical relevance of RAPTOR levels in human cancers, including HNSCC, we performed pan-cancer analyses of RAPTOR protein levels in the Cancer Proteome Atlas datasets (TCPA, USA). Strikingly, across 28 tumor types examined, we found that RAPTOR protein overexpression is most significantly associated with poor patient survival in HNSCC (P=0.00162***), followed by renal clear cell carcinoma (P=0.00198), and stomach cancer (P=0.0443; Log-Rank test; Table 1). We then extracted the original quantification data of RAPTOR protein array of HNC (TCPA, USA), and performed RAPTOR expression-survival correlation analyses on quantitative basis by Kaplan-Meier analysis with Log-Rank test. We found that HNSCC patients with RAPTOR protein overexpression in their primary tumors (mean+5SEM) have significantly poorer overall survival (median OS=27.56 months) than patients with RAPTOR protein underexpression (mean-5SEM; median OS=68.43 months). Moreover, this group of RAPTOR-high patients are found to have a higher risk of recurrences, with an Odd Ratio of 1.75 (P=0.05; Fisher’s Exact test). Notably, this poor OS of RAPTOR-high HNSCC is much shorter than that of TP53-mutated HNSCC in the same cohort (45.8 months; TCGA Provisional,N=510). Further, patients with extreme-high levels of RAPTOR protein expression (top 5% cases) have an even worst OS of only 11.56 months vs 48.16 months (the remaining 95% cases). Using our small cohort of Asian HNSCC tumors as a validation cohort, we show that RAPTOR protein overexpression is very common in Asian HNSCC (37.5%; 6/16 cases), suggestive of its likely contribution to HNSCC in Asia as well. In conclusion, RAPTOR-high status is likely to be a useful predictive of very poor HNSCC patient survival, possibly superior than the previously known survival-related biomarker,TP53 mutation. RAPTOR is one of the first components of the PI3K pathway shown to be associated with patient outcome in HNSCC. Acknowledgements:VWYL receives fundings from Health and Medical Research Fund(#15160691), Research Grant Council, Hong Kong(GRF#1711484,#17121616,# 14168571;T12-401/13-R), UICP(UIM/329;Innovation and Technology Fund); Hong Kong Cancer Fund. YCL is supported by Postdoctoral Hub(UIM/329) from Innovation and Technology Fund, Hong Kong government.J YKC supported by Dr Stanley Ho Medical Foundation. Citation Format: Hui Yan Poon, Yuchen Liu, Yu Xiong SU, Jason Y.k. Chan, Chin Wang Lau, Vivian W y Lui. RAPTOR protein overexpression is predictive of poor clinical outcomes in head and neck squamous cell carcinoma (HNSCC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4933.

A Framework to Prioritise Health Research Proposals for Funding: Integrating Value for Money.

When making funding decisions, research organisations largely consider the merits (e.g. scientific rigour and feasibility) of submitted research proposals; yet, there is often little or no reference to their value for money. This may be attributed to the challenges of assessing and integrating value of research into existing research prioritisation processes. We propose a framework that considers both the merits of research and its value for money to guide health research funding decisions. A practical framework is developed based on current processes followed by funding organizations for assessing investigator-initiated research proposals, and analytical methods for evaluating the expected value of research. We apply the analytical methods to estimate the expected return on investment of two real-world grant applications. The framework comprises four sequential steps: (1) initial screening of applications for eligibility and completeness; (2) merit assessment of eligible proposals; (3) estimating the expected value of research for the shortlisted proposals that pass the first two steps and ranking of proposals based on return on investment; and (4) selecting research proposals for funding. We demonstrate how the expected value for money can be efficiently estimated using certain information provided in funding applications. The proposed framework integrates value-for-money assessment into the existing research prioritisation processes. Considering value for money to inform research funding decisions is vital to achieve efficient utilisation of research budgets and maximise returns on research investments.

