Can harmonisation of outcomes bridge the translation gap for pre-clinical research? A systematic review of outcomes measured in mouse models of type 2 diabetes

Background: In pre-clinical research, systematic reviews have the potential to mitigate translational challenges by facilitating understanding of how pre-clinical studies can inform future clinical research. Yet their conduct is encumbered by heterogeneity in the outcomes measured and reported, and those outcomes may not always relate to the most clinically important outcomes. We aimed to systematically review outcomes measured and reported in pre-clinical in vivo studies of pharmacological interventions to treat high blood glucose in mouse models of type 2 diabetes. Methods: A systematic review of pre-clinical in vivo studies of pharmacological interventions aimed at addressing elevated blood glucose in mouse models of type 2 diabetes was completed. Studies were screened for eligibility and outcomes extracted from the included studies. The outcomes were recorded verbatim and classified into outcome domains using an existing outcome taxonomy. Outcomes were also compared to those identified in a systematic review of registered phase 3/4 clinical trials for glucose lowering interventions in people with type 2 diabetes. Results: Review of 280 included studies identified 532 unique outcomes across 19 domains. No single outcome, or domain, was measured in all studies and only 132 (21%) had also been measured in registered phase 3/4 clinical trials. A core outcome set, representing the minimum that should be measured and reported, developed for type 2 diabetes effectiveness clinical trials includes 18 core outcomes, of these 12 (71%) outcomes were measured and reported in one or more of the included pre-clinical studies. Conclusions: There is heterogeneity of outcomes reported in pre-clinical research. Harmonisation of outcomes across the research pathway using a core outcome set may facilitate interpretation, evidence synthesis and translational success, and may contribute to the refinement of the use of animals in research. Systematic review registration: The study was prospectively registered on the PROSPERO Database, registration number CRD4201810683

Permafrost Active Layer Microbes From Ny Ålesund, Svalbard (79°N) Show Autotrophic and Heterotrophic Metabolisms With Diverse Carbon-Degrading Enzymes

The active layer of permafrost in Ny Ålesund, Svalbard (79°N) around the Bayelva River in the Leirhaugen glacier moraine is measured as a small net carbon sink at the brink of becoming a carbon source. In many permafrost-dominating ecosystems, microbes in the active layers have been shown to drive organic matter degradation and greenhouse gas production, creating positive feedback on climate change. However, the microbial metabolisms linking the environmental geochemical processes and the populations that perform them have not been fully characterized. In this paper, we present geochemical, enzymatic, and isotopic data paired with 10 Pseudomonas sp. cultures and metagenomic libraries of two active layer soil cores (BPF1 and BPF2) from Ny Ålesund, Svalbard, (79°N). Relative to BPF1, BPF2 had statistically higher C/N ratios (15 ± 1 for BPF1 vs. 29 ± 10 for BPF2; n = 30, p < 10–5), statistically lower organic carbon (2% ± 0.6% for BPF1 vs. 1.6% ± 0.4% for BPF2, p < 0.02), statistically lower nitrogen (0.1% ± 0.03% for BPF1 vs. 0.07% ± 0.02% for BPF2, p < 10–6). The d13C values for inorganic carbon did not correlate with those of organic carbon in BPF2, suggesting lower heterotrophic respiration. An increase in the δ13C of inorganic carbon with depth either reflects an autotrophic signal or mixing between a heterotrophic source at the surface and a lithotrophic source at depth. Potential enzyme activity of xylosidase and N-acetyl-β-D-glucosaminidase increases twofold at 15°C, relative to 25°C, indicating cold adaptation in the cultures and bulk soil. Potential enzyme activity of leucine aminopeptidase across soils and cultures was two orders of magnitude higher than other tested enzymes, implying that organisms use leucine as a nitrogen and carbon source in this nutrient-limited environment. Besides demonstrating large variability in carbon compositions of permafrost active layer soils only ∼84 m apart, results suggest that the Svalbard active layer microbes are often limited by organic carbon or nitrogen availability and have adaptations to the current environment, and metabolic flexibility to adapt to the warming climate.Peer Reviewe

Heterologous Systemic Prime–Intranasal Boosting Using a Spore SARS-CoV-2 Vaccine Confers Mucosal Immunity and Cross-Reactive Antibodies in Mice as well as Protection in Hamsters

Background: Current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are administered systemically and typically result in poor immunogenicity at the mucosa. As a result, vaccination is unable to reduce viral shedding and transmission, ultimately failing to prevent infection. One possible solution is that of boosting a systemic vaccine via the nasal route resulting in mucosal immunity. Here, we have evaluated the potential of bacterial spores as an intranasal boost. Method: Spores engineered to express SARS-CoV-2 antigens were administered as an intranasal boost following a prime with either recombinant Spike protein or the Oxford AZD1222 vaccine. Results: In mice, intranasal boosting following a prime of either Spike or vaccine produced antigen-specific sIgA at the mucosa together with the increased production of Th1 and Th2 cytokines. In a hamster model of infection, the clinical and virological outcomes resulting from a SARS-CoV-2 challenge were ameliorated. Wuhan-specific sIgA were shown to cross-react with Omicron antigens, suggesting that this strategy might offer protection against SARS-CoV-2 variants of concern. Conclusions: Despite being a genetically modified organism, the spore vaccine platform is attractive since it offers biological containment, the rapid and cost-efficient production of vaccines together with heat stability. As such, employed in a heterologous systemic prime–mucosal boost regimen, spore vaccines might have utility for current and future emerging diseases.info:eu-repo/semantics/publishedVersio

Heterologous Systemic Prime-Intranasal Boosting Using a Spore SARS-CoV-2 Vaccine Confers Mucosal Immunity and Cross-Reactive Antibodies in Mice as well as Protection in Hamsters

Altres ajuts: Medical Research Council MR/R026262/1Background : Current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are administered systemically and typically result in poor immunogenicity at the mucosa. As a result, vaccination is unable to reduce viral shedding and transmission, ultimately failing to prevent infection. One possible solution is that of boosting a systemic vaccine via the nasal route resulting in mucosal immunity. Here, we have evaluated the potential of bacterial spores as an intranasal boost. Method : Spores engineered to express SARS-CoV-2 antigens were administered as an intranasal boost following a prime with either recombinant Spike protein or the Oxford AZD1222 vaccine. Results : In mice, intranasal boosting following a prime of either Spike or vaccine produced antigen-specific sIgA at the mucosa together with the increased production of Th1 and Th2 cytokines. In a hamster model of infection, the clinical and virological outcomes resulting from a SARS-CoV-2 challenge were ameliorated. Wuhan-specific sIgA were shown to cross-react with Omicron antigens, suggesting that this strategy might offer protection against SARS-CoV-2 variants of concern. Conclusions : Despite being a genetically modified organism, the spore vaccine platform is attractive since it offers biological containment, the rapid and cost-efficient production of vaccines together with heat stability. As such, employed in a heterologous systemic prime-mucosal boost regimen, spore vaccines might have utility for current and future emerging diseases

Microbiota‐Dependent Metabolite Trimethylamine N‐Oxide and Coronary Artery Calcium in the Coronary Artery Risk Development in Young Adults Study (CARDIA)

BACKGROUND: Clinical studies implicate trimethylamine N-oxide (TMAO; a gut microbiota-dependent nutrient metabolite) in cardiovascular disease risk. There is a lack of population-based data on the role of TMAO in advancing early atherosclerotic disease. We tested the prospective associations between TMAO and coronary artery calcium (CAC) and carotid intima-media thickness (cIMT). METHODS AND RESULTS: Data were from the Coronary Artery Risk Development in Young Adults Study (CARDIA), a biracial cohort of US adults recruited in 1985-1986 (n=5115). We randomly sampled 817 participants (aged 33-55 years) who attended examinations in 2000-2001, 2005-2006, and 2010-2011, at which CAC was measured by computed tomography and cIMT (2005-2006) by ultrasound. TMAO was quantified using liquid chromotography mass spectrometry on plasma collected in 2000-2001. Outcomes were incident CAC, defined as Agatston units=0 in 2000-2001 and >0 over 10-year follow-up, CAC progression (any increase over 10-year follow-up), and continuous cIMT. Over the study period, 25% (n=184) of those free of CAC in 2000-2001 (n=746) developed detectable CAC. In 2000-2001, median (interquartile range) TMAO was 2.6 (1.8-4.2) μmol/L. In multivariable-adjusted models, TMAO was not associated with 10-year CAC incidence (rate ratio=1.03; 95% CI: 0.71-1.52) or CAC progression (0.97; 0.68-1.38) in Poisson regression, or cIMT (beta coefficient: -0.009; -0.03 to 0.01) in linear regression, comparing the fourth to the first quartiles of TMAO. CONCLUSIONS: In this population-based study, TMAO was not associated with measures of atherosclerosis: CAC incidence, CAC progression, or cIMT. These data indicate that TMAO may not contribute significantly to advancing early atherosclerotic disease risk among healthy early-middle-aged adults

The effect of the COVID-19 pandemic on mental health in individuals with pre-existing mental illness

BACKGROUND: There is evidence that the COVID-19 pandemic has negatively affected mental health, but most studies have been conducted in the general population. AIMS: To identify factors associated with mental health during the COVID-19 pandemic in individuals with pre-existing mental illness. METHOD: Participants (N = 2869, 78% women, ages 18–94 years) from a UK cohort (the National Centre for Mental Health) with a history of mental illness completed a cross-sectional online survey in June to August 2020. Mental health assessments were the GAD-7 (anxiety), PHQ-9 (depression) and WHO-5 (well-being) questionnaires, and a self-report question on whether their mental health had changed during the pandemic. Regressions examined associations between mental health outcomes and hypothesised risk factors. Secondary analyses examined associations between specific mental health diagnoses and mental health. RESULTS: A total of 60% of participants reported that mental health had worsened during the pandemic. Younger age, difficulty accessing mental health services, low income, income affected by COVID-19, worry about COVID-19, reduced sleep and increased alcohol/drug use were associated with increased depression and anxiety symptoms and reduced well-being. Feeling socially supported by friends/family/services was associated with better mental health and well-being. Participants with a history of anxiety, depression, post-traumatic stress disorder or eating disorder were more likely to report that mental health had worsened during the pandemic than individuals without a history of these diagnoses. CONCLUSIONS: We identified factors associated with worse mental health during the COVID-19 pandemic in individuals with pre-existing mental illness, in addition to specific groups potentially at elevated risk of poor mental health during the pandemic