Cooling is hotting up in the UK

The cooling of buildings is currently responsible for about 20% of total electricity use worldwide. It is estimated that the electricity needed for cooling will more than triple by 2050. Despite this concerning outlook, little attention has been paid to cooling demand in policy and research in the United Kingdom (UK). The demand for space cooling in the UK’s domestic and non-domestic buildings is currently small—about 10% of total electricity use. However, this has the potential to increase as the climate warms and expectations of comfort grow. This paper reviews UK cooling demand and how this has been considered in energy policy. Following a thorough review of the existing literature using a cooling decarbonisation framework (Avoid, Improve and Shift), it is clear there is a limited understanding of the future UK cooling demand for domestic buildings in a warmer future as well as how policy makers and households should act. More importantly, this sector appears under-represented in the UK research and policy landscape compared to heating despite obvious technological crossovers associated with electrification. Several policy and research recommendations have been made based on these findings

Medial and Lateral Entorhinal Cortex Differentially Excite Deep versus Superficial CA1 Pyramidal Neurons

Although hippocampal CA1 pyramidal neurons (PNs) were thought to comprise a uniform population, recent evidence supports two distinct sublayers along the radial axis, with deep neurons more likely to form place cells than superficial neurons. CA1 PNs also differ along the transverse axis with regard to direct inputs from entorhinal cortex (EC), with medial EC (MEC) providing spatial information to PNs toward CA2 (proximal CA1) and lateral EC (LEC) providing non-spatial information to PNs toward subiculum (distal CA1). We demonstrate that the two inputs differentially activate the radial sublayers and that this difference reverses along the transverse axis, with MEC preferentially targeting deep PNs in proximal CA1 and LEC preferentially exciting superficial PNs in distal CA1. This differential excitation reflects differences in dendritic spine numbers. Our results reveal a heterogeneity in EC-CA1 connectivity that may help explain differential roles of CA1 PNs in spatial and non-spatial learning and memory

Interaction between hedgehog signalling and PAX6 dosage mediates maintenance and regeneration of the corneal epithelium

PURPOSE: To investigate the roles of intracellular signaling elicited by Hedgehog (Hh) ligands in corneal maintenance and wound healing. METHODS: The expression of Hedgehog pathway components in the cornea was assayed by immunohistochemistry, western blot and reverse-transcription polymerase chain reaction (RT-PCR), in wild-type mice and mice that were heterozygous null for the gene encoding the transcription factor, paired box gene 6 (Pax6). Corneal epithelial wound healing and cell migration assays were performed after pharmacological upregulation and downregulation of the hedgehog pathway. Reporter mice, mosaic for expression of the gene encoding β-galactosidase (LacZ), were crossed to Pax6(+/-) mice, mice heterozygous for the gene encoding GLI-Kruppel family member GLI3, and Pax6(+/-)Gli3(+/-) double heterozygotes, to assay patterns of cell migration and corneal epithelial organization in vivo. RESULTS: Corneal epithelial wound healing rates increased in response to application of Sonic hedgehog (Shh), but only in mice with wild-type Pax6 dosage. Downregulation of Hedgehog signalling inhibited corneal epithelial cell proliferation. Pax6(+/-) corneal epithelia showed increased proliferation in response to exogenous Shh, but not increased migration. Desert hedgehog (Dhh) was shown to be the major endogenous ligand, with Shh detectable only by RT-PCR and only after epithelial wounding. The activity of phosphatidylinositol-3-OH kinase-γ (PI3Kγ) was not required for the increased migration response in response to Shh. Nuclear expression of the activator form of the transcription factor Gli3 (which mediates Hh signalling) was reduced in Pax6(+/-) corneal epithelia. Pax6(+/-)Gli3(+/-) double heterozygotes showed highly disrupted patterns of clonal arrangement of cells in the corneal epithelium. CONCLUSIONS: The data show key roles for endogenous Dhh signalling in maintenance and regeneration of the corneal epithelium, demonstrate an interaction between Pax6 and Hh signalling in the corneal epithelium, and show that failure of Hh signalling pathways is a feature of Pax6(+/-) corneal disease that cannot be remedied pharmacologically by addition of the ligands

Involving lay and professional stakeholders in the development of a research intervention for the DEPICTED Study

Aim: This paper focuses on stakeholders’ active involvement at key stages of the research as members of a Stakeholder Action Group (SAG), particularly in the context of lay stakeholder involvement. Some challenges that can arise and wider issues (e.g. empowerment, the impact of user involvement) are identified and explored within the literature on service user involvement in health care research, reflecting on the implications for researchers. Background: In the DEPICTED study, lay and professional stakeholders were actively involved in developing a complex research intervention. Lay stakeholders comprised teenage and adult patients with diabetes, parents and patient organization representatives. Professional stakeholders were from a range of disciplines. Methods: Three 1-day research meetings were attended by 13–17 lay stakeholders and 10–11 professional stakeholders (plus researchers). The SAG was responsible for reviewing evidence, advising on developing ideas for the research intervention and guiding plans for evaluation of the intervention in a subsequent trial. Formal evaluations were completed by stakeholders following each SAG meeting. Results: Throughout the first (developmental) stage of this two-stage study, lay and professional stakeholders participated or were actively involved in activities that provided data to inform the research intervention. Lay stakeholders identified the need for and contributed to the design of a patient-held tool, strongly influenced the detailed design and content of the research intervention and outcome questionnaire, thus making a major contribution to the trial design. Conclusion: Stakeholders, including teenagers, can be actively involved in designing a research intervention and impact significantly on study outcomes

Interleukin-13 Activates Distinct Cellular Pathways Leading to Ductular Reaction, Steatosis, and Fibrosis

Fibroproliferative diseases are driven by dysregulated tissue repair responses and are major cause of morbidity and mortality as they affect nearly every organ system. Type-2 cytokine responses are critically involved in tissue repair; however, the mechanisms that regulate beneficial regeneration versus pathological fibrosis are not well understood. Here, we have shown that the type-2 effector cytokine interleukin-13 simultaneously, yet independently, directed hepatic fibrosis and the compensatory proliferation of hepatocytes and biliary cells in progressive models of liver disease induced by interleukin-13 over-expression or following infection with Schistosoma mansoni. Using transgenic mice with interleukin-13 signaling genetically disrupted in hepatocytes, cholangiocytes, or resident tissue fibroblasts, we have revealed direct and distinct roles for interleukin-13 in fibrosis, steatosis, cholestasis, and ductular reaction. Together, these studies show that these mechanisms are simultaneously controlled but distinctly regulated by interleukin-13 signaling. Thus, it may be possible to promote interleukin-13-dependent hepatobiliary expansion without generating pathological fibrosis

An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection.peer-reviewe

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes