Efficacy of moxidectin, using various dose regimens, against JYD-34, a macrocyclic lactone resistant isolate of Dirofilaria immitis.

BACKGROUND: Macrocyclic lactones (MLs) are the only class of drugs currently commercially available that are effective for preventing heartworm disease. The data presented in this article provide information on the efficacy of oral moxidectin against JYD-34, a known ML-resistant Dirofilaria immitis isolate, when dogs are treated under various dosing regimens. METHODS: Fifty-two purpose-bred Beagle dogs were used in five laboratory studies. All dogs were inoculated with 50 D. immitis third-stage larvae (L3) (JYD-34 isolate) 30 days prior to the first treatment. Dogs were randomized to treatment (four to five animals in each group) with one, three, or five monthly doses of oral moxidectin ranging from 6 to 100 µg/kg body weight. In each study, control dogs were not treated. Five to 6 months after L3 inoculation, dogs were euthanized, and adult worms were counted to evaluate efficacy of the dosing regimens. RESULTS: Adult heartworms were recovered from all control dogs, with an overall geometric mean of 29.7 worms (range 15.2 to 38.0, individual counts ranged from 8 to 51). Five monthly doses of 6 µg/kg provided 83.3% and 90.2%, efficacy, and the same number of monthly doses of 9 µg/kg demonstrated 98.8% and 94.1% efficacy. Three monthly doses of 30 and 50 µg/kg demonstrated 97.9% and 99.0% efficacy, respectively, while a single dose of 100 µg/kg demonstrated 91.1% efficacy. CONCLUSIONS: Five monthly doses of 9 µg/kg provided similar or only marginally lower efficacy against JYD-34, a known ML-resistant isolate, compared to substantially higher doses administered for 3 months. This underscores the importance of duration of exposure to moxidectin when facing ML-resistant isolates. Repeated administration of lower doses of moxidectin are an alternative to higher doses in the prevention of heartworm disease associated with less susceptible or resistant isolates.

Safety of an oral combination of moxidectin, afoxolaner, and pyrantel pamoate in dogs.

NexGard®PLUS (moxidectin, afoxolaner, and pyrantel pamoate), is an oral combination product for dogs indicated for the prevention of heartworm disease, the treatment and prevention of flea and tick infestations, and the treatment of gastro-intestinal nematode infections. The safety of this product in dogs was evaluated in three studies. Study #1 was a margin-of-safety study conducted in puppies, dosed six times at 28-day intervals at 1X, 3X, or 5X multiples of the maximum exposure dose (equivalent to 24 µg/kg moxidectin, 5 mg/kg afoxolaner, and 10 mg/kg pyrantel). In Study #2, the product was administered to ABCB1-deficient collie dogs at a 1X dose twice at a 28-day interval, and at a 3X or 5X dose once. Study #3 evaluated the safety of the product at 1X and 3X doses administered three times at 4-week intervals, to dogs harboring adult Dirofilaria immitis. In the three studies, the safety was evaluated on the basis of multiple clinical observations and physical examinations, including a complete assessment of toxicity to macrocyclic lactones, and on comprehensive clinical and anatomical pathology evaluations in Study #1. No clinically significant combination product-related effects were observed in any of the three studies. No signs of macrocyclic lactone toxicity were observed in the ABCB1-deficient collie dogs. Some mild and self-resolving instances of emesis or diarrhea were occasionally observed in the 3X and 5X dosed dogs. NexGard® PLUS was demonstrated to be safe following multiple administrations in puppies, in ABCB1-deficient collie dogs, and in microfilaremic dogs infected with adult D. immitis.

Early Treatment of Multisystem Inflammatory Syndrome in Children.

