A quality improvement initiative to improve primary care referral rates for penicillin allergy delabeling.

BACKGROUND: Of the US population, 10% reports a penicillin allergy but more than 90% can ultimately tolerate penicillin. Confirmation of these allergies in the pediatric population may improve future health outcomes and decrease costs. Referring patients for confirmatory testing is the first step in clarifying penicillin allergies. OBJECTIVE: To increase the number of referrals of patients with listed penicillin allergies from the University of California, San Diego academic general pediatrics clinics to Rady Children's Hospital allergy clinics using an educational session and a best practice advisory (BPA) in the electronic medical record. METHODS: An educational session with attendings and 3 plan-do-study-act (PDSA) cycles were completed using a BPA alert that triggered for all patients with a documented penicillin-class drug allergy to draw attention and facilitate referral. The BPA was modified at each PDSA cycle based on physician input. RESULTS: At baseline, 1.9% of referrals to the allergy clinic were for penicillin-class drug allergies. After an attending physician educational session, the percentage increased to 13.7%. The BPA was implemented with further increase to 27.8% of all allergy referrals in the course of 3 PDSA cycles. Not all patients with penicillin-class drug allergies were referred, and the reasons were documented when the physicians dismissed the BPA. Physicians did not refer 35% of the time because of time constraints, as opposed to patient or parent disinterest, which was 8% of the time. CONCLUSION: Referrals to the allergist for confirmatory testing in patients with listed penicillin allergies increased by more than 10 fold. This study illustrates successful tools to support delabeling.

Economic burden of congenital athymia in the United States for patients receiving supportive care during the first 3 years of life.

AIMS: Congenital athymia is an ultra-rare pediatric condition characterized by the lack of thymus in utero and the naïve T cells critical for infection defense and immune regulation. Patients with congenital athymia receive supportive care to minimize and treat infections, autoimmune phenomena, and autologous graft-versus-host disease (aGVHD) manifestations, but historically, die within the first 3 years of life with supportive care only. We estimated the healthcare resource utilization and economic burden of supportive care over patients' first 3 years of life in the United States. METHODS: A medical chart audit by the treating physician was used to collect patient data from birth to age 3 on clinical manifestations associated with congenital athymia (clinical manifestations due to underlying syndromic conditions excluded). Using costs and charges from publicly available sources, the total economic burden of direct medical costs and charges for the first 3 years of life (considered "lifetime" for patients receiving supportive care) and differences in economic burden between patients with higher and lower inpatient hospitalization durations were estimated. RESULTS: All patients (n = 10) experienced frequent infections and aGVHD manifestations; 40% experienced ≥1 episode of sepsis, and 20% had recurrent sepsis episodes annually. The estimated mean 3-year economic burden per patient was US$5,534,121 (2020 US dollars). The annual mean inpatient hospitalization duration was 150.6 days. Inpatient room charges accounted for 79% of the economic burden, reflecting the high costs of specialized care settings required to prevent infection, including isolation. Patients with high inpatient utilization (n = 5; annual mean inpatient hospitalization duration, 289.6 days) had an estimated 3-year economic burden of US$9,926,229. LIMITATIONS: The total economic burden may not be adequately represented due to underestimation of some direct costs or overestimation of others. CONCLUSIONS: Current treatment of patients with congenital athymia (supportive care) presents a high economic burden to the healthcare system.

Defining the Clinical, Emotional, Social, and Financial Burden of Congenital Athymia.

INTRODUCTION: Characterize the burden of illness in pediatric patients with congen̄ital athymia who were receiving supportive care. METHODS: This cross-sectional study of adult caregivers of patients with congenital athymia used both a quantitative survey and qualitative interviews. Caregivers of patients currently receiving supportive care responded to questions about the past 12 months and completed the parent proxy version of the Pediatric Quality of Life Inventory Generic instrument (PedsQL) for patients aged 2-4 years. For caregivers of patients who had received supportive care in the past, questions were asked about the period when they were receiving supportive care only. RESULTS: The sample included caregivers of 18 patients, 5 who were currently receiving supportive care and 13 who received investigational cultured human thymus tissue implantation before study enrollment and had received supportive care in the past. The impact of congenital athymia was substantial. Reports included the need to live in isolation (100% of respondents); caregiver emotional burden such as fear of death, infection, and worries about the future (100%); financial hardship (78%); and the inability to meet family/friends (72%). Patients had frequent and prolonged hospitalizations (78%) and had high utilization of procedures, medications, and home medical supplies. Caregiver-reported PedsQL scores for patients currently receiving supportive care (n = 4) indicated low health-related quality of life. CONCLUSIONS: Caregivers of patients with congenital athymia reported high clinical, emotional, social, and financial burden on patients and their families.

