Specificity of Adaptive Immune Responses in Central Nervous System Health, Aging and Diseases

The field of neuroimmunology endorses the involvement of the adaptive immune system in central nervous system (CNS) health, disease, and aging. While immune cell trafficking into the CNS is highly regulated, small numbers of antigen-experienced lymphocytes can still enter the cerebrospinal fluid (CSF)-filled compartments for regular immune surveillance under homeostatic conditions. Meningeal lymphatics facilitate drainage of brain-derived antigens from the CSF to deep cervical lymph nodes to prime potential adaptive immune responses. During aging and CNS disorders, brain barriers and meningeal lymphatic functions are impaired, and immune cell trafficking and antigen efflux are altered. In this context, alterations in the immune cell repertoire of blood and CSF and T and B cells primed against CNS-derived autoantigens have been observed in various CNS disorders. However, for many diseases, a causal relationship between observed immune responses and neuropathological findings is lacking. Here, we review recent discoveries about the association between the adaptive immune system and CNS disorders such as autoimmune neuroinflammatory and neurodegenerative diseases. We focus on the current challenges in identifying specific T cell epitopes in CNS diseases and discuss the potential implications for future diagnostic and treatment options

Anticipated barriers and enablers to signing up for a weight management program after receiving an opportunistic referral from a General Practitioner

Introduction: General Practitioners (GP) are advised to opportunistically refer patients with overweight or obesity to a tier 2 weight management program, but few patients sign up after receiving the referral. Signing up to a weight management program is a behaviour, as such, behaviour change interventions are needed to increase sign ups. However, no research has explored the influences on signing up after an opportunistic referral specifically. Aim: To investigate the influences (i.e., barriers and enablers) on signing up to a tier 2 weight management service after receiving an opportunistic referral from a GP, using a theoretical framework to inform intervention development. Method: Semi-structured interviews were conducted with 18 residents from the London borough of Hounslow who were eligible for the service. Interview guides were informed by the Theoretical Domains Framework (TDF). Data were analyzed inductively using Reflexive Thematic Analysis and Coding Reliability to identify influences on signing up, before being deductively coded to the TDF and grouped into themes. Results: Eight theoretical domains were identified as influences on signing up. Fifteen sub-themes were developed and categorized as either a barrier (5), enabler (3), or mixed (7) influence. Beliefs about Consequences was the most frequently reported influence on signing up. Beliefs that were expressed the most often include how effective the program would be, whether the program is needed to lose weight and whether the program would be compatible with their lifestyle. Leveraging Social Influences and changing patient’s Knowledge could address these beliefs and provide a potential route for Behaviour change. Discussion: The present study provides the first insight into behavioural influences on signing up for a weight management service opportunistically using a validated theoretical framework. This study has implications for intervention development in that public health researchers can identify intervention, content and implementation options based on the findings. Interventions targeting the key domains of Knowledge, Social influences and Beliefs about consequences would likely be the most effective because of their prominence and influence on other domains

Barriers and enablers to local active travel during COVID-19: A case study of Streetspace interventions in two London boroughs [version 1; peer review: 1 approved, 2 approved with reservations]

Background: During the coronavirus disease 2019 (COVID-19) pandemic, UK local authorities increased emergency active travel interventions. This study aimed to understand what aspects of temporary Streetspace for London schemes represent barriers or enablers to walking and cycling for short local journeys. Methods: Focusing on two Inner London boroughs, we conducted 21 semi-structured stakeholder interviews and sampled 885 public comments about Streetspace schemes. We triangulated the data in a thematic analysis to identify barriers and enablers, which were categorised using the Capability, Opportunity, Motivation, Behaviour (COM-B) model. Results: Opportunity and motivation factors were reflected in the barriers (accessibility and integration of the schemes; controversy, dissatisfaction, and doubt) and enablers (new routes and spaces; sustainability and health beliefs) and mixed themes (changes to traffic and appeal of the area; feelings of safety). Capability was not reflected in the main themes. Conclusions: Although aspects of Streetspace schemes were seen to enable active travel, our findings suggest that additional processes to address the acceptability, fairness, and unintended consequences of emergency interventions will be important to their long-term success for health and sustainability

From educator to facilitator: Healthcare professionals' experiences of, and views about, delivering a type 1 diabetes structured education programme (DAFNEplus ) informed by behavioural science

Aims The DAFNEplus programme incorporates behaviour change techniques into a modified educational intervention and was developed to help address the glycaemic drift observed amongst graduates of standard DAFNE programmes. As the programme's success will be contingent on staff buy‐in, we explored healthcare professionals' experiences of, and views about, delivering DAFNEplus during a clinical trial to help inform decision making about rollout post‐trial. Methods We interviewed n = 18 nurses and dieticians who delivered DAFNEplus during the trial. Data were analysed thematically. Results While many shared initial reservations, all described how their experiences of DAFNEplus programme delivery had had a positive, transformative impact upon their perceptions and working practices. This transformation was enabled by initial training and supervision sessions, the confidence gained from using scripts to support novel programme content delivery, and experiences of delivering the programme and observing DAFNEplus principles being well received by, and having a positive impact on, attendees. Due to these positive experiences, interviewees described a strongly felt ethical mandate to use some DAFNEplus techniques and curriculum content in routine clinical care. While being supportive of a national rollout, they anticipated a variety of attitudinal and logistical (e.g. workload) challenges. Conclusions This study provides a vital dimension to the evaluation of the DAFNEplus programme. Interviewees found the intervention to be acceptable and expressed high levels of buy‐in. As well as offering potential endorsement for a national rollout, our findings offer insights which could help inform development and rollout of future behaviour change interventions to support diabetes self‐management

Design of a Nanometric AlTi Additive for MgB2-Based Reactive Hydride Composites with Superior Kinetic Properties

Solid-state hydride compounds are a promising option for efficient and safe hydrogen-storage systems. Lithium reactive hydride composite system 2LiBH4 + MgH2/2LiH + MgB2 (Li-RHC) has been widely investigated owing to its high theoretical hydrogen-storage capacity and low calculated reaction enthalpy (11.5 wt % H2 and 45.9 kJ/mol H2). In this paper, a thorough investigation into the effect of the formation of nano-TiAl alloys on the hydrogen-storage properties of Li-RHC is presented. The additive 3TiCl3·AlCl3 is used as the nanoparticle precursor. For the investigated temperatures and hydrogen pressures, the addition of ∼5 wt % 3TiCl3·AlCl3 leads to hydrogenation/dehydrogenation times of only 30 min and a reversible hydrogen-storage capacity of 9.5 wt %. The material containing 3TiCl3·AlCl3 possesses superior hydrogen-storage properties in terms of rates and a stable hydrogen capacity during several hydrogenation/dehydrogenation cycles. These enhancements are attributed to an in situ nanostructure and a hexagonal AlTi3 phase observed by high-resolution transmission electron microscopy. This phase acts in a 2-fold manner, first promoting the nucleation of MgB2 upon dehydrogenation and second suppressing the formation of Li2B12H12 upon hydrogenation/dehydrogenation cycling.Fil: Le, Thi-Thu. Helmholtz Zentrum Geesthacht; AlemaniaFil: Pistidda, Claudio. Helmholtz Zentrum Geesthacht; AlemaniaFil: Puszkiel, Julián Atilio. Helmholtz Zentrum Geesthacht; Alemania. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; ArgentinaFil: Castro Riglos, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Helmholtz Zentrum Geesthacht; Alemania. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; ArgentinaFil: Karimi, Fahim. Helmholtz Zentrum Geesthacht; AlemaniaFil: Skibsted, Jørgen. University Aarhus; DinamarcaFil: Gharibdoust, Seyedhosein Payandeh. University Aarhus; DinamarcaFil: Richter, Bo. University Aarhus; DinamarcaFil: Emmler, Thomas. Helmholtz Zentrum Geesthacht; AlemaniaFil: Milanese, Chiara. Università di Pavia; ItaliaFil: Santoru, Antonio. Helmholtz Zentrum Geesthacht; AlemaniaFil: Hoell, Armin. Helmholtz Zentrum Berlin für Materialien und Energie; AlemaniaFil: Krumrey, Michael. Physikalisch Technische Bundesanstalt; AlemaniaFil: Gericke, Eike. Universität zu Berlin; AlemaniaFil: Akiba, Etsuo. Kyushu University; JapónFil: Jensen, Torben R.. University Aarhus; DinamarcaFil: Klassen, Thomas. Helmholtz Zentrum Geesthacht; Alemania. Helmut Schmidt University; AlemaniaFil: Dornheim, Martin. Helmholtz Zentrum Geesthacht; Alemani

