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Background: Understanding the clinical course and short-term outcomes of suspected myocarditis after the coronavirus disease 2019 (COVID-19) vaccination has important public health implications in the decision to vaccinate youth. Methods: We retrospectively collected data on patients Results: We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable) at 26 centers. Most patients were male (n=126, 90.6%) and White (n=92, 66.2%); 29 (20.9%) were Hispanic; and the median age was 15.8 years (range, 12.1–20.3; interquartile range [IQR], 14.5–17.0). Suspected myocarditis occurred in 136 patients (97.8%) after the mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the second dose. Symptoms started at a median of 2 days (range, 0–22; IQR, 1–3) after vaccination. The most common symptom was chest pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%), or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the intensive care unit, 2 were treated with inotropic/vasoactive support, and none required extracorporeal membrane oxygenation or died. Median hospital stay was 2 days (range, 0–10; IQR, 2–3). All patients had elevated troponin I (n=111, 8.12 ng/mL; IQR, 3.50–15.90) or T (n=28, 0.61 ng/mL; IQR, 0.25–1.30); 69.8% had abnormal ECGs and arrhythmias (7 with nonsustained ventricular tachycardia); and 18.7% had left ventricular ejection fraction Conclusions: Most cases of suspected COVID-19 vaccine myocarditis occurring in persons

Background Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. Methods We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. Results We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki’s disease–like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). Conclusions Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.)

In support of a clinical trial in the pediatric population, available nonclinical and clinical data provide input on the study design and safety monitoring considerations. When the existing data are lacking to support the safety of the planned pediatric clinical trial, a juvenile animal toxicity study is likely required. Usually a single relevant species, preferably a rodent, is chosen as the species of choice, while a nonrodent species can be appropriate when scientifically justified. Juvenile toxicology studies, in general, are complicated both conceptually and logistically. Development in young animals is a continuous process with different organs maturing at different rates and time. Structural and functional maturational differences have been shown to affect drug safety. Key points to consider in conducting a juvenile toxicology study include a comparative development of the organ systems, differences in the pharmacokinetics/absorption, distribution, metabolism, excretion (PK/ADME) profiles of the drug between young animal and child, and logistical requirement in the juvenile study design. The purpose of this publication is to note pertinent points to consider when designing and conducting juvenile toxicology studies and to aid in future modifications and enhancements of these studies to enable a superior predictability of safety of medicines in the pediatric population.

Gasoline-vapor condensate (BGVC) or condensed vapors from gasoline blended with methyl t-butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME) diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for developmental toxicity in Sprague-Dawley rats exposed via inhalation on gestation days (GD) 5-20 for 6h/day at levels of 0 (control filtered air), 2000, 10,000, and 20,000mg/m(3). These exposure durations and levels substantially exceed typical consumer exposure during refueling (1-7mg/m(3), 5min). Dose responsive maternal effects were reduced maternal body weight and/or weight change, and/or reduced food consumption. No significant malformations were seen in any study. Developmental effects occurred at 20,000mg/m(3) of G/TAME (reduced fetal body weight, increased incidence of stunted fetuses), G/TBA (reduced fetal body weight, increased skeletal variants) and G/DIPE (reduced fetal weight) resulting in developmental NOAEL of 10,000mg/m(3) for these materials. Developmental NOAELs for other materials were 20,000mg/m(3) as no developmental toxicity was induced in those studies. Developmental NOAELs were equal to or greater than the concurrent maternal NOAELs which ranged from 2000 to 20,000mg/m(3). There were no clear cut differences in developmental toxicity between vapors of gasoline and gasoline blended with the ether or alcohol oxygenates.

Four fragrances, 6-acetyl-1,1,2,4,4,7-hexamethyltetraline (AHTN), 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-γ-2-benzopyran (HHCB), musk ketone and musk xylene were tested for developmental toxicity in Sprague–Dawley rats (25/group, 3 groups/fragrance, 2 fragrances/corn oil control). Dosages tested were HHCB: 50, 150, 500 mg/kg per day; AHTN: 5, 15, 50 mg/kg per day; musk ketone: 15, 45, 150 mg/kg per day; musk xylene: 20, 60, 200 mg/kg per day. All dosages tested exceeded multiples of the estimated maximal daily human dermal exposure. Treatment (gavage, 5 ml/kg) occurred on GDs 7–17 and Caesarean-sectioning on GD 20. Based on the results of these studies, none of the four fragrances tested were more toxic in the conceptuses than in the dams. Maternal NOAELs were 50, 5, 15 and 20 mg/kg per day for HHCB, AHTN, musk ketone and musk xylene, respectively (150, 50, 45 and 60 mg/kg per day caused clinical signs and reduced weight gain and feed consumption). Developmental NOAELs were 150, 50, 45 and 200 mg/kg per day for HHCB, AHTN, musk ketone and musk xylene, respectively. No adverse effects on embryo-fetal viability, growth or morphology occurred at the highest dosages of AHTN (50 mg/kg per day) or musk xylene (200 mg/kg per day). Developmental toxicity occurred at the high-dosages of HHCB (axial skeletal malformations at 500 mg/kg per day) and musk ketone (increased postimplantation loss and reduced fetal body weight at 150 mg/kg per day). The results of this study indicate that under conditions of normal use, the tested fragrances do not pose a risk to human conceptuses.

We described and compared population structure, growth, mortality, and reproduction of northern Squawfish Ptychocheilus oregonensis among four reservoirs of the lower Columbia River and among four reservoirs of the lower Snake River. We also pooled data for comparisons among three larger areas: Columbia River reservoirs, Snake River reservoirs, and the unimpounded Columbia River downstream from Bonneville Dam. Females made up 76–100% of northern squawfish 380 mm fork length or greater in individual reservoirs, and 87–99% of fish 380 mm or greater in the three combined areas. Females lived longer and grew faster than males in all reservoirs and areas and had lower annual mortality rates in all but two reservoirs. Proportional stock density was highest and annual mortality rates were generally lowest in Columbia River reservoirs. Northern Squawfish downstream from Bonneville Dam had a lower mean relative weight and higher relative fecundity (eggs per unit fish weight) than populations in impoundmen...

Subchronic Oral Toxicity Study of Diisopropyl Methylphosphonate in Mink. Bucci, T. J., Wustenberg, W., Perman, V., Weiss, D. J., Dacre, J. C., L. P., Parker, R. M. (1994). Fundam. Appl. Toxicol. 22, 220-230. Diisopropyl methylphosphonate (DIMP), produced during manufacture of the chemical agent GB (Sarin), is a groundwater contaminant at Rocky Mountain Arsenal, Colorado. DIMP was fed for 90 days to dark brown "Ranch Wild" mink housed under controlled indoor conditions. One-year-old mink, 10 of each sex, were fed 0, 50, 450, 2700, 5400, or 8000 ppm in standard ranch diet. Actual DIMP consumption was 0, 8, 73, 400, 827, and 1136 mg/kg body wt/day, respectively. Two additional groups of 10 served as "pair-fed" controls. Body weight and food intake were recorded weekly. Complete blood count and 15 chemical analytes were measured at Weeks 0, 3, 7, and 13. Necropsy and microscopic examination were performed on all mink. No clinical morbidity or deaths occurred. Both sexes fed 8000 ppm ate approximately 20% less and weighed approximately 20% less than the controls; 5400 ppm females had a 10% weight decrement. Plasma cholinesterase (ChE) decreased in the top three dose groups starting at Week 3. At 13 weeks, decrements were approximately 50% but returned to normal after 1 week without DIMP. Erythrocyte ChE was not reduced. Heinz bodies occurred in 10-15% of RBCs in 50% of 8000 ppm mink at 13 weeks, and 0.1-2.0% of RBCs in 25% at 2700 ppm. There were mild decreases in RBC count, hematocrit, and hemoglobin, and increases in reticulocyte count, at the 5400 and 8000 ppm doses. All recovered within 3 weeks after DIMP was withdrawn. The 8000 ppm group had marginal splenic hematopoiesis, histologically. No other treatment-related changes were noted. The 450 ppm dose was a clear no-effect level (approximately 73 mg DIMP/kg body wt/day). Compared to reports of similar studies of DIMP in rats and dogs, these mink displayed no unique species susceptibility.

The design and conduct of developmental and reproductive toxicity (DART) studies and juvenile animal studies for pediatric drugs are among the most difficult in toxicology. DART studies require highly trained and skilled technicians to properly evaluate the reproductive and developmental aspects. The article addresses testing protocols for reproductive and developmental toxicology. Keywords: reproductive toxicology; developmental toxicology; fertility; parturition; lactation