Congenital Athymia: Genetic Etiologies, Clinical Manifestations, Diagnosis, and Treatment.

Congenital athymia is an ultra-rare disease characterized by the absence of a functioning thymus. It is associated with several genetic and syndromic disorders including FOXN1 deficiency, 22q11.2 deletion, CHARGE Syndrome (Coloboma, Heart defects, Atresia of the nasal choanae, Retardation of growth and development, Genitourinary anomalies, and Ear anomalies), and Complete DiGeorge Syndrome. Congenital athymia can result from defects in genes that impact thymic organ development such as FOXN1 and PAX1 or from genes that are involved in development of the entire midline region, such as TBX1 within the 22q11.2 region, CHD7, and FOXI3. Patients with congenital athymia have profound immunodeficiency, increased susceptibility to infections, and frequently, autologous graft-versus-host disease (GVHD). Athymic patients often present with absent T cells but normal numbers of B cells and Natural Killer cells (T-B+NK+), similar to a phenotype of severe combined immunodeficiency (SCID); these patients may require additional steps to confirm the diagnosis if no known genetic cause of athymia is identified. However, distinguishing athymia from SCID is crucial, as treatments differ for these conditions. Cultured thymus tissue is being investigated as a treatment for congenital athymia. Here, we review what is known about the epidemiology, underlying etiologies, clinical manifestations, and treatments for congenital athymia.

Abnormal SCID Newborn Screening and Spontaneous Recovery Associated with a Novel Haploinsufficiency IKZF1 Mutation.

PURPOSE: IKAROS, encoded by IKZF1, is a member of the IKAROS family of zinc-finger transcription factors playing critical roles in lymphocyte development, differentiation, and tumor suppression. Several studies demonstrated that IKZF1 mutations affecting DNA binding or homo-/hetero-dimerization are mostly associated with common variable immunodeficiency, combined immunodeficiency, or hematologic manifestations. Herein we report a likely de novo, nonsense IKZF1 mutation (p.C182*) in a baby with low T cell receptor excision circles (TREC) identified by newborn screening testing for severe combined immunodeficiency. The patient also presented a profound B cell deficiency at birth. METHODS: Genetic, functional, immunologic, and clinical outcome data associated with this patient and her mutation were evaluated. RESULTS: Mutant p.C182* was detected in the cytoplasm of the patient's primary cells, in contrast to wild type (WT) IKAROS protein, only detected in the nucleus. Functional in vitro assessments revealed that p.C182* was less stable than WT IKAROS protein and failed to bind to its target DNA binding sequence and dimerize with WT IKAROS protein, resulting in impaired pericentromeric targeting and transcriptional repression by means of haploinsufficiency. During follow-up, while a spontaneous recovery of TREC and T cells was observed, B cells improved but not to sustained normal ranges. CONCLUSIONS: Patients with IKAROS-associated diseases can present with SCID-like TREC values through newborn screening testing. IKZF1 mutations should be added to the low TREC differential, although spontaneous recovery has to be considered.

Provider recommendations and maternal practices when providing breast milk to children with immunoglobulin E-mediated food allergy.

BACKGROUND: There is limited research investigating maternal dietary practices and health care provider recommendations when providing breast milk (BM) to children with immunoglobulin (Ig) E-mediated food allergy. OBJECTIVE: To explore health care provider recommendations and maternal practices when providing BM to children with IgE-mediated food allergy and to assess for possible IgE-mediated reactions to BM while the mother consumed the food to which her child has allergy. METHODS: A web-based survey was distributed to breastfeeding (BF) mothers of children with IgE-mediated food allergies. Reported reactions to BM were scored by an allergist, provided only with the details of the possible reaction and not the suspect allergen or route of exposure, as to the likelihood that the reaction was IgE mediated. RESULTS: A total of 133 mothers completed the survey. After food allergy diagnosis, 47.4% (n = 63) of the mothers reported that they were advised by their health care provider to continue BF without dietary restriction, 17.3% (n = 23) were advised to avoid eating the food(s) their child has allergy to while BF, and in 28.6% (n = 38), this concern was not addressed. A few of the mothers (12%, 16/133) reported that their child experienced an allergic reaction to BM. An allergist evaluated most of these reactions (75%, 12/16) as not likely IgE mediated. CONCLUSION: This study exposed inconsistent recommendations for mothers providing BM to children with IgE-mediated food allergies. Most mothers were able to consume the food their child has allergy to without adverse sequelae. Standardized, evidence-based recommendations would enhance the well-being of these mother-infant dyads.

