Gain-of-function (GOF) mutations in , encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.

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PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8 T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.

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Background Virtual fracture clinics are an alternative to the traditional model of fracture care. Since their introduction in 2011, they have become increasingly used in the United Kingdom and Ireland. The coronavirus disease 2019 (COVID-19) health crisis has driven institutions to examine such innovative solutions to manage patient care. The current controversies include quantifying safety outcomes, such as potential delayed or missed injuries, inadequate treatment, and medicolegal claims. Questions also exist regarding the potential for cost reductions and efficiencies that may be achieved. Physical distancing has limited the number of face-to-face consultations, so this review was conducted to determine if virtual fracture clinics can provide an acceptable alternative in these challenging times. Questions/purposes The aim of this systematic review was to describe (1) adverse outcomes, (2) cost reductions, and (3) efficiencies associated with the virtual fracture clinic model. Methods A systematic review of the PubMed, MEDLINE, and Embase databases was conducted from database inception to March 2020. The keywords “virtual” or “telemedicine” or “telehealth” or “remote” or “electronic” AND “fracture” or “trauma” or “triage” AND “clinic” or “consultation” were entered, using the preferred reporting items for systematic reviews and meta-analyses. Inclusion criteria included adults and children treated for injuries by a virtual clinic model at the initial review. Eligible injuries included injuries deemed to not need surgical intervention, and those able to be treated remotely using defined protocols. Exclusion criteria consisted of patients reviewed by telemedicine using video links or in person at the initial review. Initially, 1065 articles were identified, with 665 excluded as they did not relate to virtual fracture clinics. In all, 400 articles were screened for eligibility, and 27 full-text reviews were conducted on 18 studies (30,512 virtual fracture clinic encounters). Three subdomains focusing on adverse outcomes, cost reductions, and efficiencies were recorded. The term adverse outcomes was used to describe any complications, further surgeries, re-referrals back to the clinic, or deviations from the protocols. Efficiency described the number of patients reviewed and discharged using the model, savings in clinic slots, reduced waiting times, or a reduction in consumption of resources such as radiographs. All studies were observational and the quality was assessed using Newcastle-Ottawa tool, which demonstrated a median score of 6 ± 1.8, indicating moderate quality. Results Six studies reported adverse outcomes in detail, with events ranging from inappropriate splinting, deviations from protocols, and one patient underwent an osteotomy for a malunion. Efficiency varied from direct discharge proportions of 18% in early studies to 100% once the virtual fracture clinic model was more established. Cost reductions compared with estimates derived from conventional fracture clinics varied from USD 53 to USD 297 and USD 39,125 to USD 305876 compared with traditional fracture clinic visits. Conclusions Virtual fracture clinics may provide a means to treat patients remotely, using agreed-upon protocols. They have an important role in the current COVID-19 pandemic, due to the possibility to provide ongoing care in an otherwise challenging setting. More robust studies looking at this model of care will be needed to assess its long-term effects on patients, institutions, and health care systems. Level of Evidence Level IV, therapeutic study.

14 of those (77.8%) maintained an eliciting dose of > _1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%). Conclusions: These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen. (J

Antibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding heterozygous Pik3cd activating mutation, self-reactive B cells exhibit a cell-autonomous subversion of their response to self-antigen: instead of becoming tolerized and repressed from secreting autoantibody, Pik3cd gain-of-function B cells are activated by self-antigen to form plasmablasts that secrete high titers of germline-encoded IgM autoantibody and hypermutating germinal center B cells. However, within the germinal center, peripheral tolerance was still enforced, and there was selection against B cells with high affinity for self-antigen. These data show that the strength of PI3K signaling is a key regulator of pregerminal center B cell self-tolerance and thus represents a druggable pathway to treat antibody-mediated autoimmunity.