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Background Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. Methods Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. Discussion This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. Trial registration Trial registered on Australian New Zealand Clinical Trials Registry. Registration number: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true

We have developed two candidate vaccines to protect against multiple strains of Strep A infections. The candidates are combinatorial synthetic peptide vaccines composed of a M protein epitope (J8 or p*17) and a non-M protein epitope (K4S2). To enhance immunogenicity, each peptide is conjugated to the carrier protein CRM 197 (CRM) and formulated with aluminium hydroxide adjuvant Alhydrogel (Alum) to make the final vaccines, J8-CRM + K4S2-CRM/Alum and p*17-CRM + K4S2-CRM/Alum. The safety and toxicity of each vaccine was assessed. Sprague Dawley rats were administered three intramuscular doses, over a six-week study with a 4-week recovery period. A control group received CRM only formulated with Alum (CRM/Alum). There was no evidence of systemic toxicity in the rats administered either vaccine. There was an associated increase in white blood cell, lymphocyte and monocyte counts, increased adrenal gland weights, adrenocortical hypertrophy, and increased severity of granulomatous inflammation at the sites of injection and the associated inguinal lymph nodes. These changes were considered non-adverse. All rats administered vaccine developed a robust and sustained immunological response. The absence of clinical toxicity and the development of an immunological response in the rats suggests that the vaccines are safe for use in a phase 1 clinical trial in healthy humans.

Mucosally active subunit vaccines are an unmet clinical need due to lack of licensed immunostimulants suitable for vaccine antigens. Here, we show that intranasal administration of liposomes incorporating: the Streptococcus pyogenes peptide antigen, J8; diphtheria toxoid as a source of T cell help; and the immunostimulatory glycolipid, 3D(6-acyl) PHAD (PHAD), is able to induce long-lived humoral and cellular immunity. Mice genetically deficient in either mucosal antibodies or total antibodies are protected against S. pyogenes respiratory tract infection. Utilizing IL-17-deficient mice or depleting cellular subsets using antibodies, shows that the cellular responses encompassing, CD4 + T cells, IL-17, macrophages and neutrophils have important functions in vaccine-mediated mucosal immunity. Overall, these data demonstrate the utility of a mucosal vaccine platform to deliver multi-pronged protective responses against a highly virulent pathogen. Vaccines that specifically induce immunity against bacterial pathogens are required. Here the authors produce and characterize an intranasal liposomal vaccine against a peptide antigen from Streptococcus pyogenes and show that it induces a strong mucosal IgA response lasting for over one year, and that protection is dependent on cellular immunity mediated through IL-17, macrophages and neutrophils.

is a Gram-positive pathogen that causes a significant global burden of skin pyoderma and pharyngitis. In some cases, infection can lead to severe invasive streptococcal diseases. Previous studies have shown that IL-17 deficiency in mice (IL-17 ) can reduce clearance from the mucosal surfaces. However, the effect of IL-17 on the development of severe invasive streptococcal disease has not yet been assessed. Here, we modeled single or repeated non-lethal intranasal (IN) M1 strain infections in immunocompetent and IL-17 mice to assess bacterial colonization following a final IN or skin challenge. Immunocompetent mice that received a single infection showed long-lasting immunity to subsequent IN infection, and no bacteria were detected in the lymph nodes or spleens. However, in the absence of IL-17, a single IN infection resulted in dissemination of to the lymphoid organs, which was accentuated by repeated IN infections. In contrast to what was observed in the respiratory mucosa, skin immunity did not correlate with the systemic levels of IL-17. Instead, it was found to be associated with the activation of germinal center responses and accumulation of neutrophils in the spleen. Our results demonstrated that IL-17 plays a critical role in preventing invasive disease following infection of the respiratory tract.

A vaccine to control S. pyogenes infection is desperately warranted. S. pyogenes colonizes the upper respiratory tract (URT) and skin, from where it can progress to invasive and immune-mediated diseases. Infections with Streptococcus pyogenes and their sequelae are responsible for an estimated 18 million cases of serious disease with >700 million new primary cases and 500,000 deaths per year. Despite the burden of disease, there is currently no vaccine available for this organism. Here, we define a combination vaccine P*17/K4S2 comprising of 20-mer B-cell peptide epitopes, p*17 (a mutant derived from the highly conserved C3-repeat region of the M-protein), and K4S2 (derived from the streptococcal anti-neutrophil factor, Spy-CEP). The peptides are chemically conjugated to either diphtheria toxoid (DT) or a nontoxic mutant form of diphtheria toxin, CRM197. We demonstrate that a prime-pull immunization regimen involving two intramuscular inoculations with P*17/K4S2 adjuvanted with a two-component liposomal adjuvant system (CAF01; developed by Statens Serum Institut [SSI], Denmark), followed by an intranasal inoculation of unadjuvanted vaccine (in Tris) induces peptide- and S. pyogenes -binding antibodies and protects from mucosal and skin infection with hypervirulent covR/S mutant organisms. Prior vaccination with DT does not diminish the response to the conjugate peptide vaccines. Detailed Good Laboratory Practice (GLP) toxicological evaluation in male and female rats did not reveal any gross or histopathological adverse effects. IMPORTANCE A vaccine to control S. pyogenes infection is desperately warranted. S. pyogenes colonizes the upper respiratory tract (URT) and skin, from where it can progress to invasive and immune-mediated diseases. Global mortality estimates for S. pyogenes -associated diseases exceeds 500,000 deaths per year. S. pyogenes utilizes antigenic variation as a defense mechanism to circumvent host immune responses and thus a successful vaccine needs to provide strain-transcending and multicompartment (mucosal and skin) immunity. By defining highly conserved and protective epitopes from two critical virulence factors (M-protein and Spy-CEP) and combining them with a potent immunostimulant, CAF®01, we are addressing an unmet clinical need for a mucosally and skin-active subunit vaccine. We demonstrate that prime-pull immunization (2× intramuscular injections followed by intranasal immunization) promotes high sustained antibody levels in the airway mucosa and serum and protects against URT and invasive disease.

