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Coronary revascularization using imaging guidance is rapidly becoming the standard of care. Intravascular optical coherence tomography uses near-infrared light to obtain high resolution intravascular images. Standard optical coherence tomography imaging technique employs iodinated contrast dye to achieve the required blood clearance during acquisition. We sought to systematically evaluate the technical performance of saline as an alternative to iodinated contrast for intravascular optical coherence tomography assessment. We performed bench top optical coherence tomography analysis on nylon tubing with sequential contrast/saline dilutions to empirically derive adjustment coefficients. We then applied these coefficients in vivo in an established rabbit abdominal stenting model with both saline and contrast optical coherence tomography imaging. In this model, we assessed the impact of saline on both quantitative and qualitative vessel assessment. Nylon tubing assessment demonstrated a linear relationship between saline and contrast for both area and diameter. We then derived adjustment coefficients, allowing for accurate calculation of area and diameter when converting saline into both contrast and reference dimensions. In vivo studies confirmed reduced area with saline versus contrast [7.43 (5.67-8.36) mm.sup.2 versus 8.2 (6.34-9.39) mm.sup.2, p = 0.001] and diameter [3.08 mm versus 3.23 mm, p = 0.001]. Following correction, a strong relationship was achieved in vivo between saline and contrast in both area and diameter without compromising image quality, artefact, or strut assessment. Saline generates reduced dimensions compared to contrast during intravascular optical coherence tomography imaging. The relationship across physiologic coronary diameters is linear and can be corrected with high fidelity. Saline does not adversely impact image quality, artefact, or strut assessment.

Transcatheter aortic valve replacement (TAVR) reduces left ventricular (LV) afterload and improves prognosis in aortic stenosis (AS) patients. However, LV afterload consists of both valvular and arterial loads, and the benefits of TAVR may be attenuated if the arterial load dominates. We proposed a new hemodynamic index, the Relative Valve Load (RVL), a ratio of mean gradient (MG) and valvuloarterial impedance (Zva), to describe the relative contribution of the valvular load to the global LV load, and examined whether RVL predicted patient outcome following TAVR. A total of 258 patients with symptomatic severe AS (indexed aortic valve area (AVA)<0.6cm2/m2, AR≤2+) underwent successful TAVR at the University of Ottawa Heart Institute and had clinical follow-up to 1-year post-TAVR. Pre-TAVR MG, AVA, percent stroke work loss (%SWL), Zva and RVL were measured by echocardiography. The primary endpoint was all cause mortality at 1-year post TAVR. There were 53 deaths (20.5%) at 1-year. RVL≤7.95ml/m2 had a sensitivity of 60.4% and specificity of 75.1% for identifying all cause mortality at 1-year post-TAVR and provided better specificity than MG<40 mmHg, AVA>0.75cm2, %SWL≤25% and Zva>5mmHg/ml/m2 despite equivalent or better sensitivity. In multivariable Cox analysis, RVL≤7.95ml/m2 was an independent predictor of all cause mortality (HR 3.2, CI 1.8-5.9; p<0.0001). RVL≤7.95ml/m2 was predictive of all cause mortality in both low flow and normal flow severe AS. RVL is a strong predictor of all-cause mortality in severe AS patients undergoing TAVR. A pre-procedural RVL≤7.95ml/m2 identifies AS patients at increased risk of death despite TAVR and may assist with decision making on the benefits of TAVR.