BACKGROUND AND OBJECTIVES: Multisystem inflammatory syndrome in children (MIS-C) is a severe hyperinflammatory illness occurring after severe acute respiratory syndrome coronavirus 2 infection. The optimal treatment of MIS-C is unknown, although prior studies have indicated benefits of intravenous immunoglobulin (IVIG) and glucocorticoids. We hypothesize that early treatment with glucocorticoids is associated with shorter hospital length of stay (LOS). METHODS: This study is a multicenter retrospective cohort study of patients hospitalized with MIS-C over a roughly 1-year period. The primary outcome was hospital LOS comparing subjects who received glucocorticoids within 48 hours of arrival to the treating hospital to those who did not. Secondary outcomes included ICU LOS. Unadjusted and adjusted analyses were performed. RESULTS: The final analysis included 131 subjects. Subjects who received early glucocorticoids were more likely to receive early IVIG and to require ICU admission. Early glucocorticoid administration was associated with shorter ICU LOS (4 vs 9 days, P = .004) in the unadjusted analysis. In the adjusted analysis, early glucocorticoid administration and early IVIG administration were both independently associated with shorter hospital LOS (incidence rate ratio 0.75, P = .025; incidence rate ratio 0.56, P = .026, respectively). CONCLUSIONS: Glucocorticoids and intravenous immunoglobulin were independently associated with shorter hospital length of stay when given early in hospitalization to MIS-C patients after accounting for potential confounding factors. The optimal dose and duration of treatment require further investigation, but this study supports early combination therapy with both IVIG and glucocorticoids for all children hospitalized with MIS-C.

Hypertension after multisystem inflammatory syndrome in children (MIS-C).

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is associated with SARS-CoV-2. Long-term consequences of MIS-C remain unknown. The objective was to describe the prevalence and clinical predictors of hypertension (HTN) and elevated blood pressure (BP) following MIS-C. METHODS: A retrospective study of children ≤ 18 years admitted to a tertiary center with MIS-C was performed. HTN and elevated BP were classified as per the 2017 American Academy of Pediatrics Clinical Practice Guidelines and indexed to the 95th percentile. Data included demographics, inpatient clinical measures, and echocardiograms over 1-year follow-up. Data were analyzed using Kruskal-Wallis, chi-square, and logistic regression. RESULTS: Among 63 children hospitalized with MIS-C (mean age 9.7 ± 4.2 years, 58.7% male, body mass index (BMI) z-score 0.59 ± 1.9), 14% had HTN, and 4% had elevated BP > 30 days post-hospitalization. Multivariate linear regression analysis showed that BMI z-score was significantly associated with higher mean systolic (ß = 2.664, CI = 1.307-3.980, p < 0.001) and diastolic (ß = 2.547, CI = 0.605-4.489, p = 0.012) BP index > 30 days post-hospitalization. Acute kidney injury (AKI) (23.8%) (OR = 2.977, CI = 1.778-4.987, p < 0.001), peak inpatient serum creatinine (OR = 2.524, CI = 1.344-4.740, p = 0.004), and maximum CRP (OR = 1.009, CI = 1.002-1.016, p = 0.014) were all associated with increased odds of post-hospitalization HTN. Left ventricular hypertrophy was present in 46% while hospitalized, compared to 10% at last follow-up. All had return of normal systolic function. CONCLUSIONS: Post-hospitalization HTN and elevated BP may be associated with MIS-C. Children with greater BMI or AKI may be at greater risk for developing HTN after MIS-C. MIS-C follow-up requires careful BP monitoring and antihypertensive medication consideration. A higher resolution version of the Graphical abstract is available as Supplementary information.

Efficacy of an oral combination of moxidectin, afoxolaner, and pyrantel pamoate for the prevention of heartworm disease in dogs.

Dirofilaria immitis, the mosquito-borne agent of dirofilariosis, a chronic and sometimes fatal cardiopulmonary canine disease, is endemic in most warm and temperate regions in the world. The efficacy of an oral endectoparasiticide product (test product or TP) combining moxidectin, afoxolaner, and pyrantel pamoate was evaluated for the prevention of heartworm disease in dogs, in two laboratory and one field studies. In each laboratory study, 20 D. immitis-naïve beagle dogs were experimentally infected with D. immitis. Ten control dogs were sham-treated, and ten dogs were administered the TP targeting the minimum effective dose, six times monthly and starting 30 days post infection. At necropsy seven months after inoculations, no heartworms were found in any of the TP treated dog, whereas 19 to 42 live heartworms were found in the control dogs. In each study, treatment efficacy was 100% and the difference between treated and untreated groups was highly significant (p < 0.0001). A field study was conducted through the full transmission season in several heartworm-endemic regions of the United States. One hundred and twenty client-owned dogs that were negative for D. immitis at enrollment were administered twelve monthly oral doses of the TP at label dose. Blood tests for D. immitis antigen and modified Knott's tests for microfilariae remained negative through the full duration of the study, demonstrating that all dogs were protected from heartworm infection during the full transmission season. These studies demonstrated that TP administered monthly for at least six doses is effective at preventing dirofilariosis.

