PI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond.

The phosphoinositide 3-kinase (PI3K) pathway regulates diverse cellular processes, with finely tuned PI3Kδ activity being crucial for immune cell development and function. Genetic hyperactivation of PI3Kδ causes the inborn error of immunity activated phosphoinositide 3-kinase δ syndrome (APDS). Several PI3Kδ inhibitors have been investigated as treatment options for APDS, but only leniolisib has shown both efficacy and tolerability. In contrast, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematological malignancies. We propose that leniolisib is distinguished from other PI3Kδ inhibitors due to its structure, specific inhibitory properties selectively targeting the δ isoform without overinhibition of the δ or γ isoforms, and the precise match between APDS mechanism of disease and drug mechanism of action.

Tissue-resident B cells orchestrate macrophage polarisation and function.

B cells play a central role in humoral immunity but also have antibody-independent functions. Studies to date have focused on B cells in blood and secondary lymphoid organs but whether B cells reside in non-lymphoid organs (NLO) in homeostasis is unknown. Here we identify, using intravenous labeling and parabiosis, a bona-fide tissue-resident B cell population in lung, liver, kidney and urinary bladder, a substantial proportion of which are B-1a cells. Tissue-resident B cells are present in neonatal tissues and also in germ-free mice NLOs, albeit in lower numbers than in specific pathogen-free mice and following co-housing with 'pet-store' mice. They spatially co-localise with macrophages and regulate their polarization and function, promoting an anti-inflammatory phenotype, in-part via interleukin-10 production, with effects on bacterial clearance during urinary tract infection. Thus, our data reveal a critical role for tissue-resident B cells in determining the homeostatic 'inflammatory set-point' of myeloid cells, with important consequences for tissue immunity.

Respiratory infectious burden in a cohort of antibody deficiency patients treated with immunoglobulin replacement therapy: The impact of lung pathology and gastroesophageal reflux disease.

Background: Antibody deficiencies result from reduced immunoglobulin levels and function, increasing susceptibility to, primarily, bacterial infection. Primary antibody deficiencies comprise intrinsic defects in B-cell physiology, often due to inherited errors. Hematological malignancies or B-cell suppressive therapy are major causes of secondary antibody deficiency. Although immunoglobulin replacement therapy (IGRT) reduces infectious burden in antibody deficiency patients, respiratory tract infections remain a significant health burden. We hypothesize that lung pathology and gastroesophageal reflux disease (GORD) increase the risk of pneumonia in antibody deficiency patients, as in the general population. Objective: For our cohort of patients with primary antibody deficiency and secondary antibody deficiency, we reviewed their respiratory infectious burden and the impact of lung pathologies and GORD. Methods: The medical records of 231 patients on IGRT at a tertiary referral center, from October 26, 2014, to February 19, 2021, were reviewed to determine microbial isolates from sputum samples and prevalence of common lung pathologies and GORD. Results: Haemophilus and Pseudomonas species represent a large infectious burden, being identified in 30.2% and 21.4% of sputum samples demonstrating growth, respectively; filamentous fungal and mycobacterial infections were rare. Diagnosed lung pathology increased the proportion of patients with Pseudomonas, Klebsiella, Stenotrophomonas, and Candida species isolated in their sputum, and diagnosed GORD increased the proportion with Enterobacter and Candida species isolated. Conclusions: Bacterial respiratory infectious burden remains in primary antibody deficiency and secondary antibody deficiency despite IGRT. Lung pathologies encourage growth of species less susceptible to IGRT, so specialist respiratory medicine input and additional treatments such as inhaled antibiotics are indicated to optimize respiratory outcomes.

Preparing for the Next Pandemic: Has COVID-19 Changed American Attitudes?

