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Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventricular tachycardia in ambulatory mice, and we showed that major leukocyte subsets have opposing effects on cardiac conduction. Neutrophils increased ventricular tachycardia via lipocalin-2 in mice, whereas neutrophilia associated with ventricular tachycardia in patients. In contrast, macrophages protected against arrhythmia. Depleting recruited macrophages in Ccr2−/− mice or all macrophage subsets with Csf1 receptor inhibition increased both ventricular tachycardia and fibrillation. Higher arrhythmia burden and mortality in Cd36−/− and Mertk−/− mice, viewed together with reduced mitochondrial integrity and accelerated cardiomyocyte death in the absence of macrophages, indicated that receptor-mediated phagocytosis protects against lethal electrical storm. Thus, modulation of leukocyte function provides a potential therapeutic pathway for reducing the risk of sudden cardiac death.

Introduction The phosphocreatine-to-adenosine triphosphate ratio (PCr/ATP) is a sensitive marker of the energetic state of the heart and can be reliably measured non-invasively using 31Phosphorus magnetic resonance spectroscopy (31P-MRS). Derangements in cardiac energetics are a distinctive feature in the pathophysiology of several cardiac diseases, and thus potential therapeutic targets. Purpose We sought to compare cardiac PCr/ATP across a range of cardiac pathologies. Methods Using a 3D chemical shift 31P spectral acquisition we recorded PCr/ATP in 515 participants: athletes (n=17), healthy controls with normal weight (n=148), overweight (n=67) and with obesity (n=73), diabetes (n=23), heart failure with preserved ejection fraction (HFpEF) (n=33), heart failure with reduced ejection fraction (HFrEF) (n=63), amyloid (n=9), severe aortic stenosis (AS) (n=29), severe mitral regurgitation (MR) (n=18), and hypertrophic cardiomyopathy (HCM) (n=35). Results A spectrum of myocardial PCr/ATP exists ranging from normal in athletes (2.23±0.28) and those with normal weight (2.05±0.38) to severely impaired in severe MR (1.56±0.32) and cardiac amyloid (1.34±0.19, Figure 1). Despite normal systolic function (all LVEF >57%) those living with obesity and diabetes have lower PCr/ATP than normal (all p Conclusions We demonstrate a spectrum of energetic deficit in cardiac disease and this is affected by not only myocardial pathology but also by obesity and age. Derangements in myocardial energetics are present in myocardial pathologies independent of underlying aetiology. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): We acknowledge support from the British Heart Foundation Oxford Center of Research Excellence.

Situations like Coronavirus (COVID-19), severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) coronaviruses, and the damaged caused by Hurricane Maria in September 2017 in Puerto Rico create complex health public health management logistics problems. Disasters and pandemics often demand logistics planning to involve large-scale transportation of medical aid in the form of personnel and supplies, specialized equipment, and personnel for search and rescue, food, shelter, and other commodities used in massive relief operations. The research suggests improvements in organizational culture, modernization of recruitment strategies, and enhancement of leadership and professional development as approaches to improve gender diversity in leadership roles in emergency public health supply chain and logistics management. This paper provides emergency and disaster public health supply chain and logistics management practitioners and scholars insight into the dynamics of gender disparity in leadership roles in public health supply chain management.

The digital economy is creating significant innovations in healthcare. Thriving in this new digital era requires all kinds of healthcare organizations to shift their cultural and organizational mindsets to be more adaptive. The new adaptability means letting go of outdated business cultures and processes, especially those that not inclusive and respectful of women and their professional contributions. This case study reflects an IT healthcare organization in which several senior managers inappropriately harassed female workers at work and online through their social media accounts. The study explored the complex dynamics of management consulting organizational development intervention using an applied research approach. The results concluded a significant need for organizational change in technical healthcare organizations as healthcare goes through a significant digital transformation as a result of a growing digital economy.

Cyber marketing, digital communications, and social media practices for branding and marketing purposes have allowed colleges and universities to engage in sustainable/green marketing. For colleges, this means reducing advertising, marketing, and promotions costs in conjunction with lessening previous environmental impacts of printing, paper waste, mailing brochures, and college recruiter travel and transportation. Digital economy innovations in cyber marketing create channels for advertising and promotion without the carbon footprint issues of previous recruiting approaches. This paper uses a content analysis of the literature to explore how sustainable marketing approaches apply digital economy innovations in cyber marketing and digital communications for student global student marketing and recruiting. The goal is to gain actionable and applied knowledge about how sustainable marketing strategies apply digital economy innovations in cyber marketing and digital communication can influence the world of practice.

According to the US Federal Bureau of Investigations (FBI) the number of complaints about cyberattacks to their cyber division is up to as many as 4,000 a day. Every year in the U.S., 40,000 jobs for information security analysts go unfilled, and employers are struggling to fill 200,000 other cybersecurity-related roles. Colleges and universities have created certificate, undergraduate, and graduate programs to train professionals in these job roles. The challenge to meeting the cybersecurity workforce shortage through degree programs is intensified by the reality of the limited number of cybersecurity and engineering faculty at colleges and universities. This chapter explores the essential need to develop more doctorate faculty in technology-related areas and explains some unique and non-traditional paths to doctoral completion that allow professionals with significant real-world work experience to complete a doctorate without career interruption and relocation from highly respected and established universities in the US and the UK.

The Master of Business Administration (MBA) plays a significant role in developing managers in a plethora of global organizations. In most circles, it is considered a degree to develop corporate managers. With the leadership failures of organizations like pharmaceutical price collusion and price increase of 539% of Perrigo Pharmaceuticals, the fake account fraud practices at Wells Fargo, sexual harassment issues at Uber, the Equifax data breach, and the video of a forcible, bloody removal of a passenger on a United Airlines in the U.S., there has been increased criticism concerning the effectiveness of current MBA programs and leadership development in general. This qualitative research study explores how the curriculum of the MBA of the future should look.

As the year 2020 emerges, many universities are facing declining student enrollments. Six private liberal arts colleges in New England in the United States have announced they will close their doors. Savvy techniques are needed to stop the decline of enrollments and reach new students. Institutions of higher learning are investigating and using effective marketing strategies to propel recruitment and maintain established enrollment number goals. Changing marketing strategies to include the use of media organizations is driven by the Internet to include social media and artificial intelligence. Robust advertising enrollment techniques to attract potential learners is game-changing. This article explores the 2020 function of Internet practices for branding and marketing purposes at colleges and universities.

Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20–21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.

Summary Background A preventive vaccine for HIV is a crucial public health need; adeno-associated virus (AAV)-mediated antibody gene delivery could be an alternative to immunisation to induce sustained expression of neutralising antibodies to prevent HIV. We assessed safety and tolerability of rAAV1-PG9DP, a recombinant AAV1 vector encoding the gene for PG9, a broadly neutralising antibody against HIV. Methods This first-in-human, proof-of-concept, double-blind, phase 1, randomised, placebo-controlled, dose-escalation trial was done at one clinical research centre in the UK. Healthy men aged 18–45 years without HIV infection were randomly assigned to receive intramuscular injection with rAAV1-PG9DP or placebo in the deltoid or quadriceps in one of four dose-escalating cohorts (group A, 4 × 10 12 vector genomes; group B, 4 × 10 13 vector genomes; group C, 8 × 10 13 vector genomes; and group D, 1·2 × 10 14 vector genomes). Volunteers were followed up for 48 weeks. The primary objective was to assess safety and tolerability. A secondary objective was to assess PG9 expression in serum and related HIV neutralisation activity. All volunteers were included in primary and safety analyses. The trial is complete and is registered with ClinicalTrials.gov, number NCT01937455. Findings Between Jan 30, 2014, and Feb 28, 2017, 111 volunteers were screened for eligibility. 21 volunteers were eligible and provided consent, and all 21 completed 48 weeks of follow-up. Reactogenicity was generally mild or moderate and resolved without intervention. No probably or definitely related adverse events or serious adverse events were recorded. We detected PG9 by HIV neutralisation in the serum of four volunteers, and by RT-PCR in muscle biopsy samples from four volunteers. We did not detect PG9 by ELISA in serum. PG9 anti-drug antibody was present in ten volunteers in the higher dose groups. Both anti-AAV1 antibodies and AAV1-specific T-cell responses were detected. Interpretation Future studies should explore higher doses of AAV, alternative AAV serotypes and gene expression cassettes, or other broadly neutralising HIV antibodies. Funding International AIDS Vaccine Initiative, United States Agency for International Development, Bill & Melinda Gates Foundation, US National Institutes of Health.

