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A genotype-first approach in carriers of CDH1 rare germline variants: a European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS) multicentre study
No full textBackgroundTruncating CDH1 pathogenic/likely pathogenic variants (PV/LPV) cause Hereditary Diffuse Gastric Cancer (HDGC), predisposing to diffuse gastric (DGC) and to lobular breast cancer (LBC). Rare CDH1 missense variants often classify as variants of unknown significance (VUS). We conducted a genotype-phenotype analysis in CDH1 rare-variant carrier families, comparing the cancer landscape of PV/LPV and missense-VUS, assessing frequency of LBC-centered families among PV/LPV carrier families, and testing performance of LBC-expanded criteria for CDH1 testing.MethodsThis genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 CDH1 rare-variants and 1021 relatives, irrespective of HDGC clinical criteria, from ten European Reference Network on Tumour Risk Syndromes (ERN-GENTURIS) countries. Variants were classified for molecular type and clinical actionability with ACMG/AMP CDH1 guidelines v2. Families were categorized for compliance with 2015 and 2020 HDGC clinical criteria. From 1971 phenotypes (probands and relatives aged 1-93 years), 460 had gastric and breast cancer histology available. Genotype-phenotype associations were analysed by student’s t-test, Kruskal Wallis, chi-square and multivariable logistic regression models. Performance of HDGC clinical criteria sets were tested with equivalence test, Youden index, and the Area Under the Curve (AUC) of the Receiver operating characteristic (ROC) curves were compared with Z-test.FindingsCDH1-truncating PV/LPV occurred in 176/854 (21%) and missense-VUS in 169/854 (20%) families. Multivariable logistic regression comparing phenotypes presented by PV/LPVs and Missense-VUS carrier families showed that LBC has the greatest positive-association with presence of PV/LPVs (OR=12·4, 95% CI [2·66-57·7], p=0·0014), followed by DGC (8·00, 95%; [2·18-29·4], p=0·0017) and gastric cancer (GC) (7·81, 95%, [2·03-30·0], p=0·0027). 136/176 (77%) PV/LPV carrying families fulfilled HDGC 2015 criteria and 40/176 (23%) did not. 11/40 fulfilled 2020 HDGC criteria, and 18/40 presented LBC-only or LBC+GC, but no criteria. No specific CDH1 variant seemed predisposing specifically to LBC, although 7% (12/176) of all PV/LPV-carrier families were LBC-only. Addition of three new LBC-centered criteria improved testing sensitivity while retaining high specificity. Probability of finding CDH1 PV/LPV in patients fulfilling LBC-expanded criteria compared to former criteria increased significantly (AUC: 0·92 vs. 0·88; z-score=3·536; p<0·0001).InterpretationCDH1 PV/LPV are positively associated with HDGC-related phenotypes (LBC, DGC and GC), and no evidence for a positive association was found for CDH1 missense-VUS. CDH1 PV/LPV occurred often in LBC-enriched families lacking 2020 HDGC criteria, supporting the expansion of LBC-centered criteria
Characterisation of C101248: a novel selective THIK-1 channel inhibitor for the modulation of microglial NLRP3-inflammasome
No full textNeuroinflammation, specifically the NLRP3 inflammasome cascade, is a common underlying pathological feature of many neurodegenerative diseases. Evidence suggests that NLRP3 activation involves changes in intracellular K+. Nuclear Enriched Transcript Sort Sequencing (NETSseq), which allows for deep sequencing of purified cell types from human post-mortem brain tissue, demonstrated a highly specific expression of the tandem pore domain halothane-inhibited K+ channel 1 (THIK-1) in microglia compared to other glial and neuronal cell types in the human brain. NETSseq also showed a significant increase of THIK-1 in microglia isolated from cortical regions of brains with Alzheimer’s disease (AD) relative to control donors. Herein, we report the discovery and pharmacological characterisation of C101248, the first selective small-molecule inhibitor of THIK-1. C101248 showed a concentration-dependent inhibition of both mouse and human THIK-1 (IC50: ~50 nM) and was inactive against K2P family members TREK-1 and TWIK-2, and Kv2.1. Whole-cell patch-clamp recordings of microglia from mouse hippocampal slices showed that C101248 potently blocked both tonic and ATP-evoked THIK-1 K+ currents. Notably, C101248 had no effect on other constitutively active resting conductance in slices from THIK-1-depleted mice. In isolated microglia, C101248 prevented NLRP3-dependent release of IL-1β, an effect not seen in THIK-1-depleted microglia.In conclusion, we demonstrated that inhibiting THIK-1 (a microglia specific gene that is upregulated in brains from donors with AD) using a novel selective modulator attenuates the NLRP3-dependent release of IL-1β from microglia, which suggests that this channel may be a potential therapeutic target for the modulation of neuroinflammation in AD
Association of vocational interventions and work-related factors with disease and work outcomes in people with RMDs: A Systematic Review
No full textObjective: A EULAR taskforce was convened to develop recommendations for lifestyle behaviours among people with rheumatic and musculoskeletal diseases (RMDs). This paper reviews the literature on work-related factors and disease-specific outcomes for people with osteoarthritis, rheumatoid arthritis (RA), systemic lupus erythematosus, axial spondyloarthritis (axSpA), psoriatic arthritis, systemic sclerosis (SSc) and gout.Methods: Two separate systematic literature reviews (SLRs) were conducted. The first identified SLRs, published between 01/2013 and 09/2018. The second identified original observational and intervention studies published before 05/2019. Manuscripts were included if they assessed the effects of vocational interventions on disease-specific outcomes (i.e. clinical outcomes, patient-reported outcomes, and work outcomes) or if they assessed the association between work-related factors and these outcomes. Medline, Embase, Cochrane Library of systematic reviews and CENTRAL databases were searched. Results: Two SLRs were identified including individuals with SSc and inflammatory arthritis. Subsequently, 23 original manuscripts were identified, with most of them (43.5%) including people with RA and no manuscripts on gout. Most observational studies evaluated the association between work-related factors and work outcomes while limited information was available on the impact of work on clinical outcomes. A few studies suggested that physically demanding jobs have a small detrimental effect on radiographic progression in axSpA and PsA. Intervention studies showed beneficial effects of vocational interventions for disease-specific outcomes, but with small effect sizes.Conclusion: Many studies indicated that work participation is not likely to be detrimental and, in some cases, may be beneficial for RMD-specific outcomes and should therefore receive attention within healthcare consultations.<br/
Virtual wards: A rapid evidence synthesis and implications for the care of older people
No full textBackgroundVirtual wards are being rapidly developed within the National Health Service in the UK, and frailty is one of the first clinical pathways. Virtual wards for older people and existing hospital at home services are closely related.MethodsIn March 2022 we searched Medline, CINAHL, the Cochrane Database of Systematic Reviews and medRxiv for evidence syntheses which addressed clinical-effectiveness, cost-effectiveness, barriers and facilitators, or staff, patient or carer experience for virtual wards, hospital at home or remote monitoring alternatives to inpatient care.ResultsWe included 28 evidence syntheses mostly relating to hospital at home. There is low to moderate certainty evidence that clinical outcomes including mortality (example pooled RR 0.77, 95% CI 0.60 to 0.99) were probably equivalent or better for hospital at home. Subsequent residential care admissions are probably reduced (example pooled RR 0.35, 95% CI 0.22 to 0.57). Cost-effectiveness evidence demonstrated methodological issues which mean the results are uncertain. Evidence is lacking on cost implications for patients and carers. Barriers and facilitators operate at multiple levels (organisational, clinical and patient). Patient satisfaction may be improved by hospital at home relative to inpatient care. Evidence for carer experience is limited.ConclusionsThere is substantial evidence for the clinical effectiveness of hospital at home but less evidence for virtual wards. Guidance for virtual wards is lacking on key aspects including team characteristics, outcome selection and data protection. We recommend that research and evaluation is integrated into development of virtual ward models. The issue of carer strain is particularly relevant
Meta-Analysis of the Effect of Colchicine on C-Reactive Protein in Patients with Acute and Chronic Coronary Syndromes
No full textObjective: The anti-inflammatory drug Colchicine has recently shown benefits in the prevention of major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS) and chronic coronary syndromes (CCS). This meta-analysis focuses on understanding Colchicine's effects on the high sensitivity C-reactive protein (hs-CRP) to provide mechanistic insight to explain its clinical event reduction.Methods: A computerized search of MEDLINE was conducted to retrieve journal articles with studies performed on humans from January 1, 2005, to January 1, 2022, using keywords: “Colchicine AND Coronary”, “Colchicine AND CRP”, and “Colchicine AND Coronary Artery Disease”. Studies were included if they measured hs-CRP changes from baseline, and Colchicine or placebo were given to patients with ACS or CCS. Results: Thirteen studies with a biomarker subgroup population of 1636 patients were included in the hs-CRP meta-analysis. Of those 13 studies, 8 studies with a total population of 6016 reported clinical events defined as myocardial infarction (MI), stroke, cardiovascular death, periprocedural MI, repeat angina after PCI, and repeat revascularization. . A multivariate analysis revealed a weak negative correlation of -0.1056 (p= 0.805) between change in CRP and clinical events. Overall, colchicine treatment resulted in greater reduction in hs-CRP levels compared with placebo (standardized mean difference [MD-1.59 [95% CI: -2.40, -0.79], p=0.0001) and clinical events (Odds Ratio: 0.78 [0.64, 0.95], p=0.01).Conclusion: Colchicine therapy is associated with a reduction in hs-CRP and clinical events in patients with ACS and CCS. This finding supports colchicine’s anti-inflammatory efficacy via CRP reduction to explain its clinical benefit.<br/
How Cosmic Rays Mediate the Evolution of the Interstellar Medium