Temporal Associations of Nocturnal Sleep Duration with Physical Activity and Sedentary Time in Preschool Children

PURPOSE: To examine the associations between nocturnal sleep duration and physical activity (PA), sitting time (ST) and sit-to-stand transitions the following days among young children in Hong Kong. METHODS: 114 young children (71 boys) aged 3-6 years were recruited from 3 kindergartens. They were instructed to wear an activPALTM for 24-hour over 7 consecutive days to determine PA, ST, sleep duration, and sit-to-stand transitions. For each participant, 7 pairs of sleep → PA/ST/transitions were generated, representing unique rows of sleep duration the preceding evening (e.g., Monday) and PA/ST/transitions the following day (e.g., Tuesday). To account for total waking hours, the outcomes were presented in relative values (e.g., PA/waking hour). Linear mixed models were performed to determine the associations of nighttime sleep duration with PA, ST, and sit-to-stand transitions the following days, adjusting for age, sex, body weight status, parental educational attainment, and number of wear days. The repeated outcomes of sleep duration and activity patterns the following day nested within participants were treated as random effect. RESULTS: Seventy children provided valid data of PA, ST, and sleep. On average, the children accumulated 2.37 hours of PA a day (SD 0.45) and slept for 9.72 hours per night (SD 0.97). Sleep duration in the preceding night was positively associated with daytime PA (b = 0.007; 95% CI, 0.002 to 0.012; p = 0.011) and sit-to-stand transitions (b = 0.573; 95% CI, 0.336 to 0.810; p < 0.001), while was negatively associated with ST (b = −0.016; 95% CI, −0.028 to −0.004; p = 0.008) the following day. CONCLUSIONS: Longer nocturnal sleep duration was associated with more PA, frequent posture transitions, and less sitting time in the following day for preschool children. More work is needed to investigate how sleep parameters other than duration affect daytime activity behaviors. This study was supported by Health and Medical Research Fund Research Fellowship Scheme from Food and Health Bureau, the Government of the Hong Kong Special Administrative Region of the PRC (#02160127).

1724-P: Interaction between Genetic Variants and Hemoglobin A1c Level on the Risk of Sight-Threatening Diabetic Retinopathy in Patients with Type 2 Diabetes

Objectives: While hemoglobin A1c (HbA1c) is a well-established risk factor of diabetic retinopathy (DR), it only accounts for limited variation in DR risk. Recent genome-wide association studies (GWAS) have identified some susceptibility single nucleotide polymorphisms (SNPs) for DR. This study aimed to evaluate the possible SNPxHbA1c interaction for the risk of sight-threatening DR (STDR) among patients with type 2 diabetes (T2DM). Methods: Sixty-nine SNPs that showed top association signals (P&amp;lt;5x10-4; r2&amp;lt;0.9) in previous GWAS of DR were genotyped in 1106 STDR cases and 2069 non-DR controls. The associations between the SNPs and STDR were examined by multiple logistic regression analyses with adjustment for the traditional risk factors. HbA1c level was dichotomized according to a cut-off of 7% as suggested for an optimal glycemic control of diabetes. Interaction with HbA1c was examined by implementing an interaction term of SNP x dichotomized HbA1c in the logistic regression model. Results: COL5A1 rs59126004 (P=0.016;OR=0.82), IGSF21-KLHDC7A rs3007729 (P=0.022;OR=0.86), LOC728275-LOC728316 rs227455 (P=0.031;OR=0.88), C6orf170 rs17083119 (P=0.035;OR=0.82) and SLC25A32 rs3098241 (P=0.046;OR=0.88) showed significant associations with STDR. Among these, COL5A1 rs59126004 also showed a significant interaction with HbA1c for the risk of STDR (Pinteraction=0.002). Stratified analysis showed that the minor allele of this SNP was associated with a reduced risk of STDR only in the patients with HbA1c &amp;lt;7% (P=1.79x10-4; OR=0.58), but not in patients with HbA1c ≥7%. Conclusions: We have demonstrated a potential interaction between the COL5A1 rs59126004 and HbA1c for the susceptibility to STDR. Further studies to validate our findings are warranted. Disclosure K. Ng: None. C. Lee: None. Y. Woo: None. H. Fong: None. R. Wong: None. K.S. Lam: None. C.Y. Cheung: None. Funding Hong Kong Health and Medical Research Fund; Hong Kong Special Administrative Region

12-week of Tai Chi Training Reduces Visceral Fat in Centrally Obese Older Adults

Excess visceral fat is associated with metabolic abnormality and increased susceptibility to diabetes and cardiovascular diseases. It is known that visceral fat is reduced with strenuous physical exercise. However, older adults (age≥ 50) may prefer to manage their visceral fat with alternate exercise modalities. PURPOSE: To examined the effectiveness of Tai Chi, a popular mind-body exercise among older adults, in the reduction of visceral fat in centrally obese older adults. METHODS: This randomized controlled trial was conducted from March to August, 2018. In this three-arm, single-blinded randomized controlled trial, 102 Chinese adults aged ≥50 years with central obesity (male with waist circumference (WC) ≥ 90 cm / female ≥ 80 cm) were randomly assigned to Control (n= 33; received no intervention), Fitness (n= 35; received 12-week conventional exercise intervention) or Tai Chi groups (n= 34; received 12-week Tai Chi intervention). The primary outcome was the determination of visceral fat mass by dual-energy x-ray absorptiometry at 12-week post-randomization, while the secondary endpoints were the risk factors of metabolic syndrome (i.e. WC, blood pressure, fasting blood glucose, high-density lipoprotein-cholesterol and triglyceride). Data were analyzed by Generalized linear model with baseline as covariate. Pairwise comparison was done by closed test procedure. RESULTS: Visceral fat was reduced by 1.6% and 4.1% in the Tai Chi and Fitness groups respectively whereas the control group manifested a 3.8% increase. A main effect of intervention was observed in visceral fat (P<0.001). The pairwise comparison shown that both the Tai Chi (P=0.001) and Fitness (P=0.022) groups exhibited lower visceral fat content compared with their control counterpart. A main effect of intervention was observed in waist circumference (P<0.013) and triglyceride (P<0.046). Pairwise comparisons showed that the waist circumference (P=0.011) and triglyceride level (P=0.043) were reduced significantly in response to Tai Chi intervention. CONCLUSIONS: These data suggest that Tai Chi training reduces visceral fat, waist circumference and blood triglyceride. Supported by Health and Medical Research Fund 12131841

1071-P: Uptake of Continuous Subcutaneous Insulin Infusion Therapy by Adults with Type 1 Diabetes

Introduction: Continuous Subcutaneous Insulin Infusion (CSII) treatment for people with type 1 diabetes (T1D) is fully funded in Ireland via the Long-Term Illness scheme (LTI) and, similarly as in some other developed countries such as Germany, Sweden or the UK, does not involve any out-of-pocket expenses for the person with T1D. Uptake of CSII in adults has been reported to vary from 6.7% (Wales, 2018), through 15.6% (England, 2018) up to &amp;gt;50% in the United States (in 2012). However, available evidence on the uptake of CSII, particularly in adults, is scarce. The aim of this study was to estimate the uptake of CSII in Ireland. Methods: A retrospective cross-sectional study was conducted utilizing the Irish Health Service Executive Primary Care Reimbursement Service (HSE-PCRS) national pharmacy claims database data from the years 2011-2016. Individuals with T1D were identified by co-prescription of insulin and glucometer test strips without any prolonged course (&amp;gt;12 months) of oral hypoglycemic agents prior to commencing insulin. Individuals using CSII were identified by a prescription of infusion sets. Results: Of all adults with T1D (&amp;gt;18 years of age) meeting our criteria (n=19,551), only 5.84% (n=1141) were claiming infusion sets (95% CI 5.51% - 6.16%). The uptake of CSII varied geographically across Ireland from as low as 1.68% to 8.35%. Conclusions: In comparison to other countries where CSII therapy is fully covered, uptake of CSII was low in Irish adults. The determinants of the uptake (barriers to and facilitators in accessing this diabetes-related technology) are under more in-depth investigation. Disclosure K.A. Gajewska: None. S. Sreenan: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. Other Relationship; Self; Eli Lilly and Company. R. Biesma: None. K. Bennett: None. Funding Health Research Board (SPHeRE/2013/1)

A realist review of community engagement with health research.

