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Background: The relationship between minute ventilation and the rate of CO2 elimination (VE/VCO2 slope) is associated with mortality in patients with congestive heart failure (CHF). The VE/VCO2 slope > or =34 denotes a poor prognosis and has been proposed to reflect abnormalities in pulmonary perfusion. Aims: To study whether increased VE/VCO2 slope is associated with elevated right ventricular (RV) oxidative metabolism relative to the left ventricle (LV). Methods: 21 patients with stable NYHA II-III CHF underwent symptom limited cardiopulmonary exercise testing. Dynamic [(11)C]acetate positron emission tomography (PET) was used to measure oxidative metabolism (k(mono)) of the LV and RV. Corrected RV oxidative metabolism (RVOx) was calculated as RV/LV k(mono) ratio. Results: Peak VO2 was 16.2+/-4.1 ml/min/kg and the VE/VCO2 slope was 33.4+/-6.1. LV and RV k(mono) were 0.046+/-0.009 and 0.037+/-0.007 min(-1), respectively, with a RVOx of 0.83+/-0.17. There was a good correlation between RVOx and the VE/VCO2 slope (r=0.61, p=0.0034). RVOx was 0.77+/-0.16 in patients with a VE/VCO2 slope <34 and 0.93+/-0.16 in patients with VE/VCO2 slope > or =34 (p=0.047). Conclusion: RVOx correlates with VE/VCO2 slope in CHF patients. This supports the hypothesis that pulmonary vascular resistance is a determinant of the VE/VCO2 slope. [ABSTRACT FROM AUTHOR]

Sample preparation can present a significant hurdle within single particle cryo-electron microscopy (cryoEM), resulting in issues with reproducibility, data quality or an inability to visualise the sample. There are several factors which can influence this, including sample or buffer composition, grid type, route of sample preparation and interactions with the air-water interface (AWI). Here, we review some of the current routes for sample preparation and the associated challenges. We discuss a range of approaches for overcoming these challenges, such as minimising the grid preparation time, surfactants, grid type and biochemical approaches such as nanomagnetic beads. Finally, we discuss how a set of commercially available protein samples may serve as a benchmark suite for future technologies. This provides a route to compare techniques' abilities not just to generate high-resolution structures but also to overcome the challenges traditionally associated with cryoEM. As the field continues to produce new approaches to sample preparation and we start to better understand the underlying principles behind the behaviour of proteins within a thin film and in response to different environments, especially grid composition, it is hoped that more universal solutions can be provided that make the intractable systems tractable, improve resolution and, importantly, speed up data collection and reduce the currently required dataset sizes., (© 2024 The Author(s).)

Gated radionuclide angiography and myocardial perfusion imaging were developed in the United States and Europe in the 1970's and soon adopted in Canadian centers. Much of the early development of nuclear cardiology in Canada was in Toronto, Ontario and was quickly followed by new programs across the country. Clinical research in Canada contributed to the further development of nuclear cardiology and cardiac PET. The Canadian Nuclear Cardiology Society (CNCS) was formed in 1995 and became the Canadian Society of Cardiovascular Nuclear and CT Imaging (CNCT) in 2014. The CNCS had a major role in education and advocacy for cardiovascular nuclear medicine testing. The CNCS established the Dr Robert Burns Lecture and CNCT named the Canadian Society of Cardiovascular Nuclear and CT Imaging Annual Achievement Award for Dr Michael Freeman in memoriam of these two outstanding Canadian leaders in nuclear cardiology. The future of nuclear cardiology in Canada is exciting with the expanding use of SPECT imaging to include Tc-99m-pyrophosphate for diagnosis of transthyretin cardiac amyloidosis and the ongoing introduction of cardiac PET imaging., (Copyright © 2024. Published by Elsevier Inc.)

A prolonged QT interval on the electrocardiogram is associated with an increased risk of the torsades de pointes form of ventricular arrhythmia resulting in syncope, sudden cardiac arrest or death, or misdiagnosis as a seizure disorder. The cause of QT prolongation can be congenital and inherited as an autosomal dominant variant, or it can be transient and acquired, often because of QT-prolonging drugs or electrolyte abnormalities. Automated measurement of the QT interval can be inaccurate, especially when the baseline electrocardiogram is abnormal, and manual verification is recommended. In this clinical practice update we provide practical tips about measurement of the QT interval, diagnosis, and management of congenital long QT syndrome and acquired prolongation of the QT interval. For congenital long QT syndrome, certain β-adrenergic-blocking drugs are highly effective, and implantable defibrillators are infrequently required. Many commonly prescribed drugs such as antidepressants and antibiotics can prolong the QT interval, and recommendations are provided on their safe use., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