Introduction/Background Although rare, in-hospital paediatric mortality occurs at a rate of 12.66 per 1000 admissions. Delayed recognition of clinical deterioration is a modifiable factor in such adverse events. In paediatric patients, subtle changes in vital signs often precede acute deterioration and provide an opportunity for early intervention and prevention of further deterioration. Based on this rationale, rapid response systems (RRS), which include a critical care response team (CCRT) and a Paediatric Early Warning Score (PEWS), have been established to facilitate the detection of clinical deterioration and mobilize resources for timely treatment. There is evidence that RRS can significantly decrease inpatient clinical deterioration events and PICU utilization. Objectives At our institution, serious patient safety events identified system failures in recognition, communication, and escalation of care in response to clinical deterioration. The root cause analysis led to a quality improvement and patient safety initiative to implement an RRS at our tertiary paediatric care centre. Design/Methods Process implementation of this pilot project required consultations with key stakeholders and designation of unit champions to mobilize resources and promote buy-in. Based on other successful implementation strategies, we adopted the Modified Brighton PEWS, defined a response algorithm, created bedside tools, constructed an interdisciplinary CCRT, and organized simulation activities to implement the new process. We used the Plan-Do-Study-Act method to carry out change based on weekly feedback from frontline workers. To assess the feasibility and acceptability of this initiative, all CCRT activations during the pilot phase were reviewed and a survey was distributed pre- and post-implementation. The number of code blues and mortality data will also be measured. Results The pilot period spanned June to September 2022 on our medical inpatient unit. Average response time to CCRT activation was 12 minutes (IQR 7-13.5), a median of three therapeutic interventions were required per activation, and 33% of activations resulted in PICU admissions. Among the 27 post–implementation survey respondents, 87% identified CCRT as a useful addition to optimize care and address patient safety concerns. Qualitatively, it has created a shared safety culture and empowered junior members of healthcare teams to escalate care. Conclusion This quality improvement initiative pilot study has demonstrated feasibility and acceptability of RRS implementation with a positive impact on patient safety culture and earlier detection and intervention for deteriorating patients. Further prospective comparative clinical benefits and cost-benefit analyses are needed to support hospital-wide implementation.

Abstract Objective To examine the effect on length of stay (LOS) of a preprinted order (PPO) set for children admitted to hospital with a diagnosis of bronchiolitis, as well as on quality improvement measures, medical errors, and resource utilization. Patients and methods A retrospective chart review was performed of children admitted to the inpatient units at the Children’s Hospital of Eastern Ontario (CHEO) with a discharge diagnosis of bronchiolitis. Primary and secondary outcomes were compared between the pre-PPO (December 1, 2014 to June 30, 2015) and post-PPO (December 1, 2015 to June 30, 2016) periods. The primary outcome was LOS in days. Secondary outcomes included the proportion of quality improvement measures reached, the number of medical errors, and resource utilization. Results A total of 245 patients were included; 122 patients from the pre-PPO period (December 1, 2014 to June 30, 2015) and 123 patients from the post-PPO period (December 1, 2015 to June 30, 2016). Mean LOS was 3.1 days (2.7 to 3.5 days) and 2.8 days (2.4 to 3.2 days) in the pre- and post-PPO periods, respectively (multivariate analysis, P-value = 0.13). There were significant differences between the pre- and post-PPO periods in a number of quality improvement measures, although not in the number of medical errors. Significant reductions in oxygen, corticosteroid, antibiotic, and bronchodilator use were noted post-PPO implementation. Conclusion Although our bronchiolitis PPO did not significantly shorten LOS, it led to important improvements in quality improvement measures and in resource utilization efficiency.

Acute kidney injury occurs in up to a quarter of patients following transcatheter aortic valve replacement (TAVR) and has been associated with increased short and long-term mortality rates. A variety of patient characteristics predictive of post-TAVR acute kidney injury (AKI) have been identified, however discrepancies among studies exist almost uniformly. We investigated the hypothesis that the change in glomerular filtration rate (ΔGFR) in response to contrast administered during pre-TAVR coronary angiography is predictive of ΔGFR post-TAVR. The study comprised 195 patients who underwent TAVR at a single center between August 2008 and June 2015 and were prospectively included in the CAPITAL TAVR registry. Multiple linear regression analysis was conducted to estimate the effect of independent variables on the change in renal function post-TAVR. There was no relationship identified between the ΔGFR post-angiogram and the ΔGFR post-TAVR (r=0.043, P=0.582). Multiple linear regression analysis revealed that a significant amount of the change in renal function post-TAVR can be explained by the patient's baseline creatinine (beta coefficient, -0.310, P.