Introduction: Community engagement is increasingly recognized as a critical aspect of global health. Recent years have seen an expansion of community engagement activities linked to health research, but debates and inconsistencies remain about the aims of different types of engagement, mechanisms underpinning their implementation and impact, and influential contextual factors. Greater commitment to and consistency around community engagement by health research programs, implementers and funders requires a more coherent evidence base. This realist review is designed to improve our understanding of how and why community engagement contributes to intended and unintended outcomes (including research and ethical outcomes) in different contexts. Given the breadth and diversity of the literature on community engagement in health research, the review will initially focus on malaria research in low- and middle-income countries (LMICs) and draw on wider global health literature where needed. Methods and analysis: Community engagement in practice is often a complex set of interventions. We will conduct a realist review - a theory driven approach to evidence synthesis - to provide explanations for how and why community engagement with health research produces the pattern of outcomes observed across different contexts of application. We will consolidate evidence from a range of documents, including qualitative, quantitative and mixed method studies. The review will follow several stages: devising an initial programme theory, searching evidence, selecting appropriate documents, extracting data, synthesizing and refining the programme theory, and reiteration of these steps as needed. Ethics and dissemination: A formal ethics review is not required for this literature review. Findings will be disseminated in a peer reviewed journal, through national and international conferences, and through a set of short briefings tailored for audiences with an interest in community engagement. Outputs and presentations will be informed by and feed into our network of community engagement experts. PROSPERO registration number: CRD42019125687.

Barriers to recruitment when conducting a commissioned randomised controlled trial of medication versus psychological therapy for generalised anxiety disorder: some lessons learned

BackgroundPoor recruitment is the most common reason for premature discontinuation of randomised controlled trials (RCTs). An RCT of medication versus psychological therapy for generalised anxiety disorder (GAD) was discontinued prematurely by the UK National Institute of Health Research funders because of recruitment failure. In order to inform future research studies, this article explores the reasons for poor recruitment and aspects which could have been improved.MethodsThe trial recruited participants via psychological well-being practitioners (PWPs) employed within local Improving Assess to Psychological Therapies (IAPT) services at four sites in England. For this study, we initially examined the recruitment data to identify reasons why potential participants were reluctant to participate in the trial. We then investigated reasons the PWPs did not identify more potential participants. Finally, we performed retrospective analyses of a computerised clinical records system used by the IAPT services in this study. These analyses aimed to establish the number of potential participants who had not been approached about the trial as well as whether there were additional factors affecting the numbers of people who might be eligible to take part. Data were obtained for all patients assessed during the period from the date on which recruitment commenced until the closure of the trial.ResultsThree quarters of those patients identified as possibly suitable for the trial declined to take part; the great majority did so because they did not want to be randomly assigned to receive medication. Our retrospective database analyses showed that only around 12% of potentially eligible patients for the trial were identified by the PWPs at the pilot sites. The results also indicated that only 5% of those noted at entry to the IAPT services to have a score of at least 10 on the GAD-7 questionnaire (a self-completed questionnaire with high sensitivity and specificity for GAD) would have been eligible for the trial.ConclusionsOur findings suggest that poor recruitment to RCTs can be significantly affected by participants’ treatment preferences and by factors influencing the recruiting clinicians. It may also be important not to include too many restrictions on inclusion criteria for pragmatic trials aiming for generalisable results.Trial registrationISCRTN14845583. Registration date: 5 February 2015.

'We're passengers sailing in the same ship, but we have our own berths to sleep in': Evaluating patient and public involvement within a regional research programme: An action research project informed by Normalisation Process Theory.

