A public relations guide for military commanders

Thesis (M.S.)--Boston Universit

Epoxide-Mediated Differential Packaging of Cif and Other Virulence Factors into Outer Membrane Vesicles

Pseudomonas aeruginosa produces outer membrane vesicles (OMVs) that contain a number of secreted bacterial proteins, including phospholipases, alkaline phosphatase, and the CFTR inhibitory factor (Cif). Previously, Cif, an epoxide hydrolase, was shown to be regulated at the transcriptional level by epoxides, which serve as ligands of the repressor, CifR. Here, we tested whether epoxides have an effect on Cif levels in OMVs. We showed that growth of P. aeruginosa in the presence of specific epox

The Microbiome in Pediatric Cystic Fibrosis Patients: The Role of Shared Environment Suggests a Window of Intervention

Cystic fibrosis (CF) is caused by mutations in the CFTR gene that predispose the airway to infection. Chronic infection by pathogens such as Pseudomonas aeruginosa leads to inflammation that gradually degrades lung function, resulting in morbidity and early mortality. In a previous study of CF monozygotic twins, we demonstrate that genetic modifiers significantly affect the establishment of persistent P. aeruginosa colonization in CF. Recognizing that bacteria other than P. aeruginosa contribute to the CF microbiome and associated pathology, we used deep sequencing of sputum from pediatric monozygotic twins and nontwin siblings with CF to characterize pediatric bacterial communities and the role that genetics plays in their evolution. We found that the microbial communities in sputum from pediatric patients living together were much more alike than those from pediatric individuals living apart, regardless of whether samples were taken from monozygous twins or from nontwin CF siblings living together, which we used as a proxy for dizygous twins. In contrast, adult communities were comparatively monolithic and much less diverse than the microbiome of pediatric patients

A mediation approach to understanding socio-economic inequalities in maternal health-seeking behaviours in Egypt.

BACKGROUND: The levels and origins of socio-economic inequalities in health-seeking behaviours in Egypt are poorly understood. This paper assesses the levels of health-seeking behaviours related to maternal care (antenatal care [ANC] and facility delivery) and their accumulation during pregnancy and childbirth. Secondly, it explores the mechanisms underlying the association between socio-economic position (SEP) and maternal health-seeking behaviours. Thirdly, it examines the effectiveness of targeting of free public ANC and delivery care. METHODS: Data from the 2008 Demographic and Health Survey were used to capture two latent constructs of SEP: individual socio-cultural capital and household-level economic capital. These variables were entered into an adjusted mediation model, predicting twelve dimensions of maternal health-seeking; including any ANC, private ANC, first ANC visit in first trimester, regular ANC (four or more visits during pregnancy), facility delivery, and private delivery. ANC and delivery care costs were examined separately by provider type (public or private). RESULTS: While 74.2% of women with a birth in the 5-year recall period obtained any ANC and 72.4% delivered in a facility, only 48.8% obtained the complete maternal care package (timely and regular facility-based ANC as well as facility delivery) for their most recent live birth. Both socio-cultural capital and economic capital were independently positively associated with receiving any ANC and delivering in a facility. The strongest direct effect of socio-cultural capital was seen in models predicting private provider use of both ANC and delivery. Despite substantial proportions of women using public providers reporting receipt of free care (ANC: 38%, delivery: 24%), this free-of-charge public care was not effectively targeted to women with lowest economic resources. CONCLUSIONS: Socio-cultural capital is the primary mechanism leading to inequalities in maternal health-seeking in Egypt. Future studies should therefore examine the objective and perceived quality of care from different types of providers. Improvements in the targeting of free public care could help reduce the existing SEP-based inequalities in maternal care coverage in the short term

Assessing Anti-HCMV Cell Mediated Immune Responses in Transplant Recipients and Healthy Controls Using a Novel Functional Assay

HCMV infection, reinfection or reactivation occurs in 60% of untreated solid organ transplant (SOT) recipients. Current clinical approaches to HCMV management include pre-emptive and prophylactic antiviral treatment strategies. The introduction of immune monitoring to better stratify patients at risk of viraemia and HCMV mediated disease could improve clinical management. Current approaches quantify T cell IFNγ responses specific for predominantly IE and pp65 proteins ex vivo, as a proxy for functional control of HCMV in vivo. However, these approaches have only a limited predictive ability. We measured the IFNγ T cell responses to an expanded panel of overlapping peptide pools specific for immunodominant HCMV proteins IE1/2, pp65, pp71, gB, UL144, and US3 in a cohort of D+R– kidney transplant recipients in a longitudinal analysis. Even with this increased antigen diversity, the results show that while all patients had detectable T cell responses, this did not correlate with control of HCMV replication in some. We wished to develop an assay that could directly measure anti-HCMV cell-mediated immunity. We evaluated three approaches, stimulation of PBMC with (i) whole HCMV lysate or (ii) a defined panel of immunodominant HCMV peptides, or (iii) fully autologous infected cells co-cultured with PBMC or isolated CD8+ T cells or NK cells. Stimulation with HCMV lysate often generated non-specific antiviral responses while stimulation with immunodominant HCMV peptide pools produced responses which were not necessarily antiviral despite strong IFNγ production. We demonstrated that IFNγ was only a minor component of secreted antiviral activity. Finally, we used an antiviral assay system to measure the effect of whole PBMC, and isolated CD8+ T cells and NK cells to control HCMV in infected autologous dermal fibroblasts. The results show that both PBMC and especially CD8+ T cells from HCMV seropositive donors have highly specific antiviral activity against HCMV. In addition, we were able to show that NK cells were also antiviral, but the level of this control was highly variable between donors and not dependant on HCMV seropositivity. Using this approach, we show that non-viraemic D+R+ SOT recipients had significant and specific antiviral activity against HCMV

Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (≥ 50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated. Mechanistically, we showed that hyperglycemia and diabetes decreased PKM2 tetramer formation and activity by sulfenylation in mouse glomeruli and cultured podocytes. Pkm-knockdown immortalized mouse podocytes had higher levels of toxic glucose metabolites, mitochondrial dysfunction and apoptosis. Podocyte-specific Pkm2-knockout (KO) mice with diabetes developed worse albuminuria and glomerular pathology. Conversely, we found that pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, reversed hyperglycemia-induced elevation in toxic glucose metabolites and mitochondrial dysfunction, partially by increasing glycolytic flux and PGC-1α mRNA in cultured podocytes. In intervention studies using DBA2/J and Nos3 (eNos) KO mouse models of diabetes, TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology. Thus, PKM2 activation may protect against DN by increasing glucose metabolic flux, inhibiting the production of toxic glucose metabolites and inducing mitochondrial biogenesis to restore mitochondrial function

Efficacy of expressive helping in adult hematologic cancer patients undergoing stem cell transplant: : Protocol for the Writing for Insight, Strength, and Ease (WISE) study’s two-arm randomized controlled trial

Funding Information: This study was supported by the National Cancer Institute of the National Institutes of Health under award number R01CA223963. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding body had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2021, The Author(s).Background: During, shortly after, and sometimes for years after hematopoietic stem cell transplant, a large proportion of hematological cancer patients undergoing transplant report significant physical and psychological symptoms and reduced health-related quality of life. To address these survivorship problems, we developed a low-burden, brief psychological intervention called expressive helping that includes two theory- and evidence-based components designed to work together synergistically: emotionally expressive writing and peer support writing. Building on evidence from a prior randomized control trial showing reductions in physical symptoms and distress in long-term transplant survivors with persistent survivorship problems, the Writing for Insight, Strength, and Ease (WISE) trial will evaluate the efficacy of expressive helping when used during transplant and in the early post-transplant period, when symptoms peak, and when intervention could prevent development of persistent symptoms. Methods: WISE is a multi-site, two-arm randomized controlled efficacy trial. Adult hematological cancer patients scheduled for a hematopoietic stem cell transplant will complete baseline measures and then, after hospitalization but prior to transplant, they will be randomized to complete either expressive helping or a time and attention “neutral writing” task. Both expressive helping and neutral writing involve four brief writing sessions, beginning immediately after randomization and ending approximately 4 weeks after hospital discharge. Measures of symptom burden (primary outcome), distress, health-related quality of life, and fatigue (secondary outcomes) will be administered in seven assessments coinciding with medically relevant time points from baseline and to a year post-intervention. Discussion: The steady and continuing increase in use of stem cell transplantation has created growing need for efficacious, accessible interventions to reduce the short- and long-term negative physical and psychosocial effects of this challenging but potentially life-saving treatment. Expressive helping is a psychological intervention that was designed to fill this gap. It has been shown to be efficacious in long-term transplant survivors but could have even greater impact if it is capable of reducing symptoms during and soon after transplant. The WISE study will evaluate these benefits in a rigorous randomized controlled trial. Trial registration: Clinicaltrial.govNCT03800758. Registered January 11, 2019Peer reviewe

Digital endpoints in clinical trials: emerging themes from a multi-stakeholder Knowledge Exchange event

© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, to view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Background: Digital technologies, such as wearable devices and smartphone applications (apps), can enable the decentralisation of clinical trials by measuring endpoints in people’s chosen locations rather than in traditional clinical settings. Digital endpoints can allow high-frequency and sensitive measurements of health outcomes compared to visit-based endpoints which provide an episodic snapshot of a person’s health. However, there are underexplored challenges in this emerging space that require interdisciplinary and cross-sector collaboration. A multi-stakeholder Knowledge Exchange event was organised to facilitate conversations across silos within this research ecosystem. Methods: A survey was sent to an initial list of stakeholders to identify potential discussion topics. Additional stakeholders were identified through iterative discussions on perspectives that needed representation. Co-design meetings with attendees were held to discuss the scope, format and ethos of the event. The event itself featured a cross-disciplinary selection of talks, a panel discussion, small-group discussions facilitated via a rolling seating plan and audience participation via Slido. A transcript was generated from the day, which, together with the output from Slido, provided a record of the day’s discussions. Finally, meetings were held following the event to identify the key challenges for digital endpoints which emerged and reflections and recommendations for dissemination. Results: Several challenges for digital endpoints were identified in the following areas: patient adherence and acceptability; algorithms and software for devices; design, analysis and conduct of clinical trials with digital endpoints; the environmental impact of digital endpoints; and the need for ongoing ethical support. Learnings taken for next generation events include the need to include additional stakeholder perspectives, such as those of funders and regulators, and the need for additional resources and facilitation to allow patient and public contributors to engage meaningfully during the event. Conclusions: The event emphasised the importance of consortium building and highlighted the critical role that collaborative, multi-disciplinary, and cross-sector efforts play in driving innovation in research design and strategic partnership building moving forward. This necessitates enhanced recognition by funders to support multi-stakeholder projects with patient involvement, standardised terminology, and the utilisation of open-source software.Peer reviewe

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts