Florio, Damian N. Di

Background: Viral myocarditis presents a significant burden of disease, particularly among children and young adults. However, clinical guidelines and treatment strategies for pediatric patients are derived from those for adult patients due to a lack of pediatric data. Current animal models of viral myocarditis use adult mice, so conclusions from these models cannot necessarily be extrapolated to the pediatric population. We sought to develop a juvenile mouse model of myocarditis to examine differences between these two distinct clinical populations. Methods: Male and female BALB/c 3-4-week-old 'juvenile' and 8-week-old 'adult' mice were infected intraperitoneally with 103 PFU of heart-passaged coxsackievirus B3. Sera was used to evaluate testosterone and estradiol levels. Cardiac histological evaluations included overall inflammation, fibrosis, and specific cell-type infiltration. RNA was extracted from cardiac tissue and evaluated for changes in gene expression of cell-type markers, complement components, and NLRP3 inflammasome components. Results: Juvenile mice exhibited more severe inflammation than adult mice but no sex differences in overall inflammation. Juvenile mice demonstrated increased infiltration of CD11b+ cells, F4/80+ cells, and CD3+ T-cells vs. adults. Inflammasome genes NLRP3 and caspase-1 were significantly increased in juvenile compared with adult myocarditis. Conclusions: This paper is the first to describe a juvenile mouse model of coxsackievirus B3 myocarditis and provides a direct comparison to a translational adult mouse model. Juvenile mice had greater cardiac inflammation than adults. This model replicates clinical populations and provides a valuable tool to study age as a factor in the pathogenesis of myocarditis.

Abstract Background Radiation-induced heart disease (RIHD) may develop months to years following radiation therapy for cancers near the heart such as lung or breast cancer. Several mouse models of RIHD exist to study the pathogenesis of disease, but to our knowledge no studies have examined whether sex differences exist in RIHD in mice. Methods Female and male BALB/cJ mice received one whole heart dose of 22 Gray (Gy) radiation via a C5 collimator vs. sham controls that received 0 Gy, anesthesia and were placed in the X-ray machine for the same length of time. Mechanisms of cardiotoxicity were examined at 24 h (innate cardiotoxicity), day 10 (acute cardiotoxicity) and day 35 (chronic cardiotoxicity) post irradiation. Results Females and males developed dsDNA breaks from radiation at day 10 but females had more damage than males ( p < 0.001). Vessel area and cardiac hypertrophy were increased by radiation at day 10 and 35 but were higher in males than females at day 35 ( p < 0.001, p = 0.001, respectively). Bulk RNA sequencing of the heart at day 10 revealed that females and males developed similar gene pathway responses to radiation by upregulating cellular repair pathways and downregulated mitochondrial function. However, females upregulated the master regulator of mitochondrial function, Pgc1α ( p = 0.0001), suggesting improved mitochondrial repair in females. By day 35, males developed heart failure with reduced ejection fraction (HFrEF), inflammatory dilated cardiomyopathy (iDCM) and fibrosis while females developed heart failure with preserved ejection fraction (HFpEF) without inflammation or fibrosis. Conclusions We observed sex differences in nearly every cardiac parameter that we examined following radiation exposure. BALB/c males exposed to 22 Gy radiation developed HFrEF and iDCM by day 35 while females developed HFpEF. Further research is needed to better understand mechanisms driving sex differences in RIHD using translational animal models.

Abstract Genetic loss of the mitochondrial control enzyme PINK1 leads to Parkinson’s disease, characterized by dopaminergic neuron degeneration and neuroinflammation, yet its role in glia remains poorly understood. To address this gap, we investigated how the function of astrocytes and their ability to support neurons is influenced by PINK1 deficiency. For the first time, we demonstrate that human astrocytes exhibit robust PINK1 activity. Next, the first bulk transcriptomic study of human PINK1 mutant astrocytes was performed followed by biochemical validation at the protein level, uncovering homeostatic collapse. Co-culture experiments demonstrated that this astrocyte dysfunction drives neuronal damage through non-cell-autonomous mechanisms. Notably, pharmacological enhancement of autophagy successfully mitigated this inflammatory secretome, indicating that mitochondrial quality control deficits are reversible. These findings establish an unexpected role for PINK1 in glial biology, reveal that astrocytes are vulnerable to mitophagy deficits, and highlight a novel mechanistic link connecting mitochondrial dysfunction, neuroinflammation, and neurodegeneration.

