Male pathology regardless of behaviour drives transmission in an avian host-pathogen system.

Host sex is an important source of heterogeneity in the severity of epidemics. Pinpointing the mechanisms causing this heterogeneity can be difficult because differences in behaviour among sexes (e.g. greater territorial aggression in males) can bias exposure risk, obfuscating the role of immune function, which can lead to differences in pathology, in driving differential susceptibility between sexes. Thus, sex-biased transmission driven by differences in immune function independent of behaviour is poorly understood, especially in non-mammalian systems. Here we examine the previously unexplored potential for male-biased pathology to affect transmission using an avian host-pathogen system. We employ a sex-dependent multistate transmission model parameterized with isolated, individual-based experimental exposures of domestic canaries and experimental transmission data of house finches. The experiment revealed that male birds have shorter incubation periods, longer recovery periods, higher pathogen burdens and greater disease pathology than females. Our model revealed that male-biased pathology led to epidemic size rapidly increasing with the proportion of male birds, with a nearly 10-fold increase in total epidemic size from an all-female to an all-male simulation. Our results demonstrate that female-biased resistance, independent of male behaviour, can drive sex-dependent transmission in wildlife, indicating that sex-based differences in immune function, not just differences in exposure risk, can shape epidemic dynamics.

Team Communication and Expectations Following Pediatric Cardiac Surgery: A Multi-Disciplinary Survey.

Patients and families desire an accurate understanding of the expected recovery following congenital cardiac surgery. Variation in knowledge and expectations within the care team may be under-recognized and impact communication and care delivery. Our objective was to assess knowledge of common postoperative milestones and perceived efficacy of communication with patients and families and within the care team. An 18-question survey measuring knowledge of expected milestones for recovery after four index operations and team communication in the postoperative period was distributed electronically to multidisciplinary care team members at 16 academic pediatric heart centers. Answers were compared to local median data for each respondent's heart center to assess accuracy and stratified by heart center role and years of experience. We obtained 874 responses with broad representation of disciplines. More than half of all respondent predictions (55.3%) did not match their local median data. Percent matching did not vary by care team role but improved with increasing experience (35.8% < 2 years vs. 46.4% > 10 years, p = 0.2133). Of all respondents, 62.7% expressed confidence discussing the anticipated postoperative course, 78.6% denoted confidence discussing postoperative complications, and 55.3% conveyed that not all members of their care team share a common expectation for typical postoperative recovery. Most respondents (94.6%) stated that increased knowledge of local data would positively impact communication. Confidence in communication exceeded accuracy in predicting the timing of postoperative milestones. Important variation in knowledge and expectations for postoperative recovery in pediatric cardiac surgery exists and may impact communication and clinical effectiveness.

MicroRNA antagonist therapy during normothermic machine perfusion of donor kidneys.

Normothermic machine perfusion (NMP) is a novel clinical approach to overcome the limitations of traditional hypothermic organ preservation. NMP can be used to assess and recondition organs prior to transplant and is the subject of clinical trials in solid organ transplantation. In addition, NMP provides an opportunity to deliver therapeutic agents directly to the organ, thus avoiding many limitations associated with systemic treatment of the recipient. We report the delivery of oligonucleotide-based therapy to human kidneys during NMP, in this case to target microRNA function (antagomir). An antagomir targeting mir-24-3p localized to the endothelium and proximal tubular epithelium. Endosomal uptake during NMP conditions facilitated antagomir co-localization with proteins involved in the RNA-induced silencing complex (RISC) and demonstrated engagement of the miRNA target. This pattern of uptake was not seen during cold perfusion. Targeting mir-24-3p action increased expression of genes controlled by this microRNA, including heme oxygenase-1 and sphingosine-1-phosphate receptor 1. The expression of genes not under the control of mir-24-3p was unchanged, indicating specificity of the antagomir effect. In summary, this is the first report of ex vivo gymnotic delivery of oligonucleotide to the human kidney and demonstrates that NMP provides the platform to bind and block detrimental microRNAs in donor kidneys prior to transplantation.

