Contribution of caregiver and child anxiety and depressive symptoms to child asthma-related quality of life.

BACKGROUND: Depression and anxiety negatively affect asthma-related quality of life (QoL). Yet, little is known regarding mood and asthma-related factors that best uniquely explain asthma-related QoL in children. OBJECTIVE: This cross-sectional study evaluated the unique variance explained by caregiver and child depressive and anxiety symptom severity in child asthma-related QoL, apart from that explained by demographics and asthma control. METHODS: Children aged 7 to 17 years with asthma (n = 205) and their caregivers with major depressive disorder were included. A 3-stage hierarchical linear regression analysis was conducted with the Pediatric Asthma Quality of Life Questionnaire total scores considered as the outcome. Predictors included demographic characteristics (stage 1); asthma control assessed by the Asthma Control Test (stage 2); and caregiver depression and anxiety (Hamilton Rating Scale for Depression and the Spielberger State/Trait Anxiety Scale) and child depression and anxiety (Children's Depression Inventory and the Screen for Child Anxiety-Related Disorders) (stage 3). RESULTS: Demographic characteristics accounted for only 5.5% of the Pediatric Asthma Quality of Life Questionnaire scores. Asthma control significantly increased variance explained in QoL to 32.6%, whereas caregiver and child depression and anxiety symptoms significantly increased variance explained to 42.6%. Child anxiety was found to uniquely explain the largest proportion of variance in QoL (rs2 = 0.584). CONCLUSION: After adjusting variance in QoL for demographic characteristics and asthma control, caregiver and child depression and anxiety measures significantly increased the proportion of variance explained in a child's asthma-related QoL. In addition to better asthma control, child and caregiver depression and anxiety should be addressed to increase child asthma-related QoL. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02809677.

PEGylated Recombinant Adenosine Deaminase Maintains Detoxification and Lymphocyte Counts in Patients with ADA-SCID.

PURPOSE: Metabolic detoxification with enzyme replacement therapy (ERT) promotes immune recovery in patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (ADA-SCID). Elapegademase is a PEGylated recombinant bovine ADA ERT developed to replace the now-discontinued bovine-derived pegademase. This study was a 1-way crossover from pegademase to elapegademase in 7 patients with ADA-SCID to assess efficacy and safety outcomes for elapegademase. METHODS: After once-weekly pegademase dosage was adjusted to achieve therapeutic metabolic detoxification and trough ADA activity, patients transitioned to a bioequivalent dose of elapegademase. Maintenance of metabolic detoxification and adequate ADA activity were evaluated periodically. RESULTS: One patient withdrew after 2 doses of an early elapegademase formulation due to injection-site pain caused by EDTA. The 6 remaining patients completed 71-216 weeks of elapegademase therapy with a formulation that did not contain EDTA. In these patients, elapegademase improved ADA activity compared with pegademase and maintained metabolic detoxification. Total lymphocyte counts increased for all completer patients from between 1.2- and 2.1-fold at the end of study compared with baseline. Elapegademase had a comparable safety profile to pegademase; no patient developed a severe infectious complication. Three patients had transient, non-neutralizing antibodies to pegademase, elapegademase, and/or polyethylene glycol ≤ 47 weeks of treatment without effect on trough plasma ADA activity or trough erythrocyte deoxyadenosine nucleotide levels. CONCLUSION: Elapegademase was safe, well tolerated, achieved stable trough plasma ADA activity with weekly dosing, was effective in maintaining metabolic detoxification, and was associated with maintenance or improvements in lymphocyte counts compared with pegademase therapy in patients with ADA-SCID.

Egg Introduction during Infancy is Associated with Lower Fat Mass Index in Females at Early Adolescence.