A prospective cohort study of 13,862 patients showed that among those who underwent isolated coronary-artery bypass grafting or aortic-valve replacement or repair, the threshold high-sensitivity cardiac troponin I level (within 1 day after surgery) associated with an adjusted hazard ratio for death within 30 days of more than 1.00 was 5670 ng per liter — 218 times the upper reference limit.

Launched in 1974, the Expanded Program on Immunization (EPI) is estimated to prevent two-three million deaths annually from polio, diphtheria, tuberculosis, pertussis, measles, and tetanus. Additional lives could be saved through better understanding what influences adherence to the EPI schedule in specific settings. The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study followed cohorts in eight sites in South Asia, Africa, and South America and monitored vaccine receipt over the first two years of life for the children enrolled in the study. Vaccination histories were obtained monthly from vaccination cards, local clinic records and/or caregiver reports. Vaccination histories were compared against the prescribed EPI schedules for each country, and coverage rates were examined in relation to the timing of vaccination. The influence of socioeconomic factors on vaccine timing and coverage was also considered. Coverage rates for EPI vaccines varied between sites and by type of vaccine; overall, coverage was highest in the Nepal and Bangladesh sites and lowest in the Tanzania and Brazil sites. Bacillus Calmette-Guérin coverage was high across all sites, 87–100%, whereas measles vaccination rates ranged widely, 73–100%. Significant delays between the scheduled administration age and actual vaccination date were present in all sites, especially for measles vaccine where less than 40% were administered on schedule. A range of socioeconomic factors were significantly associated with vaccination status in study children but these results were largely site-specific. Our findings highlight the need to improve measles vaccination rates and reduce delayed vaccination to achieve EPI targets related to the establishment of herd immunity and reduction in disease transmission.

Our genomes influence nearly every aspect of human biology—from molecular and cellular functions to phenotypes in health and disease. Studying the differences in DNA sequence between individuals (genomic variation) could reveal previously unknown mechanisms of human biology, uncover the basis of genetic predispositions to diseases, and guide the development of new diagnostic tools and therapeutic agents. Yet, understanding how genomic variation alters genome function to influence phenotype has proved challenging. To unlock these insights, we need a systematic and comprehensive catalogue of genome function and the molecular and cellular effects of genomic variants. Towards this goal, the Impact of Genomic Variation on Function (IGVF) Consortium will combine approaches in single-cell mapping, genomic perturbations and predictive modelling to investigate the relationships among genomic variation, genome function and phenotypes. IGVF will create maps across hundreds of cell types and states describing how coding variants alter protein activity, how noncoding variants change the regulation of gene expression, and how such effects connect through gene-regulatory and protein-interaction networks. These experimental data, computational predictions and accompanying standards and pipelines will be integrated into an open resource that will catalyse community efforts to explore how our genomes influence biology and disease across populations. The Impact of Genomic Variation on Function Consortium is combining single-cell mapping, genomic perturbations and predictive modelling to investigate relationships between human genomic variation, genome function and phenotypes and will provide an open resource to the community.

We evaluated vaccination against Streptococcus pyogenes with the candidate vaccine, J8-DT, delivered by a high-density microarray patch (HD-MAP). We showed that vaccination with J8-DT eluted from a coated HD-MAP (J8-DT/HD-MAP), induced similar total IgG responses to that generated by vaccination with J8-DT adjuvanted with Alum (J8-DT/Alum). We evaluated the effect of dose reduction and the number of vaccinations on the antibody response profile of vaccinated mice. A reduction in the number of vaccinations (from three to two) with J8-DT/HD-MAP induced comparable antibody responses to three vaccinations with intramuscular J8-DT/Alum. Vaccine-induced protection against an S. pyogenes skin challenge was assessed. J8-DT/HD-MAP vaccination led to a significant reduction in the number of S. pyogenes colony forming units in skin (92.9%) and blood (100%) compared to intramuscular vaccination with unadjuvanted J8-DT. The protection profile was comparable to that of intramuscular J8-DT/Alum. J8-DT/HD-MAP induced a shift in the antibody isotype profile, with a bias towards Th1-related isotypes, compared to J8-DT/Alum (Th2 bias). Based on the results of this study, the use of J8-DT/HD-MAP should be considered in future clinical development and control programs against S. pyogenes . Furthermore, the innate characteristics of the technology, such as vaccine stability and increased coverage, ease of use, reduction of sharp waste and the potential reduction of dose may be advantageous compared to current vaccination methods.