This study addresses the viability of sol-gel encapsulated HRP (HRP:sol-gel) as a recyclable solid-state catalytic material. Ferric, ferric-CN, ferrous, and ferrous-CO forms of HRP:sol-gel were investigated by resonance Raman and UV-visible methods. Electronic and vibrational spectroscopic changes associated with changes in spin state, oxidation state, and ligation of the heme in HRP:sol-gel were shown to correlate with those of HRP in solution, showing that the heme remains a viable ligand-binding complex. Furthermore, the high-valent HRP:sol-gel intermediates, compound I and compound II, were generated and identified by time-resolved UV-visible spectroscopy. Catalytic activity of the HRP:sol-gel material was demonstrated by enzymatic assays by using I(-), guaiacol, and ABTS as substrates. Encapsulated HRP was shown to be homogeneously distributed throughout the sol-gel host. Differences in turnover rates between guaiacol and I(-) implicate mass transport of substrate through the silicate matrix as a defining parameter in the peroxidase activity of HRP:sol-gel. HRP:sol-gel was reused as a peroxidation catalyst for multiple reaction cycles without loss of activity, indicating that such materials show promise as reusable catalytic materials.

Reductions in testicular mass, sperm motility, and mating frequency have been attributed to the stresses caused by confinement of Sprague-Dawley male rats in nose-only inhalation exposure tubes. Testicular changes, including an increase in testicular atrophy, have been detected at an increased incidence in male rats used in inhalation studies as compared with rats of the same age and strain used in oral toxicity studies. This study was designed to determine whether nose-only exposure of male rats caused testicular toxicity under conditions of cooling of the exposure room and appropriate acclimation to the exposure tubes. In order to acclimate the rats to the nose-only inhalation exposure apparatus, all male rats were placed in the exposure tubes for at least four successively increasing time intervals (15, 30, 45, and 60 min) on 4 separate days, with a rest period of approximately 48 h between the first and second acclimation. Twenty male rats were exposed nose-only to filtered air for approximately 2 h per day for 28 days before cohabitation and continuing throughout a 14-day cohabitation period. To reduce thermal stress, the exposure room temperature was maintained at 64 to 70 degrees F. Twenty control rats were housed in the same room as the exposed rats but were not placed in exposure tubes. End points monitored were body weight, testicular weight, sperm count, sperm motility, and histopathology of the testes, epididymides, prostate, and seminal vesicles. The control rats gained weight more rapidly than the exposed rats. All the rats in both groups mated successfully, and testicular weights, normalized to body weight, were similar for both groups. More importantly, there were no microscopic changes that could be considered an adverse effect on the reproductive tissues in the male rats placed in exposure tubes. Thus, nose-only exposure for up to 2 h per day for a total of 42 days did not cause adverse effects on the reproductive organs, fertility, or reproductive performance of male rats under the conditions of this study.

Many pharmaceuticals are administered to children and adults as sprays provided in nebulizers or metered-dose inhalers. Stress associated with possible eye irritation and injury attributable to exposure to vapors and particulates during the required safety testing procedures of such medicines is a potential confounding factor in these studies. Reducing stress and the potential changes associated with stress is particularly important in safety studies involving pregnant animals because maternal stress has been known to be associated with adverse outcomes for the offspring. Training and acclimating rabbits to wearing modified pediatric swim goggles during exposure to vapors and aerosol particles provides a simple, inexpensive method to reduce or eliminate potential stress from eye irritation.

The Publisher wishes to appologise that the dosages of HHCB and AHTN were listed incorrectly in the above article. Page 173, left column, lines 11 to 21 should correctly read: Based on estimated maximal daily dermal dosages of 0.11 mg/kg/day of HHCB and 0.043 mg/kg/day of AHTN and 0.025 mg/kg/day of musk ketone and 0.014 mg/kg/day of musk xylene in humans (unpublished industry survey), the maternal dosage of fragrance ingredient during gestation would have to exceed the estimated maximum daily exposure by 165–2043 fold before adverse effects would be expected in the developing conceptus.

Early morphogenesis of the brain and its derivatives was studied in sixty-nine baboon and rhesus monkey embryos representing developmental stages 8--16, and compared with the staged human embryo. The baboon and rhesus monkey embryos develop in a similar temporal sequence when compared with human embryos with the following exceptions: 1) The respective developmental events for otic disc, adenohypophyseal pouch, and hippocampal internal sulcus formation in the baboon and rhesus monkey occur at stage 10, stages 11-12, and after stage 16, while the comparable stages in humans are 9, 10, and 16; 2) Alternatively, formation of the trigeminal primordium and the motor root of the trigeminal nerve and evagination of the neurohypophysis occur earlier in the baboon and rhesus monkey (i.e., stages 12-13, stage 14, and stage 15, respectively) than observed in the human embryo (stage 14, stage 15, and stage 16, respectively); and 3) Lens pore closure in baboon and human embryos takes place during stage 14, while in the rhesus monkey closure occurs during stage 15.