When Screening for Severe Combined Immunodeficiency (SCID) with T Cell Receptor Excision Circles Is Not SCID: a Case-Based Review.

Newborn screening efforts focusing on the quantification of T cell receptor excision circles (TRECs), as a biomarker for abnormal thymic production of T cells, have allowed for the identification and definitive treatment of severe combined immunodeficiency (SCID) in asymptomatic neonates. With the adoption of TREC quantification in Guthrie cards across the USA and abroad, typical, and atypical SCID constitutes only ~ 10% of cases identified with abnormal TRECs associated with T cell lymphopenia. Several other non-SCID-related conditions may be identified by newborn screening in a term infant. Thus, it is important for physicians to recognize that other factors, such as prematurity, are often associated with low TRECs initially, but often improve with age. This paper focuses on a challenge that immunologists face: the diagnostic evaluation and management of cases in which abnormal TRECs are associated with variants of T cell lymphopenia in the absence of a genetically defined form of typical or atypical SCID. Various syndromes associated with T cell impairment, secondary forms of T cell lymphopenia, and idiopathic T cell lymphopenia are identified using this screening approach. Yet there is no consensus or guidelines to assist in the evaluation and management of these newborns, despite representing 90% of the patients identified, resulting in significant work for the clinical teams until a diagnosis is made. Using a case-based approach, we review pearls relevant to the evaluation of these newborns, as well as the management dilemmas for the families and team related to the resolution of genetic ambiguities.

Pediatric nurse practitioners' attitudes/beliefs and knowledge/perceived competence in caring for transgender and gender-nonconforming youth.

PURPOSE: There is a growing number of youth and their parents seeking assistance from care providers related to gender dysphoria and transitional care for transgender and gender-nonconforming (TGNC) youth. The purpose of this study was to determine pediatric nurse practitioners' (PNP) attitudes/beliefs and knowledge/competence in caring for TGNC youth. DESIGN AND METHODS: This cross-sectional descriptive study surveyed PNPs (N = 93) from eight states using two survey instruments to measure attitudes and beliefs and knowledge and perceived competence related to caring for TGNC youth. RESULTS: Eighty-one percent of PNPs reported caring for TGNC youth in their practice. Despite this, only 15% of the PNPs received education related to transgender patients during their advanced practice education. Results showed that attending continuing education offerings related to caring for TGNC patients increases PNP perceived competence as well as knowledge. Attitudes and behaviors towards the transgender population were also more positive if the PNP had attended continuing nursing education offerings. Three themes emerged from a qualitative portion of the survey, asking the participant to share thoughts related to caring for transgender youth: lack of education for healthcare providers, the need to refer patients to comprehensive gender services, and the need for support for transgender patients and their families. PRACTICE IMPLICATIONS: Education plays an important part in nurses' attitudes, beliefs, and perceived competence in caring for transgender patients. Because the PNP is likely to be exposed to patients with TGNC, it is imperative they seek out opportunities to learn about transgender issues and caring for transgender patients.

Measles Maternal Antibodies With Low Avidity Do Not Interfere With the Establishment of Robust Quantity and Quality Antibody Responses After the Primary Dose of Measles, Mumps, and Rubella Vaccine Administered at 12-Months of Age.

In this study, we illustrate, for the first time, that preexisting low-avidity neutralizing measles maternal antibodies do not interfere with the development of high concentrations of high-avidity measles antibodies in children immunized at age 12 months. This suggests that the quality of measles maternal antibodies, rather than the quantity, impacts immunogenicity of primary measles immunization.