PI3-kinase (PI3K) is an intracellular signaling complex that is stimulated upon cocaine exposure and linked with the behavioral consequences of cocaine. We recently genetically silenced the PI3K p110β subunit in the medial prefrontal cortex following repeated cocaine in mice, reinstating the capacity of these mice to engage in prospective goal-seeking behavior. In the present short report, we address two follow-up hypotheses: 1) The control of decision-making behavior by PI3K p110β is attributable to neuronal signaling, and 2) PI3K p110β in the healthy (i.e., drug-naïve) medial prefrontal cortex has functional consequences in the control of reward-related decision-making strategies. In Experiment 1, we found that silencing neuronal p110β improved action flexibility following cocaine. In Experiment 2, we reduced PI3K p110β in drug-naïve mice that were extensively trained to respond for food reinforcers. Gene silencing caused mice to abandon goal-seeking strategies, unmasking habit-based behaviors that were propelled by interactions with the nucleus accumbens. Thus, PI3K control of goal-directed action strategies appears to act in accordance with an inverted U-shaped function, with "too much" (following cocaine) or "too little" (following p110β subunit silencing) obstructing goal seeking and causing mice to defer to habit-like response sequences., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Acute cellular rejection (ACR), an alloimmune response involving CD4+ and CD8+ T cells, occurs in up to 20% of patients within the first year following heart transplantation. The balance between a conventional versus regulatory CD4+ T cell alloimmune response is believed to contribute to developing ACR. Therefore, tracking these cells may elucidate whether changes in these cell populations could signal ACR risk., Methods: We used a CD4+ T cell gene signature (TGS) panel that tracks CD4+ conventional T cells (Tconv) and regulatory T cells (Treg) on longitudinal samples from 94 adult heart transplant recipients. We evaluated combined diagnostic performance of the TGS panel with a previously developed biomarker panel for ACR diagnosis, HEARTBiT, while also investigating TGS' prognostic utility., Results: Compared with nonrejection samples, rejection samples showed decreased Treg- and increased Tconv-gene expression. The TGS panel was able to discriminate between ACR and nonrejection samples and, when combined with HEARTBiT, showed improved specificity compared with either model alone. Furthermore, the increased risk of ACR in the TGS model was associated with lower expression of Treg genes in patients who later developed ACR. Reduced Treg gene expression was positively associated with younger recipient age and higher intrapatient tacrolimus variability., Conclusions: We demonstrated that expression of genes associated with CD4+ Tconv and Treg could identify patients at risk of ACR. In our post hoc analysis, complementing HEARTBiT with TGS resulted in an improved classification of ACR. Our study suggests that HEARTBiT and TGS may serve as useful tools for further research and test development., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

α-Pyrrolidinohexiophenone (α-PHP) is the one-carbon unit α-extended homolog of the better-known and widely abused synthetic cathinone central stimulant α-PVP ("flakka"); both are now U.S. Schedule I controlled substances. Structurally, α-PVP and α-PHP possess a common terminal N-pyrrolidine moiety and differ only with respect to the length of their α-alkyl chain. Using a synaptosomal assay, we previously reported that α-PHP is at least as potent as α-PVP as a dopamine transporter (DAT) reuptake inhibitor. A systematic structure-activity study of synthetic cathinones (e.g., α-PHP) as DAT reuptake inhibitors (i.e., transport blockers), a mechanism thought responsible for their abuse liability, has yet to be conducted. Here, we examined a series of 4-substituted α-PHP analogues and found that, with one exception, all behaved as relatively (28- to >300-fold) selective DAT versus serotonin transporter (SERT) reuptake inhibitors with DAT inhibition potencies of most falling within a very narrow (i.e., <3-fold) range. The 4-CF 3 analogue of α-PHP was a confirmed "outlier" in that it was at least 80-fold less potent than the other analogues and displayed reduced (i.e., no) DAT vs SERT selectivity. Consideration of various physicochemical properties of the CF 3 group, relative to that of the other substituents involved here, provided relatively little insight. Unlike with DAT-releasing agents, as previously reported by us, a QSAR study was precluded because of the limited range of empirical results (with the exception of the 4-CF 3 analogue) for DAT reuptake inhibition.

