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Navigating complexities and considerations for suspected anastomotic leakage in the upper gastrointestinal tract:A state of the art review
No full textThis state-of-the-art review explores the intricacies of anastomotic leaks following oesophagectomy and gastrectomy, crucial surgeries for globally increasing esophageal and gastric cancers. Despite advancements, anastomotic leaks occur in up to 30 % and 10 % of oesophagectomy and gastrectomy cases, respectively, leading to prolonged hospital stays, substantial impact upon short- and long-term health-related quality of life and greater mortality. Recognising factors contributing to leaks, including patient characteristics and surgical techniques, are vital for preoperative risk stratification. Diagnosis is challenging, involving clinical signs, biochemical markers, and various imaging modalities. Management strategies range from non-invasive approaches, including antibiotic therapy and nutritional support, to endoscopic interventions such as stent placement and emerging vacuum-assisted closure devices, and surgical interventions, necessitating timely recognition and tailored interventions. A step-up approach, beginning non-invasively and progressing based on treatment success, is more commonly advocated. This comprehensive review highlights the absence of standardised treatment algorithms, emphasizing the importance of individualised patient-specific management
DNA damage response defects in hematologic malignancies:mechanistic insights and therapeutic strategies
No full textThe DNA damage response (DDR) encompasses the detection and repair of DNA lesions and is fundamental to the maintenance of genome integrity. Germ line DDR alterations underlie hereditary chromosome instability syndromes by promoting the acquisition of pathogenic structural variants in hematopoietic cells, resulting in increased predisposition to hematologic malignancies. Also frequent in hematologic malignancies are somatic mutations of DDR genes, typically arising from replication stress triggered by oncogene activation or deregulated tumor proliferation that provides a selective pressure for DDR loss. These defects impair homology–directed DNA repair or replication stress response, leading to an excessive reliance on error-prone DNA repair mechanisms that results in genomic instability and tumor progression. In hematologic malignancies, loss-of-function DDR alterations confer clonal growth advantage and adverse prognostic impact but may also provide therapeutic opportunities. Selective targeting of functional dependencies arising from these defects could achieve synthetic lethality, a therapeutic concept exemplified by inhibition of poly-(adenosine 5′-diphosphate ribose) polymerase or the ataxia telangiectasia and Rad 3 related-CHK1-WEE1 axis in malignancies harboring the BRCAness phenotype or genetic defects that increase replication stress. Furthermore, the role of DDR defects as a source of tumor immunogenicity, as well as their impact on the cross talk between DDR, inflammation, and tumor immunity are increasingly recognized, thus providing rationale for combining DDR modulation with immune modulation. The nature of the DDR–immune interface and the cellular vulnerabilities conferred by DDR defects may nonetheless be disease-specific and remain incompletely understood in many hematologic malignancies. Their comprehensive elucidation will be critical for optimizing therapeutic strategies to target DDR defects in these diseases
A perspective on cell bill of materials using BatPaC
Get PDFWith the development of new technology in the battery sector, it is increasingly important to be able to predict and compare the potential of developments, particularly in energy density, cost and sustainability. Assessing any of these requires detailed breakdowns of the contents of a comparable battery pack, module and cells. This perspective article aims to provide a bill of materials (BOM) for 14 current and next generation battery technologies, using the Argonne Labs BatPaC software and specifying what the voltage used is at the beginning of life. The BOM is not specified towards a particular automotive case, and hence changes the model average voltage used compared to Argonne lab BatPaC software. The BOM gives comparable cells targeted at energy rather than power, which have 5 mA/cm2 cathode, the N:P ratio 1.1:1, and a 0.25 kWh cell from a 100 kWh pack, with 25 % porosity. This approach enables sustainability assessments to be made using these comparable cells of current and emerging technologies without assumption on the aging process or automotive use case, and hence provides an avenue to widen the discussion from R&D lab to scale up
Programme Recipient and Facilitator Experiences of Positive Family Connections for Families of Children With Intellectual Disabilities and/or Who Are Autistic
Get PDFBackground: Family members of children with developmental disabilities on average report poorer family functioning and mental health. Positive Family Connections is a co-produced, positively-oriented, family-systems support programme for families of children with developmental disabilities aged 8–13. We investigated experiences of Positive Family Connections, and the processes involved in change. Method: We conducted semi-structured interviews with eight family carers who took part in Positive Family Connections and nine facilitators. Data were analysed using framework analysis. Results: Programme recipients' and facilitators generally reported positive experiences of Positive Family Connections and described beneficial effects on wellbeing and family relationships. We developed a model showing how the lived experience of facilitators and positive approach led to reductions in isolation and perceived changes in mindset that were described as improving family carers' wellbeing and family relationships. Conclusions: Positive Family Connections appears to be an acceptable programme which programme recipients and facilitators perceive to be beneficial.</p
The connectivity of the normalising and permuting graph of a finite soluble group
No full textWe introduce the normalising graph of a group and study the connectivity of the normalising and permuting graphs of a group when the group is finite and soluble. In particular, we classify finite soluble groups with disconnected normalising graph. The main results shows that if a finite soluble group has connected normalising graph then this graph has diameter at most . Furthermore, this bound is tight. A corollary then presents the connectivity properties of the permuting graph
A Critical Review of the Decarbonisation Potential in the U.K. Cement Industry
Get PDFAs urbanisation and infrastructure development continue to drive rising cement demand, the imperative to significantly reduce emissions from this emissions-intensive sector has become increasingly urgent, especially in the context of global climate goals such as achieving net zero emissions by 2050. This review examines the status, challenges and prospects of low-carbon cement technologies and mitigation strategies through the lens of the U.K. cement industry. A mixed-methods approach was employed, combining structured literature searches across academic databases with analyses of industry reports, market data and technological roadmaps to ensure a comprehensive evaluation. Following an outline of cement production, resource flows and the sector’s landscape in the U.K., the review delves into an array of decarbonisation pathways. This includes deploying the best available technologies (BATs), fuel switching, carbon capture utilisation and storage (CCUS), clinker substitution and low-carbon cement formulations. A critical assessment is provided on the technological readiness, costs, resource availability considerations and scalability aspects governing the widespread implementation prospects of these approaches within the U.K. cement industry. Furthermore, this study proposes a roadmap that considers priority avenues and policy needs essential for facilitating the transition towards sustainable cement production aligned with the U.K.’s net zero obligations by 2050. This evaluation contributes significantly to the ongoing decarbonisation discourse by holistically mapping technological solutions and strategic imperatives tailored to the unique challenges and opportunities presented by the U.K. cement sector
Genetic variants of accessory proteins and G proteins in human genetic disease
Get PDFWe present a series of three articles on the genetics and pharmacogenetics of G protein- coupled receptors (GPCR). In the first article, we discuss genetic variants of the G protein subunits and accessory proteins that are associated with human phenotypes; in the second article, we build upon this to discuss "G protein-coupled receptor (GPCR) gene variants and human genetic disease" and in the third article, we survey "G protein-coupled receptor pharmacogenomics". In the present article, we review the processes of ligand binding, GPCR activation, inactivation, and receptor trafficking to the membrane in the context of human genetic disease resulting from pathogenic variants of accessory proteins and G proteins. Pathogenic variants of the genes encoding G protein α and β subunits are examined in diverse phenotypes. Variants in the genes encoding accessory proteins that modify or organize G protein coupling have been associated with disease; these include the contribution of variants of the regulator of G protein signaling (RGS) to hypertension; the role of variants of activator of G protein signaling type III in phenotypes such as hypoxia; the contribution of variation at the RGS10 gene to short stature and immunological compromise; and the involvement of variants of G protein-coupled receptor kinases (GRKs), such as GRK4, in hypertension. Variation in genes that encode proteins involved in GPCR signaling are outlined in the context of the changes in structure and function that may be associated with human phenotypes. </p
Obesity-associated MRAP2 variants impair multiple MC4R-mediated signaling pathways
Get PDFThe melanocortin-4 receptor (MC4R) is a G protein-coupled receptor expressed at hypothalamic neurons that has an important role in appetite suppression and food intake. Mutations in MC4R are the most common cause of monogenic obesity and can affect multiple signaling pathways including Gs-cAMP, Gq, ERK1/2, β-arrestin recruitment, internalization and cell surface expression. The melanocortin-2 receptor accessory protein 2 (MRAP2), is a single-pass transmembrane protein that interacts with and regulates signaling by MC4R. Variants in MRAP2 have also been identified in overweight and obese individuals. However, functional studies that have only measured the effect of MRAP2 variants on MC4R-mediated cAMP signaling have produced inconsistent findings and most do not reduce MC4R function. Here we investigated the effect of twelve of these previously reported MRAP2 variants and showed that all variants that have been identified in overweight or obese individuals impair MC4R function. When expressed at equal concentrations, seven MRAP2 variants impaired MC4R-mediated cAMP signaling, while nine variants impaired IP3 signaling. Four mutations in the MRAP2 C-terminus affected internalization. MRAP2 variants had no effect on total or cell surface expression of either the MRAP2 or MC4R proteins. Structural models predicted that MRAP2 interacts with MC4R transmembrane helices 5 and 6, and mutations in two MRAP2 residues in putative contact sites impaired the ability of MRAP2 to facilitate MC4R signaling. In summary, our studies demonstrate that human MRAP2 variants associated with obesity impair multiple MC4R signaling pathways and that both Gs-cAMP and Gq-IP3 pathways should be assessed to determine variant pathogenicity.</p
Measurement of CP violation in B<sup>0</sup> → D<sup>+</sup>D<sup>−</sup> and B<sup>0</sup><sub>s </sub>→ D<sup>+</sup><sub>s</sub> D<sup>−</sup><sub>s</sub> decays
Get PDFA time-dependent, flavour-tagged measurement of CP violation is performed with B0→D+D− and B0s→D+sD−s decays, using data collected by the LHCb detector in proton-proton collisions at a centre-of-mass energy of 13 TeV corresponding to an integrated luminosity of 6 fb−1. In B0→D+D− decays the CP-violation parameters are measured to be SD+D− = −0.552 ± 0.100(stat) ± 0.010(syst),CD+D− = 0.128 ± 0.103(stat) ± 0.010(syst). In B0s→D+sD−s decays the CP-violating parameter formulation in terms of ϕs and |λ| results in ϕs = −0.086 ± 0.106(stat) ± 0.028(syst) rad,|λD+sD−s| = 1.145 ± 0.126(stat) ± 0.031(syst). These results represent the most precise single measurement of the CP-violation parameters in their respective channels. For the first time in a single measurement, CP symmetry is observed to be violated in B0→D+D− decays with a significance exceeding six standard deviations.</p
Why and how do workplaces invest in mental health and wellbeing?:A systematic review and process tracing study
Get PDFIn recent years, investment in workplace mental health and wellbeing has grown. However, there is little understanding of how resource allocation decisions are made in such settings. To ensure evaluative research can support resource allocation, a process-based understanding of decision-making would be helpful. In phase one a systematic review of the literature on the implementation of workplace mental health and wellbeing schemes was conducted to draw insights on workplace resource allocation processes. In phase two an in-depth case study of a large company was conducted with interviews with those involved in resource allocation and wellbeing. Interviews were coded and analysed using descriptive and explanatory accounts. The findings from the review and case study were combined and developed into a causal process theory. This study shows that the stages in mental health and wellbeing investment revolve around ensuring organisational buy-in, workforce investment, and continual evaluation. Further work is needed to explore the transferability of the resulting process theory across different types of workplaces. However, it is clear that the features of real world decision-making in workplaces present challenges and opportunities for the research community
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