Evaluation of long-term course in children with eosinophilic esophagitis reveals distinct histologic patterns and clinical characteristics.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic and increasingly prevalent antigen-driven disease. There is a paucity of information on long-term course in children. OBJECTIVE: We sought to understand the longitudinal trajectory of pediatric EoE during routine clinical care. METHODS: We prospectively enrolled children into an EoE database and reviewed their medical and pathologic records over 13 years. RESULTS: From 2011 to 2015, 146 children with EoE seen for their first visit at our center had 2 or more years of follow-up and 3 or more endoscopies over an average follow-up period of 5.13 years (range, 2-13 years). Longitudinal eosinophilic inflammation during treatment demonstrated 3 patterns over time. Children with less than 15 eosinophils/high-power field (hpf) for greater than 75% of their follow-up period were termed continuous responders (CRs). Children with waxing and waning inflammation of less than 15 eosinophils/hpf for less than 75% but 25% or more of the follow-up period were termed intermittent responders (IRs). Nonresponders (NRs) were defined as having less than 15 eosinophils/hpf for less than 25% of their follow-up. Fifty-nine (40%) of 146 patients were CRs, 65 (45%) of 146 were IRs, and 22 (15%) of 146 were NRs. CRs differed from IRs and NRs on the parameter of male/female ratio (1:1 in CRs, 4:1 in IRs, and 6:1 in NRs; P < .001) and in their initial response to any therapy, including proton pump inhibitors (P < .001). Endoscopic severity correlated with esophageal eosinophilia (r = 0.73, P < .001). On multivariate analysis, female sex and initial therapeutic response to medications or elimination diet were associated with long-term control of esophageal eosinophilia. CONCLUSIONS: Long-term pediatric EoE followed 3 different longitudinal trajectories of inflammation. The long-term histologic groups differed significantly in biological sex and initial therapeutic response.

Evaluation of a Clinical Cancer Trial Research Training Workshop: Helping Nurses Build Capacity in Southwest Virginia.

Residents of Southwest Virginia (SWVA) face significant barriers in accessing the most advanced forms of cancer care, cancer risk reduction, and clinical trials involvement. A collaboration between the University of Virginia (UVA) Cancer Center and UVA School of Nursing was forged with oncology caregivers in this region to build community capacity to support Cancer Clinical trials (CCT) by strengthening the workforce, and thus improving health outcomes for this underserved region of Appalachia. The UVA School of Nursing designed an educational workshop focusing on the basics of CCT to facilitate the development of a skilled nursing workforce in the SWVA region that could provide care to patients on protocol and/or to encourage residents to participate in trials. The goal of the workshop was to offer a CCT training session for oncology nurses that fostered the knowledge and skills necessary to facilitate and support CCT infrastructure across this high-risk region. This evaluation reports the learning outcomes of the CCT training on 32 nurse participants from SWVA. Evaluations of the training program showed high rates of satisfaction, increased comfort level with CCTs, and increased knowledge and attitude toward CCTs. These findings provide information about a curriculum that could be useful in educating other oncology nurses and student nurses how to care for patients who may be enrolled in a clinical trial. Nurses can also be advocates for participation in clinical trials once they have the knowledge and are comfortable in their own understanding of a trial's usefulness. Educating the nursing workforce is an essential component of building capacity and infrastructure to support clinical trials research.

Predictors of student outcomes on perceived knowledge and competence of genetic family history risk assessment.

The publication of the human genome project has launched a number of discoveries set to change the landscape of healthcare. Unfortunately, nursing faculty across the United States report they are unprepared to teach students who will be practicing in the genomic era. The purpose of this study, utilizing Rogers' (2003) Diffusion of Innovation theory as a framework, was to determine the degree to which nursing school characteristics predict graduating undergraduate nursing students' perceived knowledge and competence of genetic family history risk assessment. School characteristics included school size, proximity to a large city, faculty's perceived barriers to diffusion of genomics into nursing practice, faculty innovativeness, faculty who have attended a genetics program for nursing faculty, and the integration of genomics into the curriculum. Faculty and students from 103 nursing schools across the United States participated in the study by completing online surveys. Hierarchical multiple regression was employed to determine how well the independent variables predicted student perceived knowledge and student perceived competence. No combination of the independent variables in this study predicted student knowledge or competence to the degree expected. This could be attributed to a lack of diffusion of genomics content across nursing curricula, based on Rogers' (2003) theory. Other findings included faculty continue to believe they are not competent to teach genomics, and the curriculum is too dense to include more content. However, contrary to prior research, faculty did believe genomics was valuable. The findings of this study give direction for further research into student outcomes and curriculum evaluation after 2011, when a consensus panel working to diffuse genomics into nursing curriculum and practice will have implemented their strategic plan for this diffusion.

Cytosol as battleground: ubiquitin as a weapon for both host and pathogen.

Ubiquitin was first described as a tag allowing cells to degrade and recycle their own proteins. Recent research has shown ubiquitin to be central for immune system recognition of invading bacteria. This review describes a set of complex host-pathogen interactions that are dependent on ubiquitination. From the host perspective, ubiquitin-dependent activation of inflammation and degradation of bacterial effectors is protective. Several pathogens become ubiquitinated in the host cell cytosol, and recent research suggests that this could trigger a form of autophagy, increasingly recognized as an important mechanism for the control of infection by a variety of human pathogens. Meanwhile, bacteria have developed mechanisms to evade or exploit the fundamental processes activated by ubiquitination, producing both ubiquitin ligases and deubiquitinases that modulate host responses.

