Summary SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2 1 , and is a major antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days. However, following convalescent plasma therapy we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro , the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type, possibly compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with evidence of reduced susceptibility to neutralising antibodies.

Genetic mutations cause primary immunodeficiencies (PIDs), which predispose to infections. Here we describe Activated PI3K-δ Syndrome (APDS), a PID associated with a dominant gain-offunction mutation E1021K in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated

BackgroundActivated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).ObjectiveWe sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort.MethodsWe applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS.ResultsRecurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS.ConclusionAPDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

WHAT'S KNOWN ON THIS SUBJECT:Deployment is a period of transition and potential stress for military families; however, there is limited understanding of the experience of children from military families. In addition, there is little information with respect to their overall well-being. WHAT THIS STUDY ADDS:We examined how children from military families manage across social, emotional, and academic domains. In addition, we uniquely examine these issues through the lens of both the child and caregiver. abstract OBJECTIVE: Although studies have begun to explore the impact of the current wars on child well-being, none have examined how children are doing across social, emotional, and academic domains. In this study, we describe the health and well-being of children from military families from the perspectives of the child and nondeployed parent. We also assessed the experience of deployment for children and how it varies according to deployment length and military service component. PARTICIPANTS AND METHODS.Data from a computer-assisted telephone interview with military children, aged 11 to 17 years, and nondeployed caregivers (n ϭ 1507) were used to assess child well-being and difficulties with deployment. Multivariate regression analyses assessed the association between family characteristics, deployment histories, and child outcomes. RESULTS:After controlling for family and service-member characteristics, children in this study had more emotional difficulties compared with national samples. Older youth and girls of all ages reported significantly more school-, family-, and peer-related difficulties with parental deployment (P Ͻ .01). Length of parental deployment and poorer nondeployed caregiver mental health were significantly associated with a greater number of challenges for children both during deployment and deployed-parent reintegration (P Ͻ .01). Family characteristics (eg, living in rented housing) were also associated with difficulties with deployment. CONCLUSIONS:Families that experienced more total months of parental deployment may benefit from targeted support to deal with stressors that emerge over time. Also, families in which caregivers experience poorer mental health may benefit from programs that support the caregiver and child.

No abstract

Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS) or p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.

No abstract

Community resilience (CR)--ability to withstand and recover from a disaster--is a national policy expectation that challenges health departments to merge disaster preparedness and community health promotion and to build stronger partnerships with organizations outside government, yet guidance is limited. A baseline survey documented community resilience-building barriers and facilitators for health department and community-based organization (CBO) staff. Questions focused on CBO engagement, government-CBO partnerships, and community education. Most health department staff and CBO members devoted minimal time to community disaster preparedness though many serve populations that would benefit. Respondents observed limited CR activities to activate in a disaster. The findings highlighted opportunities for engaging communities in disaster preparedness and informed the development of a community action plan and toolkit.