A retrospective multicenter study on clinical and serological parameters in patients with MuSK myasthenia gravis with and without general immunosuppression.

Introduction: Muscle-specific kinase (MuSK)- myasthenia gravis (MG) is caused by pathogenic autoantibodies against MuSK that correlate with disease severity and are predominantly of the IgG4 subclass. The first-line treatment for MuSK-MG is general immunosuppression with corticosteroids, but the effect of treatment on IgG4 and MuSK IgG4 levels has not been studied. Methods: We analyzed the clinical data and sera from 52 MuSK-MG patients (45 female, 7 male, median age 49 (range 17-79) years) from Italy, the Netherlands, Greece and Belgium, and 43 AChR-MG patients (22 female, 21 male, median age 63 (range 2-82) years) from Italy, receiving different types of immunosuppression, and sera from 46 age- and sex-matched non-disease controls (with no diagnosed diseases, 38 female, 8 male, median age 51.5 (range 20-68) years) from the Netherlands. We analyzed the disease severity (assessed by MGFA or QMG score), and measured concentrations of MuSK IgG4, MuSK IgG, total IgG4 and total IgG in the sera by ELISA, RIA and nephelometry. Results: We observed that MuSK-MG patients showed a robust clinical improvement and reduction of MuSK IgG after therapy, and that MuSK IgG4 concentrations, but not total IgG4 concentrations, correlated with clinical severity. MuSK IgG and MuSK IgG4 concentrations were reduced after immunosuppression in 4/5 individuals with before-after data, but data from non-linked patient samples showed no difference. Total serum IgG4 levels were within the normal range, with IgG4 levels above threshold (1.35g/L) in 1/52 MuSK-MG, 2/43 AChR-MG patients and 1/45 non-disease controls. MuSK-MG patients improved within the first four years after disease onset, but no further clinical improvement or reduction of MuSK IgG4 were observed four years later, and only 14/52 (26.92%) patients in total, of which 13 (93.3%) received general immunosuppression, reached clinical remission. Discussion: We conclude that MuSK-MG patients improve clinically with general immunosuppression but may require further treatment to reach remission. Longitudinal testing of individual patients may be clinically more useful than single measurements of MuSK IgG4. No significant differences in the serum IgG4 concentrations and IgG4/IgG ratio between AChR- and MuSK-MG patients were found during follow-up. Further studies with larger patient and control cohorts are necessary to validate the findings.

The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis.

OBJECTIVE: Simultaneous activation of ß2- and ß3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of ß1-ARs - and thus inducing cardiovascular complications - are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel ß2-and ß3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models. METHODS: In the developmental phase, we assessed the impact of ATR-127's on cAMP accumulation in relation to the non-selective ß-AR agonist isoprenaline across various rodent ß-AR subtypes, including neonatal rat cardiomyocytes. Following these experiments, L6 muscle cells were stimulated with ATR-127 to assess the impact on GLUT4-mediated glucose uptake and intramyocellular cAMP accumulation. Additionally, in vitro, and in vivo assessments are conducted to measure ATR-127's effects on BAT glucose uptake and thermogenesis. Finally, diet-induced obese mice were treated with 5 mg/kg ATR-127 for 21 days to investigate the effects on glucose homeostasis, body weight, fat mass, skeletal muscle glucose uptake, BAT thermogenesis and hepatic steatosis. RESULTS: Exposure of L6 muscle cells to ATR-127 robustly enhanced GLUT4-mediated glucose uptake despite low intramyocellular cAMP accumulation. Similarly, ATR-127 markedly increased BAT glucose uptake and thermogenesis both in vitro and in vivo. Prolonged treatment of diet-induced obese mice with ATR-127 dramatically improved glucose homeostasis, an effect accompanied by decreases in body weight and fat mass. These effects were paralleled by an enhanced skeletal muscle glucose uptake, BAT thermogenesis, and improvements in hepatic steatosis. CONCLUSIONS: Our results demonstrate that ATR-127 is a highly effective, novel ß2- and ß3-ARs agonist holding great therapeutic promise for the treatment of obesity and its comorbidities, whilst potentially limiting cardiovascular complications. As such, the therapeutic effects of ATR-127 should be investigated in more detail in clinical studies.

