Patterns of Electrocardiographic Abnormalities in Children with Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), a common cardiomyopathy in children, is an important cause of morbidity and mortality. Early recognition and appropriate management are important. An electrocardiogram (ECG) is often used as a screening tool in children to detect heart disease. The ECG patterns in children with HCM are not well described.ECGs collected from an international cohort of children, and adolescents (≤ 21 years) with HCM were reviewed. 482 ECGs met inclusion criteria. Age ranged from 1 day to 21 years, median 13 years. Of the 482 ECGs, 57 (12%) were normal. The most common abnormalities noted were left ventricular hypertrophy (LVH) in 108/482 (22%) and biventricular hypertrophy (BVH) in 116/482 (24%) Of the patients with LVH/BVH (n = 224), 135 (60%) also had a strain pattern (LVH in 83, BVH in 52). Isolated strain pattern (in the absence of criteria for hypertrophy) was seen in 43/482 (9%). Isolated pathologic Q waves were seen in 71/482 (15%). Pediatric HCM, 88% have an abnormal ECG. The most common ECG abnormalities were LVH or BVH with or without strain. Strain pattern without hypertrophy and a pathologic Q wave were present in a significant proportion (24%) of patients. Thus, a significant number of children with HCM have ECG abnormalities that are not typical for "hypertrophy". The presence of the ECG abnormalities described above in a child should prompt further examination with an echocardiogram to rule out HCM.

Impact of cannabidiol treatment on regulatory T-17 cells and neutrophil polarization in acute kidney injury.

Hallmark features of acute kidney injury (AKI) include mobilization of immune and inflammatory mechanisms culminating in tissue injury. Emerging information indicates heterogeneity of neutrophils with pro- and anti-inflammatory functions (N1 and N2, respectively). Also, regulatory T-17 (Treg17) cells curtail T helper 17 (Th-17)-mediated proinflammatory responses. However, the status of Treg17 cells and neutrophil phenotypes in AKI are not established. Furthermore, cannabidiol exerts immunoregulatory effects, but its impact on Treg17 cells and neutrophil subtypes is not established. Thus, we examined the status of Treg17 cells and neutrophil subtypes in AKI and determined whether cannabidiol favors regulatory neutrophils and T cells accompanied with renoprotection. Accordingly, mice were subjected to bilateral renal ischemia-reperfusion injury (IRI), without or with cannabidiol treatment; thereafter, kidneys were processed for flow cytometry analyses. Renal IRI increased N1 and Th-17 but reduced N2 and Treg17 cells accompanied with disruption of mitochondrial membrane potential (ψm) and increased apoptosis/necrosis and kidney injury molecule-1 (KIM-1) immunostaining compared with their sham controls. Importantly, cannabidiol treatment preserved ψm and reduced cell death and KIM-1 accompanied by restoration of N1 and N2 imbalance and preservation of Treg17 cells while decreasing Th-17 cells. The ability of cannabidiol to favor development of Treg17 cells was further established using functional mixed lymphocytic reaction. Subsequent studies showed higher renal blood flow and reduced serum creatinine in cannabidiol-treated IRI animals. Collectively, our novel observations establish that renal IRI causes neutrophil polarization in favor of N1 and also reduces Treg17 cells in favor of Th-17, effects that are reversed by cannabidiol treatment accompanied with significant renoprotection.

Glucocorticoid-Induced Leucine Zipper Promotes Neutrophil and T-Cell Polarization with Protective Effects in Acute Kidney Injury.