Building Evidence for Principles to Guide the Development of Products for Adults with Intellectual and Developmental Disabilities and Extreme Low Literacy-A Product Development Tool.

This article presented a new product development tool for adults with intellectual and developmental disabilities (IDD) developed by the Centers for Disease Control and Prevention (CDC). People with IDD who also have extreme low literacy (ELL) have unique communication needs; public health communicators often face challenges developing effective communication materials for this audience. To support CDC communication specialists with the development of communication products for adults with IDD/ELL, CDC, with its partners RTI International and CommunicateHealth, created a product development tool for this audience through literature review, expert input, and interviews with adults with IDD/ELL and caregivers of adults with IDD/ELL. To build evidence around the principles described in the tool, RTI conducted interviewer-administered surveys with 100 caregivers who support people with IDD/ELL. During the interviews, we presented caregivers with stimuli (portions of a communication product) that either did or did not apply a single principle and asked which would be easier for the person they support to understand. Across all 14 principles tested, the caregiver respondents indicated that the principle-based version would be easier for the person they support to understand compared with the non-principle-based version(s). These findings provide additional evidence to support the principles included in CDC's Tool for Developing Products for People with IDD/ELL.

Isogenic Mammary Models of Intraductal Carcinoma Reveal Progression to Invasiveness in the Absence of a Non-Obligatory In Situ Stage.

In breast cancer, progression to invasive ductal carcinoma (IDC) involves interactions between immune, myoepithelial, and tumor cells. Development of IDC can proceed through ductal carcinoma in situ (DCIS), a non-obligate, non-invasive stage, or IDC can develop without evidence of DCIS and these cases associate with poorer prognosis. Tractable, immune-competent mouse models are needed to help delineate distinct mechanisms of local tumor cell invasion and prognostic implications. To address these gaps, we delivered murine mammary carcinoma cell lines directly into the main mammary lactiferous duct of immune-competent mice. Using two strains of immune-competent mice (BALB/c, C57BL/6), one immune-compromised (severe combined immunodeficiency; SCID) C57BL/6 strain, and six different murine mammary cancer cell lines (D2.OR, D2A1, 4T1, EMT6, EO771, Py230), we found early loss of ductal myoepithelial cell differentiation markers p63, α-smooth muscle actin, and calponin, and rapid formation of IDC in the absence of DCIS. Rapid IDC formation also occurred in the absence of adaptive immunity. Combined, these studies demonstrate that loss of myoepithelial barrier function does not require an intact immune system, and suggest that these isogenic murine models may prove a useful tool to study IDC in the absence of a non-obligatory DCIS stage-an under-investigated subset of poor prognostic human breast cancer.

Examination of Adverse Reactions After COVID-19 Vaccination Among Patients With a History of Multisystem Inflammatory Syndrome in Children.

Importance: Data are limited regarding adverse reactions after COVID-19 vaccination in patients with a history of multisystem inflammatory syndrome in children (MIS-C). The lack of vaccine safety data in this unique population may cause hesitancy and concern for many families and health care professionals. Objective: To describe adverse reactions following COVID-19 vaccination in patients with a history of MIS-C. Design, Setting, and Participants: In this multicenter cross-sectional study including 22 North American centers participating in a National Heart, Lung, and Blood Institute, National Institutes of Health-sponsored study, Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children (MUSIC), patients with a prior diagnosis of MIS-C who were eligible for COVID-19 vaccination (age ≥5 years; ≥90 days after MIS-C diagnosis) were surveyed between December 13, 2021, and February 18, 2022, regarding COVID-19 vaccination status and adverse reactions. Exposures: COVID-19 vaccination after MIS-C diagnosis. Main Outcomes and Measures: The main outcome was adverse reactions following COVID-19 vaccination. Comparisons were made using the Wilcoxon rank sum test for continuous variables and the χ2 or Fisher exact test for categorical variables. Results: Of 385 vaccine-eligible patients who were surveyed, 185 (48.1%) received at least 1 vaccine dose; 136 of the vaccinated patients (73.5%) were male, and the median age was 12.2 years (IQR, 9.5-14.7 years). Among vaccinated patients, 1 (0.5%) identified as American Indian/Alaska Native, non-Hispanic; 9 (4.9%) as Asian, non-Hispanic; 45 (24.3%) as Black, non-Hispanic; 59 (31.9%) as Hispanic or Latino; 53 (28.6%) as White, non-Hispanic; 2 (1.1%) as multiracial, non-Hispanic; and 2 (1.1%) as other, non-Hispanic; 14 (7.6%) had unknown or undeclared race and ethnicity. The median time from MIS-C diagnosis to first vaccine dose was 9.0 months (IQR, 5.1-11.9 months); 31 patients (16.8%) received 1 dose, 142 (76.8%) received 2 doses, and 12 (6.5%) received 3 doses. Almost all patients received the BNT162b2 vaccine (347 of 351 vaccine doses [98.9%]). Minor adverse reactions were observed in 90 patients (48.6%) and were most often arm soreness (62 patients [33.5%]) and/or fatigue (32 [17.3%]). In 32 patients (17.3%), adverse reactions were treated with medications, most commonly acetaminophen (21 patients [11.4%]) or ibuprofen (11 [5.9%]). Four patients (2.2%) sought medical evaluation, but none required testing or hospitalization. There were no patients with any serious adverse events, including myocarditis or recurrence of MIS-C. Conclusions and Relevance: In this cross-sectional study of patients with a history of MIS-C, no serious adverse events were reported after COVID-19 vaccination. These findings suggest that the safety profile of COVID-19 vaccination administered at least 90 days following MIS-C diagnosis appears to be similar to that in the general population.

What helps people to reduce or stop self-harm? A systematic review and meta-synthesis of first-hand accounts.

BACKGROUND: Self-harm is an important public health problem but therapeutic interventions, particularly for people who have a history of multiple repetition, are not always taken up or effective when they are. The aim of this review is to explore first-hand accounts of what helps outside therapy and identify actions and processes, which can support the reduction or cessation of self-harm. METHODS: A systematic review and thematic meta-synthesis of the first-person accounts of what has helped to reduce or stop self-harm reported in primary studies. RESULTS: The meta-synthesis combined 546 participant excerpts from 56 studies. Two over-arching themes were identified: (i) breaking the chain incorporated actions taken to break the link between a person's current psychological or social state and the act of self-harm and (ii) building a new foundation for change captured actions over the longer-term, focusing on practical changes in relationships and in a person's way of life, such as work or living arrangements. CONCLUSIONS: The results emphasize the importance of interpersonal change in reducing or stopping self-harm. While interpersonal factors are acknowledged as important reasons behind self-harm, they are often under-represented in self-management advice and therapeutic interventions that focus on individual psychopathology.

Assessment of Mental Health and Coping Disparities Among Racial and Ethnic Groups Amid COVID-19 From the "How Right Now" Campaign.

OBJECTIVES: How Right Now (HRN) is an evidence-based, culturally responsive communication campaign developed to facilitate coping and resilience among US groups disproportionately affected by the COVID-19 pandemic. To inform the development of this campaign, we examined patterns in emotional health, stress, and coping strategies among HRN's audiences, focusing on differences among racial and ethnic groups. METHODS: We used a national probability panel, AmeriSpeak, to collect survey data from HRN's priority audience members in English and Spanish at 2 time points (May 2020 and May 2021). We conducted statistical testing to examine differences between time points for each subgroup (Hispanic, non-Hispanic Black, and non-Hispanic White) and differences among subgroups at each time point. RESULTS: We found disparities in COVID-19-related mental health challenges and differences in coping strategies. Non-Hispanic Black respondents were more likely than non-Hispanic White respondents to report challenges related to the social determinants of health, such as affording food and housing (26.4% vs 9.4% in May 2020) and experiencing personal financial loss (46.6% vs 29.2% in May 2020). In May 2021, 30.6% of Hispanic respondents reported being unable to meet basic food or housing needs versus 8.2% of non-Hispanic White respondents, and 51.6% reported personal financial loss versus 26.5% of non-Hispanic White respondents. CONCLUSIONS: Our study further illuminates what is needed to build emotional well-being pathways for people who historically have been economically and socially marginalized. Our findings underscore the need for public health interventions to provide culturally responsive mental health support to populations disproportionately affected by COVID-19 during the pandemic and into the future, with a focus on racial and ethnic disparities.

The devil is in the details: Variable impacts of season, BMI, sampling site temperature, and presence of insects on the post-mortem microbiome.

Background: Post-mortem microbial communities are increasingly investigated as proxy evidence for a variety of factors of interest in forensic science. The reported predictive power of the microbial community to determine aspects of the individual's post-mortem history (e.g., the post-mortem interval) varies substantially among published research. This observed variation is partially driven by the local environment or the individual themselves. In the current study, we investigated the impact of BMI, sex, insect activity, season, repeat sampling, decomposition time, and temperature on the microbial community sampled from donated human remains in San Marcos, TX using a high-throughput gene-fragment metabarcoding approach. Materials and methods: In the current study, we investigated the impact of BMI, sex, insect activity, season, repeat sampling, decomposition time, and temperature on the microbial community sampled from donated human remains in San Marcos, TX using a high-throughput gene-fragment metabarcoding approach. Results: We found that season, temperature at the sampling site, BMI, and sex had a significant effect on the post-mortem microbiome, the presence of insects has a homogenizing influence on the total bacterial community, and that community consistency from repeat sampling decreases as the decomposition process progresses. Moreover, we demonstrate the importance of temperature at the site of sampling on the abundance of important diagnostic taxa. Conclusion: The results of this study suggest that while the bacterial community or specific bacterial species may prove to be useful for forensic applications, a clearer understanding of the mechanisms underpinning microbial decomposition will greatly increase the utility of microbial evidence in forensic casework.

Safety of oral afoxolaner formulated with or without milbemycin oxime in homozygous MDR1-deficient collie dogs.

Afoxolaner, an insecticide and acaricide compound of the isoxazoline class, is available for dogs as an oral ectoparasiticide medicine (NexGard®) and as an oral endectoparasiticide medicine in combination with milbemycin oxime (MO), a macrocyclic lactone (NexGard® Spectra). The safety of these two compounds, alone or in combination, was investigated in homozygous MDR1-deficient collie dogs, in two studies. Overall, 30 adult collie dogs were treated once orally, 9 with a placebo, 9 with afoxolaner, 6 with MO, and 6 with a combination of afoxolaner and MO. For afoxolaner, the mean investigated dosage corresponded to 3.8 and 4.7 multiples of the maximum recommended therapeutic doses (RTD) in NexGard® and NexGard® Spectra, respectively. For MO, the mean investigated dosage corresponded to 4.7 multiples of the maximum RTD in NexGard® Spectra. Dogs were closely monitored for adverse reactions on the day of treatment and for the following two days. No significant adverse reaction was observed in any dog from the afoxolaner or the afoxolaner + MO groups; in the MO-only treated group, mild and transient neurological signs were observed during the 4-8 h post-treatment window. These studies demonstrated a high level of safety of oral afoxolaner, alone or in combination with milbemycin oxime, in homozygous MDR1-deficient dogs.

Phylogenetic diversity of two common Trypanosoma cruzi lineages in the Southwestern United States.

Trypanosoma cruzi is the causative agent of Chagas disease, a devastating parasitic disease endemic to Central and South America, Mexico, and the USA. We characterized the genetic diversity of Trypanosoma cruzi circulating in five triatomine species (Triatoma gerstaeckeri, T. lecticularia, T.indictiva, T. sanguisuga and T. recurva) collected in Texas and Southern Arizona using multilocus sequence typing (MLST) with four single-copy loci (cytochrome oxidase subunit II- NADH dehydrogensase subunit 1 region (COII-ND1), mismatch-repair class 2 (MSH2), dihydrofolate reductase-thymidylate synthase (DHFR-TS) and a nuclear gene with ID TcCLB.506529.310). All T. cruzi variants fall in two main genetic lineages: 75% of the samples corresponded to T. cruzi Discrete Typing Unit (DTU) I (TcI), and 25% to a North American specific lineage previously labelled TcIV-USA. Phylogenetic and sequence divergence analyses of our new data plus all previously published sequence data from those four loci collected in the USA, show that TcIV-USA is significantly different from any other previously defined T. cruzi DTUs. The significant level of genetic divergence between TcIV-USA and other T. cruzi DTUs should lead to an increased focus on understanding the epidemiological importance of this DTU, as well as its geographical range and pathogenicity in humans and domestic animals. Our findings further corroborate the fact that there is a high genetic diversity of the parasite in North America and emphasize the need for appropriate surveillance and vector control programs for Chagas disease in southern USA and Mexico.

Valued attributes of professional support for people who repeatedly self-harm: A systematic review and meta-synthesis of first-hand accounts.