Both genetic drift and natural selection cause the frequencies of alleles in a population to vary over time. Discriminating between these two evolutionary forces, based on a time series of samples from a population, remains an outstanding problem with increasing relevance to modern data sets. Even in the idealized situation when the sampled locus is independent of all other loci, this problem is difficult to solve, especially when the size of the population from which the samples are drawn is unknown. A standard χ2-based likelihood-ratio test was previously proposed to address this problem. Here we show that the χ2-test of selection substantially underestimates the probability of type I error, leading to more false positives than indicated by its P-value, especially at stringent P-values. We introduce two methods to correct this bias. The empirical likelihood-ratio test (ELRT) rejects neutrality when the likelihood-ratio statistic falls in the tail of the empirical distribution obtained under the most likely neutral population size. The frequency increment test (FIT) rejects neutrality if the distribution of normalized allele-frequency increments exhibits a mean that deviates significantly from zero. We characterize the statistical power of these two tests for selection, and we apply them to three experimental data sets. We demonstrate that both ELRT and FIT have power to detect selection in practical parameter regimes, such as those encountered in microbial evolution experiments. Our analysis applies to a single diallelic locus, assumed independent of all other loci, which is most relevant to full-genome selection scans in sexual organisms, and also to evolution experiments in asexual organisms as long as clonal interference is weak. Different techniques will be required to detect selection in time series of cosegregating linked loci.

BackgroundHematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies. In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy.MethodsHuman primary T cells and dendritic cells (DCs) were investigated with CompK treatment under conditions relevant to tumor microenvironment (TME). Syngeneic tumor models were used to assess the in vivo pharmacology of CompK followed by human tumor interrogation ex vivo.ResultsCompK treatment demonstrated markedly enhanced human T-cell immune responses under immunosuppressive conditions relevant to the TME and an increased avidity of the T-cell receptor (TCR) to recognize viral and tumor-associated antigens (TAAs) in significant synergy with anti-PD1. Animal model studies, including 1956 sarcoma and MC38 syngeneic models, revealed improved immune responses and superb antitumor efficacy in combination of CompK with anti-PD-1. An elevated immune response induced by CompK was observed with fresh tumor samples from multiple patients with colorectal carcinoma, suggesting a mechanistic translation from mouse model to human disease.ConclusionCompK treatment significantly improved human T-cell functions, with enhanced TCR avidity to recognize TAAs and tumor cytolytic activity by CD8+ T cells. Additional benefits include DC maturation and priming facilitation in tumor draining lymph node. CompK represents a novel pharmacological agent to address cancer treatment resistance.

In daily life, perceivers often need to predict and interpret the behavior of group agents, such as corporations and governments. Although research has investigated how perceivers reason about individual members of particular groups, less is known about how perceivers reason about group agents themselves. The present studies investigate how perceivers understand group agents by investigating the extent to which understanding the 'mind' of the group as a whole shares important properties and processes with understanding the minds of individuals. Experiment 1 demonstrates that perceivers are sometimes willing to attribute a mental state to a group as a whole even when they are not willing to attribute that mental state to any of the individual members of the group, suggesting that perceivers can reason about the beliefs and desires of group agents over and above those of their individual members. Experiment 2 demonstrates that the degree of activation in brain regions associated with attributing mental states to individuals--i.e., brain regions associated with mentalizing or theory-of-mind, including the medial prefrontal cortex (MPFC), temporo-parietal junction (TPJ), and precuneus--does not distinguish individual from group targets, either when reading statements about those targets' mental states (directed) or when attributing mental states implicitly in order to predict their behavior (spontaneous). Together, these results help to illuminate the processes that support understanding group agents themselves.

Background The Covid-19 pandemic has been characterized by the emergence of novel SARS-CoV-2 variants, each with distinct properties influencing transmission dynamics, immune escape, and virulence, which, in turn, influence their impact on local populations. Swift analysis of the properties of newly emerged variants is essential in the initial days and weeks to enhance readiness and facilitate the scaling of clinical and public health system responses. Methods This paper introduces a two-variant metapopulation compartmental model of disease transmission to simulate the dynamics of disease transmission during a period of transition to a newly dominant strain. Leveraging novel S-gene dropout analysis data and genomic sequencing data, combined with confirmed Covid-19 case data, we estimate the epidemiological characteristics of the Omicron variant, which replaced the Delta variant in late 2021 in Philadelphia, PA. We utilized a grid-search method to identify plausible combinations of model parameters, followed by an ensemble adjustment Kalman filter for parameter inference. Results The model successfully estimated key epidemiological parameters; we estimated the ascertainment rate of 0.22 (95% credible interval 0.15–0.29) and transmission rate of 5.0 (95% CI 2.4–6.6) for the Omicron variant. Conclusions The study demonstrates the potential for this model-inference framework to provide real-time insights during the emergence of novel variants, aiding in timely public health responses.