Subgrouping with Chain Graphical VAR Models.

Recent years have seen the emergence of an "idio-thetic" class of methods to bridge the gap between nomothetic and idiographic inference. These methods describe nomothetic trends in idiographic processes by pooling intraindividual information across individuals to inform group-level inference or vice versa. The current work introduces a novel "idio-thetic" model: the subgrouped chain graphical vector autoregression (scGVAR). The scGVAR is unique in its ability to identify subgroups of individuals who share common dynamic network structures in both lag(1) and contemporaneous effects. Results from Monte Carlo simulations indicate that the scGVAR shows promise over similar approaches when clusters of individuals differ in their contemporaneous dynamics and in showing increased sensitivity in detecting nuanced group differences while keeping Type-I error rates low. In contrast, a competing approach-the Alternating Least Squares VAR (ALS VAR) performs well when groups were separated by larger distances. Further considerations are provided regarding applications of the ALS VAR and scGVAR on real data and the strengths and limitations of both methods.

Examining timing effects in the intergenerational transmission of anxiety and depressive symptoms: A genetically informed study.

The present study examined genetic, prenatal, and postnatal environmental pathways in the intergenerational transmission of anxiety and depressive symptoms from parents to early adolescents (when these symptoms start to increase), while considering timing effects of exposure to parent anxiety and depressive symptoms postnatally. The sample was from the Early Growth and Development Study, including 561 adopted children (57% male, 55% White, 13% Black/African American, 11% Hispanic/Latine, 20% multiracial, 1% other; 407 provided data in early adolescence) and their birth (BP) and adoptive parents (AP). Using a trait-state-occasion model with eight assessments from child ages 9 months to 11 years, we partitioned trait-like AP anxiety and depressive symptoms from time-specific fluctuations of AP anxiety and depressive symptoms. Offspring anxiety and depressive symptoms were assessed at 11 years (while controlling for similar symptoms at 4.5 years). Results suggested that time-specific fluctuations of AP1 (mostly mothers) anxiety/depressive symptoms in infancy (9 months) were indirectly associated with offspring anxiety/depressive symptoms at 11 years via offspring anxiety/depressive symptoms at 4.5 years; time-specific fluctuations of AP1 anxiety/depressive symptoms at child age 11 years were concurrently associated with offspring anxiety/depressive symptoms at 11 years. AP2 (mostly fathers) anxiety/depressive symptoms were not associated with offspring symptoms. Genetic and prenatal influences measured by BP internalizing problems were not associated with offspring symptoms. Results suggested infancy and early adolescence as developmental periods when children are susceptible to influences of parent anxiety and depressive symptoms. Preventive interventions should consider time-specific fluctuations in parent anxiety and depressive symptoms during these developmental periods. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Evaluating Discrete Time Methods for Subgrouping Continuous Processes.

Rapid developments over the last several decades have brought increased focus and attention to the role of time scales and heterogeneity in the modeling of human processes. To address these emerging questions, subgrouping methods developed in the discrete-time framework-such as the vector autoregression (VAR)-have undergone widespread development to identify shared nomothetic trends from idiographic modeling results. Given the dependence of VAR-based parameters on the measurement intervals of the data, we sought to clarify the strengths and limitations of these methods in recovering subgroup dynamics under different measurement intervals. Building on the work of Molenaar and collaborators for subgrouping individual time-series by means of the subgrouped chain graphical VAR (scgVAR) and the subgrouping option in the group iterative multiple model estimation (S-GIMME), we present results from a Monte Carlo study aimed at addressing the implications of identifying subgroups using these discrete-time methods when applied to continuous-time data. Results indicate that discrete-time subgrouping methods perform well at recovering true subgroups when the measurement intervals are large enough to capture the full range of a system's dynamics, either via lagged or contemporaneous effects. Further implications and limitations are discussed therein.