Therapeutic interventions are an important adjunct to self-help strategies for people who self-harm. There is little guidance for those offering therapy on the effective components of interventions for people who self-harm. This was a systematic review aiming to identify the factors that contribute to positive experiences of therapy as described by people who have reduced or stopped self-harm. The review followed PRISMA guidelines to locate and synthesize peer-reviewed qualitative studies describing experiences of therapy among people who had reduced or stopped self-harm. Study selection, data extraction, and quality assessment were peer reviewed and conducted for at least two researchers independently. Relevant first-hand quotations were extracted from eligible studies and synthesized using a thematic analysis in collaboration with experts with personal and professional experience of self-harm. Twenty-three studies met eligibility criteria. Themes identified in the reported accounts were arranged under two meta-themes. 'Positive aspects of seeing a professional' identified aspects of professional care that were common to all encounters: the value of sharing, space to talk and reflect, and the boundaries inherent in contact with a professional. 'Positive attributes of individual professionals' depended upon individual characteristics: the ability to build reciprocal trust by being non-judgemental, showing genuine empathic concern, and being confident to talk about and respond directly to self-harm. Our review indicates that therapeutic alliance is perceived as key to effective professional help for self-harm, irrespective of underlying principles of therapy. All forms of therapy should be timely and reliable and centred around the needs of the individual and their experience of self-harm.

Barriers and facilitators to accessing and utilising post-treatment psychosocial support by Black men treated for prostate cancer-a systematic review and qualitative synthesis.

PURPOSE: To synthesise findings from published studies on barriers and facilitators to Black men accessing and utilising post-treatment psychosocial support after prostate cancer (CaP) treatment. METHODS: Searches of Medline, Embase, PsycInfo, Cochrane Database of Systematic Reviews and Central, CINAHL plus and Scopus were undertaken from inception to May 2021. English language studies involving Black men aged ≥18 and reporting experiences of, or suggestions for, psychosocial support after CaP treatment were included. Low or moderate quality studies were excluded. Searches identified 4,453 articles and following deduplication, 2,325 were screened for eligibility. Two independent reviewers carried out screening, quality appraisal and data extraction. Data were analysed using thematic synthesis. RESULTS: Ten qualitative studies involving 139 Black men were included. Data analysis identified four analytical constructs: experience of psychosocial support for dealing with treatment side effects (including impact on self-esteem and fear of recurrence); barriers to use of psychosocial support (such as perceptions of masculinity and stigma around sexual dysfunction); facilitators to use of psychosocial support (including the influence of others and self-motivation); and practical solutions for designing and delivering post-treatment psychosocial support (the need for trusted healthcare and cultural channels). CONCLUSIONS: Few intervention studies have focused on behaviours among Black CaP survivors, with existing research predominantly involving Caucasian men. There is a need for a collaborative approach to CaP care that recognises not only medical expertise but also the autonomy of Black men as experts of their illness experience, and the influence of cultural and social networks.

Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults: Suspected Myocarditis After COVID-19 Vaccination.

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 <21 years old presenting before July 4, 2021, with suspected myocarditis within 30 days of COVID-19 vaccination. Lake Louise criteria were used for cardiac MRI findings. Myocarditis cases were classified as confirmed or probable on the basis of the Centers for Disease Control and Prevention definitions. 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 <55% on echocardiogram. Of 97 patients who underwent cardiac MRI at a median 5 days (range, 0-88; IQR, 3-17) from symptom onset, 75 (77.3%) had abnormal findings: 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria. Among 26 patients with left ventricular ejection fraction <55% on echocardiogram, all with follow-up had normalized function (n=25). CONCLUSIONS: Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms. Abnormal findings on cardiac MRI were frequent. Future studies should evaluate risk factors, mechanisms, and long-term outcomes.

Mammary collagen is under reproductive control with implications for breast cancer.