Engaged and experiential learning approaches encourage experimentation and expand teaching entrepreneurial leadership beyond just classroom lectures, textbooks, and PowerPoint slides. The use of experiential and scenario-based learning approaches helps students develop real-world problem solving and critical thinking leadership skills that demonstrate competencies and abilities beyond course grades and transcripts. Entrepreneurial leadership is the ability to think strategically, adapt to changing competitive forces, identify threats to longevity, and exploit business opportunities in a hyper-competitive and volatile entrepreneurial business environment. This case study research approach explores how leadership skills and abilities can be developed using real world embedded simulations that create beneficial relationships that help business owners, students, and the quality of graduate instruction.

Cardiac metabolism and function are intrinsically linked. High-energy phosphates occupy a central and obligate position in cardiac metabolism, coupling oxygen and substrate fuel delivery to the myocardium with external work. This insight underlies the widespread clinical use of ischaemia testing. However, other deficits in high-energy phosphate metabolism (not secondary to supply-demand mismatch of oxygen and substrate fuels) may also be documented, and are of particular interest when found in the context of structural heart disease. This review introduces the scope of deficits in high-energy phosphate metabolism that may be observed in the myocardium, how to assess for them, and how they might be interpreted.

Supplemental Digital Content is available in the text., Rationale: The recent development of hyperpolarized 13C magnetic resonance spectroscopy has made it possible to measure cellular metabolism in vivo, in real time. Objective: By comparing participants with and without type 2 diabetes mellitus (T2DM), we report the first case-control study to use this technique to record changes in cardiac metabolism in the healthy and diseased human heart. Methods and Results: Thirteen people with T2DM (glycated hemoglobin, 6.9±1.0%) and 12 age-matched healthy controls underwent assessment of cardiac systolic and diastolic function, myocardial energetics (31P-magnetic resonance spectroscopy), and lipid content (1H-magnetic resonance spectroscopy) in the fasted state. In a subset (5 T2DM, 5 control), hyperpolarized [1-13C]pyruvate magnetic resonance spectra were also acquired and in 5 of these participants (3 T2DM, 2 controls), this was successfully repeated 45 minutes after a 75 g oral glucose challenge. Downstream metabolism of [1-13C]pyruvate via PDH (pyruvate dehydrogenase, [13C]bicarbonate), lactate dehydrogenase ([1-13C]lactate), and alanine transaminase ([1-13C]alanine) was assessed. Metabolic flux through cardiac PDH was significantly reduced in the people with T2DM (Fasted: 0.0084±0.0067 [Control] versus 0.0016±0.0014 [T2DM], Fed: 0.0184±0.0109 versus 0.0053±0.0041; P=0.013). In addition, a significant increase in metabolic flux through PDH was observed after the oral glucose challenge (P

Vaccines prevent infectious diseases, but vaccination is not without risk and adverse events are reported although they are more commonly reported for biologicals than for vaccines. Vaccines and biologicals must undergo vigorous assessment before and after licensure to minimise safety concerns. Potential safety concerns should be identified as early as possible during the development for vaccines and biologicals to minimize investment risk. State-of-the art tools and methods to identify safety concerns and biomarkers that are predictive of clinical outcomes are indispensable. For vaccines and adjuvant formulations, systems biology approaches, supported by single-cell microfluidics applied to translational studies between preclinical and clinical studies, could improve reactogenicity and safety predictions. Next-generation animal models for clinical assessment of injection-site reactions with greater relevance for target human population and criteria to define the level of acceptability of local reactogenicity at vaccine injection sites in pre-clinical animal species should be assessed. Advanced in silico machine-learning-based analytics, species-specific cell or tissue expression, receptor occupancy and kinetics and cell-based assays for functional activity are needed to improve pre-clinical safety assessment of biologicals. The in vitro MIMIC® system could be used to compliment preclinical and clinical studies for assessing immune-toxicity, immunogenicity, immuno-inflammatory and mode of action of biologicals and vaccines. Sanofi Pasteur brought together leading experts in this field to review the state-of-the-art at a unique 'Safety Biomarkers Symposium' on 28-29 November 2017. Here we summarise the proceedings of this symposium. This unique scientific meeting confirmed the importance for institutions and industrial organizations to collaborate to develop tools and methods needed for predicting reactogenicity and immune-inflammatory reactions to vaccines and biologicals, and to develop more accuracy, reliability safety biomarkers, to inform decisions on the attrition or advancement of vaccines and biologicals.