Anti-GAD65 autoantibody levels measured by ELISA and alternative types of immunoassays in relation to neuropsychiatric diseases versus diabetes mellitus type 1.

Background: Anti-GAD65 autoantibodies (GAD65-Abs) may occur in patients with epilepsy and other neurological disorders, but the clinical significance is not clear-cut. Whereas high levels of GAD65-Abs are considered pathogenic in neuropsychiatric disorders, low or moderate levels are only considered as mere bystanders in, e.g., diabetes mellitus type 1 (DM1). The value of cell-based assays (CBA) and immunohistochemistry (IHC) for GAD65-Abs detection has not been clearly evaluated in this context. Objective: To re-evaluate the assumption that high levels of GAD65-Abs are related to neuropsychiatric disorders and lower levels only to DM1 and to compare ELISA results with CBA and IHC to determine the additional value of these tests. Methods: 111 sera previously assessed for GAD65-Abs by ELISA in routine clinical practice were studied. Clinical indications for testing were, e.g., suspected autoimmune encephalitis or epilepsy (neuropsychiatric cohort; n = 71, 7 cases were initially tested positive for GAD65-Abs by ELISA), and DM1 or latent autoimmune diabetes in adults (DM1/LADA cohort (n = 40, all were initially tested positive)). Sera were re-tested for GAD65-Abs by ELISA, CBA, and IHC. Also, we examined the possible presence of GAD67-Abs by CBA and of other neuronal autoantibodies by IHC. Samples that showed IHC patterns different from GAD65 were further tested by selected CBAs. Results: ELISA retested GAD65-Abs level in patients with neuropsychiatric diseases was higher than in patients with DM1/LADA (only retested positive samples were compared; 6 vs. 38; median 47,092 U/mL vs. 581 U/mL; p = 0.02). GAD-Abs showed positive both by CBA and IHC only if antibody levels were above 10,000 U/mL, without a difference in prevalence between the studied cohorts. We found other neuronal antibodies in one patient with epilepsy (mGluR1-Abs, GAD-Abs negative), and in a patient with encephalitis, and two patients with LADA. Conclusion: GAD65-Abs levels are significantly higher in patients with neuropsychiatric disease than in patients with DM1/LADA, however, positivity in CBA and IHC only correlates with high levels of GAD65-Abs, and not with the underlying diseases.

Donor heart ischemic time can be extended beyond 9 hours using hypothermic machine perfusion in sheep.

BACKGROUND: The global shortage of donor hearts available for transplantation is a major problem for the treatment of end-stage heart failure. The ischemic time for donor hearts using traditional preservation by standard static cold storage (SCS) is limited to approximately 4 hours, beyond which the risk for primary graft dysfunction (PGD) significantly increases. Hypothermic machine perfusion (HMP) of donor hearts has been proposed to safely extend ischemic time without increasing the risk of PGD. METHODS: Using our sheep model of 24 hours brain death (BD) followed by orthotopic heart transplantation (HTx), we examined post-transplant outcomes in recipients following donor heart preservation by HMP for 8 hours, compared to donor heart preservation for 2 hours by either SCS or HMP. RESULTS: Following HTx, all HMP recipients (both 2 hours and 8 hours groups) survived to the end of the study (6 hours after transplantation and successful weaning from cardiopulmonary bypass), required less vasoactive support for hemodynamic stability, and exhibited superior metabolic, fluid status and inflammatory profiles compared to SCS recipients. Contractile function and cardiac damage (troponin I release and histological assessment) was comparable between groups. CONCLUSIONS: Overall, compared to current clinical SCS, recipient outcomes following transplantation are not adversely impacted by extending HMP to 8 hours. These results have important implications for clinical transplantation where longer ischemic times may be required (e.g., complex surgical cases, transport across long distances). Additionally, HMP may allow safe preservation of "marginal" donor hearts that are more susceptible to myocardial injury and facilitate increased utilization of these hearts for transplantation.