BackgroundPatient and public involvement (PPI) is a requirement for UK health and social care research funding. Evidence for how best to implement PPI in research programmes, such as National Institute for Health Research (NIHR) Collaborations for Applied Health Research and Care (CLAHRCs), remains limited. This paper reports findings from an action research (AR) project called IMPRESS, which aims to strengthen PPI within CLAHRC East of England (EoE). IMPRESS combines AR with Normalisation Process Theory (NPT) to explore PPI within diverse case study projects, identifying actions to implement, test and refine to further embed PPI.MethodsWe purposively selected CLAHRC EoE case study projects for in-depth analysis of PPI using NPT. Data were generated from project PPI documentation, semi-structured qualitative interviews with researchers and PPI contributors and focus groups. Transcripts and documents were subjected to abductive thematic analysis and triangulation within case. Systematic across case comparison of themes was undertaken with findings and implications refined through stakeholder consultation.ResultsWe interviewed 24 researchers and 13 PPI contributors and analysed 28 documents from 10 case studies. Three focus groups were held: two with researchers (n = 4 and n = 6) and one with PPI contributors (n = 5). Findings detail to what extent projects made sense of PPI, bought in to PPI, operationalised PPI and appraised it, thus identifying barriers and enablers to fully embedded PPI.ConclusionCombining NPT with AR allows us to assess the embeddedness of PPI within projects and programme, to inform specific local action and report broader conceptual lessons for PPI knowledge and practice informing the development of an action framework for embedding PPI in research programmes. To embed PPI within similar programmes teams, professionals, disciplines and institutions should be recognised as variably networked into existing PPI support. Further focus and research is needed on sharing PPI learning and supporting innovation in PPI.

A Novel Medical Blockchain Model for Drug Supply Chain Integrity Management in a Smart Hospital

At present, in pharmacology one of the most serious problems is counterfeit drugs. The Health Research Funding organization reported that in developing countries, nearly 10–30% of the drugs are fake. Counterfeiting is not the main issue itself, but, rather, the fact that, as compared to traditional drugs, these counterfeit drugs produce different side effects to human health. According to WHO, around 30% of the total medicine sold in Africa, Asia, and Latin America is counterfeit. This is the major worldwide problem, and the situation is worse in developing countries, where one out of every 10 medicines are either fake or do not follow drug regulations. The rise of Internet pharmacies has made it more difficult to standardize drug safety. It is difficult to detect counterfeits because these drugs pass through different complex distributed networks, thus forming opportunities for counterfeits to enter the authentic supply chain. The safety of the pharmaceutical supply chain has become a major concern for public health, which is a collective process. In this paper, we propose a novel drug supply chain management using Hyperledger Fabric based on blockchain technology to handle secure drug supply chain records. The proposed system solves this problem by conducting drug record transactions on a blockchain to create a smart healthcare ecosystem with a drug supply chain. A smart contract is launched to give time-limited access to electronic drug records and also patient electronic health records. We also carried out a number of experiments in order to demonstrate the usability and efficiency of the designed platform. Finally, we used Hyperledger Caliper as a benchmarking tool to conduct the performance of the designed system in terms of transactions per second, transaction latency, and resource utilization.

Strengthening and measuring research impact in global health: lessons from applying the FAIT framework

BackgroundTo date, efforts to measure impact have largely focused on health research in high-income countries, reflecting where the majority of health research funding is spent. Nevertheless, there is a growing body of health and medical research being undertaken in low- and middle-income countries (LMICs), supported by both development aid and established research funders. The Framework to Assess the Impact of Translational health research (FAIT) combines three approaches to measuring research impact (Payback, economic assessment and case study narrative). Its aim is to strengthen the focus on translation and impact measurement in health research. FAIT has been used by several Australian research initiatives; however, it has not been used in LMICs. Our aim was to apply FAIT in an LMIC context and evaluate its utility.MethodsWe retrospectively applied all three FAIT methods to two LMIC studies using available data, supplemented with group discussion and further economic analyses. Results were presented in a scorecard format.ResultsFAIT helped clarify pathways of impact for the projects and provided new knowledge on areas of impact in several domains, including capacity-building for research, policy development and economic impact. However, there were constraints, particularly associated with calculating the return on investment in the LMIC context. The case study narrative provided a layperson’s summary of the research that helped to explain outcomes and succinctly communicate lessons learnt.ConclusionUse of FAIT to assess the impact of LMIC research was both feasible and useful. We make recommendations related to prospective use, identification of metrics to support use of the Payback framework, and simplification of the economic assessment, which may facilitate further application in LMIC environments.