Protein tyrosine phosphatase SHP-1 positively regulates TLR-induced IL-12p40 production in macrophages through inhibition of phosphatidylinositol 3-kinase.

SHP-1 is a cytoplasm protein tyrosine phosphatase expressed primarily in hematopoietic cells. In the immune system, SHP-1 plays critical roles in regulation of many receptor-mediated signaling cascades, and SHP-1 deficiency in mice causes spontaneous inflammation and autoimmunity. Here, we report a unique requirement for SHP-1 in interleukin-12/23 p40 (IL-12p40) production in response to Toll-like receptor (TLR) stimulation in macrophages. Bone marrow-derived macrophages (BMDMs) lacking significant SHP-1 activity display a profound defect in IL-12p40 synthesis in response to lipopolysaccharide, peptidoglycan, and synthetic TLR ligands, while producing normal amounts of other proinflammatory cytokines, such as TNFalpha and IL-6. Inhibition of SHP-1 function in wild-type BMDMs decreases IL-12p40, and expression of functional SHP-1 protein in mutant cells restores IL-12p40 production following TLR ligation. SHP-1 regulation of IL-12p40 transcription requires both its catalytic activity and phosphotyrosine binding by its N-terminal SH2 domain and is mediated via repression of, and interaction with, phosphatidylinositol 3-kinase, without affecting c-Rel activation. In contrast to normal NF-kappaB activation, SHP-1-defective me(v)/me(v) macrophages display a defect in nucleosome remodeling at the IL-12p40 promoter, and phosphatidylinositol 3-kinase inhibition significantly restores normal nucleosome remodeling in me(v)/me(v) macrophages. Thus, there is a critical role for the tyrosine phosphatase activity of SHP-1 for induction of IL-12p40 production in macrophages in response to TLR ligands, a novel mechanism for host regulation of a specific proinflammatory cytokine important in both innate and adaptive immunity.

Atg5-independent sequestration of ubiquitinated mycobacteria.

Like several other intracellular pathogens, Mycobacterium marinum (Mm) escapes from phagosomes into the host cytosol where it can polymerize actin, leading to motility that promotes spread to neighboring cells. However, only approximately 25% of internalized Mm form actin tails, and the fate of the remaining bacteria has been unknown. Here we show that cytosolic access results in a new and intricate host pathogen interaction: host macrophages ubiquitinate Mm, while Mm shed their ubiquitinated cell walls. Phagosomal escape and ubiquitination of Mm occurred rapidly, prior to 3.5 hours post infection; at the same time, ubiquitinated Mm cell wall material mixed with host-derived dense membrane networks appeared in close proximity to cytosolic bacteria, suggesting cell wall shedding and association with remnants of the lysed phagosome. At 24 hours post-infection, Mm that polymerized actin were not ubiquitinated, whereas ubiquitinated Mm were found within LAMP-1-positive vacuoles resembling lysosomes. Though double membranes were observed which sequestered Mm away from the cytosol, targeting of Mm to the LAMP-1-positive vacuoles was independent of classical autophagy, as demonstrated by absence of LC3 association and by Atg5-independence of their formation. Further, ubiquitination and LAMP-1 association did not occur with mutant avirulent Mm lacking ESX-1 (type VII) secretion, which fail to escape the primary phagosome; apart from its function in phagosome escape, ESX-1 was not directly required for Mm ubiquitination in macrophages or in vitro. These data suggest that virulent Mm follow two distinct paths in the cytosol of infected host cells: bacterial ubiquitination is followed by sequestration into lysosome-like organelles via an autophagy-independent pathway, while cell wall shedding may allow escape from this fate to permit continued residence in the cytosol and formation of actin tails.

Reinventing practice and education partnerships for capacity expansion.

Two alternative models offering solutions to the nursing shortage in Texas enhance communication between schools of nursing and acute care service agencies to strengthen the partnership between education and practice. These initiatives use the valuable asset of onsite nurses in practice to clinically instruct nursing students, thus replenishing the number of clinical instructors and freeing clinical space to overcome the obstacles in increasing capacity. Forming practice-education partnerships and integrating technology support, including using simulations and online courseware to train qualified nurses, reinvent the combining resources to address a common need. Moving into the last year of grant funding, both projects show initial promise in meeting project goals of increasing capacity in nursing education.