Conjugation of a peptide autoantigen to gold nanoparticles for intradermally administered antigen specific immunotherapy

Antigen specific immunotherapy aims to tolerise patients to specific autoantigens that are responsible for the pathology of an autoimmune disease. Immune tolerance is generated in conditions where the immune response is suppressed and thus gold nanoparticles (AuNPs) are an attractive drug delivery platform due to their anti-inflammatory effects and their potential to facilitate temporal and spatial delivery of a peptide autoantigen in conjunction with pro-tolerogenic elements. In this study we have covalently attached an autoantigen, currently under clinical evaluation for the treatment of type 1 diabetes (PIC19-A3 peptide), to AuNPs to create nanoscale (<5 nm), negatively charged (−40 to −60 mV) AuNP-peptide complexes for immunotherapy. We also employ a clinically approved microneedle delivery system, MicronJet600, to facilitate minimally-invasive intradermal delivery of the nanoparticle constructs to target skin-resident antigen presenting cells, which are known to be apposite target cells for immunotherapy. The AuNP-peptide complexes remain physically stable upon extrusion through microneedles and when delivered into ex vivo human skin they are able to diffuse rapidly and widely throughout the dermis (their site of deposition) and, perhaps more surprisingly, the overlying epidermal layer. Intracellular uptake was extensive, with Langerhans cells proving to be the most efficient cells at internalising the AuNP-peptide complex (94% of the local population within the treated region of skin). In vitro studies showed that uptake of the AuNP-peptide complexes by dendritic cells reduced the capacity of these cells to activate naïve T cells. This indicator of biological functionality encourages further development of the AuNP-peptide formulation, which is now being evaluated in clinical trials

Observations of Low Frequency Solar Radio Bursts from the Rosse Solar-Terrestrial Observatory

The Rosse Solar-Terrestrial Observatory (RSTO; www.rosseobservatory.ie) was established at Birr Castle, Co. Offaly, Ireland (53 05'38.9", 7 55'12.7") in 2010 to study solar radio bursts and the response of the Earth's ionosphere and geomagnetic field. To date, three Compound Astronomical Low-cost Low-frequency Instrument for Spectroscopy and Transportable Observatory (CALLISTO) spectrometers have been installed, with the capability of observing in the frequency range 10-870 MHz. The receivers are fed simultaneously by biconical and log-periodic antennas. Nominally, frequency spectra in the range 10-400 MHz are obtained with 4 sweeps per second over 600 channels. Here, we describe the RSTO solar radio spectrometer set-up, and present dynamic spectra of a sample of Type II, III and IV radio bursts. In particular, we describe fine-scale structure observed in Type II bursts, including band splitting and rapidly varying herringbone features

The Origin, Early Evolution and Predictability of Solar Eruptions

Coronal mass ejections (CMEs) were discovered in the early 1970s when space-borne coronagraphs revealed that eruptions of plasma are ejected from the Sun. Today, it is known that the Sun produces eruptive flares, filament eruptions, coronal mass ejections and failed eruptions; all thought to be due to a release of energy stored in the coronal magnetic field during its drastic reconfiguration. This review discusses the observations and physical mechanisms behind this eruptive activity, with a view to making an assessment of the current capability of forecasting these events for space weather risk and impact mitigation. Whilst a wealth of observations exist, and detailed models have been developed, there still exists a need to draw these approaches together. In particular more realistic models are encouraged in order to asses the full range of complexity of the solar atmosphere and the criteria for which an eruption is formed. From the observational side, a more detailed understanding of the role of photospheric flows and reconnection is needed in order to identify the evolutionary path that ultimately means a magnetic structure will erupt

An Observational Overview of Solar Flares

We present an overview of solar flares and associated phenomena, drawing upon a wide range of observational data primarily from the RHESSI era. Following an introductory discussion and overview of the status of observational capabilities, the article is split into topical sections which deal with different areas of flare phenomena (footpoints and ribbons, coronal sources, relationship to coronal mass ejections) and their interconnections. We also discuss flare soft X-ray spectroscopy and the energetics of the process. The emphasis is to describe the observations from multiple points of view, while bearing in mind the models that link them to each other and to theory. The present theoretical and observational understanding of solar flares is far from complete, so we conclude with a brief discussion of models, and a list of missing but important observations.Comment: This is an article for a monograph on the physics of solar flares, inspired by RHESSI observations. The individual articles are to appear in Space Science Reviews (2011

Service provision for Frailty in European Emergency Departments (FEED): a survey of operational characteristics

Background The observational Frailty in European Emergency Departments (FEED) study found 40% of older people attending for care to be living with frailty. Older people with frailty have poorer outcomes from emergency care. Current best practice calls for early identification of frailty and holistic multidisciplinary assessment. This survey of FEED sites explores variations in frailty-attuned service definitions and provision. Methods This cross-sectional survey included study sites across Europe identified through snowball recruitment. Site co-ordinators (healthcare professionals in emergency and geriatric care) were surveyed online using Microsoft Forms. Items covered department and hospital capacity, frailty and delirium identification methods, staffing, and frailty-focused healthcare services in the ED. Descriptive statistics were reported. Results A total of 68 sites from 17 countries participated. Emergency departments had median 30 (IQR 21–53) trolley spaces. Most defined "older people" by age 65+ (64%) or 75+ (25%). Frailty screening was used at 69% of sites and mandated at 38%. Night-time staffing was lower compared to day-time for nursing (10 [IQR 8–14] vs. 14 [IQR 10–18]) and physicians (5 [IQR 3–8] vs. 10 [IQR 7–15]). Most sites had provision for ED frailty specialist services by day, but these services were rarely available at night. Sites mostly had accessible facilities; however, hot meals were rarely available at night (18%). Conclusion This survey demonstrated variability in case definitions, screening practices, and frailty-attuned service provision. There is no unanimous definition for older age, and while the Clinical Frailty Scale was commonly used, this was rarely mandated or captured in electronic records. Frailty services were often unavailable overnight. Appreciation of the variation in frailty service models could inform operational configuration and workforce development

Prevalence of Frailty in European Emergency Departments (FEED): an international flash mob study

Introduction Current emergency care systems are not optimized to respond to multiple and complex problems associated with frailty. Services may require reconfiguration to effectively deliver comprehensive frailty care, yet its prevalence and variation are poorly understood. This study primarily determined the prevalence of frailty among older people attending emergency care. Methods This cross-sectional study used a flash mob approach to collect observational European emergency care data over a 24-h period (04 July 2023). Sites were identified through the European Task Force for Geriatric Emergency Medicine collaboration and social media. Data were collected for all individuals aged 65 + who attended emergency care, and for all adults aged 18 + at a subset of sites. Variables included demographics, Clinical Frailty Scale (CFS), vital signs, and disposition. European and national frailty prevalence was determined with proportions with each CFS level and with dichotomized CFS 5 + (mild or more severe frailty). Results Sixty-two sites in fourteen European countries recruited five thousand seven hundred eighty-five individuals. 40% of 3479 older people had at least mild frailty, with countries ranging from 26 to 51%. They had median age 77 (IQR, 13) years and 53% were female. Across 22 sites observing all adult attenders, older people living with frailty comprised 14%. Conclusion 40% of older people using European emergency care had CFS 5 + . Frailty prevalence varied widely among European care systems. These differences likely reflected entrance selection and provide windows of opportunity for system configuration and workforce planning

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe