A Case Series of Children with Acute Hepatitis and Human Adenovirus Infection.

BACKGROUND: Human adenoviruses typically cause self-limited respiratory, gastrointestinal, and conjunctival infections in healthy children. In late 2021 and early 2022, several previously healthy children were identified with acute hepatitis and human adenovirus viremia. METHODS: We used International Classification of Diseases, 10th Revision, codes to identify all children (<18 years of age) with hepatitis who were admitted to Children's of Alabama hospital between October 1, 2021, and February 28, 2022; those with acute hepatitis who also tested positive for human adenovirus by whole-blood quantitative polymerase chain reaction (PCR) were included in our case series. Demographic, clinical, laboratory, and treatment data were obtained from medical records. Residual blood specimens were sent for diagnostic confirmation and human adenovirus typing. RESULTS: A total of 15 children were identified with acute hepatitis - 6 (40%) who had hepatitis with an identified cause and 9 (60%) who had hepatitis without a known cause. Eight (89%) of the patients with hepatitis of unknown cause tested positive for human adenovirus. These 8 patients plus 1 additional patient referred to this facility for follow-up were included in this case series (median age, 2 years 11 months; age range, 1 year 1 month to 6 years 5 months). Liver biopsies indicated mild-to-moderate active hepatitis in 6 children, some with and some without cholestasis, but did not show evidence of human adenovirus on immunohistochemical examination or electron microscopy. PCR testing of liver tissue for human adenovirus was positive in 3 children (50%). Sequencing of specimens from 5 children showed three distinct human adenovirus type 41 hexon variants. Two children underwent liver transplantation; all the others recovered with supportive care. CONCLUSIONS: Human adenovirus viremia was present in the majority of children with acute hepatitis of unknown cause admitted to Children's of Alabama from October 1, 2021, to February 28, 2022, but whether human adenovirus was causative remains unclear. Sequencing results suggest that if human adenovirus was causative, this was not an outbreak driven by a single strain. (Funded in part by the Centers for Disease Control and Prevention.).

Carnosic acid inhibits secretion of allergic inflammatory mediators in IgE-activated mast cells via direct regulation of Syk activation.

Mast cells are essential regulators of inflammation most recognized for their central role in allergic inflammatory disorders. Signaling via the high-affinity immunoglobulin E (IgE) receptor, FcεRI, leads to rapid degranulation of preformed granules and the sustained release of newly synthesized proinflammatory mediators. Our group recently established rosemary extract as a potent regulator of mast cell functions, attenuating MAPK and NF-κB signaling. Carnosic acid (CA)-a major polyphenolic constituent of rosemary extract-has been shown to exhibit anti-inflammatory effects in other immune cell models, but its role as a potential modulator of mast cell activation is undefined. Therefore, we sought here to determine the modulatory effects of CA in a mast cell model of allergic inflammation. We sensitized bone marrow-derived mast cells with anti-trinitrophenyl IgE and activated with allergen (TNP-BSA) under stem cell factor potentiation, in addition to treatment with CA. Our results indicate that CA significantly inhibits allergen-induced early phase responses including Ca2+ mobilization, ROS production, and subsequent degranulation. We also show CA treatment reduced late phase responses, including the release of all cytokines and chemokines examined following IgE stimulation and corresponding gene expression excepting that of CCL2. Importantly, we determined that CA mediates its inhibitory effects through modulation of tyrosine kinase Syk and downstream effectors TAK1 (Ser412) and Akt (Ser473) as well as NFκB signaling, while phosphorylation of FcεRI (γ chain) and MAPK proteins remained unaltered. These novel findings establish CA as a potent modulator of mast cell activation, warranting further investigation as a putative anti-allergy therapeutic.

Targeting glycogen synthase kinase 3 with CHIR99021 negatively regulates allergen-induced mast cell activation.

