Publications by authors named "Anita Chandra"

93 Publications

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

Nature 2021 Feb 5. Epub 2021 Feb 5.

Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.

SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03291-yDOI Listing
February 2021

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.

BMC Public Health 2021 Jan 21;21(1):175. Epub 2021 Jan 21.

RAND Corporation, 4570 Fifth Avenue, Suite 600, Pittsburgh, PA, 15213, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12889-021-10179-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817761PMC
January 2021

Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation.

medRxiv 2020 Dec 29. Epub 2020 Dec 29.

SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, and amino acid variation in Spike is increasingly appreciated. Given both vaccines and therapeutics are designed around Wuhan-1 Spike, this raises the theoretical possibility of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs. 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 by both short and long read technologies over 23 time points spanning 101 days. Although little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days, N501Y in Spike was transiently detected at day 55 and V157L in RdRp emerged. However, following convalescent plasma we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and H69/ V70 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 H69/ V70 and D796H conferred 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 H69/ V70 single mutant had two-fold higher infectivity compared to wild type and appeared to compensate for the reduced infectivity of D796H. Consistent with the observed mutations being outside the RBD, monoclonal antibodies targeting the RBD were not impacted by either or both mutations, but a non RBD binding monoclonal antibody was less potent against H69/ V70 and the double mutant. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with reduced susceptibility to neutralising antibodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.12.05.20241927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781345PMC
December 2020

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

Front Immunol 2020 22;11:1514. Epub 2020 Jul 22.

Cancer Research UK Cambridge Centre, Cambridge, United Kingdom.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.01514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387409PMC
July 2020

Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

Nature 2020 Aug;584(7819):E2

Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2556-6DOI Listing
August 2020

Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate.

Nat Commun 2020 07 8;11(1):3412. Epub 2020 Jul 8.

Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, King's College London, London, SE1 1UL, UK.

Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17179-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343868PMC
July 2020

Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

Nature 2020 07 6;583(7814):90-95. Epub 2020 May 6.

Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK.

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2265-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334047PMC
July 2020

Factors related to health civic engagement: results from the 2018 National Survey of Health Attitudes to understand progress towards a Culture of Health.

BMC Public Health 2020 May 7;20(1):635. Epub 2020 May 7.

RAND Corporation, Social & Economic Wellbeing, Santa Monica, USA.

Background: Civic engagement, including voting, volunteering, and participating in civic organizations, is associated with better psychological, physical and behavioral health and well-being. In addition, civic engagement is increasingly viewed (e.g., in Robert Wood Johnson Foundation's Culture of Health action framework) as a potentially important driver for raising awareness of and addressing unhealthy conditions in communities. As such, it is important to understand the factors that may promote civic engagement, with a particular focus on the less-understood, health civic engagement, or civic engagement in health-related and health-specific activities. Using data from a nationally representative sample of adults in the United States (U.S.), we examined whether the extent to which individuals feel they belong in their community (i.e., perceived sense of community) and the value they placed on investing in community health were associated with individuals' health civic engagement.

Methods: Using data collected on 7187 nationally representative respondents from the 2018 National Survey of Health Attitudes, we examined associations between sense of community, valued investment in community health, and perceived barriers to taking action to invest in community health, with health civic engagement. We constructed continuous scales for each of these constructs and employed multiple linear regressions adjusting for multiple covariates including U.S. region and city size of residence, educational attainment, family income, race/ethnicity, household size, employment status, and years living in the community.

Results: Participants who endorsed (i.e., responded with mostly or completely) all 16 sense of community scale items endorsed an average of 22.8% (95%CI: 19.8-25.7%) more of the health civic engagement scale items compared with respondents who did not endorse any of the sense of community items. Those who endorsed (responded that it was an important or top priority) all items capturing valued investment in community health endorsed 14.0% (95%CI: 11.2-16.8%) more of the health civic engagement items than those who did not endorse any valued investment in community health items.

Conclusions: Health civic engagement, including voting and volunteering to ultimately guide government decisions about health issues, may help improve conditions that influence health and well-being for all. Focusing on individuals' sense of community and highlighting investments in community health may concurrently be associated with increased health civic engagement and improved community and population health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12889-020-08507-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203885PMC
May 2020

An Evaluation of U.S. Military Non-Medical Counseling Programs.