Systematic review of the associations between prenatal sleep behaviours and components of energy balance for regulating weight gain.

This systematic review aimed to examine the magnitude and direction of the associations between prenatal sleep behaviours (i.e. nighttime sleep duration, sleep quality, night awakenings and daytime nap duration) and eating behaviours, physical activity and gestational weight gain. A systematic search was conducted using Medline/PubMed, PsychINFO, CINAHL Complete, ProQuest Dissertations and Thesis A&I, and Web of Science to identify studies with at least one sleep measure, and either eating behaviours, physical activity and/or gestational weight gain. In summary, 11 studies met the review criteria and generated 11 total effect size across 10,900 participants. The majority of the studies were conducted after 2010, which highlights the infancy of this research. Overall, the strengths of the effect size were small: sleep-gestational weight gain (effect size = 0.29), sleep-eating behaviours (effect size = 0.13) and sleep-physical activity (effect size = 0.13). The only effect size that emerged as significant was for the pooled sleep behaviours-physical activity association; good sleep behaviours were positively associated with higher levels of physical activity. These findings summarize and provide insight on how sleep behaviours are related to prenatal gestational weight gain, eating behaviours and physical activity by identifying the strength and direction of the associations that have been previously unknown. Results support the rationale for future longitudinal and randomized control trials to examine the effects of sleep behaviours on gestational weight gain, eating behaviours and physical activity over the course of pregnancy.

Estimating both directed and undirected contemporaneous relations in time series data using hybrid-group iterative multiple model estimation.

Researchers across varied fields increasingly are collecting and analyzing intensive longitudinal data (ILD) to examine processes across time at the individual level. Two types of relations are typically examined: lagged and contemporaneous. Lagged relations capture how variables at a prior time point can be used to explain variance in variables at a later time point. These are always modeled using auto- and cross-regressions by means of vector autoregression (VAR). By contrast, there are two types of relations commonly used to model the contemporaneous relations, which model how variables relate instantaneously. Until now, researchers must opt to either model contemporaneous relations as undirected relations among residuals (e.g., partial or full correlations) or as directed relations among the variables (e.g., paths or regressions). The choice for how to model contemporaneous relations has implications for inferences as well as the potential to introduce bias in the VAR lagged relations if the wrong type of relation is used. This article introduces a novel data-driven method, hybrid-group iterative multiple model estimation (GIMME), that provides a solution to the problem of having to choose one or the other type of contemporaneous relation to model. The modeling framework utilized in hybrid-GIMME allows for both types of contemporaneous relations in addition to the standard VAR relations. Both simulated and empirical data were used to test the performance of hybrid-GIMME. Results suggest this is a robust method for recovering contemporaneous relations in an exploratory manner, particularly with an ample number of time points per person. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Novel treatment strategies for acetylcholine receptor antibody-positive myasthenia gravis and related disorders.

The presence of autoantibodies directed against the muscle nicotinic acetylcholine receptor (AChR) is the most common cause of myasthenia gravis (MG). These antibodies damage the postsynaptic membrane of the neuromuscular junction and cause muscle weakness by depleting AChRs and thus impairing synaptic transmission. As one of the best-characterized antibody-mediated autoimmune diseases, AChR-MG has often served as a reference model for other autoimmune disorders. Classical pharmacological treatments, including broad-spectrum immunosuppressive drugs, are effective in many patients. However, complete remission cannot be achieved in all patients, and 10% of patients do not respond to currently used therapies. This may be attributed to production of autoantibodies by long-lived plasma cells which are resistant to conventional immunosuppressive drugs. Hence, novel therapies specifically targeting plasma cells might be a suitable therapeutic approach for selected patients. Additionally, in order to reduce side effects of broad-spectrum immunosuppression, targeted immunotherapies and symptomatic treatments will be required. This review presents established therapies as well as novel therapeutic approaches for MG and related conditions, with a focus on AChR-MG.