Background: To review the outcomes of surgically resected lung neuroendocrine neoplasms (LNEN) at a tertiary referral centre and to validate a previously published LNEN-specific staging system (NETL)., Methods: All patients who were identified on histopathology to have LNEN were included. Pre-, intra- and post-operative outcomes were collected, including long-term survival. Patients were staged by both the TNM (seventh and eighth edition) and NETL staging (seventh and eighth edition definitions). Kaplan-Meier (KM) survival analysis was performed according to histopathology and stage, along with uni- and multivariate analyses., Result: A total of 132 patients were included in the study, with a median age of 65 years; 55% were female. Typical carcinoid (TC) was the most common pathology (53.4%) followed by large cell neuroendocrine carcinoma (LCNEC - 23.5%), atypical carcinoid (AC - 20.5%) and small cell carcinoma (3.0%). The most common operation performed was a lobectomy (55.3%). Overall survival at 5 years was 80% (100% TC, 78.2% AC, LCNEC 40.9%) and 5-year disease free survival was 76.8% (TC 94.3%, AC 56.8%, LCNEC 56.4%). KM curves showed a trend towards NETL performing better than TNM, however, in multivariate analysis only the histological subtype was found to be significant in our study., Conclusion: This is the largest known Australian series of LNEN to date, showing survival comparable to international outcomes. We have demonstrated large variations in outcome, driven by histological grade. The TNM system does not correlate with survival and we have not been able to show that currently proposed NETL staging is superior., (© 2023 Royal Australasian College of Surgeons.)

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'What is the best choice for third conduit when using bilateral internal mammary arteries for coronary artery bypass grafting-radial artery or saphenous vein graft?'. Altogether >525 papers were found using the reported search, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Overall, there was no survival benefit demonstrated with the use of a radial artery over the use of a saphenous vein graft as a choice of third conduit following bilateral internal mammary artery grafts for coronary artery bypass grafting. The main limitation of the current evidence available is the restricted follow-up periods and the high attrition rates with small sample sizes affecting the strength of conclusions that can be drawn beyond 10 years of follow-up. We conclude that despite previous evidence supporting improved long-term patency of radial arterial grafts, there is no strong evidence that the use of a radial artery, over a saphenous vein graft, has any survival benefit when used as the third conduit following bilateral internal mammary artery grafts., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: Myocardial blood flow (MBF) quantification by Rubidium-82 positron emission tomography (PET) has shown promise for cardiac allograft vasculopathy (CAV) surveillance and risk stratification post heart transplantation. The objective was to determine the prognostic value of serial PET performed early post transplantation., Methods and Result: Heart transplant (HT) recipients at the University of Ottawa Heart Institute with 2 PET examinations (PET1 = baseline, PET2 = follow-up) within 6 years of transplant were included in the study. Evaluation of PET flow quantification included stress MBF, coronary vascular resistance (CVR), and myocardial flow reserve (MFR). The primary composite outcome was all-cause death, re-transplant, myocardial infarction, revascularization, allograft dysfunction, cardiac allograft vasculopathy (CAV), or heart failure hospitalization. A total of 121 patients were evaluated (79% male, mean age 56 ± 11 years) with consecutive scans performed at mean 1.4 ± 0.7 and 2.6 ± 1.0 years post HT for PET1 and PET2, respectively. Over a mean follow-up of 3.0 (IQR 1.8, 4.6) years, 26 (22%) patients developed the primary outcome: 1 death, 11 new or progressive angiographic CAV, 2 percutaneous coronary interventions, 12 allograft dysfunction. Unadjusted Cox analysis showed a significant reduction in event-free survival in patients with PET1 stress MBF < 2.1 (HR: 2.43, 95% CI 1.11-5.29 P = 0.047) and persistent abnormal PET1 to PET2 CVR > 76 (HR: 2.19, 95% CI 0.87-5.51 P = 0.045). There was no association between MFR and outcomes., Conclusion: Low-stress MBF and persistent increased CVR on serial PET imaging early post HT are associated with adverse cardiovascular outcomes. Early post-transplant and longitudinal assessment by PET may identify at-risk patients for increased surveillance post HT., (© 2020. American Society of Nuclear Cardiology.)

In day-to-day life, we often must choose between pursuing familiar behaviors or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for arbitrating between old and new action strategies. To uncover molecular mechanisms, we trained mice to generate nose poke responses for food, then uncoupled the predictive relationship between one action and its outcome. We then bred the mice that failed to rapidly modify responding. This breeding created offspring with the same tendencies, failing to inhibit behaviors that were not reinforced. These mice had less post-synaptic density protein 95 in the DMS. Also, densities of the melanocortin-4 receptor (MC4R), a high-affinity receptor for α-melanocyte-stimulating hormone, predicted individuals' response strategies. Specifically, high MC4R levels were associated with poor response inhibition. We next found that reducing Mc4r in the DMS in otherwise typical mice expedited response inhibition, allowing mice to modify behavior when rewards were unavailable or lost value. This process required inputs from the orbitofrontal cortex, a brain region canonically associated with response strategy switching. Thus, MC4R in the DMS appears to propel reward-seeking behavior, even when it is not fruitful, while moderating MC4R presence increases the capacity of mice to inhibit such behaviors., (© 2022. The Author(s).)

Aim : Previous studies have demonstrated increased glucose uptake by 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) in lung parenchyma in animal models or small pulmonary arterial hypertension (PAH) cohorts. However, it is not well known whether increased FDG uptake in the lung is a unique phenomenon in PAH or whether elevated pulmonary artery pressure (PAP) induces FDG uptake. Methods and results : Nineteen patients with PAH, 8 patients with pulmonary hypertension due to left heart disease (PH-LHD), and 14 age matched control subjects were included. All PH patients underwent right heart catheterization and FDG-PET. The mean standard uptake value (SUV g/mL) of FDG in each lung was obtained and average values of both lungs were calculated as mean lung FDG SUV. The correlation between hemodynamics and mean lung FDG SUV was also analyzed in PH patients. Mean PAP (mPAP) was not significantly different between PAH and PH-LHD (45±11 vs 43±5 mmHg, p=0.51). PAH patients demonstrated significantly increased mean lung FDG SUV compared with PH-LHD and controls (PAH: 0.76±0.26 vs PH-LHD: 0.51±0.12 vs controls: 0.53±0.16, p=0.0025). The mean lung FDG SUV did not correlate with mPAP either in PAH or PH-LHD. Conclusion : PAH is associated with increased lung FDG uptake indicating increased glucose utilization in the lung. This may represent metabolic shift to glycolysis and/or active inflammation in the remodeled pulmonary vasculature, and is observed to a greater extent in PAH than in patients with PH secondary to LHD and control subjects without PH., Competing Interests: L. M. has research grants and advisory board fees from Actelion and Bayer; R. B. is a consultant and has received grant funding from Lantheus Medical Imaging, Jubilant DRAX Image (JDI) and GE Healthcare; R.d.K. and R.K are consultants for and receive research funding from JDI. R.d.K., R.K. , and J.R. receive royalty revenues from rubidium generator technology and from FlowQuan tsoftware licenses; D.J.S. has equity with Northern Therapeutics and research funding from United Therapeutics; C.P. has speakers fees from Actelion and Pfizer; R.A.D. has unrestricted educational grants from Actelion and Bayer and speakers fees from Actelion; G.C. has participated in advisory board meetings for Bayer and Actelion., (2022, Japanese Society of Nuclear Cardiology.)

Background: We previously demonstrated high diagnostic accuracy of Rubidium-82 positron emission tomography (PET) myocardial blood flow (MBF) quantification for CAV. The purpose of this study was to validate multiparametric PET detection of CAV by combined rate-pressure-product-corrected myocardial flow reserve (cMFR), stress MBF, and coronary vascular resistance (CVR) assessment., Methods and Results: Diagnostic CAV cut-offs of cMFR < 2.9, stress MBF < 2.3, CVR > 55 determined in a previous study (derivation) were assessed in heart transplant recipients referred for coronary angiography and intravascular ultrasound (IVUS) (validation). CAV was defined as International Society of Heart and Lung Transplantation CAV 1-3 on angiography; and maximal intimal thickness ≥ 0.5 mm on IVUS. Eighty patients (derivation n = 40, validation n = 40) were included: 80% male, mean age 54±14 years, 4.5±5.6 years post transplant. The prevalence of CAV was 44% on angiography and 78% on IVUS. Combined PET cMFR < 2.9, stress MBF < 2.3, CVR > 55 CAV assessment yielded high 88% (specificity 75%) and 83% (specificity 40%) sensitivity for ≥ 1 abnormal parameter and high 88% (sensitivity 59%) and 90% (sensitivity 43%) specificity for 3 abnormal parameters, in the derivation and validation cohorts, respectively., Conclusion: We validate the diagnostic accuracy of multiparametric PET flow quantification by cMFR, stress MBF, and CVR for CAV., (© 2020. American Society of Nuclear Cardiology.)

There is limited knowledge of influenza-specific immune responses and their kinetics in critically ill patients. We investigated humoral and cellular immune responses after critical influenza A/H1N1 infection and hypothesized that dysfunctionality or absence of immune responses could contribute to more severe illness. We followed 12 patients hospitalized with severe influenza infection; the majority admitted to intensive care unit (ICU). Blood samples were collected at days 10 and 19 and at 5 months. Antibody responses to surface glycoproteins haemagglutinin (HA) and neuraminidase (NA) of A/H1N1pdm09 were quantified by haemagglutination inhibition (HAI), microneutralization (MN), Enzyme-linked immunosorbent assay (ELISA) and Enzyme-linked lectin assay (ELLA). Influenza-specific antibody levels and avidity were measured separately for head and stalk domains of H1. Cytokine secreting CD4 + and CD8 + T cell responses to conserved influenza epitopes (M1, NP and PB1) were analysed by FluoroSpot. Overall, the patients retained a high level of functional HA- and NA-specific antibodies over the study period. During the acute phase (up to 3 weeks from symptom onset), antibodies specific to H1 stalk increased earlier and were present in higher amount compared with H1 head-specific antibodies. The NA-specific antibodies and the non-neutralizing HA-specific antibody response for H1 head and H1 full-length showed a significant decline from acute to convalescent phase. Despite high total IgG concentrations, avidity to H1 head and H1 full-length protein remained low at all time points. Similarly, CD8 + T cell responses were continuously measured at low levels. In conclusion, our study found that critically ill patients were characterized by low HA-specific antibody avidity and CD8 + T cell response., (© 2021 The Scandinavian Foundation for Immunology.)

Repeated cocaine exposure causes dendritic spine loss in the orbitofrontal cortex, which might contribute to poor orbitofrontal cortical function following drug exposure. One challenge, however, has been verifying links between neuronal structural plasticity and behavior, if any. Here we report that cocaine self-administration triggers the loss of dendritic spines on excitatory neurons in the orbitofrontal cortex of male and female mice (as has been reported in rats). To understand functional consequences, we locally ablated neuronal β1-integrins, cell adhesion receptors that adhere cells to the extracellular matrix and thus support dendritic spine stability. Degradation of β1-integrin tone: (1) caused dendritic spine loss, (2) exaggerated cocaine-seeking responses in a cue-induced reinstatement test, and (3) impaired the ability of mice to integrate new learning into familiar routines, a key function of the orbitofrontal cortex. Stimulating Abl-related gene kinase, overexpressing Proline-rich tyrosine kinase, and inhibiting Rho-associated coiled-coil containing kinase corrected response strategies, uncovering a β1-integrin-mediated signaling axis that controls orbitofrontal cortical function. Finally, use of a combinatorial gene silencing/chemogenetic strategy revealed that β1-integrins support the ability of mice to integrate new information into established behaviors by sustaining orbitofrontal cortical connections with the basolateral amygdala. SIGNIFICANCE STATEMENT Cocaine degenerates dendritic spines in the orbitofrontal cortex, a region of the brain involved in interlacing new information into established behaviors. One challenge has been verifying links between cellular structural stability and behavior, if any. In this second of two related investigations, we study integrin family receptors, which adhere cells to the extracellular matrix and thereby stabilize dendritic spines (see also DePoy et al., 2019). We reveal that β1-integrins in the orbitofrontal cortex control food- and cocaine-seeking behaviors. For instance, β1-integrin loss amplifies cocaine-seeking behavior and impairs the ability of mice to integrate new learning into familiar routines. We identify likely intracellular signaling partners by which β1-integrins support orbitofrontal cortical function and connectivity with the basolateral amygdala., (Copyright © 2021 the authors.)

Novel psychoactive substances (NPS) threaten public health and safety while also straining the limited resources of forensic laboratories. To efficiently allocate the finite resources available, we propose a new strategy for prioritizing NPS with abuse liability testing using a preclinical behavioral procedure in rats known as intracranial self-stimulation (ICSS). To validate this assay, the recently-scheduled synthetic cathinone α-PHP was compared to cocaine, a mechanistically similar drug of abuse, as a positive control and saline as a negative control. Male Sprague-Dawley rats (n=6) were implanted with electrodes targeting the medial forebrain bundle and trained to respond by lever-press for electrical brain stimulation. The rats were tested with doses of 0.32, 1.0, and 3.2 mg/kg α-PHP as well as 10 mg/kg of cocaine and saline administered by intraperitoneal injection. Neither saline nor 0.32 mg/kg α-PHP altered ICSS response rates compared to baseline levels of responding; however, doses of 1.0 and 3.2 mg/kg α-PHP and 10 mg/kg cocaine facilitated ICSS responding. This ICSS profile suggests that α-PHP has high abuse potential, with a rapid onset of effects and a long duration of action, and supports the decision to schedule this compound. This study demonstrates the ability of ICSS to distinguish between compounds of low and high potential for abuse. A strategy is proposed here to screen NPS using ICSS and classify emerging drugs into four priority categories for further analysis.

