Report on the Working Group set up to Study the Requirements for Operating the SPS within the INB Framework (INBOPS)

The convention signed with the French authorities for the LHC defines a new Installation Nucléaire de Base (INB). The LHC machine tunnel, the experiments, some buildings which cover access shafts to the machine and the SPS with its extraction lines up to the targets are all inside the new perimeter. The new convention came into effect in September 2000 and therefore the SPS fell within the new context from that time. As a consequence, SL has to operate the SPS within this new regulatory framework and a small working group was set up to look at the requirements and to estimate the resources required. The conclusions of the working group are reported in this paper

Solution structure of a repeated unit of the ABA-1 nematode polyprotein allergen of ascaris reveals a novel fold and two discrete lipid-binding sites

Parasitic nematode worms cause serious health problems in humans and other animals. They can induce allergic-type immune responses, which can be harmful but may at the same time protect against the infections. Allergens are proteins that trigger allergic reactions and these parasites produce a type that is confined to nematodes, the nematode polyprotein allergens (NPAs). These are synthesized as large precursor proteins comprising repeating units of similar amino acid sequence that are subsequently cleaved into multiple copies of the allergen protein. NPAs bind small lipids such as fatty acids and retinol (Vitamin A) and probably transport these sensitive and insoluble compounds between the tissues of the worms. Nematodes cannot synthesize these lipids, so NPAs may also be crucial for extracting nutrients from their hosts. They may also be involved in altering immune responses by controlling the lipids by which the immune and inflammatory cells communicate. We describe the molecular structure of one unit of an NPA, the well-known ABA-1 allergen of Ascaris and find its structure to be of a type not previously found for lipid-binding proteins, and we describe the unusual sites where lipids bind within this structur

CAnceR IN PreGnancy (CARING) - a retrospective study of cancer diagnosed during pregnancy in the United Kingdom

BACKGROUND: The incidence of cancer diagnosed during pregnancy is increasing. Data relating to investigation and management, as well as maternal and foetal outcomes is lacking in a United Kingdom (UK) population.METHODS: In this retrospective study we report data from 119 patients diagnosed with cancer during pregnancy from 14 cancer centres in the UK across a five-year period (2016-2020).RESULTS: Median age at diagnosis was 33 years, with breast, skin and haematological the most common primary sites. The majority of cases were new diagnoses (109 patients, 91.6%). Most patients were treated with radical intent (96 patients, 80.7%), however, gastrointestinal cancers were associated with a high rate of palliative intent treatment (63.6%). Intervention was commenced during pregnancy in 68 (57.1%) patients; 44 (37%) had surgery and 31 (26.1%) received chemotherapy. Live births occurred in 98 (81.7%) of the cases, with 54 (55.1%) of these delivered by caesarean section. Maternal mortality during the study period was 20.2%.CONCLUSIONS: This is the first pan-tumour report of diagnosis, management and outcomes of cancer diagnosed during pregnancy in the UK. Our findings demonstrate proof of concept that data collection is feasible and highlight the need for further research in this cohort of patients.</p

Functional cognitive disorder: dementia's blind spot

An increasing proportion of cognitive difficulties are recognized to have a functional cause, the chief clinical indicator of which is internal inconsistency. When these symptoms are impairing or distressing, and not better explained by other disorders, this can be conceptualized as a cognitive variant of functional neurological disorder, termed functional cognitive disorder (FCD). FCD is likely very common in clinical practice but may be under-diagnosed. Clinicians in many settings make liberal use of the descriptive term mild cognitive impairment (MCI) for those with cognitive difficulties not impairing enough to qualify as dementia. However, MCI is an aetiology-neutral description, which therefore includes patients with a wide range of underlying causes. Consequently, a proportion of MCI cases are due to non-neurodegenerative processes, including FCD. Indeed, significant numbers of patients diagnosed with MCI do not 'convert' to dementia. The lack of diagnostic specificity for MCI 'non-progressors' is a weakness inherent in framing MCI primarily within a deterministic neurodegenerative pathway. It is recognized that depression, anxiety and behavioural changes can represent a prodrome to neurodegeneration; empirical data are required to explore whether the same might hold for subsets of individuals with FCD. Clinicians and researchers can improve study efficacy and patient outcomes by viewing MCI as a descriptive term with a wide differential diagnosis, including potentially reversible components such as FCD. We present a preliminary definition of functional neurological disorder-cognitive subtype, explain its position in relation to other cognitive diagnoses and emerging biomarkers, highlight clinical features that can lead to positive diagnosis (as opposed to a diagnosis of exclusion), and red flags that should prompt consideration of alternative diagnoses. In the research setting, positive identifiers of FCD will enhance our recognition of individuals who are not in a neurodegenerative prodrome, while greater use of this diagnosis in clinical practice will facilitate personalised interventions

A psycho-Geoinformatics approach for investigating older adults’ driving behaviours and underlying cognitive mechanisms

Introduction: Safe driving constantly challenges the driver’s ability to respond to the dynamic traffic scene under space and time constraints. It is of particular importance for older drivers to perform sufficient visual and motor actions with effective coordination due to the fact of age-related cognitive decline. However, few studies have been able to integrate drivers’ visual-motor behaviours with environmental information in a spatial-temporal context and link to the cognitive conditions of individual drivers. Little is known about the mechanisms that underpin the deterioration in visual-motor coordination of older drivers. Development: Based on a review of driving-related cognitive decline in older adults and the context of driver-vehicle-environment interactions, this paper established a conceptual framework to identify the parameters of driver’s visual and motor behaviour, and reveal the cognitive process from visual search to vehicle control in driving. The framework led to a psycho-geoinformatics approach to measure older drivers’ driving behaviours and investigate the underlying cognitive mechanisms. The proposed data collection protocol and the analysis and assessments depicted the psycho-geoinformatics approach on obtaining quantified variables and the key means of analysis, as well as outcome measures. Conclusions: Recordings of the driver and their interactions with the vehicle and environment at a detailed scale give a closer assessment of the driver’s behaviours. Using geoinformatics tools in driving behaviours assessment opens a new era of research with many possible analytical options, which do not have to rely on human observations. Instead, it receives clear indicators of the individual drivers’ interactions with the vehicle and the traffic environment. This approach should make it possible to identify lower-performing older drivers and problematic visual and motor behaviours, and the cognitive predictors of risky driving behaviours. A better targeted regulation and tailored intervention programs for older can be developed by further research

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Spatially heterogeneous ages in glassy dynamics

We construct a framework for the study of fluctuations in the nonequilibrium relaxation of glassy systems with and without quenched disorder. We study two types of two-time local correlators with the aim of characterizing the heterogeneous evolution: in one case we average the local correlators over histories of the thermal noise, in the other case we simply coarse-grain the local correlators. We explain why the former describe the fingerprint of quenched disorder when it exists, while the latter are linked to noise-induced mesoscopic fluctuations. We predict constraints on the pdfs of the fluctuations of the coarse-grained quantities. We show that locally defined correlations and responses are connected by a generalized local out-of-equilibrium fluctuation-dissipation relation. We argue that large-size heterogeneities in the age of the system survive in the long-time limit. The invariance of the theory under reparametrizations of time underlies these results. We relate the pdfs of local coarse-grained quantities and the theory of dynamic random manifolds. We define a two-time dependent correlation length from the spatial decay of the fluctuations in the two-time local functions. We present numerical tests performed on disordered spin models in finite and infinite dimensions. Finally, we explain how these ideas can be applied to the analysis of the dynamics of other glassy systems that can be either spin models without disorder or atomic and molecular glassy systems.Comment: 47 pages, 60 Fig