Left Atrial Strain in Multisystem Inflammatory Syndrome in Children and Associations with Systemic Inflammation and Cardiac Injury.

Multisystem inflammatory syndrome in children (MIS-C) commonly involves cardiac injury with both systolic and diastolic dysfunction. Left atrial strain (LAS) detects subclinical diastolic dysfunction in adults but is infrequently used in children. We evaluated LAS in MIS-C and the associations with systemic inflammation and cardiac injury. In this retrospective cohort study, LAS parameters [reservoir (LAS-r), conduit (LAS-cd), and contractile (LAS-ct)] obtained from admission echocardiograms of MIS-C patients were compared to healthy controls and between MIS-C patients with and without cardiac injury (BNP > 500 pg/ml or troponin-I > 0.04 ng/ml). Correlation and logistic regression analyses were performed to assess LAS associations with admission inflammatory and cardiac biomarkers. Reliability testing was performed. We identified 118 patients with MIS-C and 20 healthy controls. Median LAS parameters were reduced in MIS-C patients compared to controls (LAS-r: 31.8 vs. 43.1%, p < 0.001; LAS-cd: - 28.8 vs. - 34.5%, p = 0.006; LAS-ct: - 5.2 vs. - 9.3%, p < 0.001) and reduced in MIS-C patients with cardiac injury (n = 59) compared to no injury (n = 59) (LAS-r: 29.6 vs. 35.8%, p = 0.001; LAS-cd: - 26.5 vs. - 30.4%, p = 0.036; LAS-ct: - 4.6 vs. - 9.3%, p = 0.008). A discrete LAS-ct peak was absent in 65 (55%) MIS-C patients but present in all controls (p < 0.001). Procalcitonin correlated strongly with averaged E/e' (r = 0.55, p = 0.001). Moderate correlations were found for ESR and LAS-ct (r = - 0.41, p = 0.007) as well as BNP and LAS-r (r = - 0.39, p < 0.001) and LAS-ct (r = 0.31, p = 0.023). Troponin-I had only weak correlations. Intra-rater reliability was good for all LAS parameters, and inter-rater reliability was good to excellent for LAS-r, and fair for LAS-cd and LAS-ct. LAS analysis, particularly the absence of a LAS-ct peak, was reproducible and may be superior to conventional echocardiographic parameters for detecting diastolic dysfunction in MIS-C. No strain parameters on admission were independently associated with cardiac injury.

Baseline Echocardiography and Laboratory Findings in MIS-C and Associations with Clinical Illness Severity.

Children with COVID-associated multisystem inflammatory syndrome (MIS-C) may develop severe disease. We explored the association of admission echocardiographic and laboratory parameters with MIS-C disease severity. This retrospective, single center study of consecutive MIS-C patients (4/2020-12/2021) excluded those with preexisting cardiomyopathy, congenital heart disease, or prior cardiotoxic therapy. Our hypothesis was that worse admission echocardiographic and laboratory parameters were associated with more severe disease based on vasoactive medication use. Univariable and multivariable logistic regression models assessed the association between vasoactive medication use and baseline variables. Of 118 MIS-C patients, median age was 7.8 years (IQR 4.6, 11.8), 48% received vasoactive medication. Higher admission brain natriuretic peptide [OR 1.07 (95% CI 1.02,1.14), p = 0.019], C-reactive protein [OR 1.08 (1.03,1.14), p = 0.002], troponin [OR 1.05 (1.02,1.1), p = 0.015]; lower left ventricular ejection fraction [LVEF, OR 0.96 (0.92,1), p = 0.042], and worse left atrial reservoir strain [OR 0.96 (0.92,1), p = 0.04] were associated with vasoactive medication use. Only higher CRP [OR 1.07 (1.01, 1.11), p = 0.034] and lower LVEF [0.91 (0.84,0.98), p = 0.015] remained independently significant. Among those with normal admission LVEF (78%, 92/118), 43% received vasoactive medication and only higher BNP [OR 1.09 (1.02,1.19), p = 0.021 per 100 pg/mL] and higher CRP [OR 1.07 (1.02,1.14), p = 0.013] were associated with use of vasoactive medication. Nearly half of all children admitted for MIS-C subsequently received vasoactive medication, including those admitted with a normal LVEF. Similarly, admission strain parameters were not discriminatory. Laboratory markers of systemic inflammation and cardiac injury may better predict early MIS-C disease severity.

Left atrial strain in multisystem inflammatory syndrome in children (MIS-C) and associations with systemic inflammation and cardiac injury.

Background: Multisystem inflammatory syndrome in children (MIS-C) commonly involves cardiac injury with both systolic and diastolic dysfunction. Left atrial strain (LAS) detects subclinical diastolic dysfunction in adults but is infrequently used in children. We evaluated LAS in MIS-C and the associations with systemic inflammation and cardiac injury. Methods: In this retrospective cohort study, conventional parameters and LAS (reservoir [LAS-r], conduit [LAS-cd], and contractile [LAS-ct]) obtained from admission echocardiograms of MIS-C patients were compared to healthy controls and between MIS-C patients with and without cardiac injury (BNP >500 pg/ml or troponin-I >0.04 ng/ml). Correlation and logistic regression analyses were performed to assess LAS associations with admission inflammatory and cardiac biomarkers. Reliability testing was performed. Results: Median LAS components were reduced in MIS-C patients (n=118) compared to controls (n=20) (LAS-r: 31.8 vs. 43.1%, p<0.001; LAS-cd: -28.8 vs. -34.5%, p=0.006; LAS-ct: -5.2 vs. -9.3%, p<0.001) and reduced in MIS-C patients with cardiac injury (n=59) compared to no injury (n=59) (LAS-r: 29.6 vs. 35.8%, p=0.001; LAS-cd: -26.5 vs. -30.4%, p=0.036; LAS-ct: -4.6 vs. -9.3%, p=0.008). An LAS-ct peak was absent in 65 (55%) MIS-C patients but present in all controls (p<0.001). Procalcitonin had strong correlation with averaged E/e' (r=0.55, p=0.001); ESR had moderate correlation with LAS-ct (r=-0.41, p=0.007); BNP had moderate correlation with LAS-r (r=-0.39, p<0.001) and LAS-ct (r=0.31, p=0.023), and troponin-I had only weak correlations. No strain indices were independently associated with cardiac injury on regression analysis. Intra-rater reliability was good for all LAS components; and inter-rater reliability was good to excellent for LAS-r, and fair for LAS-cd and LAS-ct. Conclusions: LAS analysis, particularly the absence of a LAS-ct peak, was reproducible and may be superior to conventional echocardiographic parameters for detecting diastolic dysfunction in MIS-C. No strain parameters on admission were independently associated with cardiac injury.

Bacteria commonly associated with central nervous system catheter infections elicit distinct CSF proteome signatures.

Background: Cerebrospinal fluid (CSF) shunt infection is a common and devastating complication of the treatment of hydrocephalus. Timely and accurate diagnosis is essential as these infections can lead to long-term neurologic consequences including seizures, decreased intelligence quotient (IQ) and impaired school performance in children. Currently the diagnosis of shunt infection relies on bacterial culture; however, culture is not always accurate since these infections are frequently caused by bacteria capable of forming biofilms, such as Staphylococcus epidermidis, Cutibacterium acnes, and Pseudomonas aeruginosa resulting in few planktonic bacteria detectable in the CSF. Therefore, there is a critical need to identify a new rapid, and accurate method for diagnosis of CSF shunt infection with broad bacterial species coverage to improve the long-term outcomes of children suffering from these infections. Methods: To investigate potential biomarkers that would discriminate S. epidermidis, C. acnes and P. aeruginosa central nervous system (CNS) catheter infection we leveraged our previously published rat model of CNS catheter infection to perform serial CSF sampling to characterize the CSF proteome during these infections compared to sterile catheter placement. Results: P. aeruginosa infection demonstrated a far greater number of differentially expressed proteins when compared to S. epidermidis and C. acnes infection and sterile catheters, and these changes persisted throughout the 56-day time course. S. epidermidis demonstrated an intermediate number of differentially expressed proteins, primarily at early time points that dissipated over the course of infection. C. acnes induced the least amount of change in the CSF proteome when compared to the other pathogens. Conclusions: Despite the differences in the CSF proteome with each organism compared to sterile injury, several proteins were common across all bacterial species, especially at day 5 post-infection, which are candidate diagnostic biomarkers.

Cutibacterium acnes Central Nervous System Catheter Infection Induces Long-Term Changes in the Cerebrospinal Fluid Proteome.

Cutibacterium acnes is the third most common cause of cerebrospinal fluid (CSF) shunt infection and is likely underdiagnosed due to the difficulty in culturing this pathogen. Shunt infections lead to grave neurologic morbidity for patients especially when there is a delay in diagnosis. Currently, the gold standard for identifying CSF shunt infections is microbiologic culture. However, C. acnes infection often results in falsely negative cultures; therefore, new diagnostic methods are needed. To investigate potential CSF biomarkers of C. acnes CSF shunt infection we adapted a rat model of CSF catheter infection to C. acnes. We found elevated levels of interleukin-1ß (IL-1ß), IL-6, chemokine ligand 2, and IL-10 in the CSF and brain tissues of animals implanted with C. acnes-infected catheters compared to sterile controls at day 1 postinfection. This coincided with modest increases in neutrophils in the CSF and, to a greater extent, in the brain tissues of animals with C. acnes infection, which closely mirrors the clinical findings in patients with C. acnes shunt infection. Mass spectrometry revealed that the CSF proteome is altered during C. acnes shunt infection and changes over the course of disease, typified at day 1 postinfection by an acute-phase and pathogen neutralization response evolving to a response consistent with wound resolution at day 28 compared to a sterile catheter placement. Collectively, these results demonstrate that it is possible to distinguish C. acnes infection from sterile postoperative inflammation and that CSF proteins could be useful in a diagnostic strategy for this pathogen that is difficult to diagnose.