Background: Nine mRNA transcripts associated with acute cellular rejection (ACR) in previous microarray studies were ported to the clinically amenable NanoString nCounter platform. Here we report the diagnostic performance of the resulting blood test to exclude ACR in heart allograft recipients: HEARTBiT., Methods: Blood samples for transcriptomic profiling were collected during routine post-transplantation monitoring in 8 Canadian transplant centres participating in the Biomarkers in Transplantation initiative, a large (n = 1622) prospective observational study conducted between 2009 and 2014. All adult cardiac transplant patients were invited to participate (median age = 56 [17 to 71]). The reference standard for rejection status was histopathology grading of tissue from endomyocardial biopsy (EMB). All locally graded ISHLT ≥ 2R rejection samples were selected for analysis (n = 36). ISHLT 1R (n = 38) and 0R (n = 86) samples were randomly selected to create a cohort approximately matched for site, age, sex, and days post-transplantation, with a focus on early time points (median days post-transplant = 42 [7 to 506])., Results: ISHLT ≥ 2R rejection was confirmed by EMB in 18 and excluded in 92 samples in the test set. HEARTBiT achieved 47% specificity (95% confidence interval [CI], 36%-57%) given ≥ 90% sensitivity, with a corresponding area under the receiver operating characteristic curve of 0.69 (95% CI, 0.56-0.81)., Conclusions: HEARTBiT's diagnostic performance compares favourably to the only currently approved minimally invasive diagnostic test to rule out ACR, AlloMap (CareDx, Brisbane, CA) and may be used to inform care decisions in the first 2 months post-transplantation, when AlloMap is not approved, and most ACR episodes occur., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Risk assessment is important for prognostication and individualized treatment decisions for patients with pulmonary arterial hypertension (PAH). The purpose was (1) to compare contemporary risk assessment tools and (2) to determine the prognostic significance of risk parameters of kidney function and whether they can further improve risk prediction for patients with PAH., Methods: We identified a cohort of treatment-naive patients (n = 211) who received an incident diagnosis of PAH at the University of Ottawa Heart Institute. Using demographics, disease characteristics, and hemodynamic data at diagnosis, we categorized patients as low, intermediate, or high risk according to current European guidelines (European Society of Cardiology [ESC]) and registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL) risk scores. The primary end-point was transplant-free survival (TFS)., Results: Patients were predominantly women (64.6%) with World Health Organization function Class III symptoms (66.5%). The median TFS was 7.09 years. There was little agreement between ESC- and REVEAL-based risk estimates (weighted kappa = 0.21-0.34). Although both the ESC (log-rank, p = 0.0002) and REVEAL algorithms stratified TFS risk (p < 0.0001), the REVEAL score provided superior discrimination (C-statistic = 0.70 vs 0.59, p = 0.004). Renal function at diagnosis (p < 0.0001) and Δ renal function at 6 months (p < 0.0001) were identified as novel risk parameters and served to reclassify some patients in the intermediate-risk category to a lower or higher risk stratum (p < 0.0001)., Conclusion: REVEAL-based strategies provide superior TFS risk discrimination to ESC/European Respiratory Society-based approaches. However, the classification of intermediate-risk patients varied significantly across tools. We demonstrate the importance of renal function, which further improved the stratification of risk in patients with PAH, particularly in patients who are considered intermediate risk., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Methcathinone (MCAT; 1 ), the progenitor of numerous and widely abused "synthetic cathinone" central stimulants, exists as a pair of optical isomers. Although S (-)MCAT is several-fold more potent than R (+)MCAT in rodent locomotor stimulation and in stimulus generalization studies in rat drug discrimination assays, the individual optical isomers of MCAT have never been directly compared for their actions at monoamine transporters that seem to underlie their actions and have never been examined for their relative abuse potential. Here, we found that the isomers of MCAT are nearly equieffective at dopamine and norepinephrine transporters (DAT and NET, respectively) as transporter substrates ( i.e ., as releasing agents) and are ≥63-fold less potent at the serotonin transporter (SERT). In intracranial self-stimulation (ICSS) studies to evaluate abuse-related drug effects in rats, S (-)MCAT was approximately twice as potent as its R -enantiomer. Achiral analogs, α-methyl MCAT ( 3 ) and α- des- methyl MCAT ( 4 ), also were DAT/NET substrates and also produced abuse-related ICSS effects, indicating that they retain abuse potential and that they might be useful for the further study of the stereochemistry of synthetic cathinone analogs with chiral β- (or other) substituents.