Autoimmune Encephalitis With mGluR1 Antibodies Presenting With Epilepsy, but Without Cerebellar Signs: A Case Report.

OBJECTIVE: To describe the unique case history of a patient with mGluR1 antibodies, with mainly limbic and without cerebellar symptoms. METHODS: A 50-year-old woman initially presented with focal seizures with epigastric rising and déjà-vu sensations, next to cognitive complaints, and musical auditory hallucinations. MRI, EEG, and neuronal autoantibody tests were performed. RESULTS: EEG findings showed slow and sharp activity (sharp waves and sharp-wave-slow-wave complex) in the left temporal lobe. A test for autoantibodies was negative initially. Because of persistent symptoms, serum and CSF were tested 4 years later and found positive for mGluR1 antibodies. Treatment started with monthly IV immunoglobulins and azathioprine that was replaced by mycophenolate mofetil later. Especially cognitive symptoms and hallucinations did not respond well to the treatment. During treatment, mGluR1 antibodies remained present in CSF. DISCUSSION: Whereas cerebellar symptoms are present in 97% of mGluR1-positive cases, our patient presented without ataxia. Therefore, we suggest that the clinical presentation of patients with mGluR1 antibodies is probably more diverse than previously described. Testing for mGluR1 antibodies should be considered in patients with limbic encephalitis and epilepsy, especially when negative for more common antibodies.

Control Theory Forecasts of Optimal Training Dosage to Facilitate Children's Arithmetic Learning in a Digital Educational Application.

Education can be viewed as a control theory problem in which students seek ongoing exogenous input-either through traditional classroom teaching or other alternative training resources-to minimize the discrepancies between their actual and target (reference) performance levels. Using illustrative data from [Formula: see text] Dutch elementary school students as measured using the Math Garden, a web-based computer adaptive practice and monitoring system, we simulate and evaluate the outcomes of using off-line and finite memory linear quadratic controllers with constraintsto forecast students' optimal training durations. By integrating population standards with each student's own latent change information, we demonstrate that adoption of the control theory-guided, person- and time-specific training dosages could yield increased training benefits at reduced costs compared to students' actual observed training durations, and a fixed-duration training scheme. The control theory approach also outperforms a linear scheme that provides training recommendations based on observed scores under noisy and the presence of missing data. Design-related issues such as ways to determine the penalty cost of input administration and the size of the control horizon window are addressed through a series of illustrative and empirically (Math Garden) motivated simulations.

Psychopathological networks: Theory, methods and practice.

In recent years, network approaches to psychopathology have sparked much debate and have had a significant impact on how mental disorders are perceived in the field of clinical psychology. However, there are many important challenges in moving from theory to empirical research and clinical practice and vice versa. Therefore, in this article, we bring together different points of view on psychological networks by methodologists and clinicians to give a critical overview on these challenges, and to present an agenda for addressing these challenges. In contrast to previous reviews, we especially focus on methodological issues related to temporal networks. This includes topics such as selecting and assessing the quality of the nodes in the network, distinguishing between- and within-person effects in networks, relating items that are measured at different time scales, and dealing with changes in network structures. These issues are not only important for researchers using network models on empirical data, but also for clinicians, who are increasingly likely to encounter (person-specific) networks in the consulting room.

A Square-Root Second-Order Extended Kalman Filtering Approach for Estimating Smoothly Time-Varying Parameters.

