A Review of Syphilis Infection in Pediatric Patients.

Nearly half of all sexually transmitted infections occur in adolescents and young adults. Among them, syphilis infections are on the rise in the United States. Sexually active adolescents, especially those who do not use condoms consistently or are men who have sex with men, are at particular risk for syphilis infection. With the rise in acquired syphilis infections, the incidence of congenital syphilis has also increased. Syphilis can have a variety of presentations based on infectious stage and central nervous system involvement. Careful physical examination and history can elicit the diagnosis. Screening with a nontreponemal test followed by treponemal testing can confirm the diagnosis, and staging is determined clinically. Testing for all sexually transmitted infections should be pursued because coinfections are common. Penicillin is the first-line treatment for syphilis, and duration of therapy depends on the presence of neurologic symptoms; all infants with possible congenital syphilis should receive treatment. Posttreatment monitoring is essential to confirm successful eradication of syphilis. All sexually active, at-risk patients, including pregnant persons, should be screened for syphilis, and those diagnosed as having syphilis should be counseled on disclosure to partners. Although not often found in a pediatric population, with the increasing incidence of syphilis infections in the United States, pediatric providers should have a low threshold for syphilis screening in adolescents and a high index of suspicion for congenital syphilis in infants.

Impact of the COVID-19 Pandemic on Low-Value Testing and Treatment of Bronchiolitis.

BACKGROUND: Viral testing and treatments such as systemic steroids and inhaled corticosteroids are low-value care for routine bronchiolitis. We sought to determine the impact of the COVID-19 pandemic on low-value care in young children with bronchiolitis. METHODS: This was a retrospective, cross-sectional study using the Pediatric Health Information Systems database. We included children <2 years seen in a pediatric emergency department for bronchiolitis. We selected a priori 3 study periods: September 2018 to February 2020 (prepandemic), March 2020 to August 2022 (early pandemic), and September 2022 to January 2023 (late pandemic). Low-value care included respiratory syncytial virus testing, chest radiography, albuterol, or corticosteroids and was compared across the 3 time periods. RESULTS: At least 1 element of low-value care was provided in 45%, 47%, and 44% of encounters in the prepandemic, early pandemic, and late pandemic periods, respectively. There was little variation in the use of albuterol and chest radiography across time periods and a slight increase in systemic corticosteroid use from prepandemic to early and late pandemic groups. Viral testing increased from 36% prepandemic to 65% early pandemic and 67% late pandemic, which appeared to be driven by SARS-CoV-2 testing and combination viral testing. CONCLUSIONS: There was no clinically significant change in low-value care for bronchiolitis during the pandemic. Because of SARS-CoV-2 testing, however, overall frequency of viral testing increased dramatically over time. This marked increase in overall viral testing should be taken into consideration for future quality improvement efforts.

Structured Callouts, the Shared Mental Model, and Teamwork: A Video-Based Study in a Pediatric Emergency Department.

OBJECTIVES: The shared mental model is essential to high-quality resuscitations. A structured callout (SCO) is often performed to establish the shared mental model, but the literature on SCOs is limited. The objectives of this study are to describe performance of SCOs during pediatric medical emergencies and to determine whether a SCO is associated with better teamwork. METHODS: This was a retrospective study in the resuscitation area of an academic pediatric emergency department, where performance of a SCO is a standard expectation. Only medical or nontrauma patients were eligible for inclusion. Data collection was performed by structured video review by 2 observers and verified by a third blinded observer. A SCO was defined as team leader (Pediatric Emergency Medicine fellow or faculty physician) verbalization of at least 1 element of the patient history/examination or an assessment of patient physiology and 1 element of the diagnostic or therapeutic plan. We independently measured teamwork using the Teamwork Emergency Assessment Measure (TEAM) tool. RESULTS: We reviewed 60 patient encounters from the pediatric emergency department resuscitation area between April 2018 and June 2020. Median patient age was 6 years; the team leader was a Pediatric Emergency Medicine fellow in 55% of encounters. The physician team leader performed a SCO in 38 (63%) of patient encounters. The TEAM scores were collected for 46 encounters. Mean TEAM score (SD) was 42.3 (1.7) in patients with a SCO compared with 40.0 (3.0) in those without a SCO ( P = 0.007). CONCLUSIONS: Performance of a SCO was associated with better teamwork, but the difference was of unclear clinical significance.

HIV in youth prevention in the emergency department initiative: A survey of pediatric emergency medicine providers.

