Dysregulated actin dynamics in activated PI3Kδ syndrome.

Activated PI3Kδ syndrome (APDS) Type I results from gain-of-function mutations in PIK3CD, which encodes the p110δ subunit of PI3Kδ. Abnormal actin dynamics have been hypothesized to contribute to the lymphopenia associated with this disease but have not been studied in patients with APDS. We report a patient with APDS who had widespread necrotic skin lesions that were responsive specifically to immunosuppressive therapy. EBV-transformed lymphoblastoid cells (EBV-LCLs) from patients with APDS exhibit increased polymerized actin and increased apoptosis, suggesting a contribution of impaired actin dynamics to this disease.

A novel truncating mutation in MYD88 in a patient with BCG adenitis, neutropenia and delayed umbilical cord separation.

Mutations in MYD88 cause susceptibility to invasive bacterial infections through impaired signaling downstream of toll-like receptors (TLRs) and IL-1 receptors. We studied a patient presenting with neutropenia, delayed umbilical cord separation, BCG adenitis, andP. aeruginosapneumonia. Next-generation DNA sequencing identified a novel homozygous truncation mutation in MYD88 that abolishes MyD88 expression. The patient's dermal fibroblasts had severely impaired IL-6 production after stimulation with ligands for the MyD88-dependent receptors TLR2, TLR4 and IL-1R, while responses to ligands for the MyD88-independent receptors TLR3 and TNF-α were preserved. Notably, secretion of TNF-α, which is essential for BCG control, was also impaired after LPS stimulation. In this first report of BCG infection in MyD88 deficiency, data suggest that MyD88-dependent TNF-α production contributes to control of mycobacterial disease.

An Assessment of the Relationship Between BMI and Children Undergoing Surgical Procedures: A Retrospective Study.

Background: While multiple studies have documented that obesity increases the risk of operative complications among adults, little data exist on how obesity impacts surgical outcomes among children. We aimed to determine if children with obesity have different postoperative outcomes than their peers. Methods: A retrospective chart review was conducted of 875 patients aged between 2 and 18 years who underwent surgery during 2018. Patients were stratified, based on BMI percentile for age, as having less than healthy weight (<5th percentile), healthy weight (5th-84th percentile), excess weight (85th-94th percentile), or obesity (≥95th percentile). Demographic information and data on medical comorbidities and postoperative complications were collected. All analyses were conducted using chi-square or Kruskal-Wallis testing. Results: Eighty-two patients were excluded due to lack of BMI data and 56 were excluded as they had below healthy weight. Of the remaining 737 patients, 475 (64.4%) had healthy weight, 124 (16.8%) had excess weight, and 138 (18.70%) had obesity. Children with obesity had more tonsillectomy/adenoidectomy (p < 0.01) and vascular access (p = 0.04) procedures compared with peers. Additionally, patients with obesity were more likely to have a pre-existing history of liver disease (p < 0.01) and more frequently developed postoperative wound dehiscence (p < 0.01). No other complications occurred more frequently among children with obesity. Conclusions: Children with obesity required more tonsillectomy/adenoidectomy and vascular access procedures. Wound dehiscence was the only complication that was associated with obesity. This suggests that children with obesity are not inherently more prone to experience surgical complications and therefore elective procedures should likely not be deferred until preoperative weight loss is achieved.

Gun violence and the voices of youth on community safety in the time of COVID-19 in East Harlem, NY: a youth participatory action research cross-sectional study.