Researchers collecting intensive longitudinal data (ILD) are increasingly looking to model psychological processes, such as emotional dynamics, that organize and adapt across time in complex and meaningful ways. This is also the case for researchers looking to characterize the impact of an intervention on individual behavior. To be useful, statistical models must be capable of characterizing these processes as complex, time-dependent phenomenon, otherwise only a fraction of the system dynamics will be recovered. In this paper we introduce a Square-Root Second-Order Extended Kalman Filtering approach for estimating smoothly time-varying parameters. This approach is capable of handling dynamic factor models where the relations between variables underlying the processes of interest change in a manner that may be difficult to specify in advance. We examine the performance of our approach in a Monte Carlo simulation and show the proposed algorithm accurately recovers the unobserved states in the case of a bivariate dynamic factor model with time-varying dynamics and treatment effects. Furthermore, we illustrate the utility of our approach in characterizing the time-varying effect of a meditation intervention on day-to-day emotional experiences.

On Standardized Measurement in Behavioral Science.

That standardized measurement procedures are a sine qua non of "good" science is generally not questioned. Here we examine the meaning and use of standardized measurement in behavioral science. Procedures and methods of measurement that have served the physical sciences so well should not blindly be assumed to work in the same manner and with the same effectiveness in behavioral science. There seems to be general agreement that social/behavioral science is "different" among the sciences. Problems arising from how behavioral science is "different" begin, we believe, with measurement. We put forward the argument that the source of the difference is unique to animate objects and is first evident at the stage of measuring the behavioral attributes of interest. It is at that point in conducting scientific inquiry that the matters raised might be resolved by developing and applying alternatives to standardized measurement. One such alternative discussed is the idiographic filter (Nesselroade, Gerstorf, Hardy, & Ram, 2007).

Describing and Controlling Multivariate Nonlinear Dynamics: A Boolean Network Approach.

We introduce a discrete-time dynamical system method, the Boolean network method, that may be useful for modeling, studying, and controlling nonlinear dynamics in multivariate systems, particularly when binary time-series are available. We introduce the method in three steps: inference of the temporal relations as Boolean functions, extraction of attractors and assignment of desirability based on domain knowledge, and design of network control to direct a psychological system toward a desired attractor. To demonstrate how the Boolean network can describe and prescribe control for emotion regulation dynamics, we applied this method to data from a study of how children use bidding to an adult and/or distraction to regulate their anger during a frustrating task (N = 120, T = 480 seconds). Network control strategies were designed to move the child into attractors where anger is OFF. The sample shows heterogeneous emotion regulation dynamics across children in 22 distinct Boolean networks, and heterogeneous control strategies regarding which behavior to perturb and how to perturb it. The Boolean network method provides a novel method to describe nonlinear dynamics in multivariate psychological systems and is a method with potential to eventually inform the design of interventions that can guide those systems toward desired goals.

Adolescent effects on mothers' bedtime cortisol: Cognitive interference as a mediating mechanism.

Prior studies have shown that parent and adolescent cortisol are associated across days and that this covariation may be adolescent-driven. This study extends this literature by (a) testing whether parents' cognitive interference (i.e., distracting and ruminative thoughts potentially due to worry) mediates the linkages between adolescent and next-day parent cortisol and (b) whether these linkages were moderated by parent gender or warmth. Daily diary data, including bedtime cortisol, were collected on two samples of employees and their adolescent-aged children (N = 318 dyads, Myouth age  = 13.18 years, 74% mothers). We tested mediation with autoregressive cross-lagged models. Moderated mediation by parent gender was found in our bedtime cortisol models. Higher adolescent bedtime cortisol levels were associated with higher next-day levels of mothers' cognitive interference. In turn, higher levels of mothers' cognitive interference were linked to higher mothers' same-day bedtime cortisol levels. These linkages were not significant for fathers. Cognitive interference did not mediate the associations between child and parent area under the curve or cortisol awakening response. No moderation was evident for parental warmth. Results suggest that mothers' cognitions play a key role in the transmission of elevated bedtime cortisol levels from adolescents to their mothers.

A clinically relevant sheep model of orthotopic heart transplantation 24 h after donor brainstem death.