Rand Health Q 2018 Oct 11;8(2). Epub 2018 Oct 11.

This study evaluates two programs offered by the U.S. Department of Defense (DoD) that provide short-term, solution-focused counseling for common personal and family issues to members of the U.S. military and their families. These counseling services are collectively called non-medical counseling within the DoD and are offered through the Military and Family Life Counseling (MFLC) and Military OneSource programs. RAND's National Defense Research Institute was asked to evaluate these programs to determine whether they are effective in improving outcomes and whether effectiveness varies by problem type and/or population. Two online surveys were provided to program participants-the first two to three weeks after their initial session and the second three months later. Surveys were designed to gain information on 1) problem severity and overall problem resolution, 2) resolution of stress and anxiety, 3) problem interference with work and daily life, 4) connection to other services and referrals, 5) experiences with MFLC and Military OneSource programs, and 6) perceptions of non-medical counselors. The majority of participants experienced a decrease in problem severity and a reduction in reported frequency of feeling stressed or anxious as a result of their problem following counseling. These improvements were sustained or continued to improve in the three months after initiation of counseling. Non-medical counseling was not universally successful, however, and a small minority expressed dissatisfaction with the program or their counselor. Collectively these findings suggest a number of policy implications and programmatic improvements of interest to program leadership in the Office of the Secretary of Defense.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6183774PMC
October 2018

PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner.

Nat Commun 2018 08 9;9(1):3174. Epub 2018 Aug 9.

Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, CB21 3AT, UK.

Streptococcus pneumoniae is a major cause of pneumonia and a leading cause of death world-wide. Antibody-mediated immune responses can confer protection against repeated exposure to S. pneumoniae, yet vaccines offer only partial protection. Patients with Activated PI3Kδ Syndrome (APDS) are highly susceptible to S. pneumoniae. We generated a conditional knock-in mouse model of this disease and identify a CD19B220 B cell subset that is induced by PI3Kδ signaling, resides in the lungs, and is correlated with increased susceptibility to S. pneumoniae during early phases of infection via an antibody-independent mechanism. We show that an inhaled PI3Kδ inhibitor improves survival rates following S. pneumoniae infection in wild-type mice and in mice with activated PI3Kδ. These results suggest that a subset of B cells in the lung can promote the severity of S. pneumoniae infection, representing a potential therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-05674-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085315PMC
August 2018

Improving Disaster Resilience Among Older Adults: Insights from Public Health Departments and Aging-in-Place Efforts.

Rand Health Q 2018 Aug 2;8(1). Epub 2018 Aug 2.

This study uses interview data collected from public health departments and aging-in-place efforts-specifically, from coordinators of age-friendly communities and village executive directors-to explore how current aging-in-place efforts can be harnessed to strengthen the disaster resilience of older adults and which existing programs or new collaborations among public health departments and these organizations show promise for improving disaster resilience for older populations. Interviews with stakeholders revealed that most age-friendly communities and senior villages did not place a high priority on promoting disaster preparedness. While most public health departments conducted or took the lead on disaster preparedness and resilience activities, they were not necessarily tailored to older adults. Aligning and extending public health departments' current preparedness activities to include aging-in-place efforts and greater tailoring of existing preparedness activities to the needs of older adults could significantly improve their disaster preparedness and resilience. For jurisdictions that do not have an existing aging-in-place effort, public health departments can help initiate those efforts and work to incorporate preparedness activities at the outset of newly developing aging-in-place efforts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075802PMC
August 2018

Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry.

Front Immunol 2018 16;9:543. Epub 2018 Mar 16.

Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Freiburg, Germany.

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in (APDS1) or (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.00543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863269PMC
May 2019

Evaluating Community Partnerships Addressing Community Resilience in Los Angeles, California.

Int J Environ Res Public Health 2018 03 27;15(4). Epub 2018 Mar 27.

RAND Corporation, Santa Monica, CA 90401, USA.