Mast cells are granulated immune sentinels responsible for allergic inflammation. Allergen-induced FcεRI-signaling leads to rapid degranulation in the early-phase and sustained production and release of pro-inflammatory mediators in the late phase. Glycogen synthase kinase 3 (GSK3) is a constitutively active serine/threonine kinase and a central molecular convergence point for several pro-inflammatory pathways. GSK3 inhibition has been shown to reduce inflammation but has not yet been fully characterized in mast cell activation. Therefore, the objective of this study was to evaluate GSK3 as a putative therapeutic target in allergic inflammation using the GSK3 inhibitor, CHIR99021. Here, we found that GSK3 inhibition impaired ROS production and degranulation. Through modulation of MKK4-JNK, c-jun, and NF-κB signaling, GSK3 inhibition reduced the production/release of IL-6, IL-13, TNF, and CCL1, while only the release of CCL2 and CCL3 was impaired. Furthermore, CHIR99021-mediated GSK3 inhibition altered the pro-inflammatory phenotype of mast cells, reducing c-kit receptor levels. This implicated GSK3 in FcεRI signaling, reducing release of IL-6, TNF, and CCL1 when stimulated through FcεRI, while CCL2 and CCL3 remained unaffected, and were increased when stimulated with SCF only. These results identify GSK3 as a potential therapeutic target of utility warranting further consideration in contexts of pathological mast cell activation.

Acute activation of SERCA with CDN1163 attenuates IgE-mediated mast cell activation through selective impairment of ROS and p38 signaling.

Mast cells are granulocytic immune sentinels present in vascularized tissues that drive chronic inflammatory mechanisms characteristic of allergic pathologies. IgE-mediated mast cell activation leads to a rapid mobilization of Ca2+ from intracellular stores, which is essential for the release of preformed mediators via degranulation and de novo synthesized proinflammatory cytokines and chemokines. Given its potent signaling capacity, the dynamics of Ca2+ localization are highly regulated by various pumps and channels controlling cytosolic Ca2+ concentrations. Among these is sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA), which functions to maintain low cytosolic Ca2+ concentrations by actively transporting cytosolic Ca2+ ions into the endoplasmic reticulum. In this study, we characterized the role of SERCA in allergen-activated mast cells using IgE-sensitized bone marrow-derived mast cells (BMMCs) treated with the SERCA activating compound, CDN1163, and simultaneously stimulated with allergen through FcεRI under stem cell factor (SCF) potentiation. Acute treatment with CDN1163 was found to attenuate early phase mast cell degranulation along with reactive oxygen species (ROS) production. Additionally, treatment with CDN1163 significantly reduced secretion of IL-6, IL-13, and CCL3, suggesting a role for SERCA in the late phase mast cell response. The protective effects of SERCA activation via CDN1163 treatment on the early and late phase mast cell response may be driven by the selective suppression of p38 MAPK signaling. Together, these findings implicate SERCA as an important regulator of the mast cell response to allergen and suggest SERCA activity may offer therapeutic potential targeting allergic pathologies, warranting further investigation.

Incidence of laboratory-confirmed influenza and RSV and associated presenteeism and absenteeism among healthcare personnel, Israel, influenza seasons 2016 to 2019.

BackgroundHealthcare personnel (HCP) are at high risk for respiratory infections through occupational exposure to respiratory viruses.AimWe used data from a prospective influenza vaccine effectiveness study in HCP to quantify the incidence of acute respiratory infections (ARI) and their associated presenteeism and absenteeism.MethodsAt the start and end of each season, HCP at two Israeli hospitals provided serum to screen for antibodies to influenza virus using the haemagglutination inhibition assay. During the season, active monitoring for the development of ARI symptoms was conducted twice a week by RT-PCR testing of nasal swabs for influenza and respiratory syncytial virus (RSV). Workplace presenteeism and absenteeism were documented. We calculated incidences of influenza- and RSV-associated ARI and applied sampling weights to make estimates representative of the source population.ResultsThe median age of 2,505 participating HCP was 41 years, and 70% were female. Incidence was 9.1 per 100 person-seasons (95% CI: 5.8-14.2) for RT-PCR-confirmed influenza and 2.5 per 100 person-seasons (95% CI: 0.9-7.1) for RSV illness. Each season, 18-23% of unvaccinated and influenza-negative HCP seroconverted. The incidence of seroconversion or RT-PCR-confirmed influenza was 27.5 per 100 person-seasons (95% CI: 17.8-42.5). Work during illness occurred in 92% (95% CI: 91-93) of ARI episodes, absence from work in 38% (95% CI: 36-40).ConclusionInfluenza virus and RSV infections and associated presenteeism and absenteeism were common among HCP. Improving vaccination uptake among HCP, infection control, and encouraging sick HCP to stay home are important strategies to reduce ARI incidence and decrease the risk of in-hospital transmission.

