Translating evidence into practice: the role of health research funders

BACKGROUND: A growing body of work on knowledge translation (KT) reveals significant gaps between what is known to improve health, and what is done to improve health. The literature and practice also suggest that KT has the potential to narrow those gaps, leading to more evidence-informed healthcare. In response, Canadian health research funders and agencies have made KT a priority. This article describes how one funding agency determined its KT role and in the process developed a model that other agencies could use when considering KT programs. DISCUSSION: While ‘excellence’ is an important criterion by which to evaluate and fund health research, it alone does not ensure relevance to societal health priorities. There is increased demand for return on investments in health research in the form of societal and health system benefits. Canadian health research funding agencies are responding to these demands by emphasizing relevance as a funding criterion and supporting researchers and research users to use the evidence generated. Based on recommendations from the literature, an environmental scan, broad circulation of an iterative discussion paper, and an expert working group process, our agency developed a plan to maximize our role in KT. Key to the process was development of a model comprising five key functional areas that together create the conditions for effective KT: advancing KT science; building KT capacity; managing KT projects; funding KT activities; and advocating for KT. Observations made during the planning process of relevance to the KT enterprise are: the importance of delineating KT and communications, and information and knowledge; determining responsibility for KT; supporting implementation and evaluation; and promoting the message that both research and KT take time to realize results. SUMMARY: Challenges exist in fulfilling expectations that research evidence results in beneficial impacts for society. However, health agencies are well placed to help maximize the use of evidence in health practice and policy. We propose five key functional areas of KT for health agencies, and encourage partnerships and discussion to advance the field

RNA reference materials with defined viral RNA loads of SARS-CoV-2—A useful tool towards a better PCR assay harmonization

SARS-CoV-2, the cause of COVID-19, requires reliable diagnostic methods to track the circulation of this virus. Following the development of RT-qPCR methods to meet this diagnostic need in January 2020, it became clear from interlaboratory studies that the reported Ct values obtained for the different laboratories showed high variability. Despite this the Ct values were explored as a quantitative cut off to aid clinical decisions based on viral load. Consequently, there was a need to introduce standards to support estimation of SARS-CoV-2 viral load in diagnostic specimens. In a collaborative study, INSTAND established two reference materials (RMs) containing heat-inactivated SARS-CoV-2 with SARS-CoV-2 RNA loads of ~107 copies/mL (RM 1) and ~106 copies/mL (RM 2), respectively. Quantification was performed by RT-qPCR using synthetic SARS-CoV-2 RNA standards and digital PCR. Between November 2020 and February 2021, German laboratories were invited to use the two RMs to anchor their Ct values measured in routine diagnostic specimens, with the Ct values of the two RMs. A total of 305 laboratories in Germany were supplied with RM 1 and RM 2. The laboratories were requested to report their measured Ct values together with details on the PCR method they used to INSTAND. This resultant 1,109 data sets were differentiated by test system and targeted gene region. Our findings demonstrate that an indispensable prerequisite for linking Ct values to SARS-CoV-2 viral loads is that they are treated as being unique to an individual laboratory. For this reason, clinical guidance based on viral loads should not cite Ct values. The RMs described were a suitable tool to determine the specific laboratory Ct for a given viral load. Furthermore, as Ct values can also vary between runs when using the same instrument, such RMs could be used as run controls to ensure reproducibility of the quantitative measurements.Peer Reviewe

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (similar to 0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10(-9)]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the beta-amyloid cascade.Peer reviewe

Excluding Hollow Viscus Injury for Abdominal Seat Belt Sign Using Computed Tomography

Importance: Abdominal seat belt sign (SBS) has historically entailed admission and observation because of the diagnostic limitations of computed tomography (CT) imaging and high rates of hollow viscus injury (HVI). Recent single-institution, observational studies have questioned the utility of this practice. Objective: To evaluate whether a negative CT scan can safely predict the absence of HVI in the setting of an abdominal SBS. Design, Setting, and Participants: This prospective, observational cohort study was conducted in 9 level I trauma centers between August 2020 and October 2021 and included adult trauma patients with abdominal SBS. Exposures: Inclusion in the study required abdominal CT as part of the initial trauma evaluation and before any surgical intervention, if performed. Results of CT scans were considered positive if they revealed any of the following: abdominal wall soft tissue contusion, free fluid, bowel wall thickening, mesenteric stranding, mesenteric hematoma, bowel dilation, pneumatosis, or pneumoperitoneum. Main Outcomes and Measures: Presence of HVI diagnosed at the time of operative intervention. Results: A total of 754 patients with abdominal SBS had an HVI prevalence of 9.2% (n = 69), with only 1 patient with HVI (0.1%) having a negative CT (ie, none of the 8 a priori CT findings). On bivariate analysis comparing patients with and without HVI, there were significant associations between each of the individual CT scan findings and the presence of HVI. The strongest association was found with the presence of free fluid, with a more than 40-fold increase in the likelihood of HVI (odds ratio [OR], 42.68; 95% CI, 20.48-88.94; P \u3c .001). The presence of free fluid also served as the most effective binary classifier for presence of HVI (area under the receiver operator characteristic curve [AUC], 0.87; 95% CI, 0.83-0.91). There was also an association between a negative CT scan and the absence of HVI (OR, 41.09; 95% CI, 9.01-727.69; P \u3c .001; AUC, 0.68; 95% CI, 0.66-0.70). Conclusions and Relevance: The prevalence of HVI among patients with an abdominal SBS and negative findings on CT is extremely low, if not zero. The practice of admitting and observing all patients with abdominal SBS should be reconsidered when a high-quality CT scan is negative, which may lead to significant resource and cost savings

