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C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway (AP) of complement and treatment options remain inadequate. Factor H (FH) is a potent regulator of the AP. An in-depth analysis of FH-related protein dimerised minimal (mini)-FH constructs has recently been published. This analysis showed that addition of a dimerisation module to mini-FH not only increased serum half-life but also improved complement regulatory function, thus providing a potential treatment option for C3G. Herein, we describe the production of a murine version of homodimeric mini-FH [mHDM-FH (mFH1–5^18–20^R1–2)], developed to reduce the risk of anti-drug antibody formation during long-term experiments in murine models of C3G and other complement-driven pathologies. Our analysis of mHDM-FH indicates that it binds with higher affinity and avidity to WT mC3b when compared to mouse (m)FH (mHDM-FH KD=505 nM; mFH KD=1370 nM) analogous to what we observed with the respective human proteins. The improved binding avidity resulted in enhanced complement regulatory function in haemolytic assays. Extended interval dosing studies in CFH-/- mice (5mg/kg every 72hrs) were partially effective and bio-distribution analysis in CFH-/- mice, through in vivo imaging technologies, demonstrates that mHDM-FH is preferentially deposited and remains fixed in the kidneys (and liver) for up to 4 days. Extended dosing using an AAV- human HDM-FH (hHDM-FH) construct achieved complete normalisation of C3 levels in CFH-/- mice for 3 months and was associated with a significant reduction in glomerular C3 staining. Our data demonstrate the ability of gene therapy delivery of mini-FH constructs to enhance complement regulation in vivo and support the application of this approach as a novel treatment strategy in diseases such as C3G.

Background Congenital heart disease practices and outcomes vary significantly across centers, including postoperative chest tube (CT) management, which may impact postoperative length of stay (LOS). We used collaborative learning methods to determine whether centers could adapt and safely implement best practices for CT management, resulting in reduced postoperative CT duration and LOS. Methods and Results Nine pediatric heart centers partnered together through 2 learning networks. Patients undergoing 1 of 9 benchmark congenital heart operations were included. Baseline data were collected from June 2017 to June 2018, and intervention‐phase data were collected from July 2018 to December 2019. Collaborative learning methods included review of best practices from a model center, regular data feedback, and quality improvement coaching. Center teams adapted CT removal practices (eg, timing, volume criteria) from the model center to their local resources, practices, and setting. Postoperative CT duration in hours and LOS in days were analyzed using statistical process control methodology. Overall, 2309 patients were included. Patient characteristics did not differ between the study and intervention phases. Statistical process control analysis showed an aggregate 15.6% decrease in geometric mean CT duration (72.6 hours at baseline to 61.3 hours during intervention) and a 9.8% reduction in geometric mean LOS (9.2 days at baseline to 8.3 days during intervention). Adverse events did not increase when comparing the baseline and intervention phases: CT replacement (1.8% versus 2.0%, P =0.56) and readmission for pleural effusion (0.4% versus 0.5%, P =0.29). Conclusions We successfully lowered postoperative CT duration and observed an associated reduction in LOS across 9 centers using collaborative learning methodology.

Summary There has been increasing use of organs from extended criteria or donation after circulatory death donors to meet the demands of the transplant waiting list. Over the past decade, there has been considerable progress in technologies to preserve organs prior to transplantation to improve the function of these marginal organs. This has led to the development of normothermic machine perfusion, whereby an organ is perfused with warmed, oxygenated blood and nutrients to resume normal physiological function in an isolated ex‐vivo platform. With this advance in preservation comes significant opportunities to recondition, repair and regenerate organs prior to transplantation using cellular therapies. This review aims to discuss the possibilities of machine perfusion technology; highlighting the potential for organ‐directed reconditioning and the future avenues for investigation in this field.

Background Ohio has the fifth highest rate of prescription opioid overdose deaths in the United States. One strategy implemented to address this concern is a state-wide opioid prescribing guideline in the emergency department (ED). Objective Our aim was to explore emergency physicians’ perceptions on barriers and strategies for the Ohio ED opioid prescribing guideline. Methods Semi-structured interviews with emergency physicians in Ohio were conducted from October to December 2016. Emergency physicians were recruited through the American College of Emergency Physicians Ohio State Chapter. The interview guide explored issues related to the implementation of the guidelines. Interview data were transcribed and thematically analyzed and coded using a scheme of inductively determined labels. Results In total, we conducted 20 interviews. Of these, 11 were also the ED medical director at their institution. Main themes we identified were: 1) increased organizational responsibility, 2) improved prescription drug monitoring program (PDMP) integration, 3) concerns regarding patient satisfaction scores, and 4) increased patient involvement. In addition, some physicians wanted the guidelines to contain more clinical information and be worded more strongly against opioid prescribing. Emergency physicians felt patient satisfaction scores were perceived to negatively impact opioid prescribing guidelines, as they may encourage physicians to prescribe opioids. Furthermore, some participants reported that this is compounded if the emergency physicians’ income was linked to their patient satisfaction score. Conclusions Emergency physicians interviewed generally supported the state-wide opioid prescribing guideline but felt hospitals needed to take additional organizational responsibility for addressing inappropriate opioid prescribing.