OBJECTIVE: Coronavirus disease 2019 (COVID-19) and future pandemics have become a reality, and planners must understand how attitudes during COVID-19 may influence future preparedness activities. This study explores how personal experiences of Americans during the pandemic, attitudes about institutions, and views of social change could either pose challenges or help with planning for the next pandemic. METHODS: A longitudinal survey capturing health attitudes and COVD-19-related experiences was fielded 3 times over the course of the pandemic among historically underserved individuals in US society (racial/ethnic minority and low-income populations). RESULTS: COVID-19-related experiences increased over time. Attitudes about federal and state government and businesses' ability to respond to the pandemic varied by COVID-19-related experience and having any COVID-19-related experience was associated with a lower likelihood of reporting positive attitudes about institutions. Respondents generally perceived that COVID-19 presented an opportunity for positive social change, and those with COVID-19-related experiences had the greatest likelihood of selecting "reduce income inequality" as their top prioritized change. Those with COVID-19-related experiences were less likely to endorse other policy priorities such as protecting freedoms. CONCLUSIONS: Anticipating potential backlash or other sentiments could improve pandemic responsiveness. Strengthening public institutions is crucial to ensuring their effectiveness during a pandemic. Pandemic planning could exploit opportunities to take other social policy actions where views seem to converge.

An open label trial of nemiralisib, an inhaled PI3 kinase delta inhibitor for the treatment of Activated PI3 kinase Delta Syndrome.

Activated PI3Kδ Syndrome (APDS) is a rare inherited inborn error of immunity caused by mutations that constitutively activate the p110 delta isoform of phosphoinositide 3-kinase (PI3Kδ), resulting in recurring pulmonary infections. Currently no licensed therapies are available. Here we report the results of an open-label trial in which five subjects were treated for 12 weeks with nemiralisib, an inhaled inhibitor of PI3Kδ, to determine safety, systemic exposure, together with lung and systemic biomarker profiles (Clinicaltrial.gov: NCT02593539). Induced sputum was captured to measure changes in phospholipids and inflammatory mediators, and blood samples were collected to assess pharmacokinetics of nemiralisib, and systemic biomarkers. Nemiralisib was shown to have an acceptable safety and tolerability profile, with cough being the most common adverse event, and no severe adverse events reported during the study. No meaningful changes in phosphatidylinositol (3,4,5)-trisphosphate (PIP3; the enzyme product of PI3Kδ) or downstream inflammatory markers in induced sputum, were observed following nemiralisib treatment. Similarly, there were no meaningful changes in blood inflammatory markers, or lymphocytes subsets. Systemic levels of nemiralisib were higher in subjects in this study compared to previous observations. While nemiralisib had an acceptable safety profile, there was no convincing evidence of target engagement in the lung following inhaled dosing and no downstream effects observed in either the lung or blood compartments. We speculate that this could be explained by nemiralisib not being retained in the lung for sufficient duration, suggested by the increased systemic exposure, perhaps due to pre-existing structural lung damage. In this study investigating a small number of subjects with APDS, nemiralisib appeared to be safe and well-tolerated. However, data from this study do not support the hypothesis that inhaled treatment with nemiralisib would benefit patients with APDS.

Equity as a Guiding Principle for the Public Health Data System.

The growing centering of equity in health has elevated a conversation about how those interests should translate within the systems and sectors that influence health. In particular, the public health data system has been relatively limited in capturing the drivers and consequences of health inequity as well as the varying dimensions of equity. This article examines what it means to use equity as a guiding principle throughout the components and functions of a modern public health data system. As with other articles in this supplement, this article builds from a literature review, environmental scan, and deliberations from the National Commission to Transform Public Health Data Systems to summarize current gaps to integrate equity throughout the system. It outlines opportunities for the technology and data science sectors specifically to engage given the access that these sectors have to information that would illuminate and frame the nuances and impacts of health inequity.

What Data Should Be Included in a Modern Public Health Data System.

The public is inundated with data, both in where data are ubiquitously collected and in how organizations are using data to drive public sector and commercial decisions. The public health data system is no exception to this flood of data, both in growing data volume and variety. However, what are collected and analyzed about the health status of the nation, how particular data and measures are prioritized for parsimony, and how those data provide a signal for where to invest to address health inequities are in dire need of a reboot. As with other articles in this supplement, this article builds from a literature review, an environmental scan, and deliberations from the National Commission to Transform Public Health Data Systems. The article summarizes what data should be included and identifies where the technology and data sectors can contribute to fill current gaps to measure equity, positive health, and well-being.