Community resilience has grown in importance in national disaster response and recovery efforts. However, measurement of community resilience, particularly the content and quality of relationships aimed at improving resilience, is lacking. To address this gap, we used a social network survey to measure the number, type, and quality of relationships among organizations participating in 16 coalitions brought together to address community resilience in the Los Angeles Community Disaster Resilience project. These coalitions were randomized to one of two approaches (community resilience or preparedness). Resilience coalitions received training and support to develop these partnerships and implement new activities. Both coalition types received expert facilitation by a public health nurse or community educator. We also measured the activities each coalition engaged in and the extent to which partners participated in these activities at two time points. We found that the community resilience coalitions were initially larger and had lower trust among members than the preparedness communities. Over time, these trust differences dissipated. While both coalitions grew, the resilience community coalitions maintained their size difference throughout the project. We also found differences in the types of activities implemented by the resilience communities; these differences were directly related to the trainings provided. This information is useful to organizations seeking guidance on expanding the network of community-based organizations that participate in community resilience activities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph15040610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923652PMC
March 2018

Respiratory Manifestations of the Activated Phosphoinositide 3-Kinase Delta Syndrome.

Front Immunol 2018 5;9:338. Epub 2018 Mar 5.

Department of Medicine, University of Cambridge, Cambridge, United Kingdom.

The activated phosphoinositide 3-kinase δ syndrome (APDS), also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI), is a combined immunodeficiency syndrome caused by gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes (encoding p110δ: APDS1 or PASLI-CD) and (encoding p85α: APDS2 or PASLI-R1). While the disease is clinically heterogeneous, respiratory symptoms and complications are near universal and often severe. Infections of the ears, sinuses, and upper and lower respiratory tracts are the earliest and most frequent manifestation of APDS, secondary to both respiratory viruses and to bacterial pathogens typical of defective B cell function. End organ damage in the form of small airways disease and bronchiectasis frequently complicates APDS, but despite documented T cell defects, opportunistic infections have rarely been observed. Antimicrobial (principally antibiotic) prophylaxis and/or immunoglobulin replacement have been widely used to reduce the frequency and severity of respiratory infection in APDS, but outcome data to confirm the efficacy of these interventions are limited. Despite these measures, APDS patients are often afflicted by benign lymphoproliferative disease, which may present in the respiratory system as tonsillar/adenoidal enlargement, mediastinal lymphadenopathy, or mucosal nodular lymphoid hyperplasia, potentially causing airways obstruction and compounding the infection phenotype. Treatment with rapamycin and PI3Kδ inhibitors has been reported to be of benefit in benign lymphoproliferation, but hematopoietic stem cell transplantation (ideally undertaken before permanent airway damage is established) remains the only curative treatment for APDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.00338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844940PMC
March 2019

Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans.

J Allergy Clin Immunol 2018 10 2;142(4):1285-1296. Epub 2018 Mar 2.

NIHR BioResource-Rare Diseases, Cambridge Biomedical Campus, Cambridge, United Kingdom.

Background: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information.

Objective: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort.

Methods: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses.

Results: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21 B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases.

Conclusion: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2018.01.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148345PMC
October 2018

Characterization of innate immune viral sensors in patients following allogeneic hematopoietic stem cell transplantation.

Innate Immun 2018 02 12;24(2):112-121. Epub 2018 Feb 12.

1 MRC Laboratory of Molecular Biology, Cambridge, UK.

Viral infection is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplant (HSCT), with up to one in four deaths directly linked to viral disease. Whilst awaiting lymphocyte reconstitution post-HSCT, the innate antiviral immune response is the first line of defense against invading viruses. Several novel innate viral-sensing pathways have recently been characterized, but their physiological importance in humans is poorly understood. We analyzed a panel of innate viral-sensor genes in HSCT patients, and assessed whether differences in innate antiviral responses could account for variation in susceptibility to viral infections. Expression levels of innate viral sensors in HSCT patients with active viral infections, HSCT patients without active infections and healthy volunteers were highly homogenous. Although IFN-α expression was up-regulated in actively infected patients relative to controls, a corresponding up-regulation of innate viral sensor expression was not observed. IFN-α stimulation of patient PBMCs in vitro showed intact IFN-α signaling, but actively infected patients' PBMCs had reduced up-regulation of innate viral sensors. We show that the aberrant IFN-α responses in HSCT patients were not due to calcineurin inhibition. Our data therefore raises the possibility of an intrinsic defect in innate viral sensor up-regulation in HSCT patients following viral infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1753425918757898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830896PMC
February 2018

How Cultural Alignment and the Use of Incentives Can Promote a Culture of Health: Stakeholder Perspectives.