Abstract Introduction: Asynchronous online courses are plagued with the challenge of engaging students consistently. Behavioral interventions, such as bottlenecks (enforced deadlines) and nudges (automated reminders), may modulate behaviors that lead to engagement and can now be easily applied and measured in a Learning Management System (LMS). Methods: This study included three groups of three asynchronous online courses each over three academic quarters. Two distinct behavioral interventions, bottlenecks and nudges, were implemented to increase engagement with the course compared to non-intervention controls. Results: The results showed that behavioral intervention tools increase student engagement with course materials by measures of increased student access to the course and reduced time to quiz completion. However, there was no significant impact in grades across the three groups. Conclusion: The use of nudges and bottlenecks as behavioral interventions to increase engagement in asynchronous courses for Clinical and Translational Science Education is recommended as part of best practice in course design with the same or similar structure.

BACKGROUND Previous epidemiologic studies of autoimmune diseases in the US have included a limited number of diseases or used metaanalyses that rely on different data collection methods and analyses for each disease. METHODS To estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from 6 large medical systems in the US. We developed a software program using common methodology to compute the estimated prevalence of autoimmune diseases alone and in aggregate that can be readily used by other investigators to replicate or modify the analysis over time. RESULTS Our findings indicate that over 15 million people, or 4.6% of the US population, have been diagnosed with at least 1 autoimmune disease from January 1, 2011, to June 1, 2022, and 34% of those are diagnosed with more than 1 autoimmune disease. As expected, females (63% of those with autoimmune disease) were almost twice as likely as males to be diagnosed with an autoimmune disease. We identified the top 20 autoimmune diseases based on prevalence and according to sex and age. CONCLUSION Here, we provide, for what we believe to be the first time, a large-scale prevalence estimate of autoimmune disease in the US by sex and age. FUNDING Autoimmune Registry Inc., the National Heart Lung and Blood Institute, the National Center for Advancing Translational Sciences, the Intramural Research Program of the National Institute of Environmental Health Sciences.

AbstractPatients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease‐specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human‐platelet‐derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)‐like module‐containing mucin‐like hormone receptor‐like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll‐like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL‐1β), transforming growth factor‐beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7–9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T‐cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.

Viral infections are a leading cause of myocarditis and pericarditis worldwide, conditions that frequently coexist. Myocarditis and pericarditis were some of the early comorbidities associated with SARS-CoV-2 infection and COVID-19. Many epidemiologic studies have been conducted since that time concluding that SARS-CoV-2 increased the incidence of myocarditis/pericarditis at least 15× over pre-COVID levels although the condition remains rare. The incidence of myocarditis pre-COVID was reported at 1 to 10 cases/100 000 individuals and with COVID ranging from 150 to 4000 cases/100 000 individuals. Before COVID-19, some vaccines were reported to cause myocarditis and pericarditis in rare cases, but the use of novel mRNA platforms led to a higher number of reported cases than with previous platforms providing new insight into potential pathogenic mechanisms. The incidence of COVID-19 vaccine-associated myocarditis/pericarditis covers a large range depending on the vaccine platform, age, and sex examined. Importantly, the findings highlight that myocarditis occurs predominantly in male patients aged 12 to 40 years regardless of whether the cause was due to a virus-like SARS-CoV-2 or associated with a vaccine—a demographic that has been reported before COVID-19. This review discusses findings from COVID-19 and COVID-19 vaccine-associated myocarditis and pericarditis considering the known symptoms, diagnosis, management, treatment, and pathogenesis of disease that has been gleaned from clinical research and animal models. Sex differences in the immune response to COVID-19 are discussed, and theories for how mRNA vaccines could lead to myocarditis/pericarditis are proposed. Additionally, gaps in our understanding that need further research are raised.