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was, "In patients who have undergone Coronary Artery Bypass Grafting, does aspirin plus clopidogrel postoperatively improve vein graft patency when compared to aspirin alone?" Altogether, 165 papers were found using the reported search, of which five represented the best evidence to answer the clinical question. Overall analysis of these papers demonstrated similar rates of vein graft patency between the two groups. There was no difference between the groups with regard to mortality, adverse bleeding-related outcomes, or composite vascular events., (Copyright © 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: Psychiatric genetics has had limited success in translational efforts. A thorough understanding of the present state of translation in this field will be useful in the facilitation and assessment of future translational progress., Purpose: A narrative literature review was conducted. Combinations of 3 groups of terms were searched in EBSCOhost, Google Scholar, and PubMed. The review occurred in multiple steps, including abstract collection, inclusion/exclusion criteria review, coding, and analysis of included papers., Results: One hundred and fourteen articles were analyzed for the narrative review. Across those, 4 bottlenecks were noted that, if addressed, may provide insights and help improve and increase translation in the field of psychiatric genetics. These 4 bottlenecks are emphasizing linear translational frameworks, relying on molecular genomic findings, prioritizing certain psychiatric disorders, and publishing more reviews than experiments., Conclusions: These entwined bottlenecks are examined with one another. Awareness of these bottlenecks can inform stakeholders who work to translate and/or utilize psychiatric genetic information. Potential solutions include utilizing nonlinear translational frameworks as well as a wider array of psychiatric genetic information (e.g., family history and gene-environment interplay) in this area of research, expanding which psychiatric disorders are considered for translation, and when possible, conducting original research. Researchers are urged to consider how their research is translational in the context of the frameworks, genetic information, and psychiatric disorders discussed in this review. At a broader level, these efforts should be supported with translational efforts in funding and policy shifts., (© 2020 S. Karger AG, Basel.)

Cardiac allograft vasculopathy (CAV) limits long-term survival after heart transplantation. Non-invasive evaluation is challenging, and currently, there is no validated biomarker for CAV diagnosis or prognostication. To identify potential candidate CAV biomarkers, we utilized the Slow Off-rate Modified Aptamer (SOMAscan) assay, which evaluates over 1000 serum proteins, including many relevant to biological pathways in CAV. We evaluated three heart transplant patient groups according to angiographic ISHLT CAV grade: CAV 1-2 (mild-moderate CAV), CAV 3 (severe CAV), and CAV 0 (normal control). SOMAscan assays were performed and proteins quantitated. Comparisons of proteins between study groups were performed using one-way ANOVA (false discovery rate q-value < 0.10). Thirty-one patients (12 mild-moderate CAV, 9 severe CAV, 10 controls) were included: 81% male, median age 57 years and median 1.1 years post-transplant. Compared to controls, patients with mild-moderate CAV had similar characteristics, while patients with severe CAV had longer time from transplant and increased allosensitization. Statistical/bioinformatics analysis identified 14 novel biomarkers for CAV, including 4 specific for mild-moderate CAV. These proteins demonstrated important actions including apoptosis, inflammation, and platelet/coagulation activation. Upon preliminary receiver operating characteristics curve analysis, our protein biomarkers showed moderate-to-high discriminative ability for CAV (area under curve: 0.72 to 0.94). These candidate biomarkers are being validated in prospective studies., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Serum-free xenogen-free defined media and continuous controlled physiological cell culture conditions have been developed for stem cell therapeutics, but the effect of these conditions on the relative potency of the cell product is unknown. As such, we conducted a head-to-head comparison of cell culture conditions on human heart explant-derived cells using established in vitro measures of cell potency and in vivo functional repair., Methods: Heart explant-derived cells cultured from human atrial or ventricular biopsies within a serum-free xenogen-free media and a continuous physiological culture environment were compared to cells cultured under traditional (high serum) cell culture conditions in a standard clean room facility., Results: Transitioning from traditional high serum cell culture conditions to serum-free xenogen-free conditions had no effect on cell culture yields but provided a smaller, more homogenous, cell product with only minor antigenic changes. Culture within continuous physiologic conditions markedly boosted cell proliferation while increasing the expression of stem cell-related antigens and ability of cells to stimulate angiogenesis. Intramyocardial injection of physiologic cultured cells into immunodeficient mice 1 week after coronary ligation translated into improved cardiac function and reduced scar burden which was attributable to increased production of pro-healing cytokines, extracellular vesicles, and microRNAs., Conclusions: Continuous physiological cell culture increased cell growth, paracrine output, and treatment outcomes to provide the greatest functional benefit after experimental myocardial infarction.