BACKGROUND: The USA has failed to codify the protection of children from gun violence (GV) as a human right. This study employs a youth participatory action research methodology, within the framework of the United Nations Convention on the Rights of the Child (UNCRC), to investigate the relationships between GV exposure, self-identified gender and perceptions of children's rights and safety. METHODS: An anonymous survey based on UNICEF USA's Child Friendly Cities Initiative interactive survey tool targeting adolescents was modified by East Harlem, New York high school student co-researchers in collaboration with near-peer graduate students. The 61-question survey was administered at an East Harlem high school. Analysis consisted of univariate, bivariate and logistic regression using SPSS®. RESULTS: A total of 153 students completed the survey: 48.4% self-identified as male and 45.8% as female. Thirty-five percent reported witnessing GV. Most (79.1%) were aware of child rights regardless of gender or GV exposure but there were differences in perceptions of safety. Fifteen percent of females reported never feeling safe at school compared to 3% of males (p = 0.01). Females were 2.2 times as likely as males to report transportation waiting areas as never safe (p = 0.008). Almost a third of females reported never feeling safe from sexual harassment in public, compared to 10% of males (p = 0.004). In multivariable logistic regression adjusted for gender, race/ethnicity and grade level, students who witnessed GV were 4.6 times more likely to report never feeling safe from violence (95% CI 1.7-12.4). Thirty percent of students who witnessed GV reported not attending school because of safety concerns. Students who witnessed GV had 2.2 times the odds of carrying a weapon to school (95% CI 1.1-4.5). These patterns continued for other perceptions of safety. CONCLUSIONS: The students in this study affirmed their rights to participate and express their views on matters that may affect them, as articulated in the UNCRC. The study revealed differences in perceptions of safety by self-identified gender and identified gun violence as a major contributor of youth's perception of lack of safety. The study evinces the efficacy of employing YPAR methodology to identify and answer youth concerns of community safety and prioritize honoring child rights.

Engaging East Harlem, New York youth in action gun violence prevention research and child rights: a preliminary study.

BACKGROUND: The aim of the study was to have youth participate in the design and implementation of a research project set within a child rights framework to better understand high schoolers' perceptions of safety in their school and community. RESULTS: Between June 2020 and March 2021, a team of East Harlem, New York high school students, participated as co-researchers to modify the United Nations Children's Fund Child Friendly Cities Initiative Survey to suit their needs. Due to the COVID-19 pandemic, the final survey was conducted through an online remote classes system during advisory school classes, accompanied by brief focused group discussions. The novel process of conducting an interactive qualitative and quantitative virtual survey during a pandemic via youth participatory action research is outlined in this paper. CONCLUSIONS: Our results demonstrate that youth participatory action research can be utilized as part of a child rights framework approach to assess the views of youth regarding community safety and violence prevention.

Immune dysregulation caused by homozygous mutations in CBLB.

CBL-B is an E3 ubiquitin ligase that ubiquitinates proteins downstream of immune receptors to downregulate positive signaling cascades. Distinct homozygous mutations in CBLB were identified in 3 unrelated children with early-onset autoimmunity, one of whom also had chronic urticaria. Patient T cells exhibited hyperproliferation in response to anti-CD3 cross-linking. One of the mutations, p.R496X, abolished CBL-B expression, and a second mutation, p.C464W, resulted in preserved CBL-B expression. The third mutation, p.H285L in the SH2 domain of CBL-B, was expressed at half the normal level in the patient's cells. Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient's p.H285L mutation, had T and B cell hyperproliferation in response to antigen receptor cross-linking. CblbH257L mice had increased percentages of T regulatory cells (Tregs) that had normal in vitro suppressive function. However, T effector cells from the patient with the p.H285L mutation and CblbH257L mice were resistant to suppression by WT Tregs. Bone marrow-derived mast cells from CblbH257L mice were hyperactivated after FcεRI cross-linking, and CblbH257L mice demonstrated exaggerated IgE-mediated passive anaphylaxis. This study establishes CBL-B deficiency as a cause of immune dysregulation.

Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor 𝛋B kinase alpha (IKKα).

Inhibitor of nuclear factor kappa B kinase alpha (IKKα) is critical for p100/NF-κB2 phosphorylation and processing into p52 and activation of the noncanonical NF-κB pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKKα. The mutation preserves IKKα kinase activity but abolishes the interaction of IKKα with its activator NF-κB­inducing kinase and impairs lymphotoxin-ß­driven p100/NF-κB2 processing and VCAM1 expression. Homozygous IKKαY580C/Y580C mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired Il17a expression; and are susceptible to cutaneous Staphylococcus aureus infection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRVß repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKKα deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity.

Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex.

The coat protein I (COPI) complex mediates retrograde trafficking from the Golgi to the endoplasmic reticulum (ER). Five siblings with persistent bacterial and viral infections and defective humoral and cellular immunity had a homozygous p.K652E mutation in the γ1 subunit of COPI (γ1-COP). The mutation disrupts COPI binding to the KDEL receptor and impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER. Homozygous Copg1K652E mice had increased ER stress in activated T and B cells, poor antibody responses, and normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation. Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients. The ER stress-relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice. This study establishes the role of γ1-COP in the ER retrieval of KDEL-bearing chaperones and thereby the importance of ER homeostasis in adaptive immunity.