Early β-amyloid accumulation in the brain is associated with peripheral T cell alterations

INTRODUCTION Fast and minimally invasive approaches for early diagnosis of Alzheimer's disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral β-amyloidosis has raised the question of whether immune markers could be used as proxies for β-amyloid accumulation in the brain. METHODS Here, we apply multidimensional mass-cytometry combined with unbiased machine-learning techniques to immunophenotype peripheral blood mononuclear cells from a total of 251 participants in cross-sectional and longitudinal studies. RESULTS We show that increases in antigen-experienced adaptive immune cells in the blood, particularly CD45RA-reactivated T effector memory (TEMRA) cells, are associated with early accumulation of brain β-amyloid and with changes in plasma AD biomarkers in still cognitively healthy subjects. DISCUSSION Our results suggest that preclinical AD pathology is linked to systemic alterations of the adaptive immune system. These immunophenotype changes may help identify and develop novel diagnostic tools for early AD assessment and better understand clinical outcomes

Dynamics at polarized carbon dioxide-iron oxyhydroxide interfaces unveil the origin of multicarbon product formation

Surface-sensitive ambient pressure X-ray photoelectron spectroscopy and near-edge X-ray absorption fine structure spectroscopy combined with an electrocatalytic reactivity study, multilength-scale electron microscopy, and theoretical modeling provide insights into the gas-phase selective reduction of carbon dioxide to isopropanol on a nitrogen-doped carbon-supported iron oxyhydroxide electrocatalyst. Dissolved atomic carbon forms at relevant potentials for carbon dioxide reduction from the reduction of carbon monoxide chemisorbed on the surface of the ferrihydrite-like phase. Theoretical modeling reveals that the ferrihydrite structure allows vicinal chemisorbed carbon monoxide in the appropriate geometrical arrangement for coupling. Based on our observations, we suggest a mechanism of three-carbon-atom product formation, which involves the intermediate formation of atomic carbon that undergoes hydrogenation in the presence of hydrogen cations upon cathodic polarization. This mechanism is effective only in the case of thin ferrihydrite-like nanostructures coordinated at the edge planes of the graphitic support, where nitrogen edge sites stabilize these species and lower the overpotential for the reaction. Larger ferrihydrite-like nanoparticles are ineffective for electron transport

Interfacial chemistry in the electrocatalytic hydrogenation of CO2 over C‑supported Cu-based systems

Operando soft and hard X-ray spectroscopic techniques were used in combination with plane-wave density functional theory (DFT) simulations to rationalize the enhanced activities of Zn-containing Cu nanostructured electrocatalysts in the electrocatalytic CO2 hydrogenation reaction. We show that at a potential for CO2 hydrogenation, Zn is alloyed with Cu in the bulk of the nanoparticles with no metallic Zn segregated; at the interface, low reducible Cu­(I)–O species are consumed. Additional spectroscopic features are observed, which are identified as various surface Cu­(I) ligated species; these respond to the potential, revealing characteristic interfacial dynamics. Similar behavior was observed for the Fe–Cu system in its active state, confirming the general validity of this mechanism; however, the performance of this system deteriorates after successive applied cathodic potentials, as the hydrogen evolution reaction then becomes the main reaction pathway. In contrast to an active system, Cu­(I)–O is now consumed at cathodic potentials and not reversibly reformed when the voltage is allowed to equilibrate at the open-circuit voltage; rather, only the oxidation to Cu­(II) is observed. We show that the Cu–Zn system represents the optimal active ensembles with stabilized Cu­(I)–O; DFT simulations rationalize this observation by indicating that Cu–Zn–O neighboring atoms are able to activate CO2, whereas Cu–Cu sites provide the supply of H atoms for the hydrogenation reaction. Our results demonstrate an electronic effect exerted by the heterometal, which depends on its intimate distribution within the Cu phase and confirms the general validity of these mechanistic insights for future electrocatalyst design strategies

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov: NCT01578239, EudraCT: 2011-005049-11