The glucocorticoid-induced leucine zipper (GILZ) mediates anti-inflammatory effects of glucocorticoids. Acute kidney injury (AKI) mobilizes immune/inflammatory mechanisms, causing tissue injury, but the impact of GILZ in AKI is not known. Neutrophils play context-specific proinflammatory [type 1 neutrophil (N1)] and anti-inflammatory [type 2 neutrophil (N2)] functional roles. Also, regulatory T lymphocytes (Tregs) and regulatory T-17 (Treg17) cells exert counterinflammatory effects, including the suppression of effector T lymphocytes [e.g., T-helper (Th) 17 cells]. Thus, utilizing cell preparations of mice kidneys subjected to AKI or sham operation, we determined the effects of GILZ on T cells and neutrophil subtypes in the context of its renoprotective effect; these studies used the transactivator of transcription (TAT)-GILZ or the TAT peptide. AKI increased N1 and Th-17 cells but reduced N2, Tregs, and Treg17 cells in association with increased interleukin (IL)-17+ but reduced IL-10+ cells accompanied with the disruption of mitochondrial membrane potential (ψ m) and increased apoptosis/necrosis compared with sham kidneys. TAT-GILZ, compared with TAT, treatment reduced N1 and Th-17 cells but increased N2 and Tregs, without affecting Treg17 cells, in association with a reduction in IL-17+ cells but an increase in IL-10+ cells; TAT-GILZ caused less disruption of ψ m and reduced cell death in AKI. Importantly, TAT-GILZ increased perfusion of the ischemic-reperfused kidney but reduced tissue edema compared with TAT. Utilizing splenic T cells and bone marrow-derived neutrophils, we further showed marked reduction in the proliferation of Th cells in response to TAT-GILZ compared with response to TAT. Collectively, the results indicate that GILZ exerts renoprotection accompanied by the upregulation of the regulatory/suppressive arm of immunity in AKI, likely via regulating cross talk between T cells and neutrophils.

Sudden cardiac arrest in athletes and strategies to optimize preparedness.

Sudden cardiac arrest (SCA) is the leading cause of death in young athletes. Despite efforts to improve preparedness for cardiac emergencies, the incidence of out-of-hospital cardiac arrests in athletes remains high, and bystander awareness and readiness for SCA support are inadequate. Initiatives such as designing an emergency action plan (EAP) and mandating training in cardiopulmonary resuscitation (CPR) and automated external defibrillator use (AED) for team members and personnel can contribute to improved survival rates in SCA cases. This review provides an overview of SCA in athletes, focusing on identifying populations at the highest risk and evaluating the effectiveness of different screening practices in detecting conditions that may lead to SCA. We summarize current practices and recommendations for improving the response to SCA events, and we highlight the need for ongoing efforts to optimize preparedness through the implementation of EAPs and the training of individuals in CPR and AED use. Additionally, we propose a call to action to increase awareness and training in EAP development, CPR, and AED use for team members and personnel. To improve outcomes of SCA cases in athletes, it is crucial to enhance bystander awareness and preparedness for cardiac emergencies. Implementing EAPs and providing training in CPR and AED use for team members and personnel are essential steps toward improving survival rates in SCA cases.

Risk of Cardiovascular Events After COVID-19.

We aimed to determine absolute and relative risks of either symptomatic or asymptomatic SARS-CoV-2 infection for late cardiovascular (CV) events and all-cause mortality. We conducted a retrospective double cohort study of patients with either symptomatic or asymptomatic SARS-CoV-2 infection (COVID-19+ cohort) and its documented absence (COVID-19- cohort). The study investigators drew a simple random sample of records from all patients under the Oregon Health & Science University Healthcare (n = 65,585), with available COVID-19 test results, performed March 1, 2020 to September 13, 2020. Exclusion criteria were age <18 years and no established Oregon Health & Science University care. The primary outcome was a composite of CV morbidity and mortality. All-cause mortality was the secondary outcome. The study population included 1,355 patients (mean age 48.7 ± 20.5 years; 770 women [57%], 977 White non-Hispanic [72%]; 1,072 ensured [79%]; 563 with CV disease history [42%]). During a median 6 months at risk, the primary composite outcome was observed in 38 of 319 patients who were COVID-19+ (12%) and 65 of 1,036 patients who were COVID-19- (6%). In the Cox regression, adjusted for demographics, health insurance, and reason for COVID-19 testing, SARS-CoV-2 infection was associated with the risk for primary composite outcome (hazard ratio 1.71, 95% confidence interval 1.06 to 2.78, p = 0.029). Inverse probability-weighted estimation, conditioned for 31 covariates, showed that for every patient who was COVID-19+, the average time to all-cause death was 65.5 days less than when all these patients were COVID-19-: average treatment effect on the treated -65.5 (95% confidence interval -125.4 to -5.61) days, p = 0.032. In conclusion, either symptomatic or asymptomatic SARS-CoV-2 infection is associated with an increased risk for late CV outcomes and has a causal effect on all-cause mortality in a late post-COVID-19 period.