BACKGROUND: Egg consumption may play an important role in early-life growth given their high-quality protein, essential fatty acids, and micronutrients. OBJECTIVES: Study objectives were to examine the longitudinal associations of infant age at egg introduction with obesity outcomes in early childhood, middle childhood (mid-childhood), and early adolescence. METHODS: We used existing data from 1089 mother-child dyads from Project Viva to estimate age at egg introduction through a questionnaire completed by mothers at ∼1 y postpartum (mean ± SD, 13.3 ± 1.2 mo). Outcome measures included height and weight (early childhood, mid-childhood, and early adolescence), body composition including total fat mass, trunk fat mass, and lean mass (mid-childhood and early adolescence), and plasma adiponectin and leptin (early and mid-childhood and early adolescence). We defined childhood obesity as sex- and age-specific BMI ≥ 95th percentile. We estimated the associations of infant age at egg introduction with risk of obesity using multivariable logistic regression and multivariable linear regression models for BMI-z-score, body composition measures, and adiposity hormones; adjusted for maternal prepregnancy BMI and sociodemographics. RESULTS: Among females, those introduced to egg by the 1-y survey had a lower total fat mass index (confounder-adjusted mean difference, -1.23 kg/m2; 95% CI: -2.14, -0.31), and trunk fat mass index (confounder-adjusted mean difference, -0.57 kg/m2; 95% CI: -1.01, -0.12) in early adolescence compared to those not introduced (reference group). However, no associations between infant age at egg introduction and risk of obesity were observed among males (confounder-adjusted odd ratio [aOR], 1.97; 95% CI: 0.90, 4.30) or females (aOR, 0.68; 95% CI: 0.38, 1.24) across all ages. Egg introduction in infancy was associated with lower plasma adiponectin among females (confounder-adjusted mean difference, -1.93 µg/mL; 95% CI: -3.70, -0.16) in early childhood only. CONCLUSIONS: Egg introduction during infancy among females is associated with lower total fat mass index in early adolescence and plasma adiponectin in early childhood. This trial was registered at clinicaltrials.gov as NCT02820402.

Frequency of Infant Egg Consumption and Risk of Maternal-Reported Egg Allergy at 6 Years.

BACKGROUND: Recent research suggests that early egg introduction during infancy may help to prevent egg allergy development. However, the infant egg consumption frequency that is sufficient to induce this immune tolerance remains uncertain. OBJECTIVES: We examined the associations between the infant egg consumption frequency and maternal-reported child egg allergy at 6 y. METHODS: We analyzed data of 1252 children from the Infant Feeding Practices Study II (2005-2012). Mothers reported the frequency of infant egg consumption at 2, 3, 4, 5, 6, 7, 9, 10, and 12 mo old. Mothers reported the status of their child's egg allergy at the 6-y follow-up. We used Fisher exact test, Cochran-Armitage Trend Test, and log Poisson regression models to compare 6-y egg allergy risk by the frequency of infant egg consumption. RESULTS: The risk of maternal-reported egg allergy at 6 y significantly (P-trend = 0.004) decreased with infant egg consumption frequency at 12 mo: 2.05% (11/537) for infants not consuming eggs, 0.41% (1/244) for those consuming eggs <2 times per wk, and 0.21% (1/471) for those consuming eggs ≥2 times per wk. A similar but nonsignificant trend (P-trend=0.109) was observed for egg consumption at 10 mo (1.25%, 0.85%, and 0%, respectively). After adjusting for socioeconomic confounders, breastfeeding, complementary food introduction, and infant eczema, infants who consumed eggs ≥2 times per wk at 12 mo had a significantly lower RR of maternal-reported egg allergy at 6 y (confounder-adjusted RR: 0.11; 95% CI: 0.01, 0.88; P = 0.038), whereas those who consumed <2 times per wk (confounder-adjusted RR: 0.21; 95% CI: 0.03, 1.67; P = 0.141) did not have a significantly lower risk than those who did not consume eggs at all. CONCLUSIONS: Consumption of eggs ≥2 times per wk in late infancy is associated with a reduced risk of developing egg allergy later in childhood.

Delayed egg introduction beyond infancy and increased egg allergy risk in childhood.

AIM: Egg is a major food allergen in childhood. Recent studies suggest that early introduction of allergenic foods can decrease the risk of developing egg allergy. The impact of early egg introduction in the general population is unclear. We examined associations between age of infant egg introduction and childhood egg allergy outcomes in a general population. METHODS: The study population consisted of 1217 neonates from Project Viva, a longitudinal pre-birth cohort in eastern Massachusetts area, USA. Mothers reported age of infant egg introduction and child egg allergy using questionnaires and specific IgE to egg white was assayed. We estimated associations between age of infant egg introduction and egg allergy outcomes using Log-binomial regression models, adjusting for socio-demographics and health confounders. RESULTS: Egg allergy at 2 years was significantly higher (8.0% vs. 1.4%, P < 0.0001) in children who had delayed egg introduction beyond infancy, compared with children who were introduced to egg during infancy (adjusted relative risk or aRR 7.58; 95% CI 3.08, 18.61). At 12 years, the risk of egg allergy remained significantly higher (3.9% vs. 1.1%, P = 0.048) in children with delayed egg introduction compared with children introduced to egg during infancy (aRR 4.07; 95% CI 1.20, 13.87). CONCLUSIONS: Infants with delayed introduction of eggs after 12 months had increased risk of egg allergy in childhood (2 years) and the relationship persisted in early adolescence (12 years). Our findings suggest that introduction to eggs before 12 months could contribute to the prevention of egg allergy.

Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.

Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody loss. Clarification regarding whether the hypogammaglobulinemia is secondary or primary is important because this has implications for evaluation and management. Prior receipt of immunosuppressive medications and/or presence of conditions associated with SHG development, including protein loss syndromes, are histories that raise suspicion for SHG. In patients with these histories, a thorough investigation of potential etiologies of SHG reviewed in this report is needed to devise an effective treatment plan focused on removal of iatrogenic causes (eg, discontinuation of an offending drug) or treatment of the underlying condition (eg, management of nephrotic syndrome). When iatrogenic causes cannot be removed or underlying conditions cannot be reversed, therapeutic options are not clearly delineated but include heightened monitoring for clinical infections, supportive antimicrobials, and in some cases, immunoglobulin replacement therapy. This report serves to summarize the existing literature regarding immunosuppressive medications and populations (autoimmune, neurologic, hematologic/oncologic, pulmonary, posttransplant, protein-losing) associated with SHG and highlights key areas for future investigation.

A pilot school-based health center intervention to improve asthma chronic care in high-poverty schools.

OBJECTIVE: To test the feasibility and effectiveness of a multifaceted intervention administered through school-based health centers (SBHCs) to improve asthma control for children in high-poverty schools with not well controlled asthma. METHODS: Students 4-14 years old with persistent asthma were enrolled from three SBHCs. The centers' advanced practice providers received training on evidence-based asthma guidelines. Students randomized to the intervention received directly observed therapy of their asthma controller medication, medication adjustments as needed by the centers' providers, and daily self-management support. Students randomized to usual care were referred back to their primary care provider (PCP) for routine asthma care. RESULTS: We enrolled 29 students. Students in the intervention group received their controller medication 92% of days they were in school. Ninety-four percent of follow-up assessments were completed. During the study, 11 of 12 intervention students had a step-up in medication; 2 of 15 usual care students were stepped up by their PCP. Asthma Control Test scores did not differ between groups, although there were significant improvements from baseline to the 7 month follow-up within each group (both p < .01). Both FEV1% predicted and FEV1/FVC ratio significantly worsened in the usual care group (both p = .001), but did not change in the intervention group (p = .76 and .28 respectively). CONCLUSIONS: Our pilot data suggest that a multifaceted intervention can be feasibly administered through SBHCs in communities with health disparities. Despite the small sample size, spirometry detected advantages in the intervention group. Further study is needed to optimize the intervention and evaluate outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03032744.

Infant age at egg introduction and malnutrition-related child growth in the United States.

To evaluate the relationship between infant age of egg introduction and malnutrition-related growth outcomes in the United States, we analysed secondary data of 1716 mother-child dyads in the Infant Feeding Practices Study II and its Year 6 Follow-Up Study. Malnutrition-related growth outcomes included body mass index z-score (BMIZ), obesity (weight-for-height z-score [WHZ] ≥3 or BMIZ ≥ 2), WHZ, wasting (WHZ < -2), height-for-age z-score (HAZ), and stunting (HAZ < -2). Infant age at egg introduction was analysed as a continuous variable. We used generalised estimating equations to estimate the mean difference in continuous outcomes and relative risk [RR]) for binary outcomes, adjusting for related maternal and child confounders. We also explored interactions with child sex, maternal race/ethnicity, maternal educational level, ever breastfeeding, and formula feeding. In the total sample, a later infant age at egg introduction was associated with a lower mean difference in HAZ (confounder-adjusted mean difference = -0.08, 95% confidence interval [CI]: -0.12 to -0.03 per month) and a higher risk of stunting (confounder-adjusted RR = 1.17, 95% CI: 1.03-1.33 per month) at 6 years. The associations between infant age at egg introduction and 12-month growth outcomes differed by child sex. Among females but not among males, later introduction of eggs was associated with a lower mean WHZ (-0.06 [-0.12 to 0.00] per month) at 12 months. Later egg introduction during infancy was associated with a lower mean HAZ and a higher risk of stunting in 6-year-old children. Besides this, it was associated with a lower WHZ among females at 12 months.