Rand Health Q 2018 Jan 29;7(2). Epub 2018 Jan 29.

In 2013, the Robert Wood Johnson Foundation embarked on a pioneering effort to advance a Culture of Health. This report focuses on two questions that are central to understanding how individuals and sectors think about health and are motivated to promote it: How can the commonly understood concepts of cultural identity (e.g., ethnic or religious; lesbian, gay, bisexual, transgender plus; military) and organizational culture be harnessed to develop a Culture of Health? How can incentives be used to promote individual health and engage investors and leaders within organizations or governments to promote health and well-being broadly? This study draws on 43 one-hour semistructured interviews that RAND researchers conducted with stakeholders whose work focused on cultural alignment, incentives, or both to learn how organizations are addressing and leveraging culture and incentives to promote health and well-being, as well as to identify facilitators, barriers, potential best practices, and lessons learned. Key findings include the following: Equity is often addressed in silos, which impedes progress toward a unified goal of health equity for all; members of specific cultural groups need to be given a voice in health-related activities; systems are built around prevailing cultural norms, making it challenging for those working with specific cultures to make cultural adaptations; and not all incentives are monetary. Recommendations include institutionalizing practices that ensure ongoing input from marginalized populations, identifying ways to help smaller organizations overcome structural inequalities, and institutionalizing health promotion efforts in sectors other than public health or health care to sustain collaborative efforts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798967PMC
January 2018

How Community and Public Health Partnerships Contribute to Disaster Recovery and Resilience.

Disaster Med Public Health Prep 2018 10 1;12(5):635-643. Epub 2018 Feb 1.

1RAND Corporation,Santa Monica,California.

Objective: To summarize ways that networks of community-based organizations (CBO), in partnership with public health departments, contribute to community recovery from disaster.

Methods: The study was conducted using an online survey administered one and 2 years after Hurricane Sandy to the partnership networks of 369 CBO and the New York Department of Health and Mental Hygiene. The survey assessed the structure and durability of networks, how they were influenced by storm damage, and whether more connected networks were associated with better recovery outcomes.

Results: During response and recovery, CBOs provide an array of critical public health services often outside their usual scope. New CBO partnerships were formed to support recovery, particularly in severely impacted areas. CBOs that were more connected to other CBOs and were part of a long-term recovery committee reported greater impacts on the community; however, a partnership with the local health department was not associated with recovery impacts.

Conclusion: CBO partners are flexible in their scope of services, and CBO partnerships often emerge in areas with the greatest storm damage, and subsequently the greatest community needs. National policies will advance if they account for the dynamic and emergent nature of these partnerships and their contributions, and clarify the role of government partners. (Disaster Med Public Health Preparedness. 2018;12:635-643).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/dmp.2017.130DOI Listing
October 2018

Beyond Disaster Preparedness: Building a Resilience-Oriented Workforce for the Future.

Int J Environ Res Public Health 2017 12 13;14(12). Epub 2017 Dec 13.

RAND Corporation, 1200 South Hayes Street, Arlington, VA 22202, USA.

Enhancing citizens' and communities' resilience is critical to adapt successfully to ongoing challenges faced by communities, as well as acute shocks resulting from disasters. While significant progress has been made in this area, several research and practice gaps remain. A crucial next step to advance resilience is the development of a resilience-oriented workforce. This narrative review examines existing literature to determine key components of a resilience-oriented workforce, with a focus on organizational structures, training and education, and leadership models. Reviewed articles spanned a variety of study types, including needs assessments of existing workforce, program evaluations, and reviews/commentaries. A resilience-oriented workforce spans many disciplines and training programs will need to reflect that. It requires a collaborative organizational model that promotes information sharing structures. Leadership models should foster a balance between workforce autonomy and operation as a collective entity. Optimal strategies to develop a resilience-oriented workforce have yet to be realized and future research will need to collect and synthesize data to promote and evaluate the growth of this field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph14121563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750981PMC
December 2017

Towards More Nuanced Classification of NGOs and Their Services to Improve Integrated Planning across Disaster Phases.