BACKGROUND: The incidence of HIV among adolescents remains high, and adolescents are known to participate in sexual behaviors that increase their risk for HIV, such as unprotected sex and sex with multiple partners. HIV pre-exposure prophylaxis (PrEP) has been shown to be effective at preventing HIV when taken daily and is approved by the FDA for use in adolescents. Efforts to screen patients in adult emergency departments and connect them with PrEP services have been validated. We surveyed pediatric emergency medicine (PEM) providers to determine their knowledge of PrEP, prescribing practices, willingness to prescribe, and barriers to a screening protocol in the pediatric emergency department (PED). METHODS: We administered a survey to a multidisciplinary group of PEM providers to measure knowledge, use, willingness, and implementation barriers to PrEP as well as elements needed for a successful referral system. RESULTS: A total of 87 responses were included for analysis. While 79.1% of all providers had heard of PrEP, only 14.8% of prescribing providers had ever discussed PrEP with a patient, and none had ever prescribed PrEP. Overall, 76.3% of all providers were knowledgeable about PrEP based on answers to true/false questions, with prescribing providers significantly more likely to be knowledgeable compared to nurses (p = 0.005). Knowledgeable providers had higher willingness scores to refer for PrEP compared to providers who were not knowledgeable. Ninety-two percent of providers felt a PrEP referral process from the PED would be feasible. Creation of an eligibility algorithm and educational materials were the most common efforts providers preferred to make them more likely to refer for PrEP. The most notable barriers perceived by providers included patient noncompliance with therapy (20.9%), acceptance of PrEP discussion among patients and parents (19.8%), and cost of therapy (15.1%). CONCLUSION: PEM providers are knowledgeable about PrEP but have little experience with discussing or prescribing PrEP. Their willingness to refer for PrEP and anticipated feasibility of a PrEP referral system is encouraging. These results support the need for future educational efforts among PEM providers and creation of referral systems for PrEP services from the PED.

Differences in palliative opportunities across diagnosis groups in children with cancer.

BACKGROUND: Childhood cancer causes significant physical and emotional stress. Patients and families benefit from palliative care (PC) to reduce symptom burden, improve quality of life, and enhance family-centered care. We evaluated palliative opportunities across leukemia/lymphoma (LL), solid tumors (ST), and central nervous system (CNS) tumor groups. PROCEDURE: A priori, nine palliative opportunities were defined: disease progression/relapse, hematopoietic stem cell transplant, phase 1 trial enrollment, admission for severe symptoms, social concerns or end-of-life (EOL) care, intensive care admission, do-not-resuscitate (DNR) status, and hospice enrollment. A single-center retrospective review was completed on 0-18-year olds with cancer who died from January 1, 2012 to November 30, 2017. Demographic, disease, and treatment data were collected. Descriptive statistics were performed. Opportunities were evaluated from diagnosis to death and across disease groups. RESULTS: Included patients (n = 296) had LL (n = 87), ST (n = 114), or CNS tumors (n = 95). Palliative opportunities were more frequent in patients with ST (median 8) and CNS tumors (median 7) versus LL (median 5, p = .0005). While patients with ST had more progression/relapse opportunities (p < .0001), patients with CNS tumors had more EOL opportunities (p < .0001), earlier PC consultation, DNR status, and hospice enrollment. Palliative opportunities increased toward the EOL in all diseases (p < .0001). PC was consulted in 108 (36%) patients: LL (48%), ST (30%), and CNS (34%, p = .02). CONCLUSIONS: All children with cancer incur many events warranting PC support. Patients with ST and CNS tumors had more palliative opportunities than LL, yet received less subspecialty PC. Understanding palliative opportunities within each disease group can guide PC utilization to ease patient and family stress.

Evaluating Palliative Opportunities Across the Age Spectrum in Children and Adolescent Patients with Cancer.

Purpose: Adolescent patients with cancer experience unique stressors due to their developmental stage, with increased physical, emotional, and social distress. Palliative care (PC) serves an important role in pediatric cancer care. We examined "palliative opportunities," or events during a patient's cancer course where subspecialty PC would be warranted and compared opportunities between adolescents and younger patients. Methods: Patients from a single center, 0-18 years of age at cancer diagnosis, who died from January 1, 2012, to November 30, 2017, were included. In this secondary analysis, patients were divided into cohorts based on age at diagnosis: 0-12 and 13-18 years. Demographic, disease, and treatment data were collected. Descriptive statistics and modeling were performed. Number, type, and timing of palliative opportunities and PC consultation timing and reason were evaluated across cohorts. Results: Of the 296 patients included for analysis, 27.7% were 13-18 years (82/296) at diagnosis. Frequency of palliative opportunities did not differ by age (median 7.0 [interquartile range 4.0 and 10.0] in both cohorts). PC consultation occurred in 36.5% (108/296), with neither rate nor timing differing by age group. PC consultations in adolescents were more often for symptom management (p = 0.0001). Adolescent patients were less likely to have a do-not-resuscitate order placed before death (61.0%, 50/82) compared to younger patients (73.8%, 158/214, p = 0.03). Conclusion: Adolescent patients with cancer did not experience more palliative opportunities than younger patients in this cohort, although they often have challenging psychological, family, and social stressors that were not identified. Incorporating additional palliative opportunities could enhance identification of stress and symptoms in adolescents with cancer such that PC could be timed to meet their needs.

Evaluating palliative opportunities in pediatric patients with leukemia and lymphoma.