The role of neutrophils in host defense and disease.

Neutrophils, the most abundant circulating leukocyte, are critical for host defense. Granulopoiesis is under the control of transcriptional factors and culminates in mature neutrophils with a broad armamentarium of antimicrobial pathways. These pathways include nicotinamide adenine dinucleotide phosphate oxidase, which generates microbicidal reactive oxidants, and nonoxidant pathways that target microbes through several mechanisms. Activated neutrophils can cause or worsen tissue injury, underscoring the need for calibration of activation and resolution of inflammation when infection has been cleared. Acquired neutrophil disorders are typically caused by cytotoxic chemotherapy or immunosuppressive agents. Primary neutrophil disorders typically result from disabling mutations of individual genes that result in impaired neutrophil number or function, and provide insight into basic mechanisms of neutrophil biology. Neutrophils can also be activated by noninfectious causes, including trauma and cellular injury, and can have off-target effects in which pathways that typically defend against infection exacerbate injury and disease. These off-target effects include acute organ injury, autoimmunity, and variable effects on the tumor microenvironment that can limit or worsen tumor progression. A greater understanding of neutrophil plasticity in these conditions is likely to pave the way to new therapeutic approaches.

The effects of caregiver depression on childhood asthma: Pathways and mechanisms.

OBJECTIVE: To review the literature regarding the effects of caregiver depression on childhood asthma and integrate the findings into a multilevel model of pathways by which these effects occur to further the understanding of the complex biopsychosocial nature of childhood asthma and the key role that is played by caregiver depression. DATA SOURCES: PubMed was searched for articles published from 2007 to the present (10-year search), and Google Scholar was searched for articles published in 2017 and 2018 to identify the most recent publications. STUDY SELECTIONS: Studies selected were recent, empirical, or meta-analytic, conducted in humans, and had specific relevance to one or more of the identified pathways. Articles published before 2007 were included if deemed essential because they addressed key pathways, for which there were no more recent articles. RESULTS: Review of the literature substantiates that caregiver depression plays a key role in the socioeconomic, familial, psychological, and biological cascade of effects on childhood asthma. Childhood asthma outcomes are affected indirectly by socioeconomic status and family stress mediated by caregiver depression, which affects disease management, and/or stress and depression in the child, which, in turn, affect asthma through alterations in immune modulation and autonomic regulation. CONCLUSION: Findings indicate that future research should concentrate on mediators and moderators to further clarify the complex interplay of these factors that affect childhood asthma. The findings also have substantial translational implications. Given that child stress and depression contribute to asthma disease activity and that treating caregiver depression improves child stress and depression, there is strong rationale for treating depressed caregivers of children with asthma as a component means of improving childhood asthma control.

Idiopathic T cell lymphopenia identified in New York State Newborn Screening.

Quantification of T-cell receptor excision circles (TRECs) for newborn screening for SCID has advanced the diagnosis of severe combined immune deficiency (SCID). However, it has led to the identification of infants with T cell lymphopenia without known cause. The clinical characteristics, appropriate laboratory monitoring, and outcomes of patients remain unclear. We performed a retrospective review of clinical and laboratory studies for 26 infants collected from 7 New York State referral centers from 2010 to 2016 with low TRECs (mean, 70copies/µl) and subnormal CD3 counts (mean, 1150/cubicmm). Over time absolute CD3 counts increased in 17 and decreased in 9; 22 (85%) have done well clinically regardless of absolute T cell values. Additional infants with TCL will continue to be identified in newborn screening panels. While most patients seem to do well clinically, parameters for diagnosis and monitoring have yet to be formalized, and additional information needs to be collected, causes and outcomes reported.