The Issues of Interoperability and Data Connectedness for Public Health.

An unprecedented amount of data is being collected across a diversity of sectors, which, if harnessed, could transform public health decision-making. Yet significant challenges stand in the way of such a vision, including the need to establish standards of data sharing and interoperability, the need for innovation in both methodological approaches and workforce models, and the need for data stewardship and governance models to ensure the protection and integrity of the public health data system. As with other articles in this supplement, this article builds from a literature review, environmental scan, and deliberations from the National Commission to Transform Public Health Data Systems. The article summarizes some of the challenges around data sharing and reuse and identifies where the technology and data sectors can contribute to fill current gaps to promote interoperability and data stewardship.

Technology and Data Implications for the Public Health Workforce.

Achieving a modern equity-oriented public health system requires the development of a public health workforce with the skills and competencies needed to generate findings and integrate knowledge using diverse data. Yet current workforce capabilities and infrastructure are misaligned with what is needed to harness both new and older forms of data and to translate them into information that is equity contextualized. As with other articles in this supplement, this article builds from a literature review, environmental scan, and deliberations from the National Commission to Transform Public Health Data Systems. The article summarizes some of the challenges around current workforce capabilities and pipeline. The article identifies where the technology and data sectors can contribute skills, expertise, and assets in support of innovative workforce models and augment the development of public health workforce competencies.

The Gross Developmental Potential (GDP2): a new approach for measuring human potential and wellbeing.

Many factors influence the health and well-being of children and the adults they will become. Yet there are significant gaps in how trajectories of healthy development are measured, how the potential for leading a healthy life is evaluated, and how that information can guide upstream policies and investments. The Gross Developmental Potential (GDP2) is proposed as a new capabilities-based framework for assessing threats to thriving and understanding progress in achieving lifelong health and wellbeing. Moving beyond the Gross Domestic Product's (GDP) focus on economic productivity as a measure of progress, the GDP2 focuses on seven essential developmental capabilities for lifelong health and wellbeing. The GDP2 capability domains include Health -living a healthy life; Needs-satisfying basic human requirements; Communication-expressing and understanding thoughts and feelings; Learning-lifelong learning; Adaption -adapting to change; Connections -connecting with others; and Community -engaging in the community. The project team utilized literature reviews and meetings with the subject and technical experts to develop the framework. The framework was then vetted in focus groups of community leaders from three diverse settings. The community leaders' input refined the domains and their applications. This prototype GDP2 framework will next be used to develop specific measures and indices and guide the development of community-level GDP2 dashboards for local sense-making, learning, and application.

Assessing Health and Human Services Needs to Support an Integrated Health in All Policies Plan for Prince George's County, Maryland.

With evolving demographics and a changing health system landscape, the Prince George's County Council, acting as the County Board of Health, is considering its future policy approaches and resource allocations related to health and well-being. To inform this path forward, the authors of this study used primary and secondary data to describe both the health needs of county residents and drivers of health within the county, inclusive of the social, economic, built, natural, and health service environments. This study integrates these findings, an analysis of budget documents, and a review of promising practices from other communities to situate recommendations in a Health in All Policies framework to foster aligned and integrated planning and budgeting across the county to promote health and well-being. Findings from the assessment indicate a shared interest among leaders and residents to embrace a holistic strategy for health and well-being in the county. Inefficient uses of the health care system are identified, highlighting a need to rebalance investments in health care use and drivers of health. Additionally, challenges in navigating health and human services and inequities in drivers of health across communities are noted, signaling broader concerns related to residents' access to health and human services that influence health and well-being outcomes. Recommendations are provided for several paths forward for the county to pursue a more integrated policy approach to influence health and well-being outcomes.

Comparison of Cognitive Function in Children with Stunting and Children with Undernutrition with Normal Stature.

Background: Stunting is the impaired growth and development that children experience from poor nutrition, repeated infection, and inadequate psychosocial stimulation. Children are defined as stunted if their height-for-age is more than two standard deviations below the WHO Child Growth Standards median. According to the Indonesia Basic National Health Survey 2013, Indonesia's stunting prevalence reached 37.2%. Various studies have shown that impaired cognitive development is found in children with stunting and undernutrition. This study aims to determine cognitive development in stunted and undernutrition with normal stature children using the Bayley Scale of Infant Development III (Bayley-III). Methods: A cross-sectional study on 51 children aged one month to 3 years who fulfilled the inclusion criteria and who visited the outpatient clinic of Dr. Cipto Mangunkusumo National General Hospital from June 2017 to January 2018 was performed. Cognitive development was assessed using the Bayley Scale of Infant Development, Third Edition (Bayley-III). Results: 26 children with stunting and 25 children with undernutrition with normal stature participated in this study. There was a statistically nonsignificant trend toward lower median score percentiles in the stunted group compared to that in the undernourished with normal stature group in the motor (median (range) 1 (0.1-75) vs. 4 (0-79); p=0.183), cognitive (12.5 (0.1-75) vs. 16 (0.1-99.9); p=0.550), and adaptive behavior (7 (0.1-75) vs. 12 (0.1-58); p=0.657) domains. Conclusions: There is a trend toward lower cognitive, motor, and adaptive behavior abilities in stunted children compared to undernourished children with normal stature which needs further study. In addition, children with undernutrition have below-average abilities across all domains even before stunting has occurred.

A Multi­Center, Open­Label, Single­Arm Trial to Evaluate the Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency.

PURPOSE: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI). METHODS: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured. RESULTS: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate. CONCLUSIONS: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.

Health and Social Services in Puerto Rico Before and After Hurricane Maria: Predisaster Conditions, Hurricane Damage, and Themes for Recovery.

"In September 2017, Puerto Rico was struck by two major hurricanes-Irma and Maria-that intensified existing challenges in Puerto Rico's health and social services infrastructure. In the aftermath, the government of Puerto Rico created a long-term recovery plan built on an evidence-based assessment of the damage from the hurricanes and the ongoing needs across Puerto Rico. Development of the recovery plan was supported by the Federal Emergency Management Agency, other federal agencies, local stakeholders, and analysis from the Homeland Security Operational Analysis Center (HSOAC), operated by RAND Corporation under contract with the U.S. Department of Homeland Security. HSOAC research provided the foundation for the 31 courses of action in the recovery plan addressing the health and social services sector. These actions are a mix of social, governmental, fiscal, and economic policies and reforms. This collection of actions presents an opportunity to build a more resilient health and social services infrastructure and regional health care networks to ensure reliable access to services, promote health and well-being, and more efficiently and effectively respond to public health crises and future disasters. The actions span the areas of health care, public health and emergency preparedness, environmental health, mental and behavioral health, and social services. The damage and needs assessment and courses of actions cover four major themes: building system capacity to respond both during disasters and routine times; strengthening the health and social services workforce; strengthening support services for at-need populations; and creating health-promoting communities.

Americans' View of the Impact of COVID-19: Perspectives on Racial Impacts and Equity.

CONTEXT: The COVID-19 pandemic has had a disparate effect on African Americans and Latinos. But it is unknown how aware the public is of these differences and how the pandemic has changed perceptions of equity and access to health care. METHODS: We use panel data from nationally representative surveys fielded to the same respondents in 2018 and 2020 to assess views and changes in views over time. FINDINGS: We found that awareness of inequity is highest among Non-Hispanic Black respondents and higher-income and higher-educated groups, and there have been only small changes in perceptions of inequity over time. However, there have been significant changes in views of the government's obligation to ensure access to health care. CONCLUSIONS: Even in the face of a deadly pandemic, one that has killed disproportionately more African Americans and Latinos, many in the United States continue not to recognize that there are inequities in access to health care and the impact of COVID-19 on certain groups. But policies to address inequity may be shifting. We will continue to follow these respondents to see whether changes in attitudes endure over time or dissipate.

