Systematic review investigating multi-disciplinary team approaches to screening and early diagnosis of dementia in primary care:what are the positive and negative effects and who should deliver it?

BACKGROUND: Primary care services frequently provide the initial contact between people with dementia and health service providers. Early diagnosis and screening programmes have been suggested as a possible strategy to improve the identification of such individuals and treatment and planning health and social care support. OBJECTIVE: To determine what early diagnostic and screening programmes have been adopted in primary care practice, to explore who should deliver these and to determine the possible positive and negative effects of an early diagnostic and screening programme for people with dementia in primary care. METHODS: A systematic review of the literature was undertaken using published and unpublished research databases. All papers answering our research objectives were included. A narrative analysis of the literature was undertaken, with the CASP tools used appropriately to assess study quality. RESULTS: Thirty-three papers were identified of moderate to high quality. The limited therapeutic options for those diagnosed with dementia means that even if such a programme were instigated, the clinical value remains questionable. Furthermore accuracy of the diagnosis remains difficult to assess due to poor evidence and this raises questions regarding whether people could be over- or under-diagnosed. Given the negative social and psychological consequences of such a diagnosis, this could be devastating for individuals. CONCLUSIONS: Early diagnostic and screening programme have not been widely adopted into primary care. Until there is rigorous evidence assessing the clinical and cost-effectiveness of such programmes, there remains insufficient evidence to support the adoption of these programmes in practice

Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1

During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the immunosuppressive cytokine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line. Using this model, we demonstrated that virus-specific T cells with reduced inflammatory function, particularly Th1 cells, display elevated and sustained IL-10 expression during chronic LCMV infection. Furthermore, ablation of IL-10 from the T cell compartment partially restored T cell function and reduced viral loads in LCMV-infected animals. We found that viral persistence is needed for sustained IL-10 production by Th1 cells and that the transcription factor BLIMP-1 is required for IL-10 expression by Th1 cells. Restimulation of Th1 cells from LCMV-infected mice promoted BLIMP-1 and subsequent IL-10 expression, suggesting that constant antigen exposure likely induces the BLIMP-1/IL-10 pathway during chronic viral infection. Together, these data indicate that effector T cells self-limit their responsiveness during persistent viral infection via an IL-10-dependent negative feedback loop.This work was supported by an Australian NHMRC Overseas Biomedical Postdoctoral Fellowship (to I.A. Parish); a Yale School of Medicine Brown-Coxe Postdoctoral Fellowship (to I.A. Parish); the Alexander von Humboldt Foundation (SKA2010, to P.A. Lang); a CIHR grant (to P.S. Ohashi); and by the Howard Hughes Medical Institute and NIH grant RO1AI074699 (to S.M. Kaech). P.S. Ohashi holds a Canada Research Chair in Autoimmunity and Tumor immunity

Imaging signatures of meningioma and low-grade glioma: a diffusion tensor, magnetization transfer and quantitative longitudinal relaxation time MRI study

Differentiation of cerebral tumor pathology currently relies on interpretation of conventional structural MRI and in some cases histology. However, more advanced MRI methods may provide further insight into the organization of cerebral tumors and have the potential to aid diagnosis. The objective of this study was to use multimodal quantitative MRI to measure the imaging signatures of meningioma and low-grade glioma (LGG). Nine adults with meningioma and 11 with LGG were identified, and underwent standard structural, quantitative longitudinal relaxation time (T(1)) mapping, magnetization transfer and diffusion tensor MRI. Maps of mean (〈D〉), axial (λ(AX)) and radial (λ(RAD)) diffusivity, fractional anisotropy (FA), magnetization transfer ratio (MTR) and T(1) were generated on a voxel-by-voxel basis. Using structural and echo-planar T(2)-weighted MRI, manual region-of-interest segmentation of brain tumor, edema, ipsilateral and contralateral normal-appearing white matter (NAWM) was performed. Differences in imaging signatures between the different tissue types, both absolute mean values and ratios relative to contralateral NAWM, were assessed using t-tests with statistical significance set at p < 0.05. For both absolute mean values and ratios relative to contralateral NAWM, there were significant differences in 〈D〉, λ(AX), λ(RAD), FA, MTR and T(1) between meningioma and LGG tumor tissue, respectively. Only T(1) and FA differed significantly between edematous tissue associated with the two tumor types. These results suggest that multimodal MRI biomarkers are significantly different, particularly in tumor tissue, between meningioma and LGG. By using quantitative multimodal MRI it may be possible to identify tumor pathology non-invasively

The Attitudes to Ageing Questionnaire:Mokken Scaling Analysis

BACKGROUND:Hierarchical scales are useful in understanding the structure of underlying latent traits in many questionnaires. The Attitudes to Ageing Questionnaire (AAQ) explored the attitudes to ageing of older people themselves, and originally described three distinct subscales: (1) Psychosocial Loss (2) Physical Change and (3) Psychological Growth. This study aimed to use Mokken analysis, a method of Item Response Theory, to test for hierarchies within the AAQ and to explore how these relate to underlying latent traits. METHODS:Participants in a longitudinal cohort study, the Lothian Birth Cohort 1936, completed a cross-sectional postal survey. Data from 802 participants were analysed using Mokken Scaling analysis. These results were compared with factor analysis using exploratory structural equation modelling. RESULTS:Participants were 51.6% male, mean age 74.0 years (SD 0.28). Three scales were identified from 18 of the 24 items: two weak Mokken scales and one moderate Mokken scale. (1) 'Vitality' contained a combination of items from all three previously determined factors of the AAQ, with a hierarchy from physical to psychosocial; (2) 'Legacy' contained items exclusively from the Psychological Growth scale, with a hierarchy from individual contributions to passing things on; (3) 'Exclusion' contained items from the Psychosocial Loss scale, with a hierarchy from general to specific instances. All of the scales were reliable and statistically significant with 'Legacy' showing invariant item ordering. The scales correlate as expected with personality, anxiety and depression. Exploratory SEM mostly confirmed the original factor structure. CONCLUSIONS:The concurrent use of factor analysis and Mokken scaling provides additional information about the AAQ. The previously-described factor structure is mostly confirmed. Mokken scaling identifies a new factor relating to vitality, and a hierarchy of responses within three separate scales, referring to vitality, legacy and exclusion. This shows what older people themselves consider important regarding their own ageing

SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues.

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The adequacy of consent forms for informing patients entering oncological clinical trials

Olver, I N; Buchanan, L; Laidlaw, C; Poulton,