p120-catenin down-regulation and epidermal growth factor receptor overexpression results in a transformed epithelium that mimics esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor prognosis due to its highly invasive and metastatic potential. The molecular pathogenesis underlying the invasive mechanism of ESCC is not well known because of the lack of existing models to study this disease. p120-Catenin (p120ctn) and the epidermal growth factor receptor (EGFR) have each been implicated in several cancers, including ESCC. p120ctn is down-regulated in 60% of ESCC tumors, whereas EGFR is the most commonly overexpressed oncogene in ESCC. For these reasons, we investigated the cooperation between p120ctn and EGFR and its effect on ESCC invasion. We show that p120ctn down-regulation is commonly associated with EGFR overexpression. By using a three-dimensional culture system, we demonstrate that the inverse relationship between p120ctn and EGFR has biological implications. Specifically, p120ctn down-regulation coupled with EGFR overexpression in human esophageal keratinocytes (EPC1-PE) was required to promote invasion. Morphological comparison of EPC1-PE cells grown in three-dimensional culture and human ESCC revealed identical features, including significantly increased cellularity, nuclear grade, and proliferation. Molecular characteristics were measured by keratin expression patterns, which were nearly identical between EPC1-PE cells in three-dimensional culture and ESCC samples. Altogether, our analyses have demonstrated that p120ctn down-regulation and EGFR overexpression are able to mimic human ESCC in a relevant three-dimensional culture model.

Caveolin-1 mediates inflammatory breast cancer cell invasion via the Akt1 pathway and RhoC GTPase.

With a propensity to invade the dermal lymphatic vessels of the skin overlying the breast and readily metastasize, inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer. We previously reported that caveolin-1 is overexpressed in IBC and that RhoC GTPase is a metastatic switch responsible for the invasive phenotype. RhoC-driven invasion requires phosphorylation by Akt1. Using a reliable IBC cell line we set out to determine if caveolin-1 expression affects RhoC-mediated IBC invasion. Caveolin-1 was down regulated by introduction of siRNA or a caveolin scaffolding domain. The ability of the cells to invade was tested and the status of Akt1 and RhoC GTPase examined. IBC cell invasion is significantly decreased when caveolin-1 is down regulated. Activation of Akt1 is decreased when caveolin-1 is down regulated, leading to decreased phosphorylation of RhoC GTPase. Thus, we report here that caveolin-1 overexpression mediates IBC cell invasion through activation Akt1, which phosphorylates RhoC GTPase.

Autoimmunity and Immune Dysregulation in Primary Immune Deficiency Disorders.

Primary immune deficiencies are often associated with autoimmune disease due to the dysregulation of the immune system as a whole. In many immune deficiencies, lymphocytes may be present but dysfunctional, allowing for the development of excessive autoreactivity and resultant autoimmune disease. Autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy, autoimmune lymphoproliferative syndrome, immunodyregulation polyendocrinopathy enteropathy X-linked, IL-10/IL-10 receptor deficiencies, and PLCG2-associated antibody deficiency and immune dysregulation are disorders in which autoimmunity is a hallmark of the clinical disease presentation. In contrast, adaptive and innate immune deficiencies, which are typically defined by their infectious susceptibilities, can be associated with variable rates of autoimmune manifestations, predominantly autoimmune cytopenias. This review describes the immune dysregulation and autoimmune manifestations that may be encountered in various immune deficiencies.

Review of family relational stress and pediatric asthma: the value of biopsychosocial systemic models.

Asthma is the most common chronic disease in children. Despite dramatic advances in pharmacological treatments, asthma remains a leading public health problem, especially in socially disadvantaged minority populations. Some experts believe that this health gap is due to the failure to address the impact of stress on the disease. Asthma is a complex disease that is influenced by multilevel factors, but the nature of these factors and their interrelations are not well understood. This paper aims to integrate social, psychological, and biological literatures on relations between family/parental stress and pediatric asthma, and to illustrate the utility of multilevel systemic models for guiding treatment and stimulating future research. We used electronic database searches and conducted an integrated analysis of selected epidemiological, longitudinal, and empirical studies. Evidence is substantial for the effects of family/parental stress on asthma mediated by both disease management and psychobiological stress pathways. However, integrative models containing specific pathways are scarce. We present two multilevel models, with supporting data, as potential prototypes for other such models. We conclude that these multilevel systems models may be of substantial heuristic value in organizing investigations of, and clinical approaches to, the complex social-biological aspects of family stress in pediatric asthma. However, additional systemic models are needed, and the models presented herein could serve as prototypes for model development.

Newborn screening for SCID in New York State: experience from the first two years.