SARS-CoV-2 evolution during treatment of chronic infection.

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.

Drivers of differential views of health equity in the U.S.: is the U.S. ready to make progress? Results from the 2018 National Survey of Health Attitudes.

OBJECTIVES: The public health sector has long recognized the role of the social determinants of health in health disparities and the importance of achieving health equity. We now appear to be at an inflection point, as we hear increasing demands to dismantle structures that have perpetuated inequalities. Assessing prevailing mindsets about what causes health inequalities and the value of health equity is critical to addressing larger issues of inequity, including racial inequity and other dimensions. Using data from a nationally representative sample of adults in the United States, we examined the factors that Americans think drive health outcomes and their beliefs about the importance of health equity. METHODS: Using data from the 2018 National Survey of Health Attitudes, we conducted factor analyses of 21 survey items and identified three factors from items relating to health drivers-traditional health influencers (THI), social determinants of health (SDoH), and sense of community health (SoC). Health equity beliefs were measured with three questions about opportunities to be healthy. Latent class analysis identified four groups with similar patterns of response. Factor mixture modeling combined factor structure and latent class analysis into one model. We conducted three logistic regressions using latent classes and demographics as predictors and the three equity beliefs as dependent variables. RESULTS: Nearly 90% of respondents comprised one class that was characterized by high endorsement (i.e., rating the driver as having strong effect on health) of THI, but lower endorsement of SDoH and SoC. Logistic regressions showed that respondents endorsing (i.e., rated it as a top priority) all three health equity beliefs tended to be female, older, Black or Hispanic, more educated, and have lower incomes. The class of respondents that endorsed SDoH the most was more likely to endorse all three equity beliefs. CONCLUSIONS: Results suggested that people historically impacted by inequity, e.g., people of color and people with low incomes, had the most comprehensive understanding of the drivers of health and the value of equity. However, dominant beliefs about SDoH and health equity are still generally not aligned with scientific consensus and the prevailing narrative in the public health community.

Intravital Imaging of Adoptive T-Cell Morphology, Mobility and Trafficking Following Immune Checkpoint Inhibition in a Mouse Melanoma Model.

Efficient T-cell targeting, infiltration and activation within tumors is crucial for successful adoptive T-cell therapy. Intravital microscopy is a powerful tool for the visualization of T-cell behavior within tumors, as well as spatial and temporal heterogeneity in response to immunotherapy. Here we describe an experimental approach for intravital imaging of adoptive T-cell morphology, mobility and trafficking in a skin-flap tumor model, following immune modulation with immune checkpoint inhibitors (ICIs) targeting PD-L1 and CTLA-4. A syngeneic model of ovalbumin and mCherry-expressing amelanotic mouse melanoma was used in conjunction with adoptively transferred OT-1+ cytotoxic T-cells expressing GFP to image antigen-specific live T-cell behavior within the tumor microenvironment. Dynamic image analysis of T-cell motility showed distinct CD8+ T-cell migration patterns and morpho-dynamics within different tumor compartments in response to ICIs: this approach was used to cluster T-cell behavior into four groups based on velocity and meandering index. The results showed that most T-cells within the tumor periphery demonstrated Lévy-like trajectories, consistent with tumor cell searching strategies. T-cells adjacent to tumor cells had reduced velocity and appeared to probe the local environment, consistent with cell-cell interactions. An increased number of T-cells were detected following treatment, traveling at lower mean velocities than controls, and demonstrating reduced displacement consistent with target engagement. Histogram-based analysis of immunofluorescent images from harvested tumors showed that in the ICI-treated mice there was a higher density of CD31+ vessels compared to untreated controls and a greater infiltration of T-cells towards the tumor core, consistent with increased cellular trafficking post-treatment.