Mammographically-detected breast density impacts breast cancer risk and progression, and fibrillar collagen is a key component of breast density. However, physiologic factors influencing collagen production in the breast are poorly understood. In female rats, we analyzed gene expression of the most abundantly expressed mammary collagens and collagen-associated proteins across a pregnancy, lactation, and weaning cycle. We identified a triphasic pattern of collagen gene regulation and evidence for reproductive state-dependent composition. An initial phase of collagen deposition occurred during pregnancy, followed by an active phase of collagen suppression during lactation. The third phase of collagen regulation occurred during weaning-induced mammary gland involution, which was characterized by increased collagen deposition. Concomitant changes in collagen protein abundance were confirmed by Masson's trichrome staining, second harmonic generation (SHG) imaging, and mass spectrometry. We observed similar reproductive-state dependent collagen patterns in human breast tissue obtained from premenopausal women. SHG analysis also revealed structural variation in collagen across a reproductive cycle, with higher packing density and more collagen fibers arranged perpendicular to the mammary epithelium in the involuting rat mammary gland compared to nulliparous and lactating glands. Involution was also characterized by high expression of the collagen cross-linking enzyme lysyl oxidase, which was associated with increased levels of cross-linked collagen. Breast cancer relevance is suggested, as we found that breast cancer diagnosed in recently postpartum women displayed gene expression signatures consistent with increased collagen deposition and crosslinking compared to breast cancers diagnosed in age-matched nulliparous women. Using publicly available data sets, we found this involution-like, collagen gene signature correlated with poor progression-free survival in breast cancer patients overall and in younger women. In sum, these findings of physiologic collagen regulation in the normal mammary gland may provide insight into normal breast function, the etiology of breast density, and inform breast cancer risk and outcomes.

Probable vertical transmission of Alpha variant of concern (B.1.1.7) with evidence of SARS-CoV-2 infection in the syncytiotrophoblast, a case report.

Introduction: Definitive vertical transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been rarely reported. We present a case of a third trimester pregnancy with fetal distress necessitating cesarean section that demonstrated maternal, placental, and infant infection with the SARS-CoV-2 Alpha variant/B.1.1.7. Methods: CDC's Influenza SARS-CoV-2 Multiplex RT-PCR Assay was used to test for SARS-CoV-2 in a maternal NP swab, maternal plasma, infant NP swab, and formalin-fixed paraffin-embedded (FFPE) placental tissue specimens. Whole genome sequencing (WGS) was performed on maternal plasma, infant, and placental specimens to determine the SARS-CoV-2 genotype. Histopathological evaluation, SARS-CoV-2 immunohistochemistry testing (IHC), and electron microscopy (EM) analysis were performed on placenta, umbilical cord, and membrane FFPE blocks. Results: All specimens tested positive for SARS-CoV-2 by RT-PCR. WGS further revealed identical SARS-CoV-2 sequences from clade 20I/501Y.V1 (lineage Alpha/B.1.1.7) in maternal plasma, infant, and placental specimens. Histopathologic evaluation of the placenta showed histiocytic and neutrophilic intervillositis with fibrin deposition and trophoblast necrosis with positive SARS-CoV-2 immunostaining in the syncytiotrophoblast and electron microscopy evidence of coronavirus. Discussion: These findings suggest vertical transmission of SARS-CoV-2, supported by clinical course timing, identical SARS-CoV-2 genotypes from maternal, placental, and infant samples, and IHC and EM evidence of placental infection. However, determination of the timing or distinction between prepartum and peripartum SARS-CoV-2 transmission remains unclear.

Longitudinal analysis of cardiac abnormalities in pediatric patients with sickle cell anemia and effect of hydroxyurea therapy.

Cardiac abnormalities such as left ventricular hypertrophy, left ventricular dilation, and pulmonary hypertension in sickle cell anemia have been previously described. Hydroxyurea, a disease-modifying therapy for sickle cell anemia, has been used for several decades. Longitudinal assessment of echocardiographic abnormalities in children and young adults with sickle cell anemia receiving hydroxyurea therapy is lacking. The goal of this retrospective study was to determine the prevalence of echocardiographic abnormalities in children and young adults with sickle cell anemia and to examine the effects of hydroxyurea on reverse cardiac remodeling. We reviewed the records of patients with sickle cell anemia who underwent routine cardiac screening at Cohen Children's Medical Center between 2010 and 2017, followed by retrospective longitudinal analysis of echocardiograms performed on patients receiving treatment with hydroxyurea. Data on a total of 100 patients with sickle cell anemia were analyzed; 60 (60%) were being treated with hydroxyurea. Twenty-five (41.6%) of the patients on hydroxyurea had been treated for <1 year; these patients had a significantly greater prevalence of left ventricular dilation compared with those who had been on treatment for >1 year. Serial echocardiograms of patients receiving hydroxyurea were then analyzed. Left ventricular dilation and hypertrophy improved significantly with hydroxyurea treatment. In addition, the left ventricular volume and mass correlated negatively with duration of treatment with hydroxyurea. Our study provides evidence that prolonged hydroxyurea therapy may lead to reverse cardiac remodeling. Future studies should attempt to follow up this patient cohort for a longer duration.