PURPOSE: To describe the process and assess outcomes for the first 2 years of newborn screening for severe combined immunodeficiency (SCID NBS) in New York State (NYS). METHODS: The NYS algorithm utilizes a first-tier molecular screen for TRECs (T-cell receptor excision circles), the absence of which is indicative of increased risk of immunodeficiency. RESULTS: During the first 2 years, 485,912 infants were screened for SCID. Repeat specimens were requested from 561 premature and 746 non-premature infants with low or borderline TRECs. A total of 531 infants were referred for diagnostic evaluation leading to identification of 10 infants with SCID and 87 with a clinically significant non-SCID abnormality based on flow cytometry or CBC results (positive predictive value 20.3 %). Nine infants were diagnosed with typical SCID and one with leaky SCID. SCID diagnoses included two patients with adenosine deaminase deficiency, three patients with typical and one with leaky IL2RG-related SCID, one patient with IL7Rα-related SCID, and three cases of typical SCID, etiology unknown. TRECs were undetectable in eight of the nine babies with typical SCID. Infants with other non-SCID conditions included 27 patients with a syndrome that included T-cell impairment, 18 of which had DiGeorge syndrome. Seventeen infants had T-cell impairment secondary to another clinically significant condition, and 13 were classified as 'other'. Among 30 infants classified as idiopathic T-cell lymphopenia, 11 have since resolved, and the remainder continues to be followed. One infant with undetectable TRECs had normal follow-up studies. Molecular studies revealed the presence of two changes in the infant's DNA. CONCLUSIONS: Overall, ten infants with SCID were identified during the first 2 years of screening in NYS, yielding an incidence of approximately 1 in 48,500 live births, which is consistent with the incidence observed by other states screening for SCID. The incidence of any clinically significant laboratory abnormality was approximately 1 in 5,000; both estimates are higher than estimates prior to the onset of newborn screening for SCID. Improvements to the NYS algorithm included the addition of a borderline category that reduced the proportion of infants referred for flow cytometric analysis, without decreasing sensitivity. We identified a large number of infants with abnormal TRECs and subsequent idiopathic T-cell lymphopenia. Long-term follow-up studies are needed to determine the prognosis and optimal treatment for this group of patients, some of whom may present with previously unrecognized, transient lymphopenia of infancy.

Common dermatologic manifestations of primary immune deficiencies.

The skin is the largest organ of our body; it consists of the epidermis, dermis, hair follicles, sweat glands, blood vessels, and connective tissue matrix. Its main function is to act as a barrier to the outside world and protect us from infections. Any component of the skin is subject to insults from the environment and/or from within the body. Primary immune deficiency patients present with recurrent or prolonged infections not frequently seen in healthy individuals. Oftentimes, these infections involve the skin. Primary immune deficiency may also present with noninfectious cutaneous signs, such as eczema; erythroderma; granulomas; dysplasia of the skin, hair, nails, or teeth; pigmentary changes; angioedema; urticaria; vasculitis; or autoimmune skin disease due to immune dysregulation. Prompt recognition of the underlying diagnosis and initiation of treatment decrease morbidity. This review provides the reader with an up-to-date summary of the common dermatologic manifestations of primary immune deficiency diseases.

Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States.

IMPORTANCE: Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births. OBJECTIVES: To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments. DESIGN: Epidemiological and retrospective observational study. SETTING: Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test. MAIN OUTCOMES AND MEASURES: Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. RESULTS: Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia. CONCLUSIONS AND RELEVANCE: Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.

Modeling and characterization of inflammatory breast cancer emboli grown in vitro.

Inflammatory breast cancer (IBC) is the deadliest form of breast cancer, presenting as intralymphatic emboli. Emboli within the dermal lymphatic vessels are thought to contribute to rapid metastasis. The lack of appropriate in vitro models has made it difficult to accurately study how IBC emboli metastasize. To date, attempts at creating IBC tumor emboli in vitro have used 3D culture on a solid layer of Matrigel(TM) , which does not resemble the physical properties of the lymphatic system. Dermal lymphatic fluid produces oscillatory fluid shear forces and is 1.5-1.7-fold more viscous than water with a pH range of 7.5-7.7. We have established a method for forming tumor emboli by culturing the IBC cell lines in suspension with either polyethylene glycol- or hyaluronic acid-containing medium and oscillatory fluid shear forces. Non-IBC cells do not form emboli under identical conditions. In vitro IBC emboli were analyzed for expression of markers associated with patient emboli and their ability to undergo invasion. In a direct comparison, the in vitro IBC emboli closely resemble IBC patient emboli with respect to size, composition and E-cadherin expression. Further, cells from the emboli are able to invade in clusters via RhoC GTPase-dependent amoeboid movement. Invasion by clusters of IBC cells is disrupted by exposure to TGFß. This study provides a biologically relevant in vitro model to accurately grow and study inflammatory breast cancer biology and metastasis.