Development and Validation of a Novel Hollow Viscus Injury Prediction Score for Abdominal Seatbelt Sign: A Pacific Coast Surgical Association Multicenter Study

BACKGROUND: High-quality computed tomography (CT) can exclude HVI in patients with an A-SBS but performs poorly at identifying HVI. Delay in diagnosis of HVI has significant consequences necessitating timely identification. STUDY DESIGN: This multicenter, prospective observational study conducted at nine trauma centers between August 2020-October 2021 included adult trauma patients with A-SBS who underwent abdominal CT prior to surgery. HVI was determined intra-operatively and physiologic, examination, laboratory, and imaging findings were collected. Lasso and probit regression selected predictor variables and coefficients were used to assign integer points for the HVI Score. Validation was performed by comparing area under receiver operating curves (AUROC). RESULTS: Analysis included 473 in the development set and 203 in the validation set. The HVI Score includes initial systolic blood pressure \u3c 110mmHg, abdominal tenderness, guarding, and select abdominal CT findings. The derivation set has an AUROC of 0.96 and the validation set has an AUROC of 0.91. The HVI Score ranges from 0-17 with score 0-5 having a HVI risk of 0.03-5.36%, 6-9 having a risk of 10.65-44.1%, and 10-17 having a risk of 58.59-99.72%. CONCLUSIONS: This multicenter study developed and validated a novel HVI Score incorporating readily available physiologic, examination, and CT findings to risk stratify patients with an abdominal SBS. The HVI Score can be used to guide decisions regarding management of a patient with an abdominal SBS and suspected HVI

Results of German external quality assessment schemes for SARS-CoV-2 antigen detection

Abstract The COVID-19 pandemic illustrated the important role of diagnostic tests, including lateral flow tests (LFTs), in identifying patients and their contacts to slow the spread of infections. INSTAND performed external quality assessments (EQA) for SARS-CoV-2 antigen detection with lyophilized and chemically inactivated cell culture supernatant of SARS-CoV-2 infected Vero cells. A pre-study demonstrated the suitability of the material. Participants reported qualitative and/or quantitative antigen results using either LFTs or automated immunoassays for five EQA samples per survey. 711 data sets were reported for LFT detection in three surveys in 2021. This evaluation focused on the analytical sensitivity of different LFTs and automated immunoassays. The inter-laboratory results showed at least 94% correct results for non-variant of concern (VOC) SARS-CoV-2 antigen detection for viral loads of ≥ 4.75 × 106 copies/mL and SARS-CoV-2 negative samples. Up to 85% had success for a non-VOC viral load of ~ 1.60 × 106 copies/mL. A viral load of ~ 1.42 × 107 copies/mL of the Delta VOC was reported positive in > 96% of results. A high specificity was found with almost 100% negative SARS-CoV-2 antigen results for HCoV 229E and HCoV NL63 positive samples. Quantitative results correlated with increasing SARS-CoV-2 viral load but showed a broad scatter. This study shows promising SARS-CoV-2 antigen test performance of the participating laboratories, but further investigations with the now predominant Omicron VOC are needed

COVID-19 in trauma: a propensity-matched analysis of COVID and non-COVID trauma patients.

PurposeThere is mounting evidence that surgical patients with COVID-19 have higher morbidity and mortality than patients without COVID-19. Infection is prevalent amongst the trauma population, but any effect of COVID-19 on trauma patients is unknown. We aimed to evaluate the effect of COVID-19 on a trauma population, hypothesizing increased mortality and pulmonary complications for COVID-19-positive (COVID) trauma patients compared to propensity-matched COVID-19-negative (non-COVID) patients.MethodsA retrospective analysis of trauma patients presenting to 11 Level-I and II trauma centers in California between 1/1/2019-6/30/2019 and 1/1/2020-6/30/2020 was performed. A 1:2 propensity score model was used to match COVID to non-COVID trauma patients using age, blunt/penetrating mechanism, injury severity score, Glasgow Coma Scale score, systolic blood pressure, respiratory rate, and heart rate. Outcomes were compared between the two groups.ResultsA total of 20,448 trauma patients were identified during the study period. 53 COVID trauma patients were matched with 106 non-COVID trauma patients. COVID patients had higher rates of mortality (9.4% vs 1.9%, p = 0.029) and pneumonia (7.5% vs. 0.0%, p = 0.011), as well as a longer mean length of stay (LOS) (7.47 vs 3.28&nbsp;days, p &lt; 0.001) and intensive care unit LOS (1.40 vs 0.80&nbsp;days, p = 0.008), compared to non-COVID patients.ConclusionThis multicenter retrospective study found increased rates of mortality and pneumonia, as well as a longer LOS, for COVID trauma patients compared to a propensity-matched cohort of non-COVID patients. Further studies are warranted to validate these findings and to elucidate the underlying pathways responsible for higher mortality in COVID trauma patients