Objectives: Benign Paroxysmal Positional Vertigo (BPPV) is the most common cause of dizziness. Extensive research has identified the best assessment and treatment manoeuvres for each subtype of BPPV. Education in vestibular rehabilitation (VR) is inconsistent. It is unclear if the evidence has been adopted by UK physiotherapists in clinical practice and no research has investigated this specifically., Design: An online survey with closed- and open-text answers., Participants: A purposive sample of physiotherapists interested in VR. A response rate of 67% (100/150) was obtained, from which 20 responses were excluded., Results: Participants had good evidence-based awareness in assessment (79/80, 99%) and treatment (72/80, 90%) of posterior BPPV. Horizontal BPPV assessment awareness was lower than treatment (37/80, 46% vs 60/80, 75%). Differential diagnosis was poor in subjective (20/80, 25%) and objective stages of assessment (34/80, 43%). Thirty six percent (29/80) were able to list ≥3 test precautions with all three nystagmus characteristics described by 29% (23/80). Eighty one percent (65/80) encourage activity restrictions post-treatment. Only 28% (22/80) were aware of practice guidelines or Cochrane reviews in BPPV. External courses were rated the top method for learning how to manage BPPV. Lack of peer support (26/77, 34%) was the main challenge faced whilst learning. Recommendations for improving BPPV education included more external courses (23/87, 26%) and competency guidelines (13/87, 15%)., Conclusions: Good awareness of research evidence was observed in some aspects of BPPV management but many areas require development. Translation and implementation of evidence remains poor and suggests changes in education and knowledge dissemination are warranted., (Copyright © 2018 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

A best evidence topic in cardiac surgery was written according to a structured protocol addressing the question 'for post-cardiac surgery atrial fibrillation (AF), do clinical outcomes differ between rate or rhythm control strategies?' Altogether, 2174 papers were found using the reported searches, of which 5 represented the best evidence to answer the clinical question. Hospital length of stay ranged from 5.0 to 13.2 days for rate control and 5.2 to 10.3 days for rhythm control. Freedom from AF at follow up was achieved in 84.2-91 and 84.2-96% in rate and rhythm control groups respectively. Minimal serious adverse events were noted in all studies analysed and there was no difference between rate and rhythm control groups. We conclude that in the management of post-cardiac surgery, AF, rate control and rhythm control are equivalent in terms of hospital length of stay, freedom from arrhythmia at follow up and complication rates., (© 2019 Royal Australasian College of Physicians.)

Background: The Canadian status 4S category prioritizes highly sensitized patients with a calculated panel reactive antibody (CPRA) > 80% awaiting heart transplantation. We examined the effect of sensitization and status 4S and developed a predictive model to estimate waiting time in Canada., Methods: A retrospective review was performed of patients listed for heart transplant at the Ottawa Heart Institute and Toronto General Hospital (Ontario, Canada). We evaluated the association of CPRA and priority listing status on waiting time and post-transplant outcomes. Waiting time risk factor analysis was performed using a multivariable parametric accelerated failure time model with a Weibull distribution., Results: Of 394 patients listed (75% male, 51 ± 12 years), 291 (74%) received a transplant and 33 (8%) died waiting. The cumulative incidence of transplant decreased across higher CPRA groups but was similar for moderately and highly sensitized groups: 67%, 70%, 50%, and 40% at 12 months for CPRA 0%, 1% to 50%, 51% to 80%, and > 80%, respectively (p = 0.020). Status 4S patients experienced longer waiting times compared with other high priority status 3.5 and 4 and had increased risk of death on the waiting list (p = 0.014). Over a median follow-up of 2.4 years (interquartile range, 1.2-4.1), rejection occurred in 64 sensitized patients (24%) compared with 24 non-sensitized patients (9%; p = 0.019), but there was no difference in survival, allograft dysfunction, or cardiac allograft vasculopathy. A model predicting transplant waiting time, including CPRA, blood group, priority listing status, age, and weight, was developed and showed adequate discrimination and calibration., Conclusions: Waiting time to heart transplant is increased for highly and moderately sensitized patients, suggesting the need to reevaluate the CPRA > 80% threshold for status 4S prioritization in Canada. Extended waiting times, despite 4S prioritization, supports consideration of additional factors to CPRA in ensuring equitable organ access for sensitized patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A best evidence topic was written to address if perioperative levosimendan improves mortality following cardiac surgery. Fourteen papers represented the best available evidence. An older meta-analysis summarising 11 of these trials concluded that there were fewer deaths in the levosimendan group compared to the control group (OR 0.41, p <0.001) however, this was driven by the results of three included trials by the same author. Three larger and more recent randomised controlled trials failed to demonstrate significant differences in mortality. We conclude that levosimendan lacks robust evidence to substantiate claims of mortality benefit in cardiac surgery patients and should not be used routinely in such patients., (Copyright © 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)