AMPK induces regulatory innate lymphoid cells after traumatic brain injury.

The CNS is regarded as an immunoprivileged organ, evading routine immune surveillance; however, the coordinated development of immune responses profoundly influences outcomes after brain injury. Innate lymphoid cells (ILCs) are cytokine-producing cells that are critical for the initiation, modulation, and resolution of inflammation, but the functional relevance and mechanistic regulation of ILCs are unexplored after acute brain injury. We demonstrate increased proliferation of all ILC subtypes within the meninges for up to 1 year after experimental traumatic brain injury (TBI) while ILCs were present within resected dura and elevated within cerebrospinal fluid (CSF) of moderate-to-severe TBI patients. In line with energetic derangements after TBI, inhibition of the metabolic regulator, AMPK, increased meningeal ILC expansion, whereas AMPK activation suppressed proinflammatory ILC1/ILC3 and increased the frequency of IL-10-expressing ILC2 after TBI. Moreover, intracisternal administration of IL-33 activated AMPK, expanded ILC2, and suppressed ILC1 and ILC3 within the meninges of WT and Rag1-/- mice, but not Rag1-/- IL2rg-/- mice. Taken together, we identify AMPK as a brake on the expansion of proinflammatory, CNS-resident ILCs after brain injury. These findings establish a mechanistic framework whereby immunometabolic modulation of ILCs may direct the specificity, timing, and magnitude of cerebral immunity.

Comparison of cardiovascular screening in college athletes by history and physical examination with and without an electrocardiogram: Efficacy and cost.

BACKGROUND: Preparticipation screening for conditions associated with sudden cardiac death (SCD) is required in college athletes. Previous cost analyses used theoretical models based on variable assumptions, but no study used real-life outcomes. OBJECTIVE: The purpose of this study was to compare disease prevalence, positive findings, and costs of 2 different screening strategies: history and physical examination alone (H&P) or with an electrocardiogram (H&P+ECG). METHODS: De-identified preparticipation data (2009-2017) from Pacific-12 Conference institutions were abstracted for cardiovascular history questions, cardiovascular physical examination, and ECG result. Secondary testing, cardiac diagnoses, return to play outcomes, and complications from testing were recorded. The costs of screening and secondary testing were based on the Centers for Medicare & Medicaid Services Physician Fee Schedule. RESULTS: A total of 8602 records (4955 H&P, 3647 H&P+ECG) were included. Eleven conditions associated with SCD were detected (2 H&P only, 9 H&P+ECG). The prevalence of cardiovascular conditions associated with SCD discovered with H&P alone was 0.04% (1/2454) compared to 0.24% (1/410) when ECG was added (P = .01) (odds ratio 5.17; 95% confidence interval 1.28-20.85; P = .02). Cost of screening and secondary testing with H&P alone was $130 per athlete and in the ECG-added group was $152 per athlete. The cost per diagnosis was $312,407 in the H&P group and $61,712 in the ECG-added group. There were no adverse outcomes from secondary testing or treatment. CONCLUSION: H&P with the addition of ECG is 6 times more likely to detect a cardiovascular condition associated with SCD than without. The addition of ECG improves the cost efficiency per diagnosis by 5-fold and should be considered at college institutions with appropriate resources.

Neutrophil extracellular traps exacerbate neurological deficits after traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized patients with TBI die from secondary pathological processes that develop during supervised care. Neutrophils, which orchestrate innate immune responses, worsen TBI outcomes via undefined mechanisms. We hypothesized that formation of neutrophil extracellular traps (NETs), a purported mechanism of microbial trapping, exacerbates acute neurological injury after TBI. NET formation coincided with cerebral hypoperfusion and tissue hypoxia after experimental TBI, while elevated circulating NETs correlated with reduced serum deoxyribonuclease-1 (DNase-I) activity in patients with TBI. Functionally, Toll-like receptor 4 (TLR4) and the downstream kinase peptidylarginine deiminase 4 (PAD4) mediated NET formation and cerebrovascular dysfunction after TBI. Last, recombinant human DNase-I degraded NETs and improved neurological function. Thus, therapeutically targeting NETs may provide a mechanistically innovative approach to improve TBI outcomes without the associated risks of global neutrophil depletion.

Niacin modulates macrophage polarization in Parkinson's disease.

Neuroinflammation remains a central piece in Parkinson's disease (PD) pathophysiology. However, mechanisms by which PD links to the neuroinflammation remain elusive. Here, for the first time, we report that lower dose of niacin in PD patients may affect macrophage polarization from M1 (pro-inflammatory) to M2 (counter-inflammatory) profile through the niacin receptor GPR109A. Skew in the peripheral macrophages were accompanied by improved quality of life assessments in patients. Low dose niacin supplementation may be beneficial in PD, boosting anti-inflammatory processes and suppressing inflammation. Varied niacin dosages for longer durations may further reveal the potential role of anti-inflammatory interventions in PD progression.

Applying fecal microbiota transplantation (FMT) to treat recurrent Clostridium difficile infections (rCDI) in children.

BACKGROUND: Fecal Microbiota Transplantation (FMT) is an innovative means of treating recurrent Clostridium difficile infection (rCDI), through restoration of gut floral balance. However, there is a lack of data concerning the efficacy of FMT and its impact on the gut microbiome among pediatric patients. This study analyzes clinical outcomes and microbial community composition among 15 pediatric patients treated for rCDI via FMT. METHODS: This is a prospective, observational, pilot study of 15 children ≤18 years, who presented for rCDI and who met inclusion criteria for FMT at a pediatric hospital and pediatric gastroenterology clinic. Past medical history and demographics were recorded at enrollment and subsequent follow-up. Specimens of the donors' and the patients' pre-FMT and post-FMT fecal specimen were collected and used to assess microbiome composition via 16S rRNA gene sequencing. RESULTS: FMT successfully prevented rCDI episodes for minimum of 3 months post-FMT in all patients, with no major adverse effects. Three patients reported continued GI bleeding; however, all three also had underlying Inflammatory Bowel Disease (IBD). Our analyses confirm a significant difference between pre-and post-FMT gut microbiome profiles (Shannon diversity index), whereas no significant difference was observed between post-FMT and donor microbiome profiles. At the phyla level, post-FMT profiles showed significantly increased levels of Bacteroidetes and significantly decreased levels of Proteobacteria. Subjects with underlying IBD showed no difference in their pre-and post-FMT profiles. CONCLUSION: The low rate of recurrence or re-infection by C. difficile, coupled with minimal adverse effects post-FMT, suggests that FMT is a viable therapeutic means to treat pediatric rCDI. Post-FMT microbiomes are different from pre-FMT microbiomes, and similar to those of healthy donors, suggesting successful establishment of a healthier microbiome.

Innate Immunity of Neonates and Infants.

Many important events occur at birth. The fetus is suddenly removed from a protected intra-uterine environment that is aquatic, warm, and nearly sterile, to the dry, cold external world laden with microbes. To survive, the neonate must interact with many organisms, making use of some, while vigorously defending against the others like a nation conducting trade with friendly countries and guarding against hostile ones from invading it, waging wars if necessary. Although, the neonatal immune system is plastic, however, it is highly tolerant which is due to both the fetal development during gestation as well as significant sudden changes in fetal environment and enormous exposure to the new antigens and intestinal bacteria and their products. This "quiescent mode" of innate immune system is part of a highly regulated process to fulfill all requirements of multi-layered process of early life, implemented effectively through the cells of innate immune system. While, most of the neonatal innate immune cells (e.g., neutrophils and monocytes) present contained activity and lower frequencies compared to their adult counterparts, innate lymphoid cells (ILCs), a distinct cellular component of innate immunity, show higher level of activity and presence during period of infancy compared to later stages of life and adulthood, which may suggest a role for ILCs in variable susceptibility to certain conditions during life time. In this review, while we focus on the characteristics and status of ILCs in neonatal immune system, we also draw an analogy from a national defense perspective because of the great similarities between that and the immune system by providing the known biological counterparts of all five core operational elements, the five Ds of defense, detection, discrimination, deployment, destruction, and de-escalation, with special focus on innate immunity, maternal support, and influence during the neonatal and infancy periods.