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice.

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.

Successful Reduction of Postoperative Chest Tube Duration and Length of Stay After Congenital Heart Surgery: A Multicenter Collaborative Improvement Project.

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.

Cell therapy during machine perfusion.

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.

Emergency Physicians' Perception of Barriers and Facilitators for Adopting an Opioid Prescribing Guideline in Ohio: A Qualitative Interview Study.

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.

Statewide cross-sectional survey of emergency departments' adoption and implementation of the Ohio opioid prescribing guidelines and opioid prescribing practices.

STUDY OBJECTIVE: To evaluate the implementation of the Ohio Emergency and Acute Care Facility Opioids and Other Controlled Substances Prescribing Guidelines and their perceived impact on local policies and practice. METHODS: The study design was a cross-sectional survey of emergency department (ED) medical directors, or appropriate person identified by the hospital, perception of the impact of the Ohio ED Opioid Prescribing Guidelines on their departments practice. All hospitals with an ED in Ohio were contacted throughout October and November 2016. Distribution followed Dillman's Tailored Design Method, augmented with telephone recruitment. Hospital chief executive officers were contacted when necessary to encourage ED participation. Descriptive statistics were used to assess the impact of opioid prescribing policies on prescribing practices. RESULTS: A 92% response rate was obtained (150/163 EDs). In total, 112 (75%) of the respondents stated that their ED has an opioid prescribing policy, is adopting one or is implementing prescribing guidelines without a specific policy. Of these 112 EDs, 81 (72%) based their policy on the Ohio ED Opioid Prescribing Guidelines. The majority of respondents strongly agreed/agreed that the prescribing guidelines have increased the use of the prescription drug monitoring programme (86%) and have reduced inappropriate opioid prescribing (71%). CONCLUSION: This study showed that the Ohio ED Opioid Prescribing Guidelines have been widely disseminated and that the majority of EDs in Ohio are using them to develop local policies. The majority of respondents believed that the Ohio opioid prescribing guidelines reduced inappropriate opioid prescribing. However, prescribing practices still varied greatly between EDs.

Qualitative Analysis of Student Pharmacists' Reflections of Harvard's Race Implicit Association Test.

BACKGROUND AND PURPOSE: Identify and analyze pharmacy students' perceptions about their own implicit racial biases. EDUCATIONAL ACTIVITY AND SETTING: First year pharmacy students (n = 97) enrolled in a Pharmacy Practice course completed a test, Harvard Race Implicit Association Test (IAT), for homework to uncover their unconscious black-white racial bias. All students then wrote at least one paragraph reflecting on if they agreed or disagreed with their results and why. At the beginning of class, students were given a brief survey to capture their IAT results and demographic information. Retrospectively and following Institutional Review Board approval, pharmacy students' reflections were subjected to thematic analysis with the assistance of NVivo 10 and descriptive analyses were completed of their demographic info. FINDINGS: Out of the 97 students enrolled in this course, all completed the self-reflection. But only 90 completed the survey. From those that completed the survey, 54% (N = 49) self-identified as women. The average age was 22.6 years old. Most of the students (77%) identified themselves as White Non-Hispanic. Six percent (N = 5) identified as Black. Most students (66%) reported that their results from the Race IAT indicated some level of preference for European Americans; 13% of the students reported some level of preference for African-Americans. All students' reflections were categorized by their agreement or lack of agreement with their implicit association test results. Those that agreed with their results cited family, friends, and community contributing to their implicit biases. Students who did not agree with their results were subcategorized as denying their results, believing that their implicit association did not affect their behavior, or believing that the Race IAT was invalid. DISCUSSION/SUMMARY: Many pharmacy students were found to be unaware of their implicit biases and some do not believe that these biases will negatively affect the treatment of others. Pharmacy curricula should be developed to provide adequate self-awareness training and space in the curriculum so students can challenge these unconscious beliefs.