Int J Environ Res Public Health 2017 11 21;14(11). Epub 2017 Nov 21.

RAND Corporation, 1200 S. Hayes Street, Arlington, VA 22202, USA.

Nongovernmental organizations (NGOs) are being integrated into U.S. strategies to expand the services that are available during health security threats like disasters. Identifying better ways to classify NGOs and their services could optimize disaster planning. We surveyed NGOs about the types of services they provided during different disaster phases. Survey responses were used to categorize NGO services as -critical to fulfilling their organizational mission-or -services implemented during a disaster based on community need. We also classified NGOs as being core or adaptive types of organizations by calculating the percentage of each NGO's services classified as core. Service types classified as core were mainly social services, while adaptive service types were those typically relied upon during disasters (e.g., warehousing, food services, etc.). In total, 120 NGOs were classified as core organizations, meaning they mainly provided the same services across disaster phases, while 100 NGOs were adaptive organizations, meaning their services changed. Adaptive NGOs were eight times more likely to report routinely participating in disaster planning as compared to core NGOs. One reason for this association may be that adaptive NGOs are more aware of the changing needs in their communities across disaster phases because of their involvement in disaster planning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph14111423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708062PMC
November 2017

How Do Communities Use a Participatory Public Health Approach to Build Resilience? The Los Angeles County Community Disaster Resilience Project.

Int J Environ Res Public Health 2017 10 21;14(10). Epub 2017 Oct 21.

Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.

Community resilience is a key concept in the National Health Security Strategy that emphasizes development of multi-sector partnerships and equity through community engagement. Here, we describe the advancement of CR principles through community participatory methods in the Los Angeles County Community Disaster Resilience (LACCDR) initiative. LACCDR, an initiative led by the Los Angeles County Department of Public Health with academic partners, randomized 16 community coalitions to implement either an Enhanced Standard Preparedness or Community Resilience approach over 24 months. Facilitated by a public health nurse or community educator, coalitions comprised government agencies, community-focused organizations and community members. We used thematic analysis of data from focus groups ( = 5) and interviews ( = 6 coalition members; = 16 facilitators) to compare coalitions' strategies for operationalizing community resilience levers of change (engagement, partnership, self-sufficiency, education). We find that strategies that included bidirectional learning helped coalitions understand and adopt resilience principles. Strategies that operationalized community resilience levers in mutually reinforcing ways (e.g., disseminating information while strengthening partnerships) also secured commitment to resilience principles. We review additional challenges and successes in achieving cross-sector collaboration and engaging at-risk groups in the resilience versus preparedness coalitions. The LACCDR example can inform strategies for uptake and implementation of community resilience and uptake of the resilience concept and methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph14101267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664768PMC
October 2017

An Agenda to Advance Integrative Resilience Research and Practice: Key Themes From a Resilience Roundtable.

Rand Health Q 2017 Jan 1;7(1). Epub 2017 Jan 1.

People are facing an increasing variety and number of stressors, ranging from interpersonal difficulties to environmental hazards and societal forces. Resilience is the process of, capacity for, or outcome of adapting well in the face of adversity, trauma, tragedy, threats, or significant sources of stress. The science of resilience has advanced greatly since 2000, but there is an increasing recognition of the need for researchers and practitioners from different disciplines and sectors to work better together on this topic and for a shared agenda for promoting transdisciplinary resilience research. The study provides a path forward, primarily built on proceedings from a Resilience Roundtable, held in June 2016, and supplemented with relevant literature review. The Resilience Roundtable brought together researchers, practitioners, and policymakers, across disciplines and sectors for a daylong discussion of where and how we can move to a more integrated and cohesive resilience agenda, with attention to critical factors that would motivate more collaborative work. The roundtable identified priorities for advancing a shared resilience agenda and made ten recommendations for implementing it.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644771PMC
January 2017

Anterior Chamber Invasion in Retinoblastoma: Not an Indication for Adjuvant Chemotherapy.