The importance of CD4+ T helper (Th) cells is well appreciated in view of their essential role in the elicitation of antibody and cytotoxic T cell responses. However, the mechanisms that determine the selection of immunodominant epitopes within complex protein antigens remain elusive. Here, we used ex vivo stimulation of memory T cells and screening of naive and memory T cell libraries, combined with T cell cloning and TCR sequencing, to dissect the human naive and memory CD4+ T cell repertoire against the influenza pandemic H1 hemagglutinin (H1-HA). We found that naive CD4+ T cells have a broad repertoire, being able to recognize naturally processed as well as cryptic peptides spanning the whole H1-HA sequence. In contrast, memory Th cells were primarily directed against just a few immunodominant peptides that were readily detected by mass spectrometry–based MHC-II peptidomics and predicted by structural accessibility analysis. Collectively, these findings reveal the presence of a broad repertoire of naive T cells specific for cryptic H1-HA peptides and demonstrate that antigen processing represents a major constraint determining immunodominance., Journal of Experimental Medicine, 217 (10), ISSN:0022-1007, ISSN:1540-0069, ISSN:1540-9538

Summary Background Approximately 164,000 deaths yearly are due to shigellosis, primarily in developing countries. Thus, a safe and affordable Shigella vaccine is an important public health priority. The GSK Vaccines Institute for Global Health (GVGH) developed a candidate Shigella sonnei vaccine (1790GAHB) using the Generalized Modules for Membrane Antigens (GMMA) technology. The paper reports results of 1790GAHB Phase 1 studies in healthy European adults. Methods To evaluate the safety and immunogenicity profiles of 1790GAHB, we performed two parallel, phase 1, observer-blind, randomized, placebo-controlled, dose escalation studies in France (“study 1”) and the United Kingdom (“study 2”) between February 2014 and April 2015 (ClinicalTrials.gov, number NCT02017899 and NCT02034500, respectively) in 18–45 years old subjects (50 in study 1, 52 in study 2). Increasing doses of Alhydrogel adsorbed 1790, expressed by both O Antigen (OAg) and protein quantity, or placebo were given either by intramuscular route (0.059/1, 0.29/5, 1.5/25, 2.9/50, 5.9/100 μg of OAg/μg of protein; study 1) or by intradermal (ID), intranasal (IN) or intramuscular (IM) route of immunization (0.0059/0.1, 0.059/1, 0.59/10 μg ID, 0.29/5, 1.2/20, 4.8/80 μg IN and 0.29/5 μg IM, respectively; study 2). In absence of serologic correlates of protection for Shigella sonnei, vaccine induced immunogenicity was compared to anti-LPS antibody in a population naturally exposed to S. sonnei. Findings Vaccines were well tolerated in both studies and no death or vaccine related serious adverse events were reported. In study 1, doses ≥ 1.5/25 μg elicited serum IgG median antibody greater than median level in convalescent subjects after the first dose. No vaccine group in study 2 achieved median antibody greater than the median convalescent antibody. Interpretation Intramuscularly administered Shigella sonnei GMMA vaccine is well tolerated, up to and including 5.9/100 μg and induces antibody to the OAg of at least the same magnitude of those observed following natural exposure to the pathogen. Vaccine administered by ID or IN, although well tolerated, is poorly immunogenic at the doses delivered. The data support the use of the GMMA technology for the development of intramuscular multivalent Shigella vaccines., Highlights • GVGH GMMA vaccine against S. sonnei was well tolerated by IM, IN and ID routes of immunization in young European adults. • Doses ≥ 1.5/25 μg elicited serum IgG median antibody greater than median level in convalescent subjects after the first dose. • Clinical data support the use of the GMMA technology for the development of intramuscular Shigella multivalent vaccines. Shigellosis is an important cause of diarrhoea especially in children of developing countries. No vaccine is available. Based on the 2015 Global Burden of Disease, Shigella caused approximately 164,000 deaths due to diarrhoea in 2015, supporting the public health relevance of the disease and the need for a vaccine. The GMMA (Generalized Modules for Membrane Antigens) technology was used for the development of a vaccine against Shigella sonnei which, tested in these trials for the first time, was shown to be well tolerated in young adults and induced specific antibody titres at least as high as after natural infection.

Comparative immune-profiling of innate responses in humans and non-human primates is important to understand the pathogenesis of infectious and chronic inflammatory diseases as well as for the preclinical development of vaccines and immune therapies. However, direct comparisons of the two species are rare and were never performed using mass cytometry. Here, whole-blood-derived leukocytes from healthy humans and cynomolgus macaques were analyzed with mass cytometry. Two similar panels of around 30 monoclonal antibodies targeting human markers associated with innate myeloid cells to stain fixed human and macaque leukocytes were constructed. To compare the circulating innate cells from the two primate species, an analysis pipeline combining a clustering analysis by the Spanning-tree Progression Analysis of Density-normalized Events (SPADE) algorithm with a two-step hierarchical clustering of cells nodes and markers was used. Identical SPADE settings were applied to both datasets, except for the 20 clustering markers which slightly differed. A correlation analysis designed to compare the phenotypes of human and macaque cell nodes and based on 16 markers, including 15 shared clustering markers and CD19 for humans or CD20 for macaques, revealed similarities and differences between staining patterns. This study unique by the number of individuals (26 humans and 5 macaques) and the use of mass cytometry certainly contributes to better assess the advantages and limits of the use of non-human primates in preclinical research. © 2017 International Society for Advancement of Cytometry

Summary Background There is some evidence to suggest that one or two doses of the HPV vaccine provides similar protection to the three-dose regimen. The main aim of the study was to ascertain HPV-16/18 vaccine efficacy in both full and naive cohorts and to explore protection conferred against non-vaccine HPV types, by number of doses received. Methods Summary data from the Costa Rica Vaccine Trial (CVT; NCT00128661) and ~the PATRICIA trial (NCT001226810), two phase 3, double-blind, randomised controlled clinical trials of the HPV-16/18 AS04-adjuvanted vaccine in young women, were combined in a post-hoc analysis (GlaxoSmithKline [GSK] e-track number 202142) to investigate the efficacy of fewer than three doses of the HPV-16/18 vaccine after 4 years of follow-up. Women were randomly assigned to receive three doses of the HPV-16/18 vaccine or to a control vaccine; yet, some received fewer doses. After exclusion of women with less than 12 months of follow-up or those who were HPV-16/18 DNA-positive at enrolment (for the HPV-16/18 endpoint), we calculated vaccine efficacy against one-time detection of incident HPV infections after three, two, and one dose(s). The primary study endpoint was one-time detection of first incident HPV-16/18 infections accumulated during the follow-up phase. Findings We assessed vaccine efficacy against incident HPV-16/18 infection in the modified total vaccinated cohort (22 327 received three doses, 1185 two doses, 543 one dose). Vaccine efficacy against incident HPV-16/18 infections for three doses was 77·0% (95% CI 74·7–79·1), two doses was 76·0% (62·0–85·3), and one dose was 85·7% (70·7–93·7). Vaccine efficacy against incident HPV-31/33/45 infections for three doses was 59·7% (56·0–63·0), two doses was 37·7% (12·4–55·9), and one dose was 36·6% (–5·4 to 62·2). Vaccine efficacy against incident HPV-16/18 infection for two-dose women who received their second dose at 1 month was 75·3% (54·2–87·5) and 82·6% (42·3–96·1) for those who received the second dose at 6 months (CVT data only). Vaccine efficacy against HPV-31/33/45 for two-dose women who received their second dose at 6 months (68·1%, 27·0–87·0; CVT data only), but not those receiving it at one month (10·1%, −42·0 to 43·3), was similar to the three-dose group. Interpretation 4 years after vaccination of women aged 15–25 years, one and two doses of the HPV-16/18 vaccine seem to protect against cervical HPV-16/18 infections, similar to the protection provided by the three-dose schedule. Two doses separated by 6 months additionally provided some cross-protection. These data argue for a direct assessment of one-dose efficacy of the HPV-16/18 vaccine. Funding US National Cancer Institute, National Institutes of Health Office of Research on Women's Health, and Ministry of Health of Costa Rica (CVT); GlaxoSmithKline Biologicals SA (PATRICIA).

The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Pa pilloma Tri al against C ancer i n Young A dults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF 10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA 25 ) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF 10 PCR-DEIA/LiPA 25 plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. NCT00122681.)

Background: A preventive vaccine for HIV is a critical public health need. Adeno-associated virus (AAV) mediated antibody gene delivery could be an alternative to immunization to induce sustained expression of neutralizing antibodies to prevent HIV. We conducted a first-in-human, phase 1 study of rAAV1-PG9DP, a recombinant AAV1 vector encoding the gene for PG9, a broadly neutralizing antibody against HIV. Methods: The trial was a phase 1, randomized, blinded, placebo-controlled, dose-escalation study at a single center in the UK. Healthy, HIV-uninfected men aged 18-45 were randomly assigned (3:1) to intervention or control in one of four dose-escalating cohorts (4x1012 vector genomes(vg), 4x1013 vg, 8x1013 vg or 1·2x1014 vg). Volunteers received intramuscular injection with rAAV1-PG9DP or placebo in the deltoid or quadriceps and were followed for 48 weeks. The primary objective was safety and tolerability. A secondary objective was to evaluate PG9 expression in serum and related HIV neutralization activity. This trial is registered with ClinicalTrials.gov, number NCT01937455. Findings: 21 volunteers were enrolled between February 10, 2014 and February 28, 2017 and completed 48 weeks follow-up. Reactogenicity was generally mild or moderate and self-limited. There were no probably or definitely related adverse events and no serious adverse events. We detected PG9 by HIV neutralization in serum of four volunteers, and by RT-PCR in muscle biopsies of four volunteers. We did not detect PG9 by ELISA in serum. PG9 anti-drug antibody was present in 10 volunteers in the higher dose groups. Both anti-AAV1 antibodies and AAV1 specific T-cell responses were detected. Interpretation: Intramuscular administration of rAAV1-PG9DP in healthy men was safe and well-tolerated. Antibody expression was detected directly in muscle and indirectly in serum, and anti-drug antibodies were induced, indicating PG9 expression. Future studies should explore higher doses of AAV, alternative AAV serotypes and gene expression cassettes, or other broadly neutralizing HIV antibodies. Trial Registration number: This trial is registered with ClinicalTrials.gov, number NCT01937455. Funding: International AIDS Vaccine Initiative, United States Agency for International Development (USAID), Bill & Melinda Gates Foundation, US National Institutes of Health Declaration of Interest: Jim Ackland reports receiving consulting fees from International AIDS Vaccine Initiative during the course of the study. Fraser Wright reports grants from National Institutes of Health during the conduct of the study. In addition, Dr. Wright has a patent US 9,408,904 licensed to Spark Therapeutics. Ethical Approval: The protocol was approved by the University of Surrey Ethics Committee, the NRES Bristol Research Ethics Committee and the UK Medicines and Healthcare products Regulatory Authority and conducted in compliance with Good Clinical Practices and the Declaration of Helsinki guidelines.

Three dyads with a fluorene derivative as an electron-donor and with electron-acceptors of variable redox potentials were synthesized as models for two-photon activated uncaging via electron transfer. A spectroscopic and photophysical study of the component units and the dyads in solvents of different polarities demonstrated an efficient electron transfer (efficiencies > 80%) followed by charge recombination in the arrays (30 ps < tau < 1.6 ns). Recombination takes place to the ground state in all cases except for the dyad displaying the highest driving force for charge recombination in the apolar solvent. The effects of changing the solvent polarity, as well as the driving force, for electron-transfer are discussed in the frame of the current theories of electron transfer.

Current cardiovascular clinical imaging techniques offer only limited assessment of innate immune cell-driven inflammation, which is a potential therapeutic target in myocardial infarction (MI) and other diseases. Hyperpolarized magnetic resonance (MR) is an emerging imaging technology that generates contrast agents with 10- to 20 000-fold improvements in MR signal, enabling cardiac metabolite mapping.To determine whether hyperpolarized MR using [1-We performed hyperpolarized [1-Hyperpolarized MR using [1

The international effort to prevent HIV-1 infection by vaccination has failed to develop an effective vaccine. The aim of this vaccine trial in women was to administer by the vaginal mucosal route a vaccine consisting of HIV-1 gp140 linked to the chaperone 70-kDa heat shock protein (HSP70). The primary objective was to determine the safety of the vaccine. The secondary objective was to examine HIV-1 infectivity ex vivo and innate and adaptive immunity to HIV-1. Protocol-defined female volunteers were recruited. HIV-1 CN54gp140 linked to HSP70 was administered by the vaginal route. Significant adverse reactions were not detected. HIV-1 was significantly inhibited ex vivo in postimmunization CD4 + T cells compared with preimmunization CD4 + T cells. The innate antiviral restrictive factor APOBEC3G was significantly upregulated, as were CC chemokines which induce downregulation of CCR5 in CD4 + T cells. Indeed, a significant inverse correlation between the proportion of CCR5 + T cells and the concentration of CCL-3 or CCL-5 was found. Importantly, the upregulation of APOBEC3G showed a significant inverse correlation, whereas CCR5 exhibited a trend to correlate with inhibition of HIV-1 infection ( r = 0.51). Furthermore, specific CD4 + and CD8 + T cell proliferative responses were significantly increased and CD4 + T cells showed a trend to have an inverse correlation with the viral load ( r = −0.60). However, HIVgp140-specific IgG or IgA antibodies were not detected. The results provide proof of concept that an innate mechanism consisting of CC chemokines, APOBEC3G, and adaptive immunity by CD4 and CD8 T cells might be involved in controlling HIV-1 infectivity following vaginal mucosal immunization in women. (This study has been registered at ClinicalTrials.gov under registration no. NCT01285141.) IMPORTANCE Vaginal immunization of women with a vaccine consisting of HIVgp140 linked to the 70-kDa heat shock protein (HSP70) elicited ex vivo significant inhibition of HIV-1 replication in postimmunization CD4 + T cells compared with that in preimmunization peripheral blood mononuclear cells. There were no significant adverse events. The vaccine induced the significant upregulation of CC chemokines and the downmodulation of CCR5 expression in CD4 + T cells, as well as an inverse correlation between them. Furthermore, the level of CCR5 expression was directly correlated with the viral load, consistent with the protective mechanism in which a decrease in CCR5 molecules on CD4 + T cells decreases HIV-1 envelope binding. Expression of the antiviral restriction factor APOBEC3G was inversely correlated with the viral load, suggesting that it may inhibit intracellular HIV-1 replication. Both CD4 + and CD8 + T cells showed HIVgp140- and HSP70-specific proliferation. A strong inverse correlation between the proportion of CC chemokine-modulated CCR5-expressing CD4 + T cells and the stimulation of CD4 + or CD8 + T cell proliferation by HIVgp140 was found, demonstrating a significant interaction between innate and adaptive immunity. This is the first clinical trial of vaginal immunization in women using only HIVgp140 and HSP70 administered by the mucosal route (3 times) in which a dual innate protective mechanism was induced and enhanced by significant adaptive CD4 + and CD8 + T cell proliferative responses.

Human vaccine development remains challenging because of the highly sophisticated evasion mechanisms of pathogens for which vaccines are not yet available. Recent years have witnessed both successes and failures of novel vaccine design and the strength of iterative approaches is increasingly appreciated. These combine discovery of novel antigens, adjuvants and vectors in the preclinical stage with computational analyses of clinical data to accelerate vaccine design. Reverse and structural vaccinology have revealed novel antigen candidates and molecular immunology has led to the formulation of promising adjuvants. Gene expression profiles and immune parameters in patients, vaccinees and healthy controls have formed the basis for biosignatures that will provide guidelines for future vaccine design.

This Article was originally published under a CC BY NC-ND 4.0 license, but has now been made available under a CC BY 4.0 license.

Comparative immune-profiling of innate responses in humans and non-human primates is important to understand the pathogenesis of infectious and chronic inflammatory diseases as well as for the preclinical development of vaccines and immune therapies. However, direct comparisons of the two species are rare and were never performed using mass cytometry. Here, whole-blood-derived leukocytes from healthy humans and cynomolgus macaques were analyzed with mass cytometry. Two similar panels of around 30 monoclonal antibodies targeting human markers associated with innate myeloid cells to stain fixed human and macaque leukocytes were constructed. To compare the circulating innate cells from the two primate species, an analysis pipeline combining a clustering analysis by the Spanning-tree Progression Analysis of Density-normalized Events (SPADE) algorithm with a two-step hierarchical clustering of cells nodes and markers was used. Identical SPADE settings were applied to both datasets, except for the 20 clustering markers which slightly differed. A correlation analysis designed to compare the phenotypes of human and macaque cell nodes and based on 16 markers, including 15 shared clustering markers and CD19 for humans or CD20 for macaques, revealed similarities and differences between staining patterns. This study unique by the number of individuals (26 humans and 5 macaques) and the use of mass cytometry certainly contributes to better assess the advantages and limits of the use of non-human primates in preclinical research. © 2017 International Society for Advancement of Cytometry.