Identification of Potential Cerebrospinal Fluid Biomarkers To Discriminate between Infection and Sterile Inflammation in a Rat Model of Staphylococcus epidermidis Catheter Infection.

Staphylococcus epidermidis cerebrospinal fluid (CSF) shunt infection is a common complication of hydrocephalus treatment, creating grave neurological consequences for patients, especially when diagnosis is delayed. The current method of diagnosis relies on microbiological culture; however, awaiting culture results may cause treatment delays, or culture may fail to identify infection altogether, so newer methods are needed. To investigate potential CSF biomarkers of S. epidermidis shunt infection, we developed a rat model allowing for serial CSF sampling. We found elevated levels of interleukin-10 (IL-10), IL-1ß, chemokine ligand 2 (CCL2), and CCL3 in the CSF of animals implanted with S. epidermidis-infected catheters compared to sterile controls at day 1 postinfection. Along with increased chemokine and cytokine expression early in infection, neutrophil influx was significantly increased in the CSF of animals with infected catheters, suggesting that coupling leukocyte counts with inflammatory mediators may differentiate infection from sterile inflammation. Mass spectrometry analysis revealed that the CSF proteome in sterile animals was similar to that in infected animals at day 1; however, by day 5 postinfection, there was an increase in the number of differently expressed proteins in the CSF of infected compared to sterile groups. The expansion of the proteome at day 5 postinfection was interesting, as bacterial burdens began to decline by this point, yet the CSF proteome data indicated that the host response remained active, especially with regard to the complement cascade. Collectively, these results provide potential biomarkers to distinguish S. epidermidis infection from sterile postoperative inflammation.

CSF inflammatory markers differ in gram-positive versus gram-negative shunt infections.

BACKGROUND: Cerebrospinal fluid (CSF) shunt placement is frequently complicated by bacterial infection. Shunt infection diagnosis relies on bacterial culture of CSF which can often produce false-negative results. Negative cultures present a conundrum for physicians as they are left to rely on other CSF indices, which can be unremarkable. New methods are needed to swiftly and accurately diagnose shunt infections. CSF chemokines and cytokines may prove useful as diagnostic biomarkers. The objective of this study was to evaluate the potential of systemic and CSF biomarkers for identification of CSF shunt infection. METHODS: We conducted a retrospective chart review of children with culture-confirmed CSF shunt infection at Children's Hospital and Medical Center from July 2013 to December 2015. CSF cytokine analysis was performed for those patients with CSF in frozen storage from the same sample that was used for diagnostic culture. RESULTS: A total of 12 infections were included in this study. Patients with shunt infection had a median C-reactive protein (CRP) of 18.25 mg/dL. Median peripheral white blood cell count was 15.53 × 103 cells/mL. Those with shunt infection had a median CSF WBC of 332 cells/mL, median CSF protein level of 406 mg/dL, and median CSF glucose of 35.5 mg/dL. An interesting trend was observed with gram-positive infections having higher levels of the anti-inflammatory cytokine interleukin (IL)-10 as well as IL-17A and vascular endothelial growth factor (VEGF) compared to gram-negative infections, although these differences did not reach statistical significance. Conversely, gram-negative infections displayed higher levels of the pro-inflammatory cytokines IL-1ß, fractalkine (CX3CL1), chemokine ligand 2 (CCL2), and chemokine ligand 3 (CCL3), although again these were not significantly different. CSF from gram-positive and gram-negative shunt infections had similar levels of interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), IL-6, and IL-8. CONCLUSIONS: This pilot study is the first to characterize the CSF cytokine profile in patients with CSF shunt infection and supports the distinction of chemokine and cytokine profiles between gram-negative and gram-positive infections. Additionally, it demonstrates the potential of CSF chemokines and cytokines as biomarkers for the diagnosis of shunt infection.

IL-10 plays an important role in the control of inflammation but not in the bacterial burden in S. epidermidis CNS catheter infection.

BACKGROUND: Shunt infection is a frequent and serious complication in the surgical treatment in hydrocephalus. Previous studies have shown an attenuated immune response to these biofilm-mediated infections. We proposed that IL-10 reduces the inflammatory response to Staphylococcus epidermidis (S. epidermidis) CNS catheter infection. METHODS: In this study, a murine model of catheter-associated S. epidermidis biofilm infection in the CNS was generated based on a well-established similar model for S. aureus. The catheters were pre-coated with a clinically derived biofilm-forming strain of S. epidermidis (strain 1457) which were then stereotactically implanted into the lateral left ventricle of 8-week-old C57BL/6 and IL-10 knockout (IL-10 knockout) mice. Bacterial titers as well as cytokine and chemokine levels were measured at days 3, 5, 7, and 10 in mice implanted with sterile and S. epidermidis-coated catheters. RESULTS: Cultures demonstrated a catheter-associated and parenchymal infection that persisted through 10 days following infection. Cytokine analysis of the tissue surrounding the catheters revealed greater levels of IL-10, an anti-inflammatory cytokine, in the infected group compared to the sterile. In IL-10 KO mice, we noted no change in bacterial burdens, showing that IL-10 is not needed to control the infection in a CNS catheter infection model. However, IL-10 KO mice had increased levels of pro-inflammatory mediators in the tissues immediately adjacent to the infected catheter, as well as an increase in weight loss. CONCLUSIONS: Together our results indicate that IL-10 plays a key role in regulating the inflammatory response to CNS catheter infection but not in control of bacterial burdens. Therefore, IL-10 may be a useful therapeutic target for immune modulation in CNS catheter infection but this should be used in conjunction with antibiotic therapy for bacterial eradication.

Stereoelectronic Model To Explain Highly Stereoselective Reactions of Seven-Membered-Ring Oxocarbenium-Ion Intermediates.

Nucleophilic attack on seven-membered-ring oxocarbenium ions is generally highly stereoselective. The preferred mode of nucleophilic attack forms the product in a conformation that minimizes transannular interactions, thus leading to different stereoselectivity as compared to that of reactions involving six-membered-ring oxocarbenium ions.

Rhodium-catalyzed endo-selective epoxide-opening cascades: formal synthesis of (-)-brevisin.

[Rh(CO)2Cl]2 is as an effective catalyst for endo-selective cyclizations and cascades of epoxy-(E)-enoate alcohols, thus enabling the synthesis of oxepanes and oxepane-containing polyethers from di- and trisubstituted epoxides. Syntheses of the ABC and EF ring systems of (-)-brevisin via all endo-diepoxide-opening cascades using this method constitute a formal total synthesis and demonstrate the utility of this methodology in the context of the synthesis of marine ladder polyether natural products.

Ni(II) salts and 2-propanol effect catalytic reductive coupling of epoxides and alkynes.

A Ni-catalyzed reductive coupling of alkynes and epoxides using Ni(II) salts and simple alcohol reducing agents is described. Whereas previously reported conditions relied on Ni(cod)(2) and Et(3)B, this system has several advantages including the use of air-stable and inexpensive Ni(II) precatalysts (e.g., NiBr(2)·3H(2)O) as the source of Ni(0) and simple alcohols (e.g., 2-propanol) as the reducing agent. Deuterium-labeling experiments are consistent with oxidative addition of an epoxide C-O bond that occurs with inversion of configuration.

Erosion of stereochemical control with increasing nucleophilicity: O-glycosylation at the diffusion limit.

Nucleophilic substitution reactions of 2-deoxyglycosyl donors indicated that the reactivity of the oxygen nucleophile has a significant impact on stereoselectivity. Employing ethanol as the nucleophile resulted in a 1:1 (alpha:beta) ratio of diastereomers under S(N)1-like reaction conditions. Stereoselective formation of the 2-deoxy-alpha-O-glycoside was only observed when weaker nucleophiles, such as trifluoroethanol, were employed. The lack of stereoselectivity observed in reactions of common oxygen nucleophiles can be attributed to reaction rates of the stereochemistry-determining step that approach the diffusion limit. In this scenario, both faces of the prochiral oxocarbenium ion are subject to nucleophilic addition to afford a statistical mixture of diastereomeric products. Control experiments confirmed that all nucleophilic substitution reactions were performed under kinetic control.

C-glycosylation reactions of sulfur-substituted glycosyl donors: evidence against the role of neighboring-group participation.

Nucleophilic substitution reactions of C-4 sulfur-substituted tetrahydropyran acetals revealed that neighboring-group participation does not control product formation. Spectroscopic evidence for the formation of an intermediate sulfonium ion is provided, as are data from nucleophilic substitution reactions demonstrating that products are formed from oxocarbenium ion intermediates. The selectivity was not sensitive to solvent or to which Lewis acid was employed. The identity of the heteroatom at the C-4 position also did not significantly impact diastereoselectivity. Consequently, neighboring-group participation was not responsible for the formation of either the major or the minor products. These studies implicate a Curtin-Hammett kinetic scenario in which the formation of a low-energy intermediate does not necessitate its involvement in the product-forming pathway.