Pediatric Infection-Induced SARS-CoV-2 Seroprevalence Increases and Seroprevalence by Type of Clinical CareSeptember 2021 to February 2022.

BACKGROUND: Trends in estimates of US pediatric SARS-CoV-2 infection-induced seroprevalence from commercial laboratory specimens may overrepresent children with frequent health care needs. We examined seroprevalence trends and compared seroprevalence estimates by testing type and diagnostic coding. METHODS: Cross-sectional convenience samples of residual sera September 2021-February 2022 from 52 US jurisdictions were assayed for infection-induced SARS-CoV-2 antibodies; monthly seroprevalence estimates were calculated by age group. Multivariate logistic analyses compared seroprevalence estimates for specimens associated with International Classification of Diseases-Tenth Revision (ICD-10) codes and laboratory orders indicating well-child care with estimates for other pediatric specimens. RESULTS: Infection-induced SARS-CoV-2 seroprevalence increased in each age group, from 30 to 68 (14 years), 38 to 77 (511 years), and 40 to 74 (1217 years). On multivariate analysis, patients with well-child ICD-10 codes were seropositive more often than other patients aged 117 years (adjusted prevalence ratio [aPR] 1.04; 95 confidence interval [CI], 1.021.07); children aged 911 years receiving standard lipid screening were seropositive more often than those receiving other laboratory tests (aPR, 1.05; 95 CI, 1.021.08). CONCLUSIONS: Infection-induced seroprevalence more than doubled among children younger than 12 years between September 2021 and February 2022, and increased 85 in adolescents. Differences in seroprevalence by care type did not substantially impact US pediatric seroprevalence estimates.

Childhood household dysfunction is associated with reduced left ventricular mass in young adulthood.

The effect of adverse childhood experiences (ACEs) on left ventricular mass (LVM) and left ventricular function remains largely unknown across the lifespan. This study investigated the influence of ACEs on LVM and left ventricular function and whether inflammation influences this relationship. Two hundred forty-eight healthy young adults participated and a final sample of 217 (age, 22.6 ± 0.1 yr; females, 114) had complete data. Echocardiographic assessment of LVM was indexed to height2.7 (LVMHT) and body surface area (LVMBSA). Ejection fraction (EF) and fractional shortening were also assessed. Interleukin-6 (IL-6), C-reactive protein, tumor necrosis factor-α, and matrix metalloproteinase (MMP) 1-3 were measured and ACEs exposures were assessed based on exposure and nonexposure to childhood household dysfunction and maltreatment, and quantity of adversity, (i.e., <4 ACEs and ≥4 ACEs). Individuals who experienced household dysfunction demonstrated lower LVM, LVMHT, and LVMBSA (P < 0.01) and greater IL-6 (P < 0.05) than those who did not experience household dysfunction. Reduced MMP3 was present in individuals who experienced maltreatment (P < 0.05) and ≥4 ACEs (P < 0.01) compared with no maltreatment and <4 ACEs, respectively. After controlling for covariates (i.e., sex, recent life stress, height, body mass index, smoking, physical activity, and inflammation), a significant negative effect of household dysfunction on LVM, LVMHT, and LVMBSA persisted. Likewise, a negative effect on EF independent of covariates was observed in individuals who experienced ≥4 ACEs. As such, alterations in LVM and EF may be perpetuated through a toxic home environment, promoting left ventricular underdevelopment in young adulthood. The effect of which in midlife and beyond requires additional investigation.NEW & NOTEWORTHY This is the first study to investigate the influence of adverse childhood experiences (ACEs) on left ventricular mass (LVM) and function. We identified experiencing any childhood household dysfunction was associated with lower LVM in young adults independent of sex, recent life stress, BMI and height, smoking, physical activity, and inflammation. We speculate an inflection point in LVM occurs in midlife predisposing these individuals toward a hypertrophic profile and elevated risk of heart disease in later life, although this requires longitudinal investigation.

Adverse childhood experiences are associated with altered cardiovascular reactivity to head-up tilt in young adults.