BACKGROUND: Despite favorable prognoses, pediatric patients with hematologic malignancies experience significant challenges that may lead to diminished quality of life or family stress. They are less likely to receive subspecialty palliative care (PC) consultation and often undergo intensive end-of-life (EOL) care. We examined "palliative opportunities," or events when the integration of PC would have the greatest impact, present during a patient's hematologic malignancy course and relevant associations. METHODS: A single-center retrospective review was conducted on patients aged 0-18 years with a hematologic malignancy who died between 1/1/12 and 11/30/17. Demographic, disease, and treatment data were collected. A priori, nine palliative opportunity categories were defined. Descriptive statistics were performed. Palliative opportunities were evaluated over temporal quartiles from diagnosis to death. Timing and rationale of pediatric PC consultation were evaluated. RESULTS: Patients (n = 92) had a median of 5.0 (interquartile range [IQR] 6.0) palliative opportunities, incurring 522 total opportunities, increasing toward the EOL. Number and type of opportunities did not differ by demographics. PC consultation was most common in patients with lymphoid leukemia (50.9%, 28/55) and myeloid leukemia (48.5%, 16/33) versus lymphoma (0%, 0/4, p = 0.14). Forty-four of ninety-two patients (47.8%) received PC consultation a median of 1.8 months (IQR 4.1) prior to death. Receipt of PC was associated with transplant status (p = 0.0018) and a higher number of prior palliative opportunities (p = 0.0005); 70.3% (367/522) of palliative opportunities occurred without PC. CONCLUSION: Patients with hematologic malignancies experience many opportunities warranting PC support. Identifying opportunities for ideal timing of PC involvement may benefit patients with hematologic cancers and their caregivers.

Characterization of a hyperphosphorylated variant of G protein-coupled receptor kinase 5 expressed in E. coli.

G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors in humans and regulate numerous physiological processes through the activation of heterotrimeric G proteins. GPCR kinases (GRKs) selectively phosphorylate active GPCRs, which promotes arrestin binding, receptor internalization, and initiation of alternative signaling pathways. GRK5 is a representative member of one of three GRK subfamilies that does not need post-translational lipidation or other binding partners to exhibit full activity against GPCRs, rendering it a useful tool for biophysical studies directed at characterizing GRK function. However, recombinant expression of GRK5 has thus far been limited to insect and mammalian systems. Here, we describe the expression of functional GRK5 in E. coli and its purification and biochemical characterization. Bacterially expressed GRK5 is hyperphosphorylated, primarily in regions known to be flexible from prior crystal structures, which slightly decreases its catalytic activity toward receptor substrates. Mutation of a single phosphorylation site, Thr10, restores kinetic parameters to those of GRK5 purified from insect cells. Consequently, bacterial expression will allow for production of GRK5 at a reduced cost and faster pace and would facilitate production of isotopically labeled kinase for NMR studies or for the incorporation of unnatural amino acids.

Perturbation of the interactions of calmodulin with GRK5 using a natural product chemical probe.

G protein-coupled receptor (GPCR) kinases (GRKs) are responsible for initiating desensitization of activated GPCRs. GRK5 is potently inhibited by the calcium-sensing protein calmodulin (CaM), which leads to nuclear translocation of GRK5 and promotion of cardiac hypertrophy. Herein, we report the architecture of the Ca2+·CaM-GRK5 complex determined by small-angle X-ray scattering and negative-stain electron microscopy. Ca2+·CaM binds primarily to the small lobe of the kinase domain of GRK5 near elements critical for receptor interaction and membrane association, thereby inhibiting receptor phosphorylation while activating the kinase for phosphorylation of soluble substrates. To define the role of each lobe of Ca2+·CaM, we utilized the natural product malbrancheamide as a chemical probe to show that the C-terminal lobe of Ca2+·CaM regulates membrane binding while the N-terminal lobe regulates receptor phosphorylation and kinase domain activation. In cells, malbrancheamide attenuated GRK5 nuclear translocation and effectively blocked the hypertrophic response, demonstrating the utility of this natural product and its derivatives in probing Ca2+·CaM-dependent hypertrophy.

Navigating the conformational landscape of G protein-coupled receptor kinases during allosteric activation.

G protein-coupled receptors (GPCRs) are essential for transferring extracellular signals into carefully choreographed intracellular responses controlling diverse aspects of cell physiology. The duration of GPCR-mediated signaling is primarily regulated via GPCR kinase (GRK)-mediated phosphorylation of activated receptors. Although many GRK structures have been reported, the mechanisms underlying GRK activation are not well-understood, in part because it is unknown how these structures map to the conformational landscape available to this enzyme family. Unlike most other AGC kinases, GRKs rely on their interaction with GPCRs for activation and not phosphorylation. Here, we used principal component analysis of available GRK and protein kinase A crystal structures to identify their dominant domain motions and to provide a framework that helps evaluate how close each GRK structure is to being a catalytically competent state. Our results indicated that disruption of an interface formed between the large lobe of the kinase domain and the regulator of G protein signaling homology domain (RHD) is highly correlated with establishment of the active conformation. By introducing point mutations in the GRK5 RHD-kinase domain interface, we show with both in silico and in vitro experiments that perturbation of this interface leads to higher phosphorylation activity. Navigation of the conformational landscape defined by this bioinformatics-based study is likely common to all GPCR-activated GRKs.