BACKGROUND: Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for severe/end-stage cardiac disease, but is limited by a global donor heart shortage. Consequently, innovative solutions to increase donor heart availability and utilisation are rapidly expanding. Clinically relevant preclinical models are essential for evaluating interventions for human translation, yet few exist that accurately mimic all key HTx components, incorporating injuries beginning in the donor, through to the recipient. To enable future assessment of novel perfusion technologies in our research program, we thus aimed to develop a clinically relevant sheep model of HTx following 24 h of donor BSD. METHODS: BSD donors (vs. sham neurological injury, 4/group) were hemodynamically supported and monitored for 24 h, followed by heart preservation with cold static storage. Bicaval orthotopic HTx was performed in matched recipients, who were weaned from cardiopulmonary bypass (CPB), and monitored for 6 h. Donor and recipient blood were assayed for inflammatory and cardiac injury markers, and cardiac function was assessed using echocardiography. Repeated measurements between the two different groups during the study observation period were assessed by mixed ANOVA for repeated measures. RESULTS: Brainstem death caused an immediate catecholaminergic hemodynamic response (mean arterial pressure, p = 0.09), systemic inflammation (IL-6 - p = 0.025, IL-8 - p = 0.002) and cardiac injury (cardiac troponin I, p = 0.048), requiring vasopressor support (vasopressor dependency index, VDI, p = 0.023), with normalisation of biomarkers and physiology over 24 h. All hearts were weaned from CPB and monitored for 6 h post-HTx, except one (sham) recipient that died 2 h post-HTx. Hemodynamic (VDI - p = 0.592, heart rate - p = 0.747) and metabolic (blood lactate, p = 0.546) parameters post-HTx were comparable between groups, despite the observed physiological perturbations that occurred during donor BSD. All p values denote interaction among groups and time in the ANOVA for repeated measures. CONCLUSIONS: We have successfully developed an ovine HTx model following 24 h of donor BSD. After 6 h of critical care management post-HTx, there were no differences between groups, despite evident hemodynamic perturbations, systemic inflammation, and cardiac injury observed during donor BSD. This preclinical model provides a platform for critical assessment of injury development pre- and post-HTx, and novel therapeutic evaluation.

Further insights into the molecular complexity of the human sinus node - The role of 'novel' transcription factors and microRNAs.

RESEARCH PURPOSE: The sinus node (SN) is the heart's primary pacemaker. Key ion channels (mainly the funny channel, HCN4) and Ca2+-handling proteins in the SN are responsible for its function. Transcription factors (TFs) regulate gene expression through inhibition or activation and microRNAs (miRs) do this through inhibition. There is high expression of macrophages and mast cells within the SN connective tissue. 'Novel'/unexplored TFs and miRs in the regulation of ion channels and immune cells in the SN are not well understood. Using RNAseq and bioinformatics, the expression profile and predicted interaction of key TFs and cell markers with key miRs in the adult human SN vs. right atrial tissue (RA) were determined. PRINCIPAL RESULTS: 68 and 60 TFs significantly more or less expressed in the SN vs. RA respectively. Among those more expressed were ISL1 and TBX3 (involved in embryonic development of the SN) and 'novel' RUNX1-2, CEBPA, GLI1-2 and SOX2. These TFs were predicted to regulate HCN4 expression in the SN. Markers for different cells: fibroblasts (COL1A1), fat (FABP4), macrophages (CSF1R and CD209), natural killer (GZMA) and mast (TPSAB1) were significantly more expressed in the SN vs. RA. Interestingly, RUNX1-3, CEBPA and GLI1 also regulate expression of these cells. MiR-486-3p inhibits HCN4 and markers involved in immune response. MAJOR CONCLUSIONS: In conclusion, RUNX1-2, CSF1R, TPSAB1, COL1A1 and HCN4 are highly expressed in the SN but not miR-486-3p. Their complex interactions can be used to treat SN dysfunction such as bradycardia. Interestingly, another research group recently reported miR-486-3p is upregulated in blood samples from severe COVID-19 patients who suffer from bradycardia.