Invest Ophthalmol Vis Sci 2017 09;58(11):4654-4661

Shri Bhagawan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, India.

Purpose: In retinoblastoma, adjuvant chemotherapy after enucleation is given in eyes with histopathological high-risk features (HRFs) to reduced mortality. Anterior chamber seeds (AC seeds) on histopathological evaluation are a contentious finding. This study attempts to determine the effect of AC seeds on the survival rate.

Methods: This is a retrospective case record review. Eyes were divided into four groups: those with neither AC seeds nor HRFs, those with only HRFs, those with only AC seeds, and those with both HRFs and AC seeds. The groups were compared for demographic and clinical features and survival curves were plotted for each.

Results: For the 212 eyes included in the study, mean age was 30.5 ± 36.8 months. Children with only AC seeds were significantly older (75.3 ± 94.6 months) (P = 0.004). Chemotherapy was administered in 81 (38.2%) of 212 eyes; 16 (13.7%) of 117 eyes without HRF and in 65 (68.4%) of 95 eyes with HRFs (P < 0.001). The survival rate at 1, 3, and 5 years was the highest for the group with only AC seeds, although the difference was not statistically significant.

Conclusions: We conclude that AC seeds do not, by themselves, constitute an independent risk factor for metastasis. These children need not be treated with immediate adjuvant chemotherapy, but, instead, can be followed with regular screening for metastasis. However, AC seeds are seen in only a small proportion of enucleated eyes. A larger study would better validate our study results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1167/iovs.17-22111DOI Listing
September 2017

Stakeholder Perspectives on a Culture of Health: Key Findings.

Rand Health Q 2017 Jun 19;6(3). Epub 2017 Jun 19.

Since 2013, the Robert Wood Johnson Foundation (RWJF) has embarked on a pioneering effort to advance a Culture of Health. The Culture of Health action framework is founded on a vision in which "everyone in our diverse society leads healthier lives now and for generations to come." To put the Culture of Health vision into action, RWJF asked RAND Health to support the development of an action framework and measurement strategy. This article summarizes the stakeholder engagement efforts that RAND used to inform this work. It draws on a series of interviews and focus groups that RAND researchers conducted with stakeholders both within and outside the United States. It should be of interest to RWJF, as well as to those individuals and organizations interested in advancing the Culture of Health action framework. Given that RWJF is focused on using the Culture of Health action framework and measures to catalyze national dialogue about content and investments to improve population health and well-being, the study should be beneficial to a range of national, state, and local leaders across a variety of sectors that contribute to health as described by the Culture of Health action framework.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568151PMC
June 2017

Building a National Culture of Health: Background, Action Framework, Measures, and Next Steps.

Rand Health Q 2017 Jan 13;6(2). Epub 2017 Jan 13.

Because health is a function of more than medical care, solutions to U.S. health problems must encompass more than reforms to health care systems. But those working to improve health, well-being, and equity still too often find themselves traveling on parallel paths that rarely intersect. In 2013, the Robert Wood Johnson Foundation (RWJF) embarked on a pioneering effort to advance a Culture of Health initiative. A Culture of Health places well-being at the center of every aspect of life, with the goal of enabling everyone in our diverse society to lead healthier lives, now and for generations to come. To put this vision into action, RWJF worked with RAND to develop an action framework that identifies how the nation will work toward achieving these outcomes. This article provides background on the development of this action framework. The Culture of Health action framework is designed around four action areas and one outcome area. Action areas are the core areas in which investment and activity are needed: (1) making health a shared value; (2) fostering cross-sector collaboration to improve well-being; (3) creating healthier, more equitable communities; and (4) strengthening integration of health services and systems. Each action area contains a set of drivers indicating where the United States needs to accelerate change and a set of measures illustrating places for progress. Within the primary Culture of Health outcome---improved population health, well-being, and equity---the authors identified three outcome areas: enhanced individual and community well-being, managed chronic disease and reduced toxic stress, and reduced health care costs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568157PMC
January 2017

Cells with Treg-specific FOXP3 demethylation but low CD25 are prevalent in autoimmunity.

J Autoimmun 2017 Nov 23;84:75-86. Epub 2017 Jul 23.

JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust/MRC Building, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Research Campus, Cambridge, UK. Electronic address:

Identification of alterations in the cellular composition of the human immune system is key to understanding the autoimmune process. Recently, a subset of FOXP3 cells with low CD25 expression was found to be increased in peripheral blood from systemic lupus erythematosus (SLE) patients, although its functional significance remains controversial. Here we find in comparisons with healthy donors that the frequency of FOXP3 cells within CD127CD25 CD4 T cells (here defined as CD25FOXP3 T cells) is increased in patients affected by autoimmune disease of varying severity, from combined immunodeficiency with active autoimmunity, SLE to type 1 diabetes. We show that CD25FOXP3 T cells share phenotypic features resembling conventional CD127CD25FOXP3 Tregs, including demethylation of the Treg-specific epigenetic control region in FOXP3, HELIOS expression, and lack of IL-2 production. As compared to conventional Tregs, more CD25FOXP3HELIOS T cells are in cell cycle (33.0% vs 20.7% Ki-67; P = 1.3 × 10) and express the late-stage inhibitory receptor PD-1 (67.2% vs 35.5%; P = 4.0 × 10), while having reduced expression of the early-stage inhibitory receptor CTLA-4, as well as other Treg markers, such as FOXP3 and CD15s. The number of CD25FOXP3 T cells is correlated (P = 3.1 × 10) with the proportion of CD25FOXP3 T cells in cell cycle (Ki-67). These findings suggest that CD25FOXP3 T cells represent a subset of Tregs that are derived from CD25FOXP3 T cells, and are a peripheral marker of recent Treg expansion in response to an autoimmune reaction in tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaut.2017.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656572PMC
November 2017

Creating Healthier, More Equitable Communities By Improving Governance And Policy.

Health Aff (Millwood) 2016 11;35(11):1970-1975

Anita Chandra is director, RAND Justice, Infrastructure, and Environment, in Arlington, Virginia.

How can healthier, more equitable communities be created? This is a key question for public health. Even though progress has been made in understanding the impact of social, physical, and policy factors on population health, there is much room for improvement. With this in mind, the Robert Wood Johnson Foundation made creating healthier, more equitable communities the third of four Action Areas in its Culture of Health Action Framework. This Action Area focuses on the interplay of three drivers-the physical environment, social and economic conditions, and policy and governance-in influencing health equity. In this article we review some of the policy and governance challenges confronting decisionmakers as they seek to create healthy communities on a broad scale. We use these challenges as a framework for understanding where the most critical gaps still exist, where the links could be exploited more effectively, and where there are opportunities for further research and policy development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1377/hlthaff.2016.0608DOI Listing
November 2016

Cross-Sector Collaborations And Partnerships: Essential Ingredients To Help Shape Health And Well-Being.

Health Aff (Millwood) 2016 11;35(11):1964-1969

Tracy Orleans is a senior scientist at the Robert Wood Johnson Foundation.

Cross-sector collaborations and partnerships are an essential component of the strategy to improve health and well-being in the United States. While their importance is unquestioned, their impact on population health has not yet been fully observed. Cross-sector collaboration also is the second Action Area of the Robert Wood Johnson Foundation's four-part Action Framework to build a Culture of Health in the United States. This Action Area has three constituent parts or drivers: the number, breadth, and quality of successful cross-sector partnerships; the adequacy of investment in these partnerships; and the adoption of policies needed to support them. In this article we analyze outstanding examples of partnership-driven work. We also study the challenges of how partner sectors outside the formal health system, such as organizations working in the education or housing sectors, can effectively lead collaborations. We identify models of leadership that maximize the potential of all participants. We also propose the adoption of models better suited to supporting effective cross-sector collaborations. The analysis builds the evidence base for understanding and sustaining the impact of cross-sector collaboration on population health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1377/hlthaff.2016.0604DOI Listing
November 2016