No full textWe explore the impact of diffusive cosmic rays (CRs) on the evolution of the interstellar medium (ISM) under varying assumptions of supernova explosion environment. In practice, we systematically vary the relative fractions of supernovae (SN) occurring in star-forming high-density gas and those occurring in random locations decoupled from star-forming gas to account for SN from run-away stars or explosions in regions that have been cleared by prior SN, stellar winds, or radiation. We explore various mixed models by adjusting these fractions relative to each other. We find that in the simple system of a periodic stratified gas layer the ISM structure will evolve to one of two solutions: a "peak driving" state where warm gas is volume filling or a "thermal runaway" state where hot gas is volume filling. CR pressure and transport are important factors that strongly influence the solution state the ISM reaches and have the ability to flip the ISM between solutions. Observable signatures such as gamma ray emission and HI gas are explored. We find that gamma ray luminosity from pion decay is largely consistent with observations for a range of model parameters. The thickness of the HI gas layer may be too compact, however, this may be due to a large cold neutral fraction of midplane gas. The volume fraction of hot gas evolves to stable states in both solutions, but neither settles to a Milky Way-like configuration, suggesting that additional physics which is omitted here (e.g. a cosmological circum-galactic medium, radiation transport, or spectrally resolved and spatially varying CR transport) may be required
Measuring the structural complexity of music: fromstructural segmentations to the automatic evaluation of models for music generation
No full textNickel encapsulated in silicalite-1 zeolite catalysts for steam reforming of glycerol (SRG) towards renewable hydrogen production
No full textValorisation of crude glycerol via steam reforming, i.e., SRG, is a promising method to produce sustainable hydrogen. However, catalyst deactivation under harsh SRG conditions is still a main challenge which hinders the further development of practical SRG. In this work, the encapsulated Ni catalyst in siliceous silicalite-1 zeolite (Ni@Si-1) were developed to show the improved performance and enhanced anti-deactivation potentials in catalytic SRG as compared with the conventional impregnated Ni catalysts (i.e., Ni/Si-1). Importantly, the post-synthetic treatment of Ni@Si-1 using TPAOH solution formed the encapsulated Ni catalyst with the mesoporous hollow structure (i.e., Ni@HolSi-1), which demonstrate even better performance in SRG with glycerol conversion of >95%, H2 yield of ~70%, H2/CO2 molar ratio of > 2.33 and CO/CO2 molar ratio of <1 at 750 °C. Specifically, highly dispersed ultrasmall encapsulated Ni particles were retained within the hollow crystals of siliceous silicalite-1, as confirmed by XPS and HRTEM characterisation. The activation energy for glycerol conversion over Ni@HolSi-1 (i.e., Ea = ~ 19 kJ mol−1) was much lower than that of Ni/Si-1 and Ni@Si-1. 100-h longevity tests over the three catalysts were investigated at 750 °C, and the Ni@HolSi-1 catalyst exhibited an excellent stability and activity, as well as insignificant coke deposition, which could be due to the enhancement of highly dispersed yet accessible Ni NPs within the hollow Si-1 crystals. The findings of the work show the promise of the encapsulation strategy and mesoporous zeolites for developing the future reforming catalysts. <br/
How is the NHS Low-Calorie Diet Programme expected to produce behavioural change to support diabetes remission: An examination of underpinning theory
No full textBackground: In 2020, the National Health Service Low-Calorie Diet Programme (NHS-LCD) was launched, piloting a Total Diet Replacement intervention with behaviour change support for people living with Type 2 Diabetes and excess weight. Four independent service providers were commissioned to design and deliver theoretically grounded programmes in localities across England. Aims: To (1) develop a logic model detailing how the NHS-LCD programme is expected to produce changes in health behaviour, and (2) analyse and evaluate the use of behaviour change theory in providers’ NHS-LCD Programme designs. Methods: A documentary review was conducted. Information was extracted from the NHS-LCD service specification documents on how the programme expected to produce outcomes. The Theory Coding Scheme was used to analyse theory use in providers’ programme designs documents. Results: The NHS-LCD logic model included techniques aimed at enhancing positive outcome expectations of programme participation and beliefs about social approval of behaviour change to facilitate programme uptake and behaviour change intentions. This was followed by techniques aimed at shaping knowledge and enhancing the ability of participants to self-regulate their health behaviours, alongside a supportive social environment and person-centred approach. Application and type of behaviour change theory within providers’ programme designs varied: One provider explicitly linked theory to programme content; two providers linked 63% and 70% of intervention techniques to theory; and there was limited underpinning theory identified in the programme design documents for one of the providers. Conclusions: The nature and extent of theory use underpinning the NHS-LCD varied greatly amongst service providers, with some but not all intervention techniques explicitly linked to theory. How this relates to outcomes across providers should be evaluated. It is recommended that explicit theory use in programme design and evidence of its implementation becomes a requirement of future NHS commissioning processes.<br/