Adverse childhood experiences (ACEs) are associated with greater prevalence of cardiovascular disease and altered acute stress reactivity. The current study investigated the effect of ACEs on hemodynamic and autonomic responses to orthostatic stress imposed by 60° head-up tilt (HUT) in young adults. Two-hundred twenty-six healthy young adults (age = 22.6 ± 1.5 yr; n = 116 females) without cardiovascular disease participated and had complete data. Participants underwent supine blood pressure (BP), R-R interval (RRI), cardiac output (CO), total peripheral resistance (TPR), and cardiovagal baroreflex sensitivity (cvBRS) testing followed by a transition to 60° HUT where measures were reassessed. Childhood adversity exposures were assessed based on categorical exposure and nonexposure to childhood household dysfunction and maltreatment, and <4 and ≥4 types of ACEs. Significantly greater increases in SBP (P < 0.05), DBP, MAP, and TPR (P < 0.01; all) following 60° HUT were observed in individuals with ≥4 compared with those with <4 types of ACEs. Attenuated decreases in RRI and cvBRS were observed in those with ≥4 types of ACEs (P < 0.05). Experiencing ≥4 types of ACEs was associated with augmented BP and TPR reactivity and a blunted decrease in cvBRS in response to 60° HUT in young adults. Results suggest that a reduced vagal response to orthostatic stress is present in those who have experienced ≥4 types of ACEs that may promote autonomic dysfunction. Future research examining the sympathetic and vagal baroreflex branches is warranted.

Postexercise serum from humans influences the biological tug of war of APP processing in human neuronal cells.

Neurodegenerative diseases such as Alzheimer's disease (AD) are becoming more prevalent in our aging society. One specific neuropathological hallmark of this disease is the accumulation of amyloid-ß (Aß) peptides, which aggregate to form extraneuronal plaques. Increased Aß peptides are often observed well before symptoms of AD develop, highlighting the importance of targeting Aß-producing pathways early on in disease progression. Evidence indicates that exercise has the capacity to reduce Aß peptide production in the brain; however, the mechanisms remain unknown. Exercise-induced signaling mediators could be the driving force behind some of the beneficial effects observed in the brain with exercise. The purpose of this study was to examine if postexercise serum and the factors it contains can alter neuronal amyloid precursor protein (APP) processing. Human SH-SY5Y neuronal cells were differentiated with retinoic acid for 5 days and treated with 10% pre- or postexercise serum from humans for 30 min. Cells were collected for analysis of acute (30 min; n = 6) or adaptive (24 h posttreatment; n = 6) responses. There were no statistical differences in a disintegrin and metalloproteinase 10 (ADAM10) and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) mRNA or protein expression with postexercise serum treatment at either time point. However, there was an increase in the ratio of soluble amyloid precursor protein α (sAPPα) to soluble amyloid precursor protein ß (sAPPß) protein content (P = 0.05) after 30 min of postexercise serum treatment. In addition, 30 min of postexercise serum treatment increased ADAM10 (P = 0.01) and BACE1 (P = 0.02) activity. These findings suggest that postexercise serum modulates important enzymes involved in APP processing, potentially pushing the cascade toward the nonamyloidogenic arm.

Association of Trends in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Seroprevalence and State-Issued Nonpharmaceutical Interventions: United States, 1 August 2020 to 30 March 2021.

BACKGROUND: We assess if state-issued nonpharmaceutical interventions (NPIs) are associated with reduced rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as measured through anti-nucleocapsid (anti-N) seroprevalence, a proxy for cumulative prior infection that distinguishes seropositivity from vaccination. METHODS: Monthly anti-N seroprevalence during 1 August 2020 to 30 March 2021 was estimated using a nationwide blood donor serosurvey. Using multivariable logistic regression models, we measured the association of seropositivity and state-issued, county-specific NPIs for mask mandates, gathering bans, and bar closures. RESULTS: Compared with individuals living in a county with all three NPIs in place, the odds of having anti-N antibodies were 2.2 (95% confidence interval [CI]: 2.0-2.3) times higher for people living in a county that did not have any of the 3 NPIs, 1.6 (95% CI: 1.5-1.7) times higher for people living in a county that only had a mask mandate and gathering ban policy, and 1.4 (95% CI: 1.3-1.5) times higher for people living in a county that had only a mask mandate. CONCLUSIONS: Consistent with studies assessing NPIs relative to COVID-19 incidence and mortality, the presence of NPIs were associated with lower SARS-CoV-2 seroprevalence indicating lower rates of cumulative infections. Multiple NPIs are likely more effective than single NPIs.