Obesity and outcomes of Kawasaki disease and COVID-19-related multisystem inflammatory syndrome in children

IMPORTANCE: Obesity may affect the clinical course of Kawasaki disease (KD) in children and multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. OBJECTIVE: To compare the prevalence of obesity and associations with clinical outcomes in patients with KD or MIS-C. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, analysis of International Kawasaki Disease Registry (IKDR) data on contemporaneous patients was conducted between January 1, 2020, and July 31, 2022 (42 sites, 8 countries). Patients with MIS-C (defined by Centers for Disease Control and Prevention criteria) and patients with KD (defined by American Heart Association criteria) were included. Patients with KD who had evidence of a recent COVID-19 infection or missing or unknown COVID-19 status were excluded. MAIN OUTCOMES AND MEASURES: Patient demographic characteristics, clinical features, disease course, and outcome variables were collected from the IKDR data set. Using body mass index (BMI)/weight z score percentile equivalents, patient weight was categorized as normal weight (BMI \u3c85th percentile), overweight (BMI ≥85th to \u3c95th percentile), and obese (BMI ≥95th percentile). The association between adiposity category and clinical features and outcomes was determined separately for KD and MIS-C patient groups. RESULTS: Of 1767 children, 338 with KD (median age, 2.5 [IQR, 1.2-5.0] years; 60.4% male) and 1429 with MIS-C (median age, 8.7 [IQR, 5.3-12.4] years; 61.4% male) were contemporaneously included in the study. For patients with MIS-C vs KD, the prevalence of overweight (17.1% vs 11.5%) and obesity (23.7% vs 11.5%) was significantly higher (P \u3c .001), with significantly higher adiposity z scores, even after adjustment for age, sex, and race and ethnicity. For patients with KD, apart from intensive care unit admission rate, adiposity category was not associated with laboratory test features or outcomes. For patients with MIS-C, higher adiposity category was associated with worse laboratory test values and outcomes, including a greater likelihood of shock, intensive care unit admission and inotrope requirement, and increased inflammatory markers, creatinine levels, and alanine aminotransferase levels. Adiposity category was not associated with coronary artery abnormalities for either MIS-C or KD. CONCLUSIONS AND RELEVANCE: In this international cohort study, obesity was more prevalent for patients with MIS-C vs KD, and associated with more severe presentation, laboratory test features, and outcomes. These findings suggest that obesity as a comorbid factor should be considered at the clinical presentation in children with MIS-C

Analysis of Carbohydrate Storage Granules in the Diazotrophic Cyanobacterium Cyanothece sp. PCC 7822.

The unicellular diazotrophic cyanobacteria of the genus Cyanothece demonstrate oscillations in nitrogenase activity and H2 production when grown under 12 h light–12 h dark cycles. We established that Cyanothece sp. PCC 7822 allows for the construction of knock-out mutants and our objective was to improve the growth characteristics of this strain and to identify the nature of the intracellular storage granules. We report the physiological and morphological effects of reduction in nitrate and phosphate concentrations in BG-11 media on this strain. We developed a series of BG-11-derived growth media and monitored batch culture growth, nitrogenase activity and nitrogenase-mediated hydrogen production, culture synchronicity, and intracellular storage content. Reduction in NaNO3 and K2HPO4 concentrations from 17.6 and 0.23 to 4.41 and 0.06 mM, respectively, improved growth characteristics such as cell size and uniformity, and enhanced the rate of cell division. Cells grown in this low NP BG-11 were less complex, a parameter that related to the composition of the intracellular storage granules. Cells grown in low NP BG-11 had less polyphosphate, fewer polyhydroxybutyrate granules and many smaller granules became evident. Biochemical analysis and transmission electron microscopy using the histocytochemical PATO technique demonstrated that these small granules contained glycogen. The glycogen levels and the number of granules per cell correlated nicely with a 2.3 to 3.3-fold change from the minimum at L0 to the maximum at D0. The differences in granule morphology and enzymes between Cyanothece ATCC 51142 and CyanothecePCC 7822 provide insights into the formation of large starch-like granules in some cyanobacteria

Predictive Screening of M1 and M2 Macrophages Reveals the Immunomodulatory Effectiveness of Post Spinal Cord Injury Azithromycin Treatment

Spinal cord injury (SCI) triggers a heterogeneous macrophage response that when experimentally polarized toward alternative forms of activation (M2 macrophages) promotes tissue and functional recovery. There are limited pharmacological therapies that can drive this reparative inflammatory state. In the current study, we used in vitrosystems to comprehensively defined markers of macrophages with known pathological (M1) and reparative (M2) properties in SCI. We then used these markers to objectively define the macrophage activation states after SCI in response to delayed azithromycin treatment. Mice were subjected to moderate-severe thoracic contusion SCI. Azithromycin or vehicle was administered beginning 30 minutes post-SCI and then daily for 3 or 7 days post injury (dpi). We detected a dose-dependent polarization toward purportedly protective M2 macrophages with daily AZM treatment. Specifically, AZM doses of 10, 40, or 160 mg/kg decreased M1 macrophage gene expression at 3 dpi while the lowest (10 mg/kg) and highest (160 mg/kg) doses increased M2 macrophage gene expression at 7 dpi. Azithromycin has documented immunomodulatory properties and is commonly prescribed to treat infections in SCI individuals. This work demonstrates the utility of objective, comprehensive macrophage gene profiling for evaluating immunomodulatory SCI therapies and highlights azithromycin as a promising agent for SCI treatment

Expression of hepatocytic- and biliary-specific transcription factors in regenerating bile ducts during hepatocyte-to-biliary epithelial cell transdifferentiation

Background\ud Under compromised biliary regeneration, transdifferentiation of hepatocytes into biliary epithelial cells (BEC) has been previously observed in rats, upon exposure to BEC-specific toxicant methylene dianiline (DAPM) followed by bile duct ligation (BDL), and in patients with chronic biliary liver disease. However, mechanisms promoting such transdifferentiation are not fully understood. In the present study, acquisition of biliary specific transcription factors by hepatocytes leading to reprogramming of BEC-specific cellular profile was investigated as a potential mechanism of transdifferentiation in two different models of compromised biliary regeneration in rats.\ud \ud Results\ud In addition to previously examined DAPM + BDL model, an experimental model resembling chronic biliary damage was established by repeated administration of DAPM. Hepatocyte to BEC transdifferentiation was tracked using dipetidyl dipeptidase IV (DDPIV) chimeric rats that normally carry DPPIV only in hepatocytes. Following DAPM treatment, ~20% BEC population turned DPPIV-positive, indicating that they are derived from DPPIV-positive hepatocytes. New ductules emerging after DAPM + BDL and repeated DAPM exposure expressed hepatocyte-associated transcription factor hepatocyte nuclear factor (HNF) 4α and biliary specific transcription factor HNF1β. In addition, periportal hepatocytes expressed biliary marker CK19 suggesting periportal hepatocytes as a potential source of transdifferentiating cells. Although TGFβ1 was induced, there was no considerable reduction in periportal HNF6 expression, as observed during embryonic biliary development.\ud \ud Conclusions\ud Taken together, these findings indicate that gradual loss of HNF4α and acquisition of HNF1β by hepatocytes, as well as increase in TGFβ1 expression in periportal region, appear to be the underlying mechanisms of hepatocyte-to-BEC transdifferentiation

Azithromycin Drives Alternative Macrophage Activation and Improves Recovery and Tissue Sparing in Contusion Spinal Cord Injury

BACKGROUND: Macrophages persist indefinitely at sites of spinal cord injury (SCI) and contribute to both pathological and reparative processes. While the alternative, anti-inflammatory (M2) phenotype is believed to promote cell protection, regeneration, and plasticity, pro-inflammatory (M1) macrophages persist after SCI and contribute to protracted cell and tissue loss. Thus, identifying non-invasive, clinically viable, pharmacological therapies for altering macrophage phenotype is a challenging, yet promising, approach for treating SCI. Azithromycin (AZM), a commonly used macrolide antibiotic, drives anti-inflammatory macrophage activation in rodent models of inflammation and in humans with cystic fibrosis. METHODS: We hypothesized that AZM treatment can alter the macrophage response to SCI and reduce progressive tissue pathology. To test this hypothesis, mice (C57BL/6J, 3-month-old) received daily doses of AZM (160 mg/kg) or vehicle treatment via oral gavage for 3 days prior and up to 7 days after a moderate-severe thoracic contusion SCI (75-kdyn force injury). Fluorescent-activated cell sorting was used in combination with real-time PCR (rtPCR) to evaluate the disposition and activation status of microglia, monocytes, and neutrophils, as well as macrophage phenotype in response to AZM treatment. An open-field locomotor rating scale (Basso Mouse Scale) and gridwalk task were used to determine the effects of AZM treatment on SCI recovery. Bone marrow-derived macrophages (BMDMs) were used to determine the effect of AZM treatment on macrophage phenotype in vitro. RESULTS: In accordance with our hypothesis, SCI mice exhibited significantly increased anti-inflammatory and decreased pro-inflammatory macrophage activation in response to AZM treatment. In addition, AZM treatment led to improved tissue sparing and recovery of gross and coordinated locomotor function. Furthermore, AZM treatment altered macrophage phenotype in vitro and lowered the neurotoxic potential of pro-inflammatory, M1 macrophages. CONCLUSIONS: Taken together, these data suggest that pharmacologically intervening with AZM can alter SCI macrophage polarization toward a beneficial phenotype that, in turn, may potentially limit secondary injury processes. Given that pro-inflammatory macrophage activation is a hallmark of many neurological pathologies and that AZM is non-invasive and clinically viable, these data highlight a novel approach for treating SCI and other maladaptive neuroinflammatory conditions

Assessment of Apple Watch Series 6 pulse oximetry and electrocardiograms in a pediatric population

BACKGROUND: Recent technologic advances have resulted in increased development and utilization of direct-to-consumer cardiac wearable devices with various functionality. This study aimed to assess Apple Watch Series 6 (AW6) pulse oximetry and electrocardiography (ECG) in a cohort of pediatric patients. METHODS: This single-center, prospective study enrolled pediatric patients ≥ 3kg and having an ECG and/or pulse oximetry (SpO2) as part of their planned evaluation. Exclusion criteria: 1) non-English speaking patients and 2) patients in state custody. Simultaneous tracings were obtained for SpO2 and ECG with concurrent standard pulse oximeter and 12-lead ECG. AW6 automated rhythm interpretations were compared to physician over-read and categorized as accurate, accurate with missed findings, inconclusive (automated interpretation: inconclusive ), or inaccurate. RESULTS: A total of 84 patients were enrolled over a 5-week period. 68 patients (81%) were placed into the SpO2 and ECG arm, with 16 patients (19%) placed into the SpO2 only arm. Pulse oximetry data was successfully collected in 71/84 (85%) patients and ECG data in 61/68 (90%). ΔSpO2 between modalities was 2.0±2.6% (r = 0.76). ΔRR was 43±44msec (r = 0.96), ΔPR 19±23msec (r = 0.79), ΔQRS 12±13msec (r = 0.78), and ΔQT 20±19msec (r = 0.9). The AW6 automated rhythm analysis yielded a 75% specificity and found: 1) 40/61 (65.6%) accurate , 2) 6/61 (9.8%) accurate with missed findings , 3) 14/61 (23%) inconclusive , and 4) 1/61 (1.6%) incorrect. CONCLUSION: The AW6 can accurately measure oxygen saturation when compared to hospital pulse oximeters in pediatric patients and provide good quality single lead ECGs that allow for accurate measurement of RR, PR, QRS, and QT intervals with manual interpretation. The AW6-automated rhythm interpretation algorithm has limitations for smaller pediatric patients and patients with abnormal ECGs

Quasars and the Big Blue Bump

We investigate the ultraviolet-to-optical spectral energy distributions (SEDs) of 17 active galactic nuclei (AGNs) using quasi-simultaneous spectrophotometry spanning 900-9000 Angstrom (rest frame). We employ data from the Far Ultraviolet Spectroscopic Explorer (FUSE), the Hubble Space Telescope (HST), and the 2.1-meter telescope at Kitt Peak National Observatory (KPNO). Taking advantage of the short-wavelength coverage, we are able to study the so-called "big blue bump," the region where the energy output peaks, in detail. Most objects exhibit a spectral break around 1100 Angstrom. Although this result is formally associated with large uncertainty for some objects, there is strong evidence in the data that the far-ultraviolet spectral region is below the extrapolation of the near-ultraviolet-optical slope, indicating a spectral break around 1100 Angstrom. We compare the behavior of our sample to those of non-LTE thin-disk models covering a range in black-hole mass, Eddington ratio, disk inclination, and other parameters. The distribution of ultraviolet-optical spectral indices redward of the break, and far-ultraviolet indices shortward of the break, are in rough agreement with the models. However, we do not see a correlation between the far-ultraviolet spectral index and the black hole mass, as seen in some accretion disk models. We argue that the observed spectral break is intrinsic to AGNs, although intrinsic reddening as well as Comptonization can strongly affect the far-ultraviolet spectral index. We make our data available online in digital format.Comment: 32 pages (10pt), 12 figures. Accepted for publication in Ap

Understanding the effect of sheared flow on microinstabilities

The competition between the drive and stabilization of plasma microinstabilities by sheared flow is investigated, focusing on the ion temperature gradient mode. Using a twisting mode representation in sheared slab geometry, the characteristic equations have been formulated for a dissipative fluid model, developed rigorously from the gyrokinetic equation. They clearly show that perpendicular flow shear convects perturbations along the field at a speed we denote by $Mc_s$ (where $c_s$ is the sound speed), whilst parallel flow shear enters as an instability driving term analogous to the usual temperature and density gradient effects. For sufficiently strong perpendicular flow shear, $M >1$, the propagation of the system characteristics is unidirectional and no unstable eigenmodes may form. Perturbations are swept along the field, to be ultimately dissipated as they are sheared ever more strongly. Numerical studies of the equations also reveal the existence of stable regions when $M < 1$, where the driving terms conflict. However, in both cases transitory perturbations exist, which could attain substantial amplitudes before decaying. Indeed, for $M \gg 1$, they are shown to exponentiate $\sqrt{M}$ times. This may provide a subcritical route to turbulence in